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Introduction: The loss of occlusal support due to tooth loss is associated with systemic diseases. However, there was little about the association between occlusal support and cognitive impairment. The cross-sectional study aimed to investigate their association., Methods: Cognitive function was assessed and diagnosed in 1,225 community-dwelling adults aged 60 years or older in Jing'an District, Shanghai. Participants were diagnosed with mild cognitive impairment (MCI) by Peterson's criteria, or dementia, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We determined the number of functional occlusal supporting areas according to Eichner classifications. We used multivariate logistic regression models to analyze the relationship between occlusal support and cognitive impairment and mediation effect models to analyze the mediation effect of age., Results: Six hundred sixty participants were diagnosed with cognitive impairment, averaging 79.92 years old. After adjusting age, sex, education level, cigarette smoking, alcohol drinking, cardiovascular disease, and diabetes, individuals with poor occlusal support had an OR of 3.674 (95%CI 1.141-11.829) for cognitive impairment compared to those with good occlusal support. Age mediated 66.53% of the association between the number of functional occlusal supporting areas and cognitive impairment., Discussion: In this study, cognitive impairment was significantly associated with the number of missing teeth, functional occlusal areas, and Eichner classifications with older community residents. Occlusal support should be a significant concern for people with cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Da, Ge, Zhang, Zeng, Jiang, Yu, Wang, Wu, Xiao, Liang, Zhao, Ding and Zhang.)

The association between the oral microbiome and mild cognitive impairment (MCI) remains unclear. This study aimed to investigate such an association among Chinese older adults. Participants without dementia were recruited from the community. A battery of neuropsychological tests was administered to evaluate the cognitive function. The diagnosis of MCI was based on Peterson's criteria. The non-stimulated saliva was collected to extract sequences of the oral microbiome. Forty-seven MCI and 47 cognitively normal participants were included. There was significant difference in alpha diversity and insignificant difference in beta diversity between the two groups of participants. Compared with the cognitively normal group, Gemella haemolysans and Streptococcus gordonii were two significantly decreased species while Veillonella unclassified_Veillonella and Fusobacterium sp._HMT_203 were two significantly increased species in the MCI group. The richness of Gemella haemolysans presented the best discriminate value for MCI with the AUC (Area Under Curve) of 0.707, a cut-off value of 0.008 for relative abundance, the sensitivity of 63.8% and specificity of 70.2%. The dysbiosis of oral microbiome and relative abundance of Gemella haemolysans was significantly associated with MCI. Further studies were needed to develop new treatment strategies targeting the oral microbiome for cognitive impairment., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Emerging evidence suggests that both selective and non-selective Adenosine A 2A receptor (A 2A R) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes, along with its proven clinical safety, has prompted us to explore the potential of A 2A R antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of A 2A R signaling in EAE pathology has raised concerns about the feasibility of using A 2A R antagonists as a therapeutic approach for MS. This review addresses the potential effect of A 2A R antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, A 2A R antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood-brain barrier. Consequently, A 2A R signaling remains an essential immunomodulator in EAE/MS, suggesting that A 2A R antagonists hold promise as a drug class for treating MS., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: The prevalence of dentofacial deformity was reportedly higher than decades ago, to which upper airway (UA) obstruction-induced sleep-disordered breathing (SDB) might contribute a lot. Tonsil hypertrophy appears relatively common in the population of young children. Given that the association between tonsil hypertrophy and pediatric dentofacial deformity remained controversial, this cross-sectional research was designed to explore the internal relationship of those among young children in Shanghai, China., Patients and Methods: A stratified cluster sampling procedure was adopted, and a representative sample of 715 young children (8-10 years old) was recruited. The OSA-18 quality-of-life questionnaires (OSA-18) were finished by their guardians, and well-trained orthodontists performed the oral examinations. After collecting the valuable information, the descriptions and analyses were run by statistical software (SPSS, version 26.0)., Results: 715 participants (334 boys and 381 girls) were involved in the analyses. As calculated, the current prevalence of malocclusion identified by Angle's classification was 45.6% in this sample. No evident relation between OSA-18 scores and dentofacial abnormalities (P > 0.05) was found. With the enlargement of tonsil size, the proportion of children with triangular dental arch form (P < 0.05) and high vault palate (P < 0.001) was increasingly higher. More children with protruding profiles and fewer upright profiles were observed as the tonsil size increased, although it did not show a statistical difference (P = 0.103)., Conclusion: Dental and craniofacial growth deficiency has become more prevalent among children, demanding more concerns from health authorities. Tonsil hypertrophy plays an essential role in the direction of dentofacial development. More efforts from local health authorities should be made to enhance public propaganda and education on the prevention and interruption of tonsil hypertrophy and related dentofacial abnormalities., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Tong et al.)

Occlusal support was proved to be associated with type 2 diabetes. Our aim was to investigate the association between the Eichner index and the prevalence of type 2 diabetes. We included 715 participants with oral health examinations in the Shanghai Aging Study. The occlusal support status was determined by the number of functional occlusal support areas and Eichner index classifications. Those with fasting plasma glucose ≥126 mg/dL and/or hemoglobin A1c ≥6.5% and/or current medications for type 2 diabetes with relevant medical history were diagnosed with type 2 diabetes. Multiple logistic regression models were used to analyze the relationship between occlusal support status and type 2 diabetes. The average age of 715 participants was 73.74 ± 6.49 years old. There were 84 diabetics with 1.71 occlusal supporting areas on average. Seven hundred and fifteen participants were divided into 3 groups according to Eichner classifications: Eichner group A with 4 occlusal functional areas, Eichner group B with 1-3 occlusal functional areas or 0 area with anterior occlusal contact, and Eichner group C with no functional occlusal contact. Blood glucose level was significantly lower in participants of Eichner group A compared to those in group B or C. The ordinal logistic regression showed more occlusal supporting areas were significantly associated with less type 2 diabetes cases with an Odds Ratio(OR) of 0.253(95%CI 0.108-0.594) after adjusting covariates. Participants in Eichner group A had a significantly much lower OR of 0.078 for type 2 diabetes (95%CI 0.009-0.694) compared to those in Eichner group C after adjustment. The number of functional occlusal support areas might be inversely related to the blood glucose level and the prevalence of type 2 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Da, Ge, Zhang, Zeng, Jiang, Yu, Wang, Wu, Xiao, Liang, Ding and Zhang.)

Background: The purpose of the study is to examine the association between tooth loss and hypertension among older community residents in urban China., Methods: This study included 3677 participants aged ≥50 years from the Shanghai Aging Study. We determined the number of teeth missing from questionnaires. Hypertension was defined as the mean of two measurements of systolic blood pressure (SBP) (140 mmHg or higher), diastolic blood pressure (DBP) (90 mmHg or higher) or physician-diagnosed hypertension confirmed from medical records. A multivariable logistic regression model was used to investigate the association between tooth loss and hypertension., Results: The average number of missing teeth among study participants was 9.67. Among them, participants with hypertension had lost an average of 10.88 teeth, significantly higher than those without hypertension (8.95) (p < 0.0001). After adjusting for covariates (socio-demographic characteristics, health behaviors and other chronic conditions), teeth lost (15 or more) was significantly associated with grade III hypertension, with OR = 1.55(95% CI 1.09-2.20)., Conclusions: Significant tooth loss maybe associated with severe hypertension among older Chinese adults. Prevention of tooth loss is important to the overall health of this population.

P 1B -type ATPases, known as heavy metal ATPases (HMAs), play an important role in the control of cadmium (Cd) accumulation in plants. In this study, a total of 12 ZmHMA genes were identified in the maize genome and particularly classified into six clusters based on their phylogenetic relationship and motif compositions. Furthermore, the expression patterns of different ZmHMA genes varied with developmental stages, and were tissue specific under normal conditions. ZmHMA2 and ZmHMA3 genes exhibited significant up-regulation under Cd treatment. Eventually, the association analysis between 103 inbred lines and alleles in ZmHMA2 and ZmHMA3 revealed that one insertion-deletion (InDel) in the intron from ZmHMA2 was associated with leaf Cd concentration under low Cd condition at the seedling stage. Twenty polymorphisms in ZmHMA3 were significantly associated with leaf Cd concentration under various Cd levels at seedling and maturing stages. Five single nucleotide polymorphisms (SNPs) and two InDels of these significantly associated polymorphic loci from ZmHMA3 caused the amino acid substitutions and insertion or deletion events. Importantly, the proteins encoded by ZmHMA2 and ZmHMA3 genes were located in the plasma membrane. This comprehensive analysis will provide an important theoretical basis for future functional verification of ZmHMA genes to unravel the mechanisms of Cd accumulation in leaves of maize. Additionally, the favorable alleles in ZmHMA3 will lay a foundation for the marker-assisted selection of low Cd accumulation in maize., Competing Interests: The authors declare there are no competing interests., (©2019 Cao et al.)

Drought stress negatively influences the growth and physiology of perennial grasses. The objective of this study was to identify associations of candidate genes with drought tolerance traits in 96 zoysiagrass (Zoysia Willd.) accessions. Germplasm varied largely in leaf wilting, canopy and air temperature difference (CAD), leaf water content (LWC), chlorophyll fluorescence (Fv/Fm), leaf dry weight (LDW), stolon dry weight (SDW), rhizome dry weight (RZW), and root dry weight (RDW) under drought stress across the two experiments in 2014 and 2015 in a greenhouse. The population exhibited three subgroups based on molecular marker analysis and had minimum relative kinship. Associations between single nucleotide polymorphisms (SNPs) in BADH encoding betaine aldehyde dehydrogenase, DREB1 encoding DREB-like protein 1, Ndhf encoding NADH dehydrogenase subunit F, CAT encoding catalase, and VP1 encoding H + -pyrophosphatase were analyzed with trait under drought stress (D) and relative values compared to the control (R). Twenty-seven mark and trait associations were detected in year 2014, 2015, and a two-year combination across four genes, including 13 associations in 7 SNP loci in BADH, 9 associations in 5 SNP loci in DREB1, 3 associations in one SNP locus in Ndhf, and 2 associations in one SNP locus in CAT. Of them, one SNP in BADH was associated with D-RDW or D-SDW, three SNPs in DREB1 were associated with D-RZW, D-RDW, R-LWC, and D-CAD, and one SNP in CAT was associated with D-SDW. Nucleotide changes in these SNP loci caused non-synonymous amino acid substitutions. The results indicated that allelic diversity in genes involved in antioxidant metabolism, osmotic homeostasis, and dehydration responsive transcription factor could contribute to growth and physiological variations in zoysiagrass under drought stress., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Let-7 is a microRNA (miRNA) that targets the β2 adrenergic receptor ( ADRB2 ), hypoxia inducible factor 1 subunit alpha inhibitor ( HIF1AN ), and claudin 12 ( CLDN12 ) genes. Single nucleotide polymorphisms (SNPs) in the structural or regulatory regions of these miRNA let-7-related genes may be associated with breast cancer carcinogenesis and prognosis. Low let-7 expression may increase breast cancer risk. We investigated the effects of let-7-related gene SNP (mirSNPs) on breast cancer risk and clinical outcomes., Methods: The distribution frequencies of the three SNPs were genotyped in patients with breast cancer and controls. Multivariate logistic regression analysis was used to evaluate the association between the SNPs and susceptibility to breast cancer. We investigated the effects of these mirSNPs prospectively on disease-free survival (DFS) using the Kaplan-Meier method and the extended multivariate Cox model., Results: We found that rs1042713 in the ADRB2 gene and rs11292 in the 3'-UTR of the HIF1AN gene were associated with breast cancer susceptibility ( P <0.05). The CLDN12 rs1017105 genotype was associated with estrogen receptor ( P =0.031) and progesterone receptor status ( P =0.007). The number of risk alleles was associated with estrogen receptor (P=0.034) status in breast cancer patients. In the survival analysis, the extended Cox model demonstrated that rs1042713 (P=0.000) and rs1017105 (P=0.004) were independent predictors of DFS. The number of risk alleles of the ADRB2 , HIF1AN , and CLDN12 genes was an independent predictor of DFS (P<0.001)., Conclusion: Let-7-related mirSNPs might be associated with carcinogenesis and clinical outcome in breast cancer, suggesting that variants of miRNA let-7-related gene networks coregulate breast cancer characteristics., Competing Interests: None.

Triple negative breast cancer (TNBC), characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 overexpression, is a more aggressive high grade tumor and not sensitive to current targeted drugs. The clinical prognosis of TNBC is poorer than other types of breast cancer, and there is no effective therapy strategy until now. Thus, it is necessary to determine important factors involved in regulating the progression of TNBC. In this study, we found DEPDC1 was up-regulated in the tissues of TNBC compared with their paired peritumoral tissues. DEPDC1 over-expression facilitated cell proliferation and tumor growth through increasing the expression of FOXM1 in TNBC cells. Conversely, knockdown of DEPDC1 had the opposite effects. Moreover, miR-26b, acting as a tumor suppressor in TNBC, directly repressed the expression of DEPDC1 and mitigated its promotive effects on cell growth and colony formation. These results indicate that DEPDC1, negatively regulated by miR-26b, promotes cell proliferation and tumor growth via up-regulating FOXM1 expression, implying an important underlying mechanism of regulating the progression of TNBC., (Copyright © 2018. Published by Elsevier B.V.)

Breast cancer (BrCa) is the malignant tumor that most seriously threatens female health; however, the molecular mechanism underlying its progression remains unclear. Here, we found that conditional deletion of hypermethylated in cancer 1 (HIC1) in the mouse mammary gland might contribute to premalignant transformation in the early stage of tumor formation. Moreover, the chemokine (C-X-C motif) ligand 14 (CXCL14) secreted by HIC1-deleted BrCa cells bound to its cognate receptor GPR85 on mammary fibroblasts in the microenvironment and was responsible for activating these fibroblasts via the ERK1/2, Akt, and neddylation pathways, whereas the activated fibroblasts promoted BrCa progression via the induction of epithelial-mesenchymal transition (EMT) by the C-C chemokine ligand 17 (CCL17)/CC chemokine receptor 4 (CCR4) axis. Finally, we confirmed that the HIC1-CXCL14-CCL17 loop was associated with the malignant progression of BrCa. Therefore, the crosstalk between HIC1-deleted BrCa cells and mammary fibroblasts might play a critical role in BrCa development. Exploring the progression of BrCa from the perspective of microenvironment will be beneficial for identifying the potential prognostic markers of breast tumor and providing more effective treatment strategies.

Key Message: The dynamic alterations of the physiological and molecular processes in reproductive stage soybean indicated the dramatic impact caused by drought. Drought is a major abiotic stress that limits soybean (Glycine max) production. Most prior studies were focused on either model species or crops that are at their vegetative stages. It is known that the reproductive stage of soybean is more susceptible to drought. Therefore, an understanding on the responsive mechanisms during this stage will not only be important for basic plant physiology, but the knowledge can also be used for crop improvement via either genetic engineering or molecular breeding. In this study, physiological measurements and RNA-Seq analysis were used to dissect the metabolic alterations and molecular responses in the leaves of soybean grown at drought condition. Photosynthesis rate, stomata conductance, transpiration, and water potential were reduced. The activities of SOD and CAT were increased, while the activity of POD stayed unchanged. A total of 2771 annotated genes with at least twofold changes were found to be differentially expressed in the drought-stressed plants in which 1798 genes were upregulated and 973 were downregulated. Via KEGG analysis, these genes were assigned to multiple molecular pathways, including ABA biogenesis, compatible compound accumulation, secondary metabolite synthesis, fatty acid desaturation, plant transcription factors, etc. The large number of differentially expressed genes and the diverse pathways indicated that soybean employs complicated mechanisms to cope with drought. Some of the identified genes and pathways can be used as targets for genetic engineering or molecular breeding to improve drought resistance in soybean.

Switchgrass ( Panicum virgatum ) is a native prairie grass and valuable bio-energy crop. The physiological change from juvenile to reproductive adult can draw important resources away from growth into producing reproductive structures, thereby limiting the growth potential of early flowering plants. Delaying the flowering of switchgrass is one approach by which to increase total biomass. The objective of this research was to identify genetic variants and candidate genes for controlling heading and anthesis in segregating switchgrass populations. Four pseudo-F 2 populations (two pairs of reciprocal crosses) were developed from lowland (late flowering) and upland (early flowering) ecotypes, and heading and anthesis dates of these populations were collected in Lafayette, IN and DeKalb, IL in 2015 and 2016. Across 2 years, there was a 34- and 73-day difference in heading and a 52- and 75-day difference in anthesis at the Lafayette and DeKalb locations, respectively. A total of 37,901 single nucleotide polymorphisms obtained by exome capture sequencing of the populations were used in a genome-wide association study (GWAS) that identified five significant signals at three loci for heading and two loci for anthesis. Among them, a homolog of FLOWERING LOCUS T on chromosome 5b associated with heading date was identified at the Lafayette location across 2 years. A homolog of ARABIDOPSIS PSEUDO-RESPONSE REGULATOR 5, a light modulator in the circadian clock associated with heading date was detected on chromosome 8a across locations and years. These results demonstrate that genetic variants related to floral development could lend themselves to a long-term goal of developing late flowering varieties of switchgrass with high biomass yield.

Flowering is an important developmental event in switchgrass (), as the time to complete the life cycle affects overall biomass accumulation. The objective of this study was to generate a linkage map using single nucleotide polymorphism (SNP) markers to identify quantitative trait loci (QTL) associated with flowering time. A pseudo-F population was created by crossing two siblings derived from an initial cross between the lowland population Ellsworth and the upland cultivar Summer. Heading and anthesis dates were collected for 2 yr at two locations: DeKalb, IL and Lafayette, IN. Nine QTL for flowering time were detected, two of which were heading-associated, four anthesis-associated, and three associated with both heading and anthesis. One QTL on linkage group (LG) 2a was detected for heading and anthesis in each location and year when environments were analyzed separately, and in a combined analysis across both locations and years. The effect on heading and anthesis of the QTL on LG 2a ranged from 4 to 13 and 5 to 9 d, respectively, depending on environment. Our findings validate QTL for switchgrass flowering time from previous research and identified additional QTL. Based on the switchgrass reference genome version 1.1, flowering time gene homologs reside near the LG 2a QTL and include PSEUDO RESPONSE REGULATOR 5, SUPPRESSOR OF FRIGIDA 4, and APETALA 1, respectively involved in the circadian clock, vernalization, and floral meristem identity. Markers linked to the QTL can be used to improve the efficiency of breeding switchgrass for delayed flowering to increase biomass yield., (Copyright © 2018 Crop Science Society of America.)

Background: The giant ragweed (Ambrosia trifida L.) rapid-response (RR) biotype exhibits a sacrificial form of glyphosate resistance whereby an oxidative burst in mature leaves results in foliage loss, while juvenile leaves remain uninjured. This work investigated the safening capacity of antioxidant enzymes in RR juvenile leaves following glyphosate treatment and examined cross tolerance to paraquat., Results: Basal antioxidant enzyme activities were similar between glyphosate-susceptible (GS) and RR biotypes. Lipid peroxidation was first detected in RR mature leaves at 8 h after treatment (HAT) and by 32 HAT was 5.3 and 21.1 times greater than that in RR juvenile leaves and GS leaves, respectively. Preceding lipid peroxidation in the RR biotype at 2 and 4 HAT, the only increase in enzymatic activity was observed in ascorbate-glutathione cycle enzymes in RR juvenile leaves, particularly ascorbate peroxidase, dehydroascorbate reductase, and glutathione reductase. Sensitivity to paraquat was similar between biotypes., Conclusion: The RR biotype is not inherently more tolerant to oxidative stress. The difference in tissue damage between RR juvenile and mature leaves following glyphosate treatment is attributable at least partially to the transient increase in antioxidant enzyme expression in juvenile leaves (0-8 HAT), but may also be attributable to lower overall RR induction in juvenile leaves compared with mature leaves. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

Background: The aims of this study were to determine whether the quantitative HER2 gene amplification level is related to the key clinicopathological features that represent the aggressiveness of breast cancer (BC) and to determine whether the quantitative HER2 gene amplification level could predict the treatment response in the subset of HER2-positive patients who received neoadjuvant targeted therapy., Materials and Methods: Patients treated with weekly cisplatin- and paclitaxel-based neoadjuvant chemotherapy, who had undergone both immunohistochemistry and the fluorescence in situ hybridization test for HER2 , were included in the study (n=103). For HER2-positive patients, defined as immunohistochemistry score 3+ or fluorescence in situ hybridization ratio ≥2.0, trastuzumab was recommended with neoadjuvant chemotherapy (n=45). Pathological complete response was defined as complete pathological remission of tumor cells both in breast and axillary lymph nodes postoperation., Results: In all patients enrolled in the study, a higher HER2 amplification level was significantly correlated with larger tumor size and the absence of ER and PR expression. In HER2-positive patients treated with neoadjuvant trastuzumab concurrent with chemotherapy, both univariate and multivariate logistic regression showed that a higher HER2/CEP17 ratio and HER2 gene copy number were associated with a higher pathological complete response rate. When calculated by receiver operating characteristics analysis, an optimal cutoff of 4.5 for the HER2/CEP17 ratio was expected to distinguish the most sensitive candidate for treatment with a combination of trastuzumab and neoadjuvant chemotherapy., Conclusion: A higher HER2 amplification level was correlated with larger tumor size and reduced ER and PR expression, which may indicate more aggressive tumor behavior. For HER2-positive patients, the HER2/CEP17 ratio and HER2 gene copy number may be good predictive factors for concurrent neoadjuvant trastuzumab and chemotherapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Accumulation of cadmium (Cd) in maize (Zea mays L.) poses a significant risk to human health as it is ingested via the food chain. A genome-wide association study (GWAS) was conducted in a population of 269 maize accessions with 43,737 single nucleotide polymorphisms (SNPs) to identify candidate genes and favorable alleles for controlling Cd accumulation in maize., Results: When grown in contaminated soil, accessions varied significantly in leaf Cd concentration at both the seeding and maturing stages with phenotypic variation and the coefficient of variation all above 48%. The co-localized region between SYN27837 (147,034,650 bp) and SYN36598 (168,551,327 bp) on chromosome 2 was associated with leaf Cd under three soil conditions varying in Cd content in 2015 and 2016. The significant SNP (SYN25051) at position 161,275,547 could explained 27.1% of the phenotype variation. Through QTL mapping using the IBMSyn10 double haploid (DH) population, we validated the existence of a major QTL identified by GWAS; qLCd2 could explain the 39.8% average phenotype variation across the experiments. Expression of GRMZM2G175576 encoding a cadmium/zinc-transporting ATPase underlying the QTL was significantly increased in roots, stems and leaves of B73, a low Cd accumulation line in response to Cd stress., Conclusions: Our findings provide new insights into the genetic control of Cd accumulation and could aid rapid development of maize genotypes with low-Cd accumulation by manipulation of the favorable alleles.

As placental mammals, the pregnant women and the fetus have intense and prolonged interactions during gestation. There is increasing evidence that multiple molecular as well as cellular components originating in pregnant women are transferred to the fetus. The transfer of maternal antibodies has long been recognized as a central component of newborn immunity against pathogens. More recent studies indicate that inflammatory mediators, micronutrients, microbial products and maternal cells are transferred in utero and influence the fetal immune system. Together, these multiple signals are likely to form a complex network of interactions that program the neonatal immune system and tune its homeostatic regulation. Maternal disorders, in particular infectious diseases, modify these signals and may thereby alter immunity in early life. Understanding maternal programming of the newborn immune system could provide a basis for interventions promoting child health.

Agonistic antibodies, which bind specifically to death receptor 5 (DR5), can trigger apoptosis in tumor cells through the extrinsic pathway. In this present study, we describe the use of a phage display to isolate a novel fully human agonistic single chain fragment variable (scFv) antibody, which targets DR5. After five rounds of panning a large (1.2 × 10⁸ clones) phage display library on DR5, a total of over 4000 scFv clones were screened by the phage ELISA. After screening for agonism in a cell-viability assay in vitro, a novel DR5-specific scFv antibody TR2-3 was isolated, which inhibited COLO205 and MDA-MB-231 tumor cell growth without any cross-linking agents. The activity of TR2-3 in inducing apoptosis in cancer cells was evaluated by using an Annexin V-PE apoptosis detection kit in combination with flow cytometry and the Hoechst 33342 and propidium iodide double staining analysis. In addition, the activation of caspase-dependent apoptosis was evaluated by Western blot assays. The results indicated that TR2-3 induced robust apoptosis of the COLO205 and MDA-MB-231 cells in a dose-dependent and time-dependent manner, while it remarkably upregulated the cleavage of caspase-3 and caspase-8. Furthermore, TR2-3 suppressed the tumor growth significantly in the xenograft model. Taken together, these data suggest that TR2-3 exhibited potent antitumor activity both in vitro and in vivo. This work provides a novel human antibody, which might be a promising candidate for cancer therapy by targeting DR5., Competing Interests: The authors declare no conflicts of interest.

There was little evidence of weekly cisplatin regimen either for the locally advanced breast cancer or the metastatic setting. We aimed to evaluate that whether the combination of weekly paclitaxel and cisplatin could improve the efficacy of the neoadjuvant treatment for patients with locally advanced breast cancer. Patients with histologically confirmed large operable breast cancer received paclitaxel 80mg/m 2 by weekly for 16 weeks and weekly cisplatin 25mg/m 2 on day 1, 8 and 15, out of every 28 days for 4-week cycles. Trastuzumab was allowed for HER2-positive disease as weekly continuous regimen. The primary endpoint was locoregional total pathological complete response (tpCR) in breast and axilla lymph nodes after neoadjuvant treatment. One hundred and thirty-one patients were included in the study, among which 34.4% (45/131) patients achieved tpCR. Rate of pathological complete response (pCR) in the breast was 44.3% and the rate of near-pCR in breast was 48.1%. A significantly higher proportion of tpCR was seen in patients with triple negative breast cancer (64.7%, p = 0.003) and HER2 positive (non-luminal) cancer (52.4%, p = 0.018) compared with those who had luminal type tumors (24.7%). At multivariate analysis, negative estrogen receptor and high ki67 level independently predicted a better response. The most frequent toxicities were anemia, leukopenia and peripheral sensory neuropathy. Neoadjuvant chemotherapy by weekly paclitaxel and cisplatin combination was highly effective and tolerated in this study, especially in the triple negative and HER2 positive tumors ., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.

The temperate wild grass Brachypodium distachyon (Brachypodium) serves as model system for studying turf and forage grasses. Brachypodium collections show diverse responses to drought stress, but little is known about the genetic mechanisms of drought tolerance of this species. The objective of this study was to identify quantitative trait loci (QTLs) associated with drought tolerance traits in Brachypodium. We assessed leaf fresh weight (LFW), leaf dry weight (LDW), leaf water content (LWC), leaf wilting (WT), and chlorophyll fluorescence (Fv/Fm) under well-watered and drought conditions on a recombinant inbred line (RIL) population from two parents (Bd3-1 and Bd1-1) known to differ in their drought adaptation. A linkage map of the RIL population was constructed using 467 single nucleotide polymorphism (SNP) markers obtained from genotyping-by-sequencing. The Bd3-1/Bd1-1 map spanned 1,618 cM and had an average distance of 3.5 cM between adjacent single nucleotide polymorphisms (SNPs). Twenty-six QTLs were identified in chromosome 1, 2, and 3 in two experiments, with 14 of the QTLs under well-watered conditions and 12 QTLs under drought stress. In Experiment 1, a QTL located on chromosome 2 with a peak at 182 cM appeared to simultaneously control WT, LWC, and Fv/Fm under drought stress, accounting for 11-18.7% of the phenotypic variation. Allelic diversity of candidate genes DREB2B, MYB , and SPK , which reside in one multi-QTL region, may play a role in the natural variation in whole plant drought tolerance in Brachypodium. Co-localization of QTLs for multiple drought-related traits suggest that the gene(s) involved are important regulators of drought tolerance in Brachypodium.

Perennial ryegrass is a popular cool-season grass species due to its high quality for forage and turf. The objective of this study was to identify associations of candidate genes with growth and physiological traits to submergence stress and recovery after de-submergence in a global collection of 94 perennial ryegrass accessions. Accessions varied largely in leaf color, plant height (HT), leaf fresh weight (LFW), leaf dry weight (LDW), and chlorophyll fluorescence (Fv/Fm) at 7 days of submergence and in HT, LFW and LDW at 7 days of recovery in two experiments. Among 26 candidate genes tested by various models, single nucleotide polymorphisms (SNPs) in 10 genes showed significant associations with traits including 16 associations for control, 10 for submergence, and 8 for recovery. Under submergence, Lp1-SST encoding sucrose:sucrose 1-fructosyltransferase and LpGA20ox encoding gibberellin 20-oxidase were associated with LFW and LDW, and LpACO1 encoding 1-aminocyclopropane-1-carboxylic acid oxidase was associated with LFW. Associations between Lp1-SST and HT, Lp6G-FFT encoding fructan:fructan 6G-fructosyltransferase and Fv/Fm, LpCAT encoding catalase and HT were also detected under submergence stress. Upon de-submergence, Lp1-SST, Lp6G-FFT , and LpPIP1 encoding plasma membrane intrinsic protein type 1 were associated with LFW or LDW, while LpCBF1b encoding C-repeat binding factor were associated with HT. Nine significant SNPs in Lp1-SST, Lp6G-FFT, LpCAT , and LpACO1 resulted in amino acid changes with five substitutions found in Lp1-SST under submergence or recovery. The results indicated that allelic diversity in genes involved in carbohydrate and antioxidant metabolism, ethylene and gibberellin biosynthesis, and transcript factor could contribute to growth variations in perennial ryegrass under submergence stress and recovery after de-submergence.

Flowering time is a major determinant of biomass yield in switchgrass (Panicum virgatum), a perennial bioenergy crop, because later flowering allows for an extended period of vegetative growth and increased biomass production. A better understanding of the genetic regulation of flowering time in switchgrass will aid the development of switchgrass varieties with increased biomass yields, particularly at northern latitudes, where late-flowering but southern-adapted varieties have high winter mortality. We use genotypes derived from recently published exome-capture sequencing, which mitigates challenges related to the large, highly repetitive and polyploid switchgrass genome, to perform genome-wide association studies (GWAS) using flowering time data from a switchgrass association panel in an effort to characterize the genetic architecture and genes underlying flowering time regulation in switchgrass. We identify associations with flowering time at multiple loci, including in a homolog of FLOWERING LOCUS T and in a locus containing TIMELESS, a homolog of a key circadian regulator in animals. Our results suggest that flowering time variation in switchgrass is due to variation at many positions across the genome. The relationship of flowering time and geographic origin indicates likely roles for genes in the photoperiod and autonomous pathways in generating switchgrass flowering time variation., (No claim to original US government works. New Phytologist © 2016 New Phytologist Trust.)

Background and Aims: Brachypodium distachyon (Brachypodium) is a model system for studying cereal, bioenergy, forage and turf grasses. The genetic and evolutionary basis of the adaptation of this wild grass species to drought stress is largely unknown. Peroxidase (POD) may play a role in plant drought tolerance, but whether the allelic variations of genes encoding the specific POD isoenzymes are associated with plant response to drought stress is not well understood. The objectives of this study were to examine natural variation of POD isoenzyme patterns, to identify nucleotide diversity of POD genes and to relate the allelic variation of genes to drought tolerance traits of diverse Brachypodium accessions., Methods: Whole-plant drought tolerance and POD activity were examined in contrasting ecotypes. Non-denaturing PAGE and liquid chromatography-mass spectrometry were performed to detect distinct isozymes of POD in 34 accessions. Single nucleotide polymorphisms (SNPs) were identified by comparing DNA sequences of these accessions. Associations of POD genes encoding specific POD isoenzymes with drought tolerance traits were analysed using TASSEL software., Key Results: Variations of POD isoenzymes were found among accessions with contrasting drought tolerance, while the most tolerant and susceptible accessions each had their own unique POD isoenzyme band. Eight POD genes were identified and a total of 90 SNPs were found among these genes across 34 accessions. After controlling population structure, significant associations of Bradi3g41340.1 and Bradi1g26870.1 with leaf water content or leaf wilting were identified., Conclusions: Brachypodium ecotypes have distinct specific POD isozymes. This may contribute to natural variations of drought tolerance of this species. The role of specific POD genes in differentiating Brachypodium accessions with contrasting drought tolerance could be associated with the general fitness of Brachypodium during evolution., (© The Author 2016. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

As a great potential bio-fuel feedstock, the genus Miscanthus has been widely studied around the world, especially Miscanthus × giganteus owing to its high biomass yield in Europe and North America. However, the narrow genetic basis and sterile characteristics of M. × giganteus have become a limitation for utilization and adaptation to extreme climate conditions. In this study, we focused on one of the progenitors of M. × giganteus, Miscanthus sinensis, which was originally distributed in East Asia with abundant genetic resources and comparable biomass yield potential to M. × giganteus in some areas. A collection of 138 individuals was selected for conducting a 3-year trial of biomass production and analyzed by using 104 pairs of SRAP, ISAP, and SSR primers for genetic diversity as well as marker-trait association. Significant differences in biomass yield and related traits were observed among individuals. Tiller number, fresh biomass yield per plant and dry biomass yield per plant had a high level of phenotypic variation among individuals and the coefficient of variation were all above 40% in 2011, 2012, and 2013. The majority of the traits had a significant correlation with the biomass yield except for the length and width of flag leaves. Plant height was a highly stable trait correlated with biomass yield. A total of 1059 discernible loci were detected by markers across individuals. The population structure (Q) and cluster analyses identified three subpopulations in the collection and family relative kinship (K) represented high gene flow among M. sinensis populations from Southwest China. Model testing identified that Q+K was the best model for describing the associations between the markers and traits, compared to the simple linear, Q or K model. Using the Q+K model, 12 significant associations (P < 0.001) were identified including four markers with plant height and one with biomass yield. Such associations would serve an efficient tool for an early selection of M. sinensis and facilitate a genetic improvement of biomass yield for this species.

Purpose: Numerous clinical studies have suggested that chemopreventive drugs for breast cancer such as tamoxifen and exemestane can effectively reduce the incidence of estrogen receptor (ER)-positive breast cancer. However, it remains unclear how to identify those who are susceptible to ER-positive breast cancer. Accordingly, there is a great demand for a probe into the predisposing factors so as to provide precise chemoprevention. Recent evidence has indicated that ERα expression can be regulated by microRNAs (miRNAs), such as miR-206, in breast cancer. We assumed that single-nucleotide polymorphisms (SNPs) in the miR-206-binding sites of the target genes may be associated with breast cancer susceptibility with different ER statuses., Methods: We genotyped the SNPs that reside in and around the miR-206-binding sites of two target genes - heparan sulfatase 1 (SULF1) and RPTOR-independent companion of mammalian target of rapamycin Complex 2 (RICTOR) - which were related to the progression or metastasis of breast cancer cells in 710 breast cancer patients and 294 controls by the matrix-assisted laser desorption ionization-time of flight mass spectrometry method. Modified odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated by a multivariate logistic regression analysis to evaluate the potential association between the SNPs and breast cancer susceptibility., Results: For rs3802278, which is located in the 3'-untranslated region (3'-UTR) of SULF1, the frequency of the AA genotype was less in breast cancer patients than that in the controls as compared to that of the GG + GA genotype not only for ER-positive breast cancer patients (adjusted OR =0.663, P=0.032) but also for hormone receptor-positive breast cancer patients (adjusted OR =0.610, P=0.018). Besides, the frequency of the AA genotype was less than that of the GG genotype between the ER-positive breast cancer patients and the controls (adjusted OR =0.791, P=0.038). For rs66916453, which is located in the 3'-UTR of RICTOR, no significant difference was observed between the case and the control group for the genotypes or alleles (P>0.05)., Conclusion: The SNPs in the miRNA-binding sites within the 3'-UTR of SULF1 may serve as protective factors against the susceptibility to breast cancer, especially to ER-positive breast cancer in the Chinese population. These SNPs are promising candidate biomarkers to predict the susceptibility of breast cancer and guide the administration of targeted preventive endocrine therapy.

Physiological mechanisms of waterlogging (WL) and submergence (SM) tolerance are not well understood in perennial grasses used for turf and forage. The objective of this study was to characterize growth, antioxidant activity and lipid peroxidation of perennial ryegrass (Lolium perenne) exposed to short-term WL and SM. 'Silver Dollar' (turf-type cultivar), 'PI418714' (wild accession), 'Kangaroo Valley' (forage-type cultivar) and 'PI231569' (unknown status) varying in growth habits and leaf texture were subjected to 7 d of WL and SM in a growth chamber. Plant height was unaffected by WL but was significantly reduced by SM for all grasses except PI418714. The SM treatment caused greater reductions in leaf chlorophyll and total carotenoid concentrations. Substantial declines in water-soluble carbohydrate concentrations were found in the shoots and roots under SM, particularly in Kangaroo Valley and PI231569, two relatively fast-growing genotypes. Significant increases in malondialdehyde concentrations were noted in the shoots and roots of all genotypes exposed to WL and SM, but to a greater extent in Kangaroo Valley and PI231569 under SM. Shoot activities of catalase (CAT) and peroxidase (POD) increased under SM, more pronounced in Silver Dollar and PI418714, two relatively slow-growing genotypes. Waterlogging or SM stresses decreased root activities of superoxide dismutase, CAT, POD and ascorbate peroxidase, especially for Kangaroo Valley and PI231569. The results indicated that maintenance of antioxidant activity and carbohydrate and minimization of lipid peroxidation could contribute to better waterlogging or submergence tolerance of perennial ryegrasses., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Perennial ryegrass (Lolium perenne L.) is a widely cultivated cool-season grass species because of its high quality for forage and turf. Susceptibility to freezing damage limits its further use in temperate zones. The objective of this study was to identify candidate genes significantly associated with winter survival and spring regrowth in a global collection of 192 perennial ryegrass accessions. Significant differences in winter survival (WS), percentage of canopy green cover (CGC), chlorophyll index (Chl), and normalized difference vegetation index (NDVI) were found among accessions. After controlling population structure, LpLEA3 encoding a late embryogenesis abundant group 3 protein and LpCAT encoding a catalase were associated with CGC and Chl, while LpMnSOD encoding a magnesium superoxide dismutase and LpChl Cu-ZnSOD encoding a chlorophyll copper-zinc superoxide dismutase were associated with NDVI or Chl. Significant association was also discovered between C-repeat binding factor LpCBF1b and WS. Three sequence variations identified in LpCAT, LpMnSOD, and LpChl Cu-ZnSOD were synonymous substitutions, whereas one pair of adjacent single nucleotide polymorphisms (SNPs) in LpLEA3 and one SNP in LpCBF1b resulted in amino acid change. The results demonstrated that allelic variation in LpLEA3 and LpCBF1b was closely related to winter survival and spring regrowth in perennial ryegrass., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Alpha2-adrenoceptor (α2 AR) antagonists inhibit the growth of breast cancer cells. The action of beta2-adrenoceptors (β2 AR) on cell proliferation is still controversial. In this study, we investigated the association of α2a and β2 AR expression with tumor-relevant biological markers and clinical outcome., Methods: The expression of α2a and β2 AR was examined in paraffin-embedded samples of 220 operable breast tumors by immunohistochemistry. Associations between AR expression and tumor-relevant biomarkers were evaluated using the chi-square or Fisher's exact tests. Univariate analysis was modeled using Kaplan-Meier plots and multivariate analysis was modeled using the Cox test and adjusted for age, tumor size, lymph node status, and ER, PR and Her-2 status., Results: The α2a AR expression was associated with Her-2 status (P = 0.048) and a marginal significance was observed between α2a AR expression and ER (P = 0.061). In hormone receptor positive breast cancer patients, strong β2 AR expression correlated with better disease free survival (DFS) than weak expression (P = 0.031) and β2 AR (HR = 0.31, P = 0.039) and lymph node status (HR = 2.85, P = 0.031) were independent predictors of DFS on multivariate analysis., Conclusion: In hormone receptor positive breast cancer patients, strong β2 AR expression is correlated with better DFS than weak β2 AR expression and an interaction may exist between β2 AR and hormone receptor pathways. Some limitations of this study were the relatively small sample size and the intrinsic nature of retrospective study per se. Findings of the study are for hypothesis only and need to be confirmed in large prospective studies.

Natural variation in salinity response, effects of population structure on growth and physiological traits and gene-trait association were examined in 56 global collections of diverse perennial ryegrass (Lolium perenne L.) accessions. Three population structure groups were identified with 66 simple sequence repeat markers, which on average accounted for 9 and 11% of phenotypic variation for the control and salinity treatment at 300 mm NaCl. Group 1 (10 accessions) had greater plant height, leaf dry weight and water content, chlorophyll index, K(+) concentration and K(+) /Na(+) than group 2 (39 accessions) and group 3 (7 accessions) under salinity stress, while group 3 had higher Na(+) than groups 1 and 2. Eighty-seven single nucleotide polymorphisms were detected from four partial candidate genes encoding aquaporin and Na(+) /H(+) antiporter in both plasma and tonoplast membranes. Overall, rapid decay of linkage disequilibrium was observed within 500 bp. Significant associations were found between the putative LpTIP1 and Na(+) for the control and between the putative LpNHX1 and K(+) /Na(+) under the control and salinity treatments after controlling population structure. These results indicate that population structure influenced phenotypic traits, and allelic variation in LpNHX1 may affect salinity tolerance of perennial ryegrass., (© 2013 John Wiley & Sons Ltd.)

We have been investigating modulation strategies tailored around the selective stimulation of the host's immune system as an alternative to direct targeting of microbial pathogens by antibiotics. One such approach is the use of a group of small cationic peptides (BT) produced by a Gram-positive soil bacterium, Brevibacillus texasporus. These peptides have immune modulatory properties that enhance both leukocyte functional efficiency and leukocyte proinflammatory cytokine and chemokine mRNA transcription activities in vitro. In addition, when provided as a feed additive for just 4 days posthatch, BT peptides significantly induce a concentration-dependent protection against cecal and extraintestinal colonization by Salmonella enterica serovar Enteritidis. In the present studies, we assessed the effects of feeding BT peptides on transcriptional changes on proinflammatory cytokines, inflammatory chemokines, and Toll-like receptors (TLR) in the ceca of broiler chickens with and without S. Enteritidis infection. After feeding a BT peptide-supplemented diet for the first 4 days posthatch, chickens were then challenged with S. Enteritidis, and intestinal gene expression was measured at 1 or 7 days postinfection (p.i.) (5 or 11 days of age). Intestinal expression of innate immune mRNA transcripts was analyzed by quantitative real-time PCR (qRT-PCR). Analysis of relative mRNA expression showed that a BT peptide-supplemented diet did not directly induce the transcription of proinflammatory cytokine, inflammatory chemokine, type I/II interferon (IFN), or TLR mRNA in chicken cecum. However, feeding the BT peptide-supplemented diet primed cecal tissue for increased (P ≤ 0.05) transcription of TLR4, TLR15, and TLR21 upon infection with S. Enteritidis on days 1 and 7 p.i. Likewise, feeding the BT peptides primed the cecal tissue for increased transcription of proinflammatory cytokines (interleukin 1β [IL-1β], IL-6, IL-18, type I and II IFNs) and inflammatory chemokine (CxCLi2) in response to S. Enteritidis infection 1 and 7 days p.i. compared to the chickens fed the basal diet. These small cationic peptides may prove useful as alternatives to antibiotics as local immune modulators in neonatal poultry by providing prophylactic protection against Salmonella infections.

Drought is a major environmental stress limiting growth of perennial grasses in temperate regions. Plant drought tolerance is a complex trait that is controlled by multiple genes. Candidate gene association mapping provides a powerful tool for dissection of complex traits. Candidate gene association mapping of drought tolerance traits was conducted in 192 diverse perennial ryegrass (Lolium perenne L.) accessions from 43 countries. The panel showed significant variations in leaf wilting, leaf water content, canopy and air temperature difference, and chlorophyll fluorescence under well-watered and drought conditions across six environments. Analysis of 109 simple sequence repeat markers revealed five population structures in the mapping panel. A total of 2520 expression-based sequence readings were obtained for a set of candidate genes involved in antioxidant metabolism, dehydration, water movement across membranes, and signal transduction, from which 346 single nucleotide polymorphisms were identified. Significant associations were identified between a putative LpLEA3 encoding late embryogenesis abundant group 3 protein and a putative LpFeSOD encoding iron superoxide dismutase and leaf water content, as well as between a putative LpCyt Cu-ZnSOD encoding cytosolic copper-zinc superoxide dismutase and chlorophyll fluorescence under drought conditions. Four of these identified significantly associated single nucleotide polymorphisms from these three genes were also translated to amino acid substitutions in different genotypes. These results indicate that allelic variation in these genes may affect whole-plant response to drought stress in perennial ryegrass.

Brachypodium distachyon (Brachypodium) is a powerful model system for studying cereal, bioenergy, forage, and turf grasses. Nucleotide diversity (π) and linkage disequilibrium (LD) in candidate genes involved in the antioxidative pathways in this species are not known. The average π for CAT encoding catalase, GPX encoding glutathione peroxidase, DHAR encoding dehydroascorbate reductase, MDHAR encoding monodehydroascorbate reductase, and APX ecoding ascorbate peroxidase was 0.0027 among 19 accessions contrasting for drought tolerance. The highest value of π was found in APX (0.0046) and the lowest π was in MDHAR (0.0006). The average single nucleotide polymorphism (SNP) frequency across these five genes was one SNP per 131 bp between two randomly sampled sequences for the five genes in the sequence length ranging from 1,447 bp to 1,701 bp. The LD decay was slow and extended to a distance of more than 1.2kb for all genes. The neighbor-joining tree analyses of DHAR, MDHAR, and CAT generally separated accessions differing in drought tolerance. The results indicate a putative role of these candidate genes in increasing general fitness of Brachypodium., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Submergence can severely affect the growth of perennial grasses. The variations in growth and the physiological responses of perennial grass germplasm to submergence stress are not well understood. The objective of this study was to characterize the responses of diverse perennial ryegrass accessions to submergence and their recovery following de-submergence. One hundred globally collected perennial ryegrass accessions were submerged for 7d followed by 7d of recovery in two experiments (Exp 1 and Exp 2), respectively. Compared to the pattern of the controls, the overall distribution in leaf color, chlorophyll fluorescence, plant height (HT), and growth rate (GR) shifted toward a high frequency of lower values under submergence in both experiments. The accessions were generally grouped into three types: fast growth with maintenance of color (escape, T1), slow growth with maintenance of color (quiescence, T2), and slow growth with loss of color (susceptible, ST). Under submergence, T1 had higher HT and GR than the other two groups except for GR of T2 in Exp 2 and had higher water-soluble carbohydrate (WSC) and fructan concentrations, as well as fructan to WSC ratio, than ST in Exp 1. Recovery of HT and GR were generally close to that of the control level except for HT of ST in Exp 2, but the carbohydrates fully recovered in all types of plants after 7d of de-submergence. Differential responses of perennial ryegrass accessions to submergence are useful in creating more tolerant materials and in further characterizing physiological and molecular mechanisms of submergence tolerance., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Background: The effect of zoledronic acid in breast cancer adjuvant therapy concerning improvement of patient survival has yet to be confirmed. We performed a meta-analysis of published and unpublished randomised controlled trials with the aim of accurate evaluation between clinical outcome and the association of the addition of zoledronic acid to adjuvant therapy., Methods: We searched PubMed (from 1966 to present) and online abstracts from the proceeding Annual Meetings of the American Society of Clinical Oncology (ASCO) (years 1992-2010) and online abstracts from San Antonio Breast Cancer Symposium (years 2004-2010). A total of five eligible studies including 3676 subjects and 3678 controls met our search criteria and were evaluated. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end-points were the disease free survival (DFS). Secondary end-points were overall survival (OS), distant or loco-regional recurrence free survival and bone metastasis free survival., Findings: Compared with the control arm, adjuvant breast cancer treatment with zoledronic acid did not significantly improve overall survival, disease free survival, bone metastasis free survival, distant and locoregional recurrence free survival. However, in the postmenopausal subgroup, the addition of zoledronic acid to standard therapy could significantly improve DFS (relative risk (RR) = 0.763, 95% confidence interval (CI) 0.658-0.884, p < 0.001) and reduce the risk of distant (RR = 0.744, 95%CI 0.611-0.906, p = 0.003) and locoregional recurrence (RR = 0.508, 95%CI 0.340-0.760, p = 0.001)., Interpretation: Adjuvant zoledronic acid did not significantly improve the prognosis of breast cancer patients. Due to the highly variable definitions of menopause utilised in different studies, we hypothesise that zoledronic acid may have a potential effect on postmenopausal patients. Additional studies are needed to evaluate the value of adjuvant treatment of zoledronic acid in premenopausal counterparts, differing disease stages and various pathological types of breast cancer., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Capecitabine is effective and indicated for the salvage treatment of metastatic breast cancer. Therefore, it is essential to evaluate the efficacy of capecitabine in the adjuvant setting. There have been two large randomized studies to determine whether patients with high-risk early breast cancer benefit from the addition of capecitabine to standard chemotherapy, but they have yielded inconsistent results. We first undertook a meta-analysis to evaluate the efficacy of the addition of capecitabine over standard treatment., Methods: PubMed, EBSCO, Web of Science, conference proceedings and key trials were searched from 1998 to 2011. The hazard ratio (HR) was used to evaluate the efficacy of a taxane-anthracycline regimen and a taxane-anthracycline-capecitabine regimen in early breast cancer. All of the data from each study use either fixed-effects or random-effects by Stata., Findings: We found significant improvement in the additional capecitabine arm versus control in disease-free survival (DFS) (HR = 0.83, 95% CI: 0.71-0.98, P = 0.027), overall survival (OS) (HR = 0.71, 95% CI: 0.57-0.88, P = 0.002), distant recurrence (HR = 0.79, 95% CI: 0.66-0.94, P = 0.008) and the death from breast cancer only (HR = 0.65, 95% CI: 0.51-0.83, P = 0.001). Meanwhile, the subgroup analysis revealed that capecitabine improved the DFS in triple negative (HR = 0.71, 95% CI: 0.53-0.96, P = 0.028), hormone receptor negative (HR = 0.73, CI: 0.56-0.94, P = 0.017) and HER2 negative (HR = 0.81, CI: 0.67-0.98, P = 0.034) patients., Conclusion: Due to the synergistic effect of taxane and capecitabine, taxane-anthracycline-capecitabine regimen may effectively improve the efficacy in the adjuvant setting and may be a novel generation of adjuvant chemotherapy regimen. The results of the current meta-analysis support this hypothesis and indicate that taxane-based regimen with capecitabine may be an effective, convenient, and well tolerated regimen in patients with early breast cancer.

Factors that predict in favor of an aromatase inhibitors (AIs) over tamoxifen (TAM) in estrogen receptor (ER) breast cancer remains to be identified. We compared progesterone receptor (PR) and trefoil factor 1 (TTF1) status (+ve versus -ve) as predictive of superior effect of AI's over tamoxifen among a total of 1973 Chinese women with early ER+ breast cancer. The expression of TFF1 was independently associated with ER and PR. However, there was no correlation with TFF1 and HER-2 expression. Treatment effect was more pronounced in the ER+/TFF1+ postmenopausal patients with a hazard ratio favoring AIs (HR = 0.397, 95%CI 0.183-0.860), but not in the PR positive cohorts (HR = 0.466, 95%CI 0.186-1.164). We suggested that AIs was better than TAM especially in the postmenopausal patients with ER+/TFF1+ breast cancer; however the clinical application of this observation still requires further prospective studies., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Submergence stress can cause the death of grass plants. Identification of the association between molecular markers and submergence tolerance-related traits facilitates an efficient selection of the tolerant cultivars for commercial production. A global collection of 99 diverse perennial ryegrass (Lolium perenne L.) accessions was evaluated for submergence tolerance and analyzed with 109 simple sequence repeat (SSR) markers. Submergence significantly reduced leaf color, chlorophyll fluorescence (F(v)/F(m)), maximum plant height (HT), and relative growth rate (RGR). Significant variations in these trait values were observed among the accessions under submerged conditions. Rapid linkage-disequilibrium (LD) decay was identified within 4cM. The analysis of population structure (Q) identified four subpopulations in the collection, but no obvious relative kinship (K) was found. The Q model was the best to describe associations between SSR and traits, compared to the simple linear, K, and Q + K models. Fifteen SSR markers were associated with a reduction in leaf color, F(v)/F(m), HT, and RGR under submergence stress using the Q model. These markers can be used for genetic improvement of submergence tolerance of perennial ryegrass after further validation. The diverse populations of perennial ryegrass is a valuable resource for association mapping of stress tolerance-related physiological traits., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Brachypodium distachyon (Brachypodium) is a temperate wild grass species and is a powerful model system for studying grain, energy, forage and turf grasses. Exploring the natural variation in the drought response of Brachypodium provides an important basis for dissecting the genetic network of drought tolerance. Two experiments were conducted in a greenhouse to assess the drought tolerance of 57 natural populations of Brachypodium. Principle component analysis revealed that reductions in chlorophyll fluorescence (Fv/Fm) and leaf water content (LWC) under drought stress explained most of the phenotypic variation, which was used to classify the tolerant and susceptible accessions. Four groups of accessions differing in drought tolerance were identified, with 3 tolerant, 16 moderately tolerant, 32 susceptible and 6 most susceptible accessions. The tolerant group had little leaf wilting and fewer reductions in Fv/Fm and LWC, while the most susceptible groups showed severe leaf wilting and more reductions in Fv/Fm and LWC. Drought stress increased total water soluble sugar (WSS) concentration, but no differences in the increased WSS were found among different groups of accessions. The large phenotypic variation of Brachypodium in response to drought stress can be used to identify genes and alleles important for the complex trait of drought tolerance., (Copyright © Physiologia Plantarum 2010.)

Background: Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors., Methods: Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data., Findings: With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms., Conclusion: This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.

Background: Postoperative fever may serve as an indirect sign to reflect the alterations of the host milieu caused by surgery. It still remains open to investigation whether postoperative fever has a bearing on prognosis in patients with lymph node negative breast cancers., Methods: We performed a retrospective study of 883 female unilateral patients with lymph node negative breast cancer. Fever was defined as an oral temperature ≥38 in one week postoperation. Survival curves were performed with Kaplan-Meier method, and annual relapse hazard was estimated by hazard function., Findings: The fever patients were older than those without fever (P<0.0001). Hypertensive patients had a propensity for fever after surgery (P = 0.011). A statistically significant difference was yielded in the incidence of fever among HR+/ERBB2-, ERBB2+, HR-/ERBB2- subgroups (P = 0.012). In the univariate survival analysis, we observed postoperative fever patients were more likely to recur than those without fever (P = 0.0027). The Cox proportional hazards regression analysis showed that postoperative fever (P = 0.044, RR = 1.89, 95%CI 1.02-3.52) as well as the HR/ERBB2 subgroups (P = 0.013, HR = 1.60, 95%CI 1.09-2.31) was an independent prognostic factor for relapse-free survival., Conclusion: Postoperative fever may contribute to relapse in node negative breast cancer patients, which suggests that changes in host milieu related to fever might accelerate the growth of micro-metastatic foci. It may be more precise to integrate both tumor- and host-related factors for the evaluation of relapse risk.

CD44+/CD24-/low tumor cells or aldehyde dehydrogenase 1 (ALDH1) positive tumor cells are considered cancer stem cells (CSCs) that possess the properties of self-renewal and tumorigenicity. However, their clinical value and significance in breast cancer remain controversial. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the association between the presence of CSCs in clinical samples and clinical outcome. A total of 12 eligible studies with 898 cases and 1,853 controls were included. CSC positive breast cancers, in particular those positive for ALDH1, were significantly associated with high histological grade, estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, and human epidermal growth factor receptor type 2 (HER2) positivity. However, the presence of cancer stem cells was not associated with tumor size or nodal status. ALDH1 positive (RR = 2.83, 95% CI: 2.16-3.67, P < 0.001) and CD44+/CD24-/low tumor cells (RR = 2.32, 95% CI: 1.51-3.60, P < 0.001) were significantly associated with poor overall survival (OS). The stem cell markers are prognostic factors in breast cancer. Larger clinical studies are required to further evaluate the role of these markers in clinical practice.

Perennial ryegrass (Lolium perenne L.) is a widely used cool-season forage and turf grass species. Drought stress can significantly affect the growth and development of grass plants. Identification of genes involved in drought tolerance facilitates genetic improvement of perennial ryegrass. A forward and a reverse cDNA library were constructed in drought-tolerant (PI 440474) and drought-susceptible (PI 204085) accessions by using suppression subtractive hybridization (SSH). A BLAST search revealed that 95 of 256 expressed sequence tags (ESTs) obtained from the two libraries showed significant sequence homologies to genes with known functions. They were classified into different putative functional groups including amino acid metabolism, lipid metabolism, carbohydrate metabolism, transcription, protein synthesis and destination, energy, photosynthesis, signal transduction, cellular transport and detoxification. Among them, 50 ESTs were from forward library (the drought tolerant over the susceptible accession). The expression patterns (reverse transcriptase polymerase chain reaction) of the selected genes encoding mitogen-activated protein kinase, superoxide dismutase and glutathione peroxidase (GPX) in additional accessions contrasting in drought tolerance were generally consistent with patterns of differentially expressed genes identified through SSH. The GPX fragment had a high degree of nucleotide diversity (pi = 0.0251) in the selected perennial ryegrass accessions. The results suggest that differentially expressed genes between drought tolerant and susceptible accessions may play an important role in the drought tolerance of perennial ryegrass. They can be used as candidate genes in examining nucleotide polymorphisms and conducting the association analysis of genes with drought tolerance.

Background: Sulfotransferase (SULT) plays an important role in the formation of estrogen which is usually conferred as a risk factor for breast cancer. Polymorphism of the SULT1A1 may be closely associated with breast cancer. However, studies on the association between polymorphism and breast cancer have yielded inconsistent results. We performed a meta-analysis including ethnic subgroup and menopausal statue subgroup to investigate the association of SULT1A1 Arg213His polymorphism with breast cancer., Methods: PubMed, EBSCO and Web of Science databases were searched for the correlative articles up to January 2010 (10362 breast cancer patients and 14250 controls). The risk (odds ratio, OR) was used to estimate the association between SULT1A1 polymorphism and breast cancer risk. All of the data from each study use either fixed-effects or random-effects., Results: We found that SULT1A1 Arg213His had no exact effect to increase the risk of breast cancer (OR = 1.07, 95% CI: 0.97-1.17, P = 0.164), but it did increase the risk of breast cancer among postmenopausal women in the dominant model (OR = 1.28, 95%CI: 1.04-1.58, P = 0.019). No similar effect was found among premenopausal breast cancer women (OR = 1.06, 95%CI: 0.88-1.27, P = 0.537). There was a significant increase in breast cancer risk among Asian women (OR = 2.03, 95% CI: 1.00-4.14, P = 0.051) but not Caucasian women in recessive model. There was publication bias among postmenopausal women subgroup (P = 0.002), however by using the trim and fill method, if the publication bias was the only source of the funnel plot asymmetry, it needed two more studies to be symmetrical. The value of Log OR did not change too much after the adjustment and the fail-safe number of missing studies that would bring the P-value changed was 17., Conclusions: We concluded that the polymorphism of SULT1A1 Arg213His might be one of the high risk factors for breast cancer in Asian women and in postmenopausal women for all races. We should point out that the publication bias among postmenopausal women may partly account for the result, but the conclusion might not affected deeply by the publication bias.

The BT/TAMUS 2032 (BT) cationic peptides are a group of related cationic peptides produced by a Gram-positive soil bacterium, Brevibacillus texasporus. Cationic amphiphilic peptides produced by host cells have been found to stimulate or prime the innate immune responses in mammals, but little information is available on the effects of bacterial-produced peptides on host immunity. We have previously shown that BT, provided as a feed additive for 4 days after hatch, significantly induced protection against extraintestinal colonization by Salmonella enterica serovar Enteritidis. We also found that feeding BT significantly upregulated the functional efficiency of heterophils, the avian equivalent to mammalian neutrophils. The objective of the present study was to further evaluate the effect of BT as a nonantibiotic, antibacterial compound and a stimulator of the innate immune response of young chickens. BT, provided as a feed additive at three different concentrations (12, 24, or 48 ppm) for 4 days after hatch, significantly increased protection against Salmonella enterica serovar Enteritidis cecal colonization in a concentration-dependent manner. We also confirmed our previous results that the functional activities of heterophils from chickens fed the BT rations were significantly upregulated. In addition, we also found that the functional activities of peripheral blood monocytes were significantly increased in a concentration-dependent manner when compared with monocytes isolated from chickens fed a control diet. This is the first report of bacterial cationic peptides providing protection against Salmonella cecal colonization. The significance of these data is that the orally delivered cationic peptides stimulate the innate response during the first week after hatch, normally a time of immunologic inefficiency and increased susceptibility to bacterial infections. We speculate that BT given as a feed additive during the first week after hatch could provide increased protection against a variety of bacterial pathogens because of the nonspecific nature of the innate response.

This study was designed to investigate the effects of some Traditional Chinese Medicine (TCM) agents on bone resorption and morphometric features of osteoclasts as well as their relationships. TCM ShengGuZaiZaoSan and XianLingGuBao, were used to treat the experimental fracture. Thirty 6-month-old Chinchilla rabbits were used for the establishment of animal models each with a 3 mm bone defect in the middle of left radius as well as of right radius. These models were divided randomly into 3 groups : ShengGuZaiZaoSan Group (Group A), XianLingGuBao groups (Group B) and control-group (Group C). Every group was further divided into 2 subgroups: a former sacrificed group (14 days after operation) and a latter sacrificed group (31 days after operation). After the rabbits being killed, the samples of their undecalcified calli were subjected to the morphometry study of bone resorption and osteoclasts. Group A had more bone resorption, compared with Group B and C. Both Groups A and B exhibited some changed morphometric features of osteoclasts as compared with Group C (P < 0.05). Simple correlation analysis indicated that bone resorption is mainly correlated with osteoclast numbers, and that in individual group, bone resorption is correlated with osteoclast form factor, area and mean photodensity (P < 0.05). These allow us to conclude that ShengGuZaiZaoSan can increase bone resorption and accelerate bone remodeling by increasing osteoclast numbers at the former stage and can enhance osteoclast function at the latter stage. These changes are beneficial to fracture healing.

Drought stress may alter protein synthesis in turfgrasses. The objectives of this study were to investigate physiological changes associated with the synthesis of dehydrin and a cytosolic-heat shock protein (HSC 70) in response to drought stress in two tall fescue (Festuca arundinacea L.) cultivars, 'Southeast' and 'Rebel Jr.'. The effects of abscisic acid (ABA) application on the drought tolerance of the cultivars also were evaluated. The cultivars were subjected to three treatments in growth chambers: well-watered control, drought stress, and drought stress following ABA treatment. Turf quality and leaf relative water content (RWC) decreased and electrolyte leakage (EL) increased during drought stress for both cultivars. The ABA-treated plants maintained higher turf quality and RWC, and lower EL than untreated plants under drought stress conditions. Levels of 20- and 29-kDa polypeptides increased during drought stress, and a 35-kDa polypeptide was noted in both cultivars only when subjected to drought stress either with or without ABA treatment. Immunoblot analysis indicated that dehydrin-like polypeptides of about 23-60 kDa were induced by progressive water deficit in both cultivars. The 53 kDa dehydrin polypeptide was present in Southeast with or without ABA treatment at 10 d of drought stress, whereas the 40 kDa dehydrin polypeptide accumulated in Rebel Jr. in both treatment. The 23- and 27-kDa dehydrin polypeptides were present at 10 d in drought-stressed and ABA-treated plants in both cultivars, but were more pronounced in the drought-stressed plants without ABA. A cytosolic-heat shock protein (HSC 70) was detected in plants in all treatments including well-watered plants of both cultivars, but its levels were higher in drought-stressed and ABA-treated plants. No single dehydrin polypeptide was induced by ABA treatment under drought stress, however, the promotive effects of ABA on the reduced drought stress paralleled the delayed induction of protein synthesis in tall fescue.