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Background: Quantum nanodots especially carbon nanoparticles (CNPs) have been widely studied in biomedicine in imaging, and drug delivery, but anti-cancer mechanisms remain elusive. Methods: Here, we investigated a type of cell death induced by food (beet, soybean) derived CNPs in cancer cells and tested whether CNPs induced DNA damage and resistant to anti-cancer agent PARP inhibitor (PARPi) could be overcome by quantum calculations, TEM, AFM, FT-IR, soft agar assay, and cytotoxicity assay. Results: At high doses, CNPs derived from beet lead to a pop-like apoptosis (Carbopoptosis) in cancer cells. Quantum mechanical calculations confirmed CNPs binding with phosphate groups as well as DNA bases. At low doses, CNPs develop PARPi drug resistance through interactions between CNPs and PARPi. A synergistic drug effect was achieved with the combination of phosphatase inhibitor (PPi), PARPi, and CNPs. This is corroborated by the fact that sulfur modulated CNPs which exhibit super high phosphatase nanozyme activity abrogated the CNPs induced colony formation in anchorage-independent cancer cell growth. Conclusion: Thus, our data suggest the CNPs intrinsic nanozyme activity of phosphatase may crosstalk with drug resistance, which can be reversed upon modulations. [ABSTRACT FROM AUTHOR]

Purpose: The identification and targeting of biomarkers specific to prostate cancer (PCa) could improve its detection. Given the high expression of translocator protein (TSPO) in PCa, we investigated the use of [18F]VUIIS1008 (a novel TSPO-targeting radioligand) coupled with positron emission tomography (PET) to identify PCa in mice and to characterize their TSPO uptake.Procedures: Ptenpc-/-, Trp53pc-/- prostate cancer-bearing mice (n = 9, 4-6 months old) were imaged in a 7T MRI scanner for lesion localization. Within 24 h, the mice were imaged using a microPET scanner for 60 min in dynamic mode following a retro-orbital injection of ~ 18 MBq [18F]VUIIS1008. Following imaging, tumors were harvested and stained with a TSPO antibody. Regions of interest (ROIs) were drawn around the tumor and muscle (hind limb) in the PET images. Time-activity curves (TACs) were recorded over the duration of the scan for each ROI. The mean activity concentrations between 40 and 60 min post radiotracer administration between tumor and muscle were compared.Results: Tumor presence was confirmed by visual inspection of the MR images. The uptake of [18F]VUIIS1008 in the tumors was significantly higher (p < 0.05) than that in the muscle, where the percent injected dose per unit volume for tumor was 7.1 ± 1.6 % ID/ml and that of muscle was < 1 % ID/ml. In addition, positive TSPO expression was observed in tumor tissue analysis.Conclusions: The foregoing preliminary data suggest that TSPO may be a useful biomarker of PCa. Therefore, using TSPO-targeting PET ligands, such as [18F]VUIIS1008, may improve PCa detectability and characterization. [ABSTRACT FROM AUTHOR]

Key message: A new powdery mildew resistance gene Pm54 was identified on chromosome 6BL in soft red winter wheat. Abstract: Powdery mildew is causing increasing damage to wheat production in the southeastern USA. To combat the disease, a continuing need exists to discover new genes for powdery mildew resistance and to incorporate those genes into breeding programs. Pioneer variety 26R61 (shortened as 26R61) and AGS 2000 have been used as checks in the Uniform Southern Soft Red Winter Wheat Nursery for a decade, and both have provided good resistance across regions during that time. In the present study, a genetic analysis of mildew resistance was conducted on a RIL population developed from a cross of 26R61 and AGS 2000. Phenotypic evaluation was conducted in the field at Plains, GA, and Raleigh, NC, in 2012 and 2013, a total of four environments. Three quantitative trait loci (QTL) with major effect were consistently detected on wheat chromosomes 2BL, 4A and 6BL. The 2BL QTL contributed by 26R61 was different from Pm6, a widely used gene in the southeastern USA. The other two QTL were identified from AGS 2000. The 6BL QTL was subsequently characterized as a simple Mendelian factor when the population was inoculated with a single Blumeria graminis f. sp. tritici ( Bgt) isolate in controlled environments. Since there is no known powdery mildew resistance gene ( Pm) on this particular location of common wheat, the gene was designated Pm54. The closely linked marker Xbarc134 was highly polymorphic in a set of mildew differentials, indicating that the marker should be useful for pyramiding Pm54 with other Pm genes by marker-assisted selection. [ABSTRACT FROM AUTHOR]

When the National Institutes of Health Mouse Models of Human Cancer Consortium initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for 'prostate cancer mouse model' yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin promoter driving viral oncogenes such as Simian virus 40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and overexpression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question? [ABSTRACT FROM AUTHOR]

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors. [ABSTRACT FROM AUTHOR]

The discovery of several new loci for resistance to Hessian fly was reported here. QHf.uga- 6AL, the late HR61 was recognized from wheat cultivar 26R61 on the distal end of 6AL with resistance to both biotypes E and vH13. It is the first gene or QTL found on this particular chromosome. QHf.uga- 3DL and QHf.uga- 1AL, physically assigned to the deletion bins 3DL2-0.27-0.81 and 1AL1-0.17-0.61, respectively, were detected for resistance to biotype vH13. Both QTL should represent new loci for Hessian fly resistance and the latter was detectable only in the late seedling stage when tolerance was evident. In addition, QHf.uga- 6DS- C and QHf.uga- 1AS had minor effect and were identified from the susceptible parent AGS 2000 for resistance to biotype E and vH13, respectively. QHf.uga- 6DS- C is different from the known gene H13 on 6DS and QHf.uga- 1AS is different from H9 gene cluster on 1AS. These loci also might be new components of Hessian fly resistance, although their LOD values were not highly significant. The QTL detections were all conducted on a RIL mapping population of 26R61/AGS 2000 with good genome coverage of molecular markers. The strategy used in the current study will serve as a good starting point for the discovery and mapping of resistance genes including tolerance to the pest and the closely linked markers will certainly be useful in selecting or pyramiding of these loci in breeding programs. [ABSTRACT FROM AUTHOR]

Soil-borne wheat mosaic virus (SBWMV) is considered to be one of the most important diseases in winter wheat regions of the central and southeastern United States. Utilization of resistant cultivars is the most efficient and environmentally friendly means of control. To identify potential quantitative trait loci (QTL) or effective gene(s) for SBWMV resistance, two independent recombinant inbred line populations, Pioneer 26R61/AGS 2000 (PR61/A2000, 178 lines) and AGS 2020/LA 95135 (A2020/LA, 130 lines), were developed. Pioneer 26R61 and AGS 2020 were resistant to SBWMV, and AGS 2000 and LA 95135 were susceptible. Based on the whole genome genotyping for the PR61/A2000 population and targeted mapping of chromosome 5D for the A2020/LA, the same major QTL QSbm.uga- 5DL was identified in all environments with highly significant LOD values, explaining up to 62 and 65 % of the total phenotypic variation in the PR61/A2000 and A2020/LA populations, respectively. The location of the resistance QTL coincided with previously published SBCMV resistance genes Sbm1, Sbm and Sbm on the long arm of chromosome 5D. A conserved locus was therefore proposed for conditioning SBWMV/SBCMV resistance in common wheat. Validation of the QTL using the flanking markers Xbarc177 and Xbarc161 in three cultivars and three elite lines with Pioneer 26R61 in their pedigrees indicated that the markers were suitable for marker-assisted selection. [ABSTRACT FROM AUTHOR]

A panel of 55 peanut lines was analyzed for fatty acid composition with gas chromatography and also genotyped with SNP markers from the FAD2 genes by real-time PCR. Significant variation in fatty acid composition was identified, and the ratio of oleic acid to linoleic acid (O/L) ranged from 1.23 to 56.45. In terms of the FAD2 gene mutation, the assayed lines were classified into four genotypes: wild type (OlOlOlOl), single functional homozygous mutation on the A genome (ololOlOl), single functional homozygous mutation on the B genome (OlOlolol), and a double mutation on both A and B genomes (olololol). Each genotype has a significantly different fatty acid profile. Both FAD2A and FAD2B are involved in the conversion of oleic acid to linoleic acid in peanuts. Overall, these results demonstrate the combined power of genetic analysis with biochemical analysis on peanut fatty acid research. [ABSTRACT FROM AUTHOR]

Stripe rust, caused by Puccinia striiformis f. sp. tritici, is an important disease of soft red winter wheat in the eastern region of the USA. Pioneer 26R61 has provided effective resistance to stripe rust for 10 years. To elucidate the genetic basis of the resistance, a mapping population of 178 recombinant inbred lines (RILs) was developed using single-seed descent from a cross between Pioneer 26R61 and the susceptible cultivar AGS 2000. A genetic map with 895 markers covering all 21 chromosomes was used for QTL analysis. One major QTL was detected, explaining up to 56.0% of the mean phenotypic variation, flanked by markers Xbarc124 and Xgwm359, and assigned to the distal 22% of the short arm of wheat chromosome 2A. Evidence showed that it was different from Yr17 derived from Ae. ventricosa, the only formally named Yr gene in 2AS, and the QTL was temporarily designated as YrR61. In addition, a minor QTL, QYr.uga- 6AS, probably conditioned high-temperature adult plant resistance. The QTL explained 6-7% of the trait variation. Preliminary test of the flanking markers for YrR61, in two cultivars and two promising breeding lines with Pioneer 26R61 in their pedigree, indicated that YrR61 was present in these cultivars and lines, and these markers could therefore be used in marker-assisted selection. [ABSTRACT FROM AUTHOR]

Peanut ( Arachis hypogaea L.) is one of the most important oilseed and nutritional crops in the world. To efficiently utilize the germplasm collection, a peanut mini-core containing 112 accessions was established in the United States. To determine the population structure and its impact on marker-trait association, this mini-core collection was assessed by genotyping 94 accessions with 81 SSR markers and two functional SNP markers from fatty acid desaturase 2 (FAD2). Seed quality traits (including oil content, fatty acid composition, flavonoids, and resveratrol) were obtained through nuclear magnetic resonance (NMR), gas chromatography (GC), and high-performance liquid chromatography (HPLC) analysis. Genetic diversity and population structure analysis identified four major subpopulations that are related to four botanical varieties. Model comparison with different levels of population structure and kinship control was conducted for each trait and association analyses with the selected models verified that the functional SNP from the FAD2A gene is significantly associated with oleic acid (C18:1), linoleic acid (C18:2), and oleic-to-linoleic (O/L) ratio across this diverse collection. Even though the allele distribution of FAD2A was structured among the four subpopulations, the effect of FAD2A gene remained significant after controlling population structure and had a likelihood-ratio-based R ( R) value of 0.05 (oleic acid), 0.09 (linoleic acid), and 0.07 (O/L ratio) because the FAD2A alleles were not completely fixed within subpopulations. Our genetic analysis demonstrated that this peanut mini-core panel is suitable for association mapping. Phenotypic characterization for seed quality traits and association testing of the functional SNP from FAD2A gene provided information for further breeding and genetic research. [ABSTRACT FROM AUTHOR]

Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19Arf–p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19Arf–p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf–p53 response is impaired, whereas a Skp2–SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy. [ABSTRACT FROM AUTHOR]

Skp2 is an F-box protein that forms the SCF complex with Skp1 and Cullin-1 to constitute an E3 ligase for ubiquitylation. Ubiquitylation and degradation of the p27 are critical for Skp2-mediated entry to the cell cycle, and overexpression and cytosolic accumulation of Skp2 have been clearly associated with tumorigenesis, although the functional significance of the latter is still unknown. Here we show that Akt/protein kinase B (PKB) interacts with and directly phosphorylates Skp2. We find that Skp2 phosphorylation by Akt triggers SCF complex formation and E3 ligase activity. A phosphorylation-defective Skp2 mutant is drastically impaired in its ability to promote cell proliferation and tumorigenesis. Furthermore, we show that Akt-mediated phosphorylation triggers 14-3-3β-dependent Skp2 relocalization to the cytosol, and we attribute a specific role to cytosolic Skp2 in the positive regulation of cell migration. Finally, we demonstrate that high levels of activation of Akt correlate with the cytosolic accumulation of Skp2 in human cancer specimens. Our results therefore define a novel proto-oncogenic Akt/PKB-dependent signalling pathway. [ABSTRACT FROM AUTHOR]

We recently showed that aposporous apomixis, a form of gametophytic apomixis, is controlled by a single apospory-specific genomic region (ASGR) in both Pennisetum squamulatum and Cenchrus ciliaris. We present evidence that in a reciprocal cross between sexual pearl millet ( P. glaucum) and an apomictic F1 ( P. glaucum× P. squamulatum) the ASGR is not transmitted at the same rate. When pearl millet was used as the female parent and the apomictic genotype as the pollen donor, the ASGR was transmitted at a rate of 0.41 in a progeny of 57 plants, indicating a slight transmission ratio distortion. However, in a population of 52 rare sexual progenies characterized among a large progeny of a quasi-obligate apomict (an F1 hybrid of P. glaucum× P. squamulatum), the transmission rate of ASGR was only 0.12. This strong segregation distortion may have occurred at four different levels: (1) female meiosis, (2) during female gametophyte maturation, (3) upon fertilization with differential survival of embryos being a consequence of differential gene expression controlled by parent-of-origin specific effects (imprinting) and (4) at a later developmental stage of the embryo through an embryo/endosperm genetic incompatibility system. [ABSTRACT FROM AUTHOR]

Leaf rust (LR), caused by Puccinia triticina (Pt), is a major disease of wheat worldwide. Genetic resistance is the most effective, economic, and environmentally safe method to reduce losses caused by LR. Seventy-nine LR resistance genes have been identified so far; however, only a few of them are still effective due to the constant evolution of new Pt races. The objectives of this study were to characterize the genetic basis of LR resistance in the soft red winter wheat (SRWW) cultivar AGS 2000 at seedling stage, and identify markers for marker-assisted selection (MAS). A mapping population of 175 recombinant inbred lines (RILs) was developed from a cross between the susceptible cultivar Pioneer® variety 26R61 (26R61) and AGS 2000. Two out of four Pt races (MBTNB, MFGKG, TCRKG, and MCTNB) showed segregating reactions for the parental lines and RIL population at the seedling stage. Whole genome QTL analysis detected a single common QTL for resistance to both Pt races (MFGKG and MBTNB) on chromosome 2BS. The gene was flanked by wPt-666389 and wPt-2600 markers and explained up to 75.3% of phenotypic variation for Pt race MBTNB, and is therefore a Mendelian factor. LR resistance genes, Lr13, Lr16, Lr23, Lr48, and Lr73, were all detected on 2BS; however, based on their physical and genetic positions, the gene was distinct and therefore temporarily designated as LrA2K. The closely linked marker Xwmc770 to LrA2K has been validated on a set of wheat cultivars and can be used in MAS for LR resistance. [ABSTRACT FROM AUTHOR]

Arising from: Tomlins et al. 448, 595–599 (2007); Tomlins et al. replyThe first recurrent translocation event in prostate cancer has been recently described; it results in the translocation of an ETS (E26 transformation specific) transcription factor (ERG or ETV1) to the TMPRSS2 promoter region, which contains androgen responsive elements. The TMPRSS2:ERG genetic rearrangement has been reported to occur in approximately 40% of primary prostate tumours (ETV1 genetic rearrangements occur at a much lower frequency), and it results in the aberrant androgen-regulated expression of ERG. Tomlins et al. concluded that ETS genetic rearrangements are sufficient to initiate prostate neoplasia. However, here we show that ETS genetic rearrangements may in fact represent progression events rather than initiation events in prostate tumorigenesis. To this end, we demonstrate that the prostate-specific overexpression of ERG does not initiate prostate tumorigenesis. [ABSTRACT FROM AUTHOR]