Structural patterns at all scales in a nonmetallic chiral Au_133(SR)_52 nanoparticle

Structural ordering is widely present in molecules and materials. However, the organization of molecules on the curved surface of nanoparticles is still the least understood owing to the major limitations of the current surface characterization tools. By the merits of x-ray crystallography, we reveal the structural ordering at all scales in a super robust 133–gold atom nanoparticle protected by 52 thiolate ligands, which is manifested in self-assembled hierarchical patterns starting from the metal core to the interfacial –S–Au–S– ladder-like helical “stripes” and further to the “swirls” of carbon tails. These complex surface patterns have not been observed in the smaller nanoparticles. We further demonstrate that the Au133(SR)52 nanoparticle exhibits nonmetallic features in optical and electron dynamics measurements. Our work uncovers the elegant self-organization strategies in assembling a highly robust nanoparticle and provides a conceptual advance in scientific understanding of pattern structures

Association between germline variants and somatic mutations in colorectal cancer

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n similar or equal to 125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC

Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium.

BACKGROUND: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. METHODS: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. RESULTS: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). CONCLUSION: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer

Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. ;Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. ;Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P &lt; 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P &lt; 0.05. ;Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk

Study of calreticulin mediated NY-ESO-1 immunogenicity in human dendritic cells

NY-ESO-1 is one of the most immunogenic cancer/testis antigens (CTAs) ever discovered. The immunogenicity of NY-ESO-1 mainly relies on its cross presentation in dendritic cells (DCs) to generate specific cytotoxic T lymphocyte (CTL) responses against NY-ESO-1-expressing cancer cells. Calreticulin (CRT) has been identified as a receptor for NY-ESO-1 on DC surface. CRT has been shown to efficiently bind antigens to DCs and to elicit an antigen-specific CTL response. Several receptors for CRT itself on DC surface have been reported. In this thesis, two approaches have been studied to enhance the immunogenicity of NY-ESO-1. In the first approach, the level of CRT expression on DC surface was up-regulated by calyculin A and the binding of NY-ESO-1 to DCs was increased. The function of the CTLs generated from DCs pulsed with calyculin A and NY-ESO-1 protein or NY-ESO-1 protein alone was evaluated by cytotoxicity assay and CD8+ T cell activation assay. The results showed that calyculin A was able to significantly augment the specific CTL responses against NY-ESO-1-expressing cancer cells. In the second approach, the binding of NY-ESO-1 in NY-ESO-1/CRT fusion protein to DCs was found to be more efficient than NY-ESO-1 protein alone. The function of the CTLs induced by NY-ESO-1/CRT fusion protein or NY-ESO-1 protein was evaluated by cytotoxicity assay and CD8+ T cell activation assay. The results showed that NY-ESO-1/CRT fusion protein was more effective in stimulating the NY-ESO-1-specific CTL responses than NY-ESO-1 protein alone. These data demonstrate that both calyculin A and NY-ESO-1/CRT fusion protein are able to enhance the immunogenicity of NY-ESO-1. This study may provide information for developing new strategies for vaccines against NY-ESO-1-expressing cancers