The miR7125-MdARF1 module enhances the resistance of apple to Colletotrichum gloeosporioides by promoting lignin synthesis in response to salicylic acid signalling.

Apple is an important cash crop in China, and it is susceptible to fungal infections that have deleterious effects on its yield. Apple bitter rot caused by Colletorichum gloeosporioides is one of the most severe fungal diseases of apple. Salicylic acid (SA) is a key signalling molecule in the plant disease resistance signalling pathways. Lignin synthesis also plays a key role in conferring disease resistance. However, few studies have clarified the relationship between the SA disease resistance signalling pathway and the lignin disease resistance pathway in apple. MdMYB46 has previously been shown to promote lignin accumulation in apple and enhance salt and osmotic stress tolerance. Here, we investigated the relationship between MdMYB46 and biological stress; we found that MdMYB46 overexpression enhances the resistance of apple to C. gloeosporioides. We also identified MdARF1, a transcription factor upstream of MdMYB46, via yeast library screening and determined that MdARF1 was regulated by miR7125 through psRNATarget prediction. This regulatory relationship was confirmed through LUC and qRT-PCR experiments, demonstrating that miR7125 negatively regulates MdARF1. Analysis of the miR7125 promoter revealed that miR7125 responds to SA signals. The accumulation of SA level will result in the decrease of miR7125 expression level. In sum, the results of our study provide novel insights into the molecular mechanisms underlying the resistance of apple to C. gloeosporioides and reveal a new pathway that enhances lignin accumulation in apple in response to SA signals. These findings provide valuable information for future studies aimed at breeding apple for disease resistance.

Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.

PURPOSE: We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC). METHODS: Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses. RESULTS: Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01-1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03-1.09), SCC (OR 1.06, 95% CI 1.02-1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03-1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations. CONCLUSION: There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

Switch-associated protein 70 protects against nonalcoholic fatty liver disease through suppression of TAK1.

BACKGROUND AND AIMS: NAFLD is a progressive disease without known effective drug treatments. Switch-associated protein 70 (SWAP70) is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes. However, the role of SWAP70 in NAFLD remains unclear. This study aimed to identify the function and mechanism of SWAP70 in NAFLD. APPROACH AND RESULTS: The results showed that the expression of SWAP70 was significantly increased in mice and hepatocytes after metabolic stimulation. Overexpression of SWAP70 in hepatocytes suppressed lipid deposition and inflammation, and SWAP70 knockdown created the inverse effect. Using hepatocyte-specific Swap70 knockout and overexpression mice fed a high-fat, high-cholesterol diet, we demonstrated that SWAP70 suppressed the progression of nonalcoholic steatohepatitis by inhibiting lipid accumulation, inflammatory response, and fibrosis. Mechanically, RNA sequencing analysis and immunoprecipitation assays revealed that SWAP70 inhibited the interaction between transforming growth factor ß-activated kinase 1 (TAK1) binding protein 1 and TAK1 and sequentially suppressed the phosphorylation of TAK1 and subsequent c-Jun N-terminal kinase/P38 signaling. Inhibition of TAK1 activation blocked hepatocyte lipid deposition and inflammation caused by SWAP70 knockdown. CONCLUSIONS: SWAP70 is a protective molecule that can suppress the progression of NAFLD by inhibiting hepatic steatosis and inflammation. SWAP70 may be important for mitigating the progression of NAFLD.

Comparative of Forensic DNA Identification Using Cell Lysis Method and Magnetic Beads Method.

OBJECTIVES: To compare the effects of cell lysis method and magnetic beads method in forensic DNA identification and to explore these two methods in forensic DNA identification. METHODS: The genome DNA of THP-1 cells in different quantities was extracted by the cell lysis method and magnetic beads method, and the DNA content was quantified by real-time quantitative PCR. The cell lysis method and magnetic beads method were used to type the STR of human blood with different dilution ratios. RESULTS: When the numbers of THP-1 cell were 100, 400 and 800, the DNA content extracted by cell lysis method were (1.219±0.334), (5.081±0.335), (9.332±0.318) ng, respectively; and the DNA content extracted by magnetic beads method were (1.020±0.281), (3.634±0.482), (7.896±0.759) ng, respectively. When the numbers of THP-1 cells were 400 and 800, the DNA content extracted by the cell lysis method was higher than that by the magnetic beads method. The sensitivity of cell lysis method and magnetic beads method was similar in STR typing of human blood at different dilution ratios. Complete STR typing could be obtained at 100, 300 and 500-fold dilutions of blood samples, but could not be detected at 700-fold dilution. STR typing of undiluted human blood could not be detected by cell lysis method. CONCLUSIONS: The cell lysis method is easy to operate and can retain template DNA to the maximum extend. It is expected to be suitable for trace blood evidence tests.

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable-adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case-control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34-0.90; Ptrend  = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34-0.96; Ptrend  = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never-smoking women.

Assessment of Skeletal Maturation in Male Children With Unilateral Cleft Lip and Palate.

OBJECTIVES: To assess the skeletal maturation in male children with unilateral cleft lip and palate (UCLP) in comparison to that of noncleft peers using the cervical vertebral maturation (CVM) method. METHODS: A sample of 149 male UCLP patients aged from 8- to 16-year-old and 447 age-matched orthodontic individuals without clefts was retrospectively compiled. Cervical vertebral maturation was assessed based on the cephalometric radiographs. RESULTS: The proportion of children in CVMSI and CVMSII was higher in the UCLP group compared to that in the noncleft group, but there was no significant difference in the CVM stage of the cleft patients compared to their noncleft peers. In the 12- to 14-year-old group, children with UCLP showed significantly delayed skeletal maturity in comparison with their noncleft peers. No significant difference was found in the other 3 age groups. There was a statistically significant correlation between the skeletal age and chronological age in both the UCLP group and the noncleft group. There was no significant difference in the mean age at CVMII and CVMIII between the cleft patients and noncleft peers. CONCLUSIONS: Males with UCLP aged 12- to 14-year-old have a statistically significant increased risk of delayed skeletal maturity in comparison with their noncleft peers. The chronological age is not an accurate indicator to assess the degree of skeletal maturation.

Association Between Long-Term Regular Exercise and Gut Microbiota Among Middle-Aged and Older Urban Chinese.

Increasing evidence has suggested that physical activity may modulate gut microbiome composition. We investigated associations of long-term regular exercise with gut microbiota among middle-aged and older urban Chinese individuals. Gut microbiota was assessed using 16S ribosomal ribonucleic acid gene sequencing of stool samples from 2,151 participants from the Shanghai Women's Health Study and Shanghai Men's Health Study. Participants were free of cancer, diabetes, and cardiovascular diseases at the time of stool sample collection. Physical activity was assessed in repeat surveys between 1996 and 2015 using validated questionnaires. Regular exercise was defined as any type of leisure-time physical activity with a standard metabolic equivalent score >3.0. Stool samples were collected using the 95% ethanol method between 2015 and 2018 with an average of 3.0 years (SD = 0.9) after the latest exposure assessment. General linear regression and permutational multivariate analysis of variance were carried out to evaluate associations of microbial α- and ß-diversity with regular exercise participation. Logistic regression and linear regression models were used to evaluate the prevalence and relative abundance of individual taxa in association with regular exercise. Regular exercise was significantly associated with ß-diversity (Bray-Curtis and Jaccard dissimilarities, both false discovery rates = 0.03%, 0.12% and 0.09% variance explained, respectively) but not with α-diversity. Relative abundance of genus Ruminococcus was significantly lower among regular exercisers compared with nonexercisers (median relative abundance: 0.64% vs. 0.81%, false discovery rate <0.10). Further studies are needed to validate the findings from this study and evaluate health benefits of regular exercise on gut microbiota.

A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies.

Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05. Using luciferase reporter assays in both estrogen-receptor positive (ER+) and negative (ER-) cell lines, we showed that alternative alleles of potential functional single-nucleotide polymorphisms (SNPs), rs11552449 (DCLRE1B), rs7257932 (SSBP4), rs3747479 (MRPS30), rs2236007 (PAX9), and rs73134739 (ATG10), could significantly change promoter activities of their target genes compared to reference alleles. Furthermore, we performed in vitro assays in breast cancer cell lines, and our results indicated that DCLRE1B, MRPS30, and ATG10 played a vital role in breast tumorigenesis via certain disruption of cell behaviors. Our findings revealed potential target genes for associations of genetic susceptibility risk loci and provided underlying mechanisms for a better understanding of the pathogenesis of breast cancer.

Association of oral microbiota with lung cancer risk in a low-income population in the Southeastern USA.

PURPOSE: Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk. METHODS: We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk. RESULTS: No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV], Peptostreptococcaceae_[XI], and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59-0.98), 0.80 (0.66-0.97), 0.81 (0.67-0.99), and 0.83 (0.71-0.98), respectively (all p < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912, Capnocytophaga sputigena, Lactococcus lactis, Peptoniphilaceae_[G-1] sp._oral_taxon_113, Leptotrichia sp._oral_taxon_225, and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30-1.00), 0.36 (0.17-0.73), 0.53 (0.31-0.92), 0.43 (0.21-0.88), 0.43 (0.19-0.94), 0.57 (0.34-0.99), and 0.54 (0.31-0.94), respectively (all p < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12-0.66]; p = 0.00012). CONCLUSION: Results from this study suggest that oral microbiota may play a role in the development of lung cancer.

Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.

Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.

BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to ß-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women.

PURPOSE: Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case-control study conducted in Shanghai, China. METHODS: We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study. RESULTS: Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10-15). Among cases, 3.7% had a BRCA2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants. CONCLUSIONS: This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.

Resveratrol Attenuates Aortic Dissection by Increasing Endothelial Barrier Function Through the SIRT1 Pathway.

Aortic dissection (AD) is a serious condition and a health issue on a global scale. ß-Aminopropionitrile-induced AD in mice is similar to the pathogenesis of AD in humans. Resveratrol (RSV) is a natural polyphenolic substance that provides anti-inflammatory and cardiovascular effects, but the role of RSV in AD is unclear. In this study, we investigated the effects and mechanisms of RSV on ß-aminopropionitrile-induced AD in mice. Our results indicate that RSV can prevent the occurrence of AD. More meaningfully, we found that the protective effect comprises an increase in sirtuin 1 (SIRT1) expression in endothelial cells for the reconstruction of their structure, reducing the recruitment of inflammatory cells by endothelial cells and inhibiting the inflammation response, thereby suppressing the occurrence of AD.

MdHAL3, a 4'-phosphopantothenoylcysteine decarboxylase, is involved in the salt tolerance of autotetraploid apple.

KEY MESSAGE: MdHAL3 has PPCDC activity and is involved in the salt tolerance of autotetraploid apple. Apple (Malus × domestica) is the most widely planted fruit tree species worldwide. However, the growth and development of apple have been increasingly affected by abiotic stress, such as high salinity. In our previous study, RNA sequencing (RNA-seq) analysis revealed that the expression level of the MdHAL3 gene was significantly upregulated in the autotetraploid apple cultivar Hanfu. In the present study, we first isolated HAL3, whose product was shown to exert 4'-phosphopantothenoylcysteine decarboxylase (PPCDC) activity, from apple. MdHAL3 was expressed in all organs of apple, and its expression was rapidly induced by salt stress. The MdHAL3 protein was localized to the cytomembrane and cytoplasm. Five MdHAL3 overexpression (OE) lines and five MdHAL3-RNAi apple lines were obtained. We found that MdHAL3 enhanced the salt stress tolerance of apple and that the OE plants rooted more easily than the wild-type (WT) plants. The coenzyme A (CoA) content in the leaves of the OE plants was greater than that in the leaves of the WT plants, and the CoA content in the MdHAL3-RNAi plants was lower than that in the WT plants. Taken together, our findings indicate that MdHAL3 plays an essential role in the response to salt stress in apple.

Colorectal cancer susceptibility loci and influence on survival.

Genome-wide association studies (GWAS) have identified multiple single-nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. To evaluate the potential influence of colorectal cancer susceptibility SNPs on disease prognosis, we investigated whether GWAS-identified colorectal cancer risk SNPs and polygenic risk scores (PRSs) might be associated with survival among colorectal cancer patients. A total of 1374 colorectal cancer patients were recruited from the Korean National Cancer Center. For genotyping, 30 colorectal cancer-susceptibility SNPs previously identified by GWAS were selected. The Cox proportional hazard model was used to evaluate associations of these risk SNPs and PRSs with disease-free survival (DFS) and overall survival (OS). The prognostic values were compared between genetic and nongenetic models using Harrell's c index. During the follow-up period (median: 88, 91 months for DFS and OS), 570 DFS (41.5%) and 487 OS (35.4%) events were observed. We found that 5 SNPs were significantly associated with DFS or OS among colorectal cancer patients at P < .05: rs10936599 at 3q26.2 (MYNN), rs704017 at 10q22.3 (ZMIZ1-AS1), rs11196172 at 10q25.2 (TCF7L2), rs3802842 at 11q23.1 (COLCA1-2), and rs9929218 at 16q22.1 (CDH1). The PRSs constructed using these 5 SNPs were associated with worse survival (DFS: Ptrend = .02 unweighted PRS, Ptrend = .01 weighted PRS, OS: Ptrend = 3.7 × 10-3 unweighted, Ptrend = .02 weighted PRS). Our results suggest that several colorectal cancer susceptibility SNPs might also be related to survival by influencing disease progression.

Genome-wide association study in East Asians identifies two novel breast cancer susceptibility loci.

Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have been shown to play an important role in breast cancer aetiology. We conducted a two-stage genome-wide association study (GWAS) including 14 224 cases and 14 829 controls of East Asian women to search for novel genetic susceptibility loci for breast cancer. Single nucleotide polymorphisms (SNPs) in two loci were found to be associated with breast cancer risk at the genome-wide significance level. The first locus, represented by rs12118297 at 1p22.3 (near the LMO4 gene), was associated with breast cancer risk with odds ratio (OR) and (95% confidence interval (CI)) of 0.91 (0.88-0.94) and a P-value of 4.48 × 10- 8 This association was replicated in another study, DRIVE GAME-ON Consortium, including 16 003 cases and 41 335 controls of European ancestry (OR = 0.95, 95% CI = 0.91-0.99, P-value = 0.019). The second locus, rs16992204 at 21q22.12 (near the LINC00160 gene), was associated with breast cancer risk with OR (95% CI) of 1.13 (1.07-1.18) and a P-value of 4.63 × 10 - 8 The risk allele frequency for this SNP is zero in European-ancestry populations in 1000 Genomes Project and thus its association with breast cancer risk cannot be assessed in DRIVE GAME-ON Consortium. Functional annotation using the ENCODE data indicates that rs12118297 might be located in a repressed element and locus 21q22.12 may affect breast cancer risk through regulating LINC00160 expressions and interaction with oestrogen receptor signalling. Our findings provide additional insights into the genetics of breast cancer.

Three-Year Follow-Up of a Patient With Unilateral Cleft Lip and Palate Treated With Maxillary Protraction and Alveolar Bone Grafting: An Approach Exploring the Potential Power of Growth.

Clinically, patients with operated unilateral cleft lip and palate always present with a concave profile, depressed midface, maxillary hypoplasia, narrow upper dental arch, and class III malocclusion. In this clinical report, the authors describe the successful orthodontic treatment of a patient with unilateral cleft lip and palate. A boy, 7 years 11 months of age, with a history of unilateral cleft lip and cleft palate presented with a Class I malocclusion on Skeletal Class III base. A satisfactory occlusion and a favorable lateral profile were achieved after maxillary protraction (face mask) combined with fixed appliance treatment, including alveolar bone grafting surgery. An acceptable occlusion and facial proportion were maintained after a 3-year retention period. These results suggest orthodontic treatment with growth interference is an effective option for a patient with cleft lip and palate.

Optimal Computational Power Allocation in Multi-Access Mobile Edge Computing for Blockchain.

Blockchain has emerged as a decentralized and trustable ledger for recording and storing digital transactions. The mining process of Blockchain, however, incurs a heavy computational workload for miners to solve the proof-of-work puzzle (i.e., a series of the hashing computation), which is prohibitive from the perspective of the mobile terminals (MTs). The advanced multi-access mobile edge computing (MEC), which enables the MTs to offload part of the computational workloads (for solving the proof-of-work) to the nearby edge-servers (ESs), provides a promising approach to address this issue. By offloading the computational workloads via multi-access MEC, the MTs can effectively increase their successful probabilities when participating in the mining game and gain the consequent reward (i.e., winning the bitcoin). However, as a compensation to the ESs which provide the computational resources to the MTs, the MTs need to pay the ESs for the corresponding resource-acquisition costs. Thus, to investigate the trade-off between obtaining the computational resources from the ESs (for solving the proof-of-work) and paying for the consequent cost, we formulate an optimization problem in which the MTs determine their acquired computational resources from different ESs, with the objective of maximizing the MTs' social net-reward in the mining process while keeping the fairness among the MTs. In spite of the non-convexity of the formulated problem, we exploit its layered structure and propose efficient distributed algorithms for the MTs to individually determine their optimal computational resources acquired from different ESs. Numerical results are provided to validate the effectiveness of our proposed algorithms and the performance of our proposed multi-access MEC for Blockchain.

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.

BACKGROUND & AIMS: Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS: This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS: We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS: We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.