Development and validation of a sensitive UPLC-MS/MS analytical method for GFH009 in rat plasma and its application to toxicokinetics studies.

GFH009 is a potent, highly selective, small molecule that targets and inhibits the activity of the CDK9/cyclin T1 regulatory complex of P-TEFb. This study aimed to develop and validate a highly selective and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for precise quantification of GFH009 in rat plasma. This method was subsequently employed for conducting toxicokinetic studies of GFH009 in rats. Plasma was prepared using a simple protein precipitation method by acetonitrile. Chromatographic separation of the analytes was achieved on a BEH C18 analytical column with a rapid 3.0 min run time and a flow rate of 0.5 ml/min. The calibration curves for plasma samples exhibited excellent linearity over a wide concentration range of 1.0-1,000 ng/ml for GFH009. Intra- and inter-day accuracies were within 92.7-105.7%, and precisions were no more than 6.7%. Furthermore, the analyte demonstrated stability under four different storage conditions, with variations of <15.0%. This study pioneers a methodological innovation by introducing a highly reliable, specific and sensitive analytical method for GFH009 in rat plasma. The successful application of this method in toxicokinetic studies further underscores its significance, offering valuable insights for the methodology of clinical pharmacokinetic research.

Genetic factors are stressed variably by onset age-based sample selection in psoriasis: A hint from major histocompatibility complex region-based analysis.

BACKGROUND: Large cohort-based genetic association studies have been established over a decade. However, for certain diseases, different results with respect to the genome-wide association study level have been obtained among studies, even for those conducted within the same ethnic groups. We hypothesized that onset age-based sample variables might have a great impact on the results. METHODS: In the present study, we divided psoriasis patients into several subgroups according to the onset age bracket. We conducted genetic association analysis in the major histocompatibility complex (MHC) region of each patient subgroup with shared control subjects. RESULTS: We found decreases in the numbers of susceptible variants in each subgroup analysis as the onset age increased in the longitudinal analysis. Meanwhile, the pairwise analysis showed that younger patients exhibited greater numbers of genetic risks in the MHC region compared to elder patients, regardless of whether the cut-off values were defined as 20 or 30 years old. Similar results were also found among 11-20-, 21-30- and 31-40-year-old groups. Furthermore, when combining the results of both the stepwise regression analysis and the HLA-C*06:02 conditioning analysis, different variants were found to be independently associated with each psoriasis subgroup. CONCLUSIONS: Onset age-based sample variables influence the results of genetic association studies, at least in MHC region-based genetic analysis. We suggest that caution is required when selecting samples for genetic association studies to prevent confounders that might be a result of onset age.

Association analyses identify two susceptibility loci 5q31 and 5q22.1 for atopic dermatitis in Chinese Han population.

BACKGROUND: Atopic dermatitis (AD) and other atopic diseases often share some common genetic and pathogenic bases. Recent genome-wide association studies (GWAS) have identified several loci associated with atopic diseases, allergic sensitization and asthma in different populations. The aim of this study was to investigate whether these susceptibility loci were related to AD in Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNPs) from recent atopic diseases and allergic sensitization GWAS were genotyped in 3,013 AD patients and 5,483 healthy controls in Chinese Han population using Sequenom MassArray system. Data was analyzed with PLINK 1.07 software. RESULTS: We identified that the susceptibility loci at 5q31 (RAD50/IL13, rs2158177, P = 1.08×10-3, OR = 1.15) and 5q22.1 (TSLP, rs1837253, P = 2.66×10-3, OR = 0.91) were significantly associated with AD. Genotype-based association testing revealed that the dominant model provided the best fit for both rs2158177 (P = 3.75×10-3) and rs1837253 (P = 5.30×10-3). Pathway analysis conformed that both loci were associated with the JAK-STAT signaling pathway. CONCLUSIONS: We identified two susceptibility loci 5q31 and 5q22.1 for AD that might bear candidate genes conferring susceptibility to AD.

Association of the chromosome 11p13.5 variant and atopic dermatitis with a family history of atopy in the Chinese Han population.

BACKGROUND: Recent genome-wide association studies (GWAS) and a meta-analysis of GWAS for atopic dermatitis (AD) have identified some AD genetic loci in European and Japanese populations. OBJECTIVE: To investigate whether some novel susceptibility loci are associated with AD in the Chinese Han population. METHODS: We first selected eight novel susceptibility loci to replicate in 2,205 AD patients and 2,116 healthy controls using the Sequenom platform. Data were analyzed with PLINK 1.07 software. RESULTS: We found that rs12634229 (3q13.2), rs7927894 (11p13.5) and rs878860 (11p15.4) showed a slight association with AD (P = 0.012, P = 0.033, P = 0.020, respectively); rs6780220 (3p21.33) was preferentially related to AD with keratosis pilaris, but did not reach the threshold of significance after correction. The frequency of rs7927894 allele T was significantly different between AD patients with a positive and negative family history of atopy. CONCLUSION: The loci rs7927894 (11p13.5) are related to AD with a positive family history of atopy in Chinese Han population, providing novel insight into the genetic pathogenesis of AD.

Association of single nucleotide polymorphisms in the USF1, GTF2A1L and OR2W3 genes with non-obstructive azoospermia in the Chinese population.

PURPOSE: To research the association between the single nucleotide polymorphisms (SNPs) of three spermatogenesis-related genes (USF1, GTF2A1L and OR2W3) and non-obstruction azoospermia (NOA). METHODS: We investigated 361 NOA cases and 368 controls from the Chinese Han population, and we used Sequenom iplex technology to analyze the candidate 9 SNPs from the USF1, GTF2A1L and OR2W3 genes. RESULTS: In this study, we found that the variant rs2516838 of USF1 was associated with NOA susceptibility (P = 0.020, OR = 1.436), and the haplotype TCG of the variants rs1556259, rs2516838, and rs2774276 of USF1 conferred an increased risk of NOA (P = 0.019, OR = 1.436). Furthermore, we found that the rs11204546 genotype of OR2W3 and the rs11677854 genotype of GTF2A1L were correlated with the FSH level in the patients (P = 0.004 and P = 0.018, respectively). CONCLUSIONS: Our results provided a new insight into susceptibility of USF1 variant with male infertility. Clinically, the SNPs (rs11204546 of OR2W3 and rs11677854 of GTF2A1L ) might be additional valuable molecular predictive markers for assessing the treatment of NOA patients.

Association study of susceptibility loci with specific breast cancer subtypes in Chinese women.

To determine whether recent genome-wide association studies that reported 45 susceptibility loci in European women are also risk factors for breast cancer in Chinese women. We selected and genotyped 40 single nucleotide polymorphisms (SNPs) using the Sequenom iPlex platform in a female Chinese cohort of 2,901 breast cancer cases and 2,789 healthy controls. We evaluated these SNPs with the risk of breast cancer and further by estrogen receptor (ER) status, progestin (PR) status, human epidermal growth factor receptor-2 (HER-2) status, and four breast cancer subtypes (Luminal A type, Luminal B type, HER-2 overexpression type and Basal-like type). We first confirmed that the SNP rs9693444 on 8p12 was associated with breast cancer in Chinese women (P = 6.44 × 10(-4)). Furthermore, we identified four susceptibility loci that were associated with specific tumor subtypes. Statistically significant differences were detected with the association of rs6828523 (4q34.1/ADAM29) with ER-positive breast cancer (P = 1.27 × 10(-3)) and the association of rs4849887 (2q14.2) with PR-positive breast cancer (P = 1.29 × 10(-3)). Of the four breast cancer subtypes, the associations of rs12493607 (3p24.1/TGFBR2) with HER-2 overexpression in breast cancer (P = 1.09 × 10(-3)) and rs11075995 (16q12.2/FTO) with basal-like breast cancer (P = 1.64 × 10(-4)) were statistically significant. This study is the first to show that these 5 susceptibility loci (8p12, 4q34.1/ADAM29, 2q14.2, 3p24.1/TGFBR2, and 16q12.2/FTO) correlate with breast cancer (overall and specific subtypes) in Chinese women, which has improved our understanding of the genetic basis of specific breast cancer subtypes.

CREM variants rs4934540 and rs2295415 conferred susceptibility to nonobstructive azoospermia risk in the Chinese population.

To evaluate the association of variants related to spermatogenesis with susceptibility to Chinese idiopathic nonobstructive azoospermia (NOA), seventeen tag single-nucleotide polymorphisms (SNPs) in CREM, ACT, KIF17b, and SPAG8 were analyzed in 361 NOA patients and 368 controls by Sequenom iplex technology. The results showed that two CREM SNPs, rs4934540 and rs22954152, were significantly associated with NOA and played protective roles against the disease (P value with Bonferroni correction = 0.00017, odds ratio [OR] = 0.624 and P = 0.012, OR = 0.686, respectively). Haplotype analysis of CREM gene variants suggested that haplotype CGTG of the SNPs, rs4934540, rs2295415, rs11592356, and rs1148247, exhibited significant protective effect against the occurrence of NOA (P = 0.001, OR = 0.659). The haplotype TATG conferred a significantly increased risk of NOA (P = 0.011, OR = 1.317). Furthermore, making use of quantitative RT-PCR, we demonstrated that relative mRNA expression of CREM in NOA patients with maturation arrest was only one-third of that in the controls with normal spermatogenesis (P < 0.0001). Our findings indicated that the polymorphisms of CREM gene were associated with NOA in the Chinese population and low CREM expression might be involved in the pathogenesis of spermatogenesis maturation arrest.

EZH2 genetic variants affect risk of gastric cancer in the Chinese Han population.

Enhancer of zeste 2 (EZH2) gene encodes a histone methyltransferase that constitutes the catalytic component of the polycomb repressive complex-2 (PRC2) to initiate epigenetic silencing of genes. It is reported that the expression level of EZH2 in gastric cancer tissue was highly correlated with tumor progression, however, whether EZH2 genetic variants were associated with the risk of gastric cancer remains yet unknown. In this study, we conducted a genotyping analysis for EZH2 in 311 cases of gastric cancer and 425 controls from the Chinese Han population. We found five single nucleotide polymorphisms (SNP; rs12670401, rs6464926, rs2072407, rs734005, and rs734004) of EZH2 gene were significantly associated with the risk of gastric cancer. Of which, the rs12670401 with the minor allele C and rs6464926 with the minor allele T revealed strong associations with increased gastric cancer risk [P = 0.009, adjusted odds ratio (aOR) = 1.327, 95% CI = 1.075-1.683 and P = 0.012, aOR = 1.310, 95% CI = 1.059-1.619]. The other three SNPs, rs2072407, rs734005, and rs734004 contributed to significantly reduced risk of gastric cancer (P = 0.033, aOR = 0.787, 95% CI = 0.633-0.981, P = 0.045, aOR = 0.799, 95% CI = 0.642-0.995 and P = 0.048, aOR = 0.803, 95% CI = 0.645-0.999), respectively. We further found that rs12670401 and rs6464926 were in a strong LD while rs2072407, rs734005, and rs734004 were in another. Haplotype analysis of the five SNPs showed that haplotype CCTCT reduced the risk of gastric cancer (P = 0.031 and aOR = 0.784), while haplotype GTCTC significantly elevated the risk of gastric cancer (P = 0.011 and aOR = 1.310). We concluded that EZH2 variants were significantly associated with gastric cancer risk. Our results for the first time provided new insight into susceptibility factors of EZH2 gene variants in carcinogenesis of gastric cancer of the Chinese Han population.

Association analyses identifying two common susceptibility loci shared by psoriasis and systemic lupus erythematosus in the Chinese Han population.

BACKGROUND: Genome-wide association studies (GWASs) have revealed a large number of genetic risk loci for many autoimmune diseases. One clear finding emerging from the published genetic studies of autoimmunity is that different autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE), share susceptibility loci. Our study explores additional susceptibility loci shared by psoriasis and SLE in the Chinese Han population. METHODS: In total, 20 single nucleotide polymorphisms (SNPs) in 17 previously reported psoriasis susceptibility loci and 34 SNPs from 24 previously reported SLE susceptibility loci were investigated in our initial psoriasis and SLE GWAS dataset. Among these SNPs, we selected two SNPs (rs8016947 and rs4649203) with association values of p<5×10(-2) for both diseases in the GWAS data for further investigation in psoriasis (7260 cases and 9842 controls) and SLE (2207 cases and 9842 controls) using a Sequenom MassARRAY system. RESULTS: We found that these two SNPs (rs8016947 and rs4649203) in two loci (NFKBIA and IL28RA) were associated with psoriasis and SLE with genome-wide significance (Pcombined<5×10(-8) in psoriasis and Pcombined<5×10(-8) in SLE): rs8016947 at NFKBIA (Pcombined-psoriasis=3.90×10(-10), Pcombined-SLE=1.08×10(-13)) and rs4649203 at IL28RA (Pcombined-psoriasis=3.91×10(-12), Pcombined-SLE=9.90×10(-9)). CONCLUSIONS: These results showed that two common susceptibility loci (NFKBIA and IL28RA) are shared by psoriasis and SLE in the Chinese Han population.

Genomewide association study of leprosy.

BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

Synthesis and biological evaluation of noscapine analogues as microtubule-interfering agents.

A series of noscapine analogues have been synthesized via 13-step reaction starting from 2-hydroxy-3-methoxybenzaldehyde. Anti-tumor activities of these compounds were evaluated against HL-60 cell lines in vitro by the standard MTT assay. It was found that most of these derivatives showed appreciable inhibitory activity against HL-60 and tubulin polymerization. The results also indicated that the potency of compound 31 is about three times more than that ofnoscapine against HL-60 cell line and tubulin polymerization. Moreover, it induced a massive accumulation of cells in G2/M phase. These results showed noscapine and its derivatives were worth to be intensively studied further.

C-reactive protein/abumin ratio is a useful biomarker for predicting the mucosal healing in the Crohn disease: A retrospective study.

ABSTRACT: Ileocolonoscopy is currently recognized as the gold standard for evaluating mucosal healing in patients with Crohn disease (CD). However, the ideal noninvasive marker to assess mucosal healing instead of invasive ileocolonoscopy is not available. This study aimed to determine the correlations between the mucosal healing and serological optimizing markers in CD.This retrospective study consecutively included 62 CD patients with 137 hospitalizations between March 2014 and March 2020. On the basis of the Simple Endoscopic Score for Crohn's disease (SES-CD), the CD patients were divided into mucosal healing group (SES-CD ≤ 2) and nonmucosal healing group (SES-CD > 2). We collected the results of ileocolonoscopy examination and inflammatory markers and then serological optimizing markers, including C-reactive protein/albumin ratio (CRP/ALB), platelet/albumin ratio (PLT/ALB), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. The control group consisted of 50 healthy volunteers in the corresponding period.We found that CRP/ALB, PLT/ALB, NLR, and PLR were correlated with the mucosal healing of CD, and the correlation of CRP/ALB with the mucosal healing was the highest (r = -0.64). Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of CRP/ALB (0.87) was higher than NLR (0.69), PLR (0.72), and PLT/ALB (0.81). In the efficacy of assessing the mucosal healing in CD, the sensitivity of CRP/ALB, NLR, PLR, and PLT/ALB were 91.1%, 83.9%, 73.2%, and 73.2%, respectively, and the specificity was 76.5%, 46.9%, 64.2%, and 75.3%, respectively.CRP/ALB was the most appropriate marker to assess CD mucosal healing among the serological optimizing markers.

A Common Variant at 11q23.3 Is Associated with Susceptibility to Atopic Dermatitis in the Han Chinese Population.

Background: Genome-wide association studies (GWASs) have identified many genetic variants that are risk factors for numerous immune-mediated diseases. In particular, different immune-mediated diseases have been found to share the same susceptibility loci. Therefore, exploring the genetic overlap between atopic dermatitis (AD) and other immune-mediated diseases in more detail may help identify additional shared susceptibility loci among common immune-mediated diseases. Recent evidence suggests that the 11q23.3 locus is a susceptibility locus shared among multiple immune-mediated diseases. Objective: This study was designed to investigated whether SNPs at the chromosome 11q23.3 locus are associated with AD in the Han Chinese population. Methods: In total, 16 SNPs within the 11q23.3 locus were genotyped using TaqMan assays for 1,012 AD cases and 1,362 controls. From these SNPs, we selected rs638893 with an association values of p < 5 × 10-2 for AD for further analysis in an independent replication study using the Sequenom MassARRAY system to genotype an additional (consisting of 1,288 cases and 1,380 controls). The combined analyses were performed in two stages using a meta-analytical method. Results: We identified a common variant at 11q23.3 (rs638893), that was significantly associated (p = 1.58 × 10-3, OR = 1.22) with AD. The genotype-based association analysis revealed that the recessive model provided the best fit for rs638893. Conclusion: Our study identified a variant on chromosome 11q23.3 that likely confers susceptibility to AD, thereby advancing our understanding of the genetic basis of this disease.

Validation of Susceptibility Loci for Vitiligo Identified by GWAS in the Chinese Han Population.

Forty-nine susceptible loci have been reported to be significantly associated with vitiligo by genome-wide association studies (GWASs) in European-derived whites. To date, some of these reported susceptibility loci have not yet been validated in the Chinese Han population. The purpose of this study was to examine whether the 16 reported susceptible loci in European-derived whites were associated with vitiligo in the Chinese Han population. Imputation was performed using our previous GWAS dataset by IMPUTE v2.2.2. The 16 imputed top single-nucleotide polymorphisms (SNPs) with suggestive signals, together with the reported SNPs, were genotyped in a total of 2581 patients and 2579 controls by the Sequenom MassARRAY system. PLINK 2.0 software was used to perform association analysis. The dbSNP database, HaploReg, and eQTL data were adopted to annotate the biological function of the SNPs. Finally, four SNPs from three loci were significantly associated with vitiligo, including rs3747517 (P = 1.29 × 10-3, OR = 0.87) in 2q24.2, rs4807000 (P = 7.78 × 10-24, OR = 0.66) and rs6510827 (P = 3.65 × 10-5, OR = 1.19) in 19p13.3, and rs4822024 (P = 6.37 × 10-10, OR = 0.67) in 22q13.2. According to the dbSNP database, rs3747517 is a missense variant of IFIH1, rs4807000 and rs6510827 are located in TICAM1, and rs4822024 is located 6 kb upstream of TEF. Further bioinformatics analysis by HaploReg and eQTL found that rs4807000, rs6510827, and rs4822024 are involved in regulating gene expression. Our study revealed the strong association of 2q24.2 (rs3747517), 19p13.3 (rs4807000, rs6510827), and 22q13.2 (rs4822024) with the risk of vitiligo in the Chinese Han population, which implicates common factors for vitiligo across different ethnicities, and helps expand the understanding of the genetic basis of this disease.

GWAS Follow-up Study Discovers a Novel Genetic Signal on 10q21.2 for Atopic Dermatitis in Chinese Han Population.

Atopic dermatitis (AD) is a common inflammatory skin disease with high heritability. Two susceptibility loci have been confirmed in our previous AD genome-wide association study (GWAS). To look for additional genetic factors in Chinese Han ethnicity, we performed a large-scale GWAS follow-up study. Forty-nine top single nucleotide polymorphisms (SNPs) that had never been reported previously were genotyped using Sequenom Massarray system in an independent cohort, which consist of northern Chinese (1634 cases and 1263 controls) and southern Chinese (2985 cases and 9526 controls). Association analyses were performed using PLINK 2 software. Three SNPs in northern and ten SNPs in southern were found exhibiting association evidence with AD (P < 0.05). Finally, SNP rs224108 on 10q21.2 showed high significance for AD in joint analysis of GWAS and replication study (P meta = 4.55 × 10-9, OR = 1.21), and was confirmed as an independent genetic marker by Linkage disequilibrium calculation and conditional logistic regression analysis. Bioinformatics analysis strongly suggested that rs224108 may have the potential to alter the target gene expression through non-coding epigenetic regulation effects. Meanwhile, SNP rs11150780 on 17q25.3 was also found suggestive association with AD (P meta = 7.64 × 10-7, OR = 1.18). Our findings confirmed a novel susceptibility signal on 10q21.2 for AD in Chinese Han population and advanced the understanding of the genetic contribution to AD.

Genetic diagnosis in a Chinese Hailey-Hailey disease pedigree with novel ATP2C1 gene mutation.

Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by recurrent eruption of vesicles and bullae at the sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene encoding the human secretory pathway calcium ATPase 1 (hSPCA1) have been identified as the causative mutations in HHD. In this study, we used direct sequencing and restriction endonuclease digestion to analyze mutations of the ATP2C1 gene in a Chinese three-generation pedigree. A heterozygous T-to-C transition at nucleotide 1004 in exon 12 of ATP2C1 gene was detected. After summarizing the reported cases with ATP2C1 mutation, we concluded that the T1004C transition resulted in a novel missense mutation of leucine condon (CTG) to proline (CCG) at amino acid residue 335(L335P) in hSPCA1. Here, a genetic diagnosis was made for the proband's daughter before the clinical presentation. The study realized the molecular diagnosis in the HHD pedigree. Our findings should be useful for genetic counseling and prenatal diagnosis for the affected family and in demonstrating the critical role of the ATP2C1 gene in the pathogenesis of HHD further.

[Synthesis of 1-furfuryl-indolin-2-one derivatives and preliminary evaluation of their antitumor activities].

In order to find new indolin-2-one derivatives as antitumor agents, a series of 3-pyrrole substituted 1-(5-formyl-2-furanylmethyl) indolin-2-one derivatives were designed and synthesized. 5-Formyl-2 ,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester was condensed with 5-substituted indolin-2-one 2a-2d to afford 3-[(pyrrol-2-yl) -methylidenyl] indolin-2-ones 3a-3d. Through N-alkylation, 1-(5-formyl-furfuryl) -indolin-2-one 4a-4d were prepared. Compounds 4a-4d were then condensed with indolin-2-one to afford bis-indolin-2-one derivatives 5a-5d. The structures of the synthesized compounds were determined by 1H NMR, MS and element analysis. Antitumor activities of all the synthesized compounds in vitro were tested. All the 12 synthesized compounds possess antitumor activities against SPC-A1 strain. Especially the compounds 5a-5d possess potent antitumor activities better than sunitinib. Their IC50 are all below 5 micromol x L(-1).

Novel mutations in Chinese Han patients with tuberous sclerosis complex: Case series and review of the published work.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non-pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ2 -tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.

A Large-Scale, Exome-Wide Association Study of Han Chinese Women Identifies Three Novel Loci Predisposing to Breast Cancer.

Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new noncoding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10-8) and CNFN (P = 3.77 × 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087-97. ©2018 AACR.

Study on clinical effect and mechanism of jianpi qingre huayu recipe.

OBJECTIVE: To study the effects of Jianpi Qingre Huayu Recipe in curing gastric ulcer and to preliminarily probe into its pathogenic mechanism. METHODS: Fifty patients with gastric ulcer of Pi -insufficiency and stasis-heat syndrome type were assigned to the treated group (30 patients) and the control group (20 patients). They were treated respectively with JQH and Ranitidine. At the same time, another group consisting of 20 healthy persons was set up for normal control. The clinical effect on gastroscopic figure and traditional Chinese medicine (TCM) syndrome were observed. Changes of T-cell subsets and interleukin-8 (IL-8) in serum as well as IL-8 in mucosa around the gastric ulcer were determined before and after treatment by flow cytometry and ELISA. RESULTS: Comparison of the total effective rate on gastroscopic figure in the treated group and the control group (86.7% vs 80.0%) showed insignificant difference, but the cure rate and markedly effective rate in the former (50.0% and 20.0%) was higher than that in the latter (40.0% and 15.0%) respectively. Comparison of the total effective rate on TCM syndrome in the treated group and in the control group (96.7% vs 70.0%) showed insignificant difference, but the cure rate and markedly effective rate in the former (63.3% and 23.3%) was higher than that in the latter (50.0% and 20.0%) respectively. Serum levels of CD3+, CD4+, CD8+ got restored to normal range in the treated group after treatment but it was not so in the control group. IL-8 level in gastric mucosa was improved in both groups but the improvement in the treated group was better. CONCLUSION: JQH could effectively treat gastric ulcer and partly reduce its recurrence through improving patients' immune function.