Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.

Long-term exposure of 4-hydroxyestradiol induces the cancer cell characteristics via upregulating CYP1B1 in MCF-10A cells.

Life-long estrogen exposure is one of the major risk factors in the development and progression of breast cancer. However, little is known about the molecular mechanisms, by which chronic exposure to estrogen contributes to breast carcinogenesis. The aim of the present study was to investigate the effects of long-term exposure with 4-hydroxyestradiol (4-OHE2) on acquired cancer characteristics of human mammary epithelial MCF-10A cells. The possible regulators were further studied in chronic 4-OHE2-treated MCF-10A cells. We observed that MCF-10A cells long-term exposed to 4-OHE2 acquire the characteristics of cancer cells, such as enhanced cell growth, EMT properties, and increased migration and invasiveness. Moreover, the expression of CYP1B1 was significantly elevated in long-term 4-OHE2-treated MCF-10A cells. Block of CYP1B1 significantly reduced the cancer cell characteristics in long-term 4-OHE2-treated MCF-10A cells. Our results indicated that 4-OHE2 mediated enhanced cancer cell characteristics in mammary epithelial cells are an important key event for breast carcinogenesis process. CYP1B1 partially contributes to the 4-OHE2 induced cancer cell characteristics in MCF-10A cells. Targeting CYP1B1 might offer a new strategy for the treatment of estrogen-induced breast cancer.

Pharmacogenetic Correlates of Antipsychotic-Induced Weight Gain in the Chinese Population / 神经科学通报·英文版

Antipsychotic-induced weight gain (AIWG) is a common adverse effect of this treatment, particularly with second-generation antipsychotics, and it is a major health problem around the world. We aimed to review the progress of pharmacogenetic studies on AIWG in the Chinese population to compare the results for Chinese with other ethnic populations, identify the limitations and problems of current studies, and provide future research directions in China. Both English and Chinese electronic databases were searched to identify eligible studies. We determined that > 25 single-nucleotide polymorphisms in 19 genes have been investigated in association with AIWG in Chinese patients over the past few decades. HTR2C rs3813929 is the most frequently studied single-nucleotide polymorphism, and it seems to be the most strongly associated with AIWG in the Chinese population. However, many genes that have been reported to be associated with AIWG in other ethnic populations have not been included in Chinese studies. To explain the pharmacogenetic reasons for AIWG in the Chinese population, genome-wide association studies and multiple-center, standard, unified, and large samples are needed.

Aberration in translation initiation and associated diseases:Role of the eukaryotic translation initiation factor 3A / 中南大学学报(医学版)

Translation control in eukaryotes contributes significantly to gene expression regulation during cellular processes,which enables rapid changes of specific proteins to maintain cellular homeostasis.Eukaryotic translation is a multiple-step process that comprised of four phases:initiation,elongation,termination and ribosome recycling.The initiation phase is rate-limiting and orchestrated by a set of eukaryotic translation initiation factors (eIFs).Defects in translation initiation can result in a series of diseases.Among all eIFs,eIF3 is the largest and less-known initiation factor due to its intrinsic complexity.Aberration in eIF3A,the largest subunit of eIF3,is known to contribute to carcinogenesis and protection against evolution into higher-grade malignancy,and the altered expression or mutation of eIF3A affects the responses of cancer patients to platinum-based chemotherapy.Besides its role in cancinogenesis,eIF3A is also implicated in fibrosis,and the agents inhibiting eIF3A delay the progression of this disorder.The dual roles of eIF3A in tumorigenesis are probably due to the regulation of translation of different mRNAs at different stages of tumor progression by eIF3A.In tum the encoded products serve as pro-tumor or anti-tumor proteins at different stages.

Clinical research study of Familial Idiopathic Basal Ganglia Calcification from 8 family analysis / 中国神经精神疾病杂志

Objective To better understand the clinical characteristics of Familial Idiopathic Basal Ganglia Calcifi?cation (FIBGC), including at the perspective of hereditary pattern, clinical test results, onset age, clinical heterogeneity and the volume of basal ganglia calcification (VBGC). Method 8 Eight FIBGC families were collected and draw family pedigrees were draw. Analysis of was conducted on the patient's clinical test results, head CT and MRI changes, onset ag?es, relationship of clinical manifestations with VBGC. Results No significant difference was found in serum calcium, alu?minum, arsenic, cobalt, magnesium, phosphorus, iron, parathyroid hormone and calcitonin concentration between the fam?ily members of patients and healthy controls (P>0.05). Family members from 8 FIBGC families including the two with consanguineous marriage manifested autosomal dominant heredity. The severity of , symptomatic s was correlated with VBGCpatients showed the same clinical manifestations in the dyskinesia family. The psychiatric symptoms was not asso? ciated with VBGC whereas patients with dyskinesia had a large VBGC. There was a significant difference in onset age be?tween patients with psychiatric symptoms and those with dyskinesia. P.atients with dyskinesia suffer larger VBGC, and is characterized by Patients with dyskinesia had relatively later onset age (43.95 ± 2.47 y) whereas those with. psychiatric symptoms hadsymptomatic patients with early onset age (31.32±10.16y). The comparison of the onset age (43.954±2.473 vs. 31.319±10.156 y, t=4.438, P=0.001) and VBGC (1.748±0.622 vs. 0.392±0.276 cm3, t=2.518, P=0.028) with symptom?atic patients between dyskinesia and psychogenic families was significant. Conclusions Eight FIBGC families manifested autosomal dominant heredity. Patients with dyskinesia suffer have a larger VBGC and are associated with a, and is char?acterized by relatively later onset age. In contrast, patients with psychiatric symptomspsychogeny is not related withhave a the small VBGC and showedand their age of onset is young. earlier onset age.

Progress in research on genetic variations in miRNA regulatory pathway / 中华医学遗传学杂志

MicroRNAs (miRNAs) are a class of highly conserved small noncoding RNAs which can regulate gene expression by post-transcriptional degradation or translational repression. miRNAs are involved in the regulation of cell apoptosis, proliferation, differentiation and other physiological processes, and are closely related with development of cancer. More recently, it has been proposed that the presence of genetic variations in microRNA genes, their biogenesis pathway and target binding sites can affect the miRNA processing machinery and targeting, therefore have a significant genetic effect. Since polymorphisms in a miRNA regulatory pathway can result in the loss or gain of a miRNA function and can affect the expression of hundreds of genes, more and more evidence suggested a strong association of miRNA polymorphisms with disease progression, diagnosis and prognosis. Whether in the pathogenesis research of complex diseases or finding biomarkers for diagnosis and prognosis, polymorphisms in the miRNA regulatory pathway have an extremely important value for research.

Osthole ameliorates glutamate-induced toxicity in HT22 cells via activating PI3K/Akt signaling pathway / 中南大学学报(医学版)

OBJECTIVE@#To investigate the neuroprotective effects of osthole (OST) on glutamate-induced toxicity in hippocampal HT22 cells and to explore the correlation between the protection and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway.
@*METHODS@#The cell injury model of HT22 was induced by glutamate and the cell viability was detected by MTS assay. The lactate dehydrogenase (LDH) release and the caspase-3 activity were determined by commercial kits. Western blot analysis was utilized to detect the protein levels of PI3K, Akt, p-PI3K and p-Akt. 
@*RESULTS@#OST markedly improved the cell survival and decreased the LDH release in glutamate-treated HT22 cells in a dose-dependent manner. Furthermore, the levels of p-PI3K and p-Akt proteins were significantly increased in glutamate and OST-co-treated HT22 cells. The effect of OST on p-Akt phosphorylation in HT22 cells was attenuated in the presence of PI3K specific inhibitor (LY294002).
@*CONCLUSION@#OST protects HT22 cells from glutamate excitotoxicity through a mechanism involving the activation of PI3K/Akt signaling pathway.

Basic research and clinical translation of precision medicine / 中国药理学通报

Since the late twentieth century,the progress of ge-nomics,proteomics and other areas has promoted modern medi-cine from the era of evidence-based medicine to the era of preci-sion medicine.With the studies of the relationships between ge-nomic information and clinical phenotypes,precise medicine,to improve clinical outcomes and minimize unnecessary side effects,develops and implements individualized medicine ac-cording to patients’personalized specificities through pharma-cogenomics.Basic research and clinical translation of precision medicine do help to improve the health system of our country.

Effects of chrysophanol on BDNF and iNOS together with oxidative stress in rats with diabetes-associated cognitive decline / 中国药理学通报

Aim To assess the protective role of chry-sophanol in rats with diabetes-associated cognitive de-cline (DACD) and explore the potential molecular mechanisms.Methods The learning and memory performance was assessed by Morris water maze test;the activities of AChE,ChAT,iNOS and oxidative stress markers including CAT,SOD and GSH-PX in the hippocampus were detected using respective com-mercial kits.The level of BDNF was also measured with commercial ELISA kit.Results Chrysophanol significantly improved learning and memory functions in the diabetic groups.Additionally,the activities of AChE,BDNF also found to be evidently increased, while decreased activities of ChAT,iNOS,CAT,SOD and GSH-PX were observed in the hippocampus of dia-betic rats.Conclusions Collectively,chrysophanol has a protective role against DACD and this neuropro-tection is associated with increasing BDNF level.Chry-sophanol can also suppress the activities of iNOS, CAT,SOD and GSH-PX in diabetic rats.It is likely to be a novel therapeutic drug for the treatment of diabetic patients with cognitive deficits in clinical practice.

Effect of Hydroxypropyl Starch Vacant Capsules on the Content of Spironolactone / 中国药师

Objective:To investigate the effect of vacant capsules made from hydroxypropyl starch on the content of spironolac-tone. Methods:The spironolactone capsules were placed under the conditions with (4 000 ± 500) lx, 40℃ and RH (75 ± 5) % for 5 days and 10 days, respectively. An HPLC method was used to analyze the content of spironolactone, and the changes in appearance, color and the other traits were also observed. Results:The content of spironolactone was within the range of 93. 45%-100. 37% after the above tests, which was conformed to the standard(93. 0%-107. 0%). Conclusion:The vacant capsules made from hydroxypropyl starch rival have good compatibility with spironolactone.

Determination of Residual Organic Solvents in Poly(lactic-co-glycolide) / 医药导报

Objective To establish a capillary gas chromatography( GC)method for the determination of residual organic solvents in poly( lactic-co-glycolide)( PLGA),including methanol,acetone,dichloromethane,and toluene. Methods A capillary GC method was carried out. DB-624 capillary column(30 m× 0. 32 mm,1. 80 μm)with programmed temperature chromatography was employed. The initial temperature was kept at 40 ℃ for 8 min. Then the temperature was raised to 200 ℃ at a rate of 10 ℃·min-1 . The injection port temperature was 180 ℃,and the split ratio was 10:1. The carrier gas was nitrogen. The temperature of FID was set at 250 ℃,and the sample volume was set at 3 μL. Results Four residual organic solvents consisting of methanol,acetone,dichloromethane and toluene in PLGA were completely separated. The linear range of concentration of methanol,acetone,dichloromethane and toluene was within 10. 0-50. 0( r=0. 999 8 ),16. 7-83. 3( r=0.9998),2.0-10.0(r=0.9993),and3.0-14.8(r=0.9997)μg·mL-1,respectively.Therecoveryofmethanol,acetone, dichloromethane and toluene was 99. 9%( RSD=1. 5%),100. 8%( RSD=0. 9%),100. 1%( RSD=1. 1%),and 99. 5%(RSD=0. 6%),respectively. Six batches of samples met the requirements. Conclusion The method is proven to be sensitive and accurate after the validation. It is suitable for the determination of residual organic solvents in PLGA.

Advance in research on pharmacogenomics of vitamin / 中国药理学通报

Vitamin is necessary and important for humans and an-imals to maintain normal physiological function, metabolism, and growth. The studies suggest that vitamin is one of the factors which play a role in the activity of enzymes, and it is coenzyme of many enzyme or an important component of coenzyme. The lack of vitamins causes a metabolic vitamin deficiency. Pharma-cogenomics research the relationship between human genetic vari-ation and drug reaction, using the information to solve the differ-ent reactions among the different individuals of the same drug. Vitamins, which constitute human tissues and maintain normal physiological functions, are also an important part for the phar-macogenomics study.

Research progress on eIF3 a and cancer / 中国药理学通报

Translation is a fundamental step in regulation of gene expression and abnormalities in this process may lead to cancer. In eukaryotic cells, translation of mRNA is mainly regulated by many eukaryotic initiation factors ( eIFs) . EIF3 plays an impor-tant role in translational regulation, cell growth and oncogenesis. The largest subunit of eIF3, eIF3a may play a role as a regulator of mRNAs. The relationship between eIF3a and oncogenesis has been found. Moreover, the eIF3a mRNA is ubiquitously ex-pressed in different cancer cells and can modulate the cell cycle. However, some studies indicate that eIF3a could provide protec-tion against evolution into higher malignancy and reduce the re-sistance to chemotherapy . The patients of high eIF3a expression could get a better prognosis . In fact, the role of eIF3a is still un-clear in cancer cells. EIF3a may be involved in the process of tumor pathophysiology, but its regulatory role is undulatory.

Genome wide association study of obesity / 中南大学学报(医学版)

Obesity is a great risk factor for type 2 diabetes and certain types of cancer, which become a major burden for public health worldwide. As a classic complex disease, obesity is regarded as the interaction of genetic and environmental factors. However, it is controversial which of these two factors have greater effect on obesity. Several genetic loci have recently been reported to contribute to the development of obesity reported in genome-wide association study (GWAS) these years. GWAS play an important role in complex disease research and explore the potential effect of genetic variance. To further understand the genetic influence on obesity risk, we reviewed and collected articles on Pubmed for genes that reported in recent GWAS. We summarized the publications in GWAS and found 49 candidate genes, which were strongly suggested to relate to obesity risk in human. Despite the findings of this and other similar, contemporary research projects, much of the single nucleotide polymorphism details and underlying mechanism in this field of study remains, to a great extent, unknown. As a result, future studies are needed for obesity risk in human beings.

Diagnosis and treatment of warfarin resistance / 中南大学学报(医学版)

Warfarin resistance is a phenomenon that patients need to take much higher than normally prescribed dosage of warfarin to maintain the target therapeutic international normalized ratio (INR) range, or even fail to reach the target INR. Warfarin resistance can be categorized in etiologic terms as hereditary vs acquired, or in pharmacologic terms as pharmacokinetic vs pharmacodynamic. Once warfarin resistance is diagnosed, the type of resistance should be determined as soon as possible so that treatment could be oriented toward the causes. Poor compliance, genetic mutations, concurrent medications that could decrease the absorption or increase the clearance of warfarin, and consumption of diet rich in vitamin K are the major reasons for warfarin resistance. Educating patients, increasing warfarin dosage and switching to other anticoagulants would be effective for warfarin resistance.

High concentration of tacrolimus inhibits proliferation and osteoblastic differentiation of human mesenchymal stem cells / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of tacrolimus on cell proliferation and osteoblastic differentiation of primary human bone marrow-derived mesenchymal stem cells (hBMSCs). METHODS hBMSCs were cultured with tacrolimus 0.001-5 μmol·L-1. BrdU incorporation was used to assess the cell proliferation while cellular alkaline phosphatase (ALP) activity and calcium deposition were measured to evaluate the osteoblastic differentiation of hBMSCs cultures. The calcineurin (CaN) activity was also examined using commercial CaN assay kit, and core binding factor 1 alpha subunit (Cbfα1) protein level was determined by Western blotting. RESULTSTacrolimus 0.001-0.1 μmol·L-1 promoted BrdU incorporation but had no effect on ALP activity and calcium deposition, whereas tacrolimus 0.5-5 μmol·L-1 resulted in significant decrease in both cell proliferation and osteoblastic maturation, by reducing BrdU incorporation, ALP activity, and calcium deposition of hBMSCs cultures in a concentration-dependent manner. In addition, tacrolimus 0.5-5 μmol·L-1 led to concentration-dependent decrement in CaN activity, which was consistent with down-regulated Cbfα1 protein in the tacrolimus treated cells. CONCLUSION High concentration of tacrolimus might inhibit the cell proliferation and osteoblastic differentiation of hBMSCs cultures through a CaN/Cbfα1 pathway.

Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae / 中国中药杂志

<p><b>OBJECTIVE</b>To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites.</p><p><b>METHOD</b>On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition.</p><p><b>RESULT</b>On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant.</p><p><b>CONCLUSION</b>The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.</p>

Personalized medicine:current status, challenges and strategies / 中华检验医学杂志

Modern pharmacogenomics demonstrates that genetic polymorphisms account for the most important factor of adverse drug reactions and interindividual variations of drug therapy. Personalized medicine aims to choose the appropriate drugs and dosage for increasing the efficacy and safety with minimal adverse effects based on the patients' genotypes. This article introduce the progresses in pharmacogenomics in China, discusse many factors that influence the application of personalized medicine from bench to bedside, and highlighted the challenges and further development of this field in the future.

Translational approach for pharmacogenomics and personalized medicine / 药学学报

Pharmacogenetics and pharmacogenomics are promising fields that will enable personalized therapy. However, one of the most important issues to be conquered in the practice of personalized medicine is the translation of scientific discoveries into better therapeutic outcomes. The international pharmacogenetic and pharmacogenomic approaches made in the field of personalized medicine and drug discovery are summarized in this review.

Impact of retinol binding protein 4 polymorphism on rosiglitazone response in Chinese Type 2 diabetic patients / 中南大学学报(医学版)

Objective To explore the association between rs3758539G-803A and rs10882283 T-179G polymorphism of retinol binding protein 4 (RBP4) and rosiglitazone response in Chinese type 2 diabetes mellitus (T2DM) patients.Methods A total of 472 Chinese T2DM patients and 198 healthy subjects were enrolled to identify G-803A and T-179G genotypes using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP ).assay.Forty-two T2DM patients with different G-803A or T-179G genotypes were selected to undergo a 12-week rosiglitazone treatment (4 mg/d).Serum fasting plasma glucose (FPG),postprandial plasma glucose (PPG),fasting serum insulin (FINS),glycated hemoglobin (HbAlc),postprandial serum insulin ( PINS),triglyceride (TG),low-density lipoprotein-cholesterol ( LDL-c),and high-density lipoprotein-cholesterol (HDL-c) were determined before and after the rosiglitazone treatment.Results T2DM patients with RBP4 G-803A GG genotype showed lower TG and LDL-c concentrations compared with that in the GA +AA genotype subjects.T2DM patients with RBP4 T-179G TT genotype showed lower waist-to-hip ratio (WHR),FPG and FINS values compared with that in the TG + GG genotype individuals.Patients with GG genotype of RBP4 G-803A had an enhanced rosiglitazone efficacy on FPG and FINS compared with that in the GA + AA genotype group.Patients with RBP4 T179G TG + GG genotype showed an enhanced rosiglitazone efficacy on HbAlc level compared with that in the TT genotype group.Conclusion RBP4 G-803A and T-179G polymorphism might be associated with the development of T2DM and affect the therapeutic efficacy of rosignitazone in Chinese T2DM patients.