The identification of lung cancer gene-drug module based on multiplex networks algorithm / 生物医学工程学杂志

Using modular identification methods in gene-drug multiplex networks to infer new gene-drug associations can identify new therapeutic target genes for known drugs. In this paper, based on the gene expression data and drug response data of lung cancer in the genomics of drug sensitivity in cancer (GDSC) database, a multiple network algorithm is proposed. First, a heterogeneous network of genes of lung cancer and drugs in different cell lines is constructed, and then a network module identification method based on graph entropy is used. In this heterogeneous network, network modules are identified, and five lung cancer gene-drug association modules are identified through iterative convergence. Compared with other methods, the algorithm has better results in terms of running time, accuracy and robustness, and the identified modules have obvious biological significance. The research results in this article have guiding significance for the medication and treatment of lung cancer, and can provide references for the treatment of other diseases with the same targeted genes.

Pharmacogenetic implications in the management of metabolic diseases in Brazilian populations

Dyslipidemia, diabetes, obesity and hypertension are common metabolic diseases. In the last decades, unhealthy lifestyle and aging have leads to an increased incidence of these diseases, increasing morbidity and mortality by cardiovascular causes. The treatment of metabolic diseases includes life-style interventions as healthy diet and physical exercise, as well as pharmacological interventions. Several drugs are available for the management of metabolic diseases including among others lipid-lowering antidiabetics and antihypertensive drugs. Variability in response to these drugs is influenced by both genetic and non-genetic factors. Polymorphisms in genes related to drug pharmacokinetics and pharmacodynamics have been shown to influence drug efficacy and safety. This review is focused on pharmacogenetic studies related to the management of metabolic diseases in samples of the Brazilian population. Associations of variants in drug metabolizing enzymes and transporters, drug target and metabolism-related genes with the efficacy and safety of lipid-lowering, antidiabetic and antihypertensive drugs are described. Most pharmacogenetic studies in Brazil have focused in pharmacological response to a small group of drugs, as statins and some antihypertensives, while there are almost no studies on antidiabetic and antiobesity drugs. Some studies reported significant associations of gene polymorphisms with drug response confirming previous data from other populations, whereas other works did not replicate, which may relay on the genetic admixture of our population. In conclusion, further studies are necessary considering larger sample sizes, new unexplored drugs and more genetic variants to obtain stronger conclusions to explore clinical applications of pharmacogenetic studies in our population.

Mycobacterium Tuberculosis in Spinal Tuberculosis

Even in an era of remarkable medical advances, there is an issue of why tuberculosis remains in the list of disastrous diseases, afflicting humans and causing suffering. There has not been a plausible answer to this, and it has been suggested that clinicians and medical scientists could presently not win the war against the tubercle bacilli. With regards to this issue, based on the authors' own clinical and research experiences, in this review, the available literature was revisited in order to address the raised questions and to provide recent information on characteristics of tubercle bacilli and possible ways to more effectively treat tuberculosis.

Research Progress on Rapid Antidepressant of Traditional Chinese Medicine / 世界科学技术-中医药现代化

Major depression is a public health problem that seriously harms individuals and the society.But one of the major shortcomings of mainstream antidepressant is the delayed onset.Recent series of studies demonstrated that,from a variety of animal models and clinical studies,classic stagnation-removing formula Yue-Ju (Y J) pill has the advantage in rapid antidepressant efficacy,which is similar to the prototype drug ketamine.It has the mechanism of rapid and sustained enhancement of neural plasticity and individual difference in response to YJ pill.The evidence of Gardenia jasminoides (Zhi-Zi) as the monarch component of YJ pill's rapid antidepressant action has also been revealed.The further in-depth research on rapid antidepressant traditional Chinese medicine (TCM) is important for providing the scientific and reliable TCM strategies to treat depression.

Prevalence of genetic variants associated with cardiovascular disease risk and drug response in the Southern Indian population of Kerala.

BACKGROUND AND AIM: This study reports the prevalence of five clinically significant variants associated with increased risk of cardiovascular disorders, and variable responses of individuals to commonly prescribed cardiovascular drugs in a South Indian population from the state of Kerala. MATERIALS AND METHODS: Genomic DNA isolated from 100 out‑patient samples from Kerala were sequenced to examine the frequency of clinically relevant polymorphisms in the genes MYBPC3 (cardiomyopathy), SLCO1B1 (statin‑induced myopathy), CYP2C9, VKORC1 (response to warfarin) and CYP2C19 (response to clopidogrel). RESULTS: Our analyses revealed the frequency of a 25 bp deletion variant of MYBPC3 associated with risk of cardiomyopathy was 7%, and the SLCO1B1 “C” allele associated with risk for statin‑induced myopathy was 15% in this sample group. Among the other variants associated with dose‑induced toxicity of warfarin, VKORC1 (c.1639G>A), was detected at 22%, while CYP2C9*3 and CYP2C9*2 alleles were present at a frequency of 15% and 3% respectively. Significantly, the tested sample population showed high prevalence (66%) of CYP2C19*2 variant, which determines response to clopidogrel therapy. CONCLUSIONS: We have identified that certain variants associated with cardiovascular disease and related drug response in the five genes, especially those in VKORC1, CYP2C19 and MYBPC3, are highly prevalent in the Kerala population, with almost 2 times higher prevalence of CYP2C19*2 variant compared with other regions in the country. Since the variants chosen in this study have relevance in disease phenotype and/or drug response, and are detected at a higher frequency, this study is likely to encourage clinicians to perform genetic testing before prescribing therapy.

No Association between the Response to Methylphenidate and DRD4 Gene Polymorphism in Korean Attention Deficit Hyperactivity Disorder: A Case Control Study

OBJECTIVE: Recently the relationship between alleles frequency distribution, drug response and the attention deficit hyperactivity disorder (ADHD), has been actively researched. We investigated the association between the genetic type, alleles and drug response for the dopamine receptor D4 (DRD4) gene in ADHD patients in Korea. METHODS: One hundred fourteen patients diagnosed with ADHD according to the the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) diagnostic criteria were selected for the study. The clinical features of patients were confirmed by Korean version of Conners' parent rating scale, Attention deficit Diagnostic System, Korean version of Spielberger state-trait anxiety scale. Blood samples were taken from the 198 subjects. DNA was extracted from blood lymphocytes, PCR was performed for DRD4 Polymorphism. Alleles, genotype frequencies, the Clinical Global Impression (CGI) improvement score were compared using the chi-square test. Korean ADHD Rating Scale (K-ARS) and CGI severity scores were compared using the t-test. RESULTS: In comparing the ADHD with 4/4 repeats group and without the ADHD with 4/4 repeats group, no significant difference was seen between the DRD4 genetic type, alleles distribution, and CGI drug response. CONCLUSION: As a result, it is viewed that there is no relationship between ADHD and DRD4, but final decision is indefinite. Follow up studies with larger patient or pure subgroups are expected.

Circulating and tumor miR-21 could predict irinotecan sensitivity in gastric cancer / 中国癌症杂志

Background and purpose:Mir-21 has been demonstrated high expressed in many kinds of tumor tissues and cell lines. High expressed miR-21 leads to chemoresistance. Circulating miRNA is a novel biomarker for chemosensitivity prediction. The aim of our study was to investigate the role of plasma and tumor miR-21 levels as predictive biomarkers for irinotecan in gastric cancer. Methods: The histoculture drug response assay (HDRA) was used to determine irinotecan and cisplatin sensitivity on 35 freshly removed gastric tumor specimens. miR-21 expressions in tumor and plasma were determined by quantitative reverse transcription polymerase chain reaction. Results:Plasma miR-21 was closely correlated with corresponding miR-21 mRNA level in tumor tissues (rho=0.736, P<0.001) and was not correlated with sex, age, pathology type, differentiation, lymph node metastasis, TNM stage or tumor location. Patients with stage Ⅱ-Ⅲhad higher miR-21 levels. The tumor miR-21 expressions in cisplatin-sensitive group and resistant group were 1.32 (95%CI:0.73-1.90) and 4.06 (95%CI:1.71-6.41)(P=0.004), respectively. The plasma miR-21 expressions in cisplatin-sensitive group and resistant group were 5.25 (95%CI:0.14-10.64) and 5.82 (95%CI: 2.27-9.37)(P=0.19). The tumor miR-21 expressions in irinotecan-sensitive group and resistant group were 1.09 (95%CI:0.65-1.54) and 4.94 (95%CI:2.44-7.44)(P<0.001), respectively. The plasma miR-21 expressions in irinotecan-sensitive group and resistant group were 1.86 (95%CI:1.08-2.64) and 12.42 (95%CI:3.14-21.70)(P=0.001). Conclusion:A signiifcant correlation was observed between plasma and tumor miR-21 level. The low plasma miR-21 level could benefit from treatment with irinotecan. And low tumor miR-21 expression correlated with increased irinotecan and cisplatin response rate.

Clinical Predictors of Drug Response in Patients with Obsessive-Compulsive Disorder

OBJECTIVE: The aim of this study was to evaluate which clinical variables might influence the antiobsessional responses to proserotonergic drugs in a sample of patients with obsessive-compulsive disorder (OCD). METHODS: Two hundred forty-nine patients with DSM-IV OCD under-gone mean 13-month treatments with selective serotonin reuptake inhibitors. According to the treatment response, defined as a reductions of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score > or =35%, patients were divided into two groups. RESULTS: One hundred fourteen patients responded to the treatment and the other one hundred thirty five patients did not. Responders had a significant long duration of medication in YUMC OCD clinic, short total duration of past treatment in other institutes, and higher frequency of drug naive cases and lower baseline Y-BOCS scores. CONCLUSION: The pre-treatment factors including total duration of past treatment, drug naive or not, baseline OCD symptoms and the factor of duration of the treatment may influence drug treatment response in OCD patients.

Gene Expression Signatures for Compound Response in Cancers

Recent trends in generating multiple, large-scale datasets provide new challenges to manipulating the relationship of different types of components, such as gene expression and drug response data. Integrative analysis of compound response and gene expression datasets generates an opportunity to capture the possible mechanism of compounds by using signature genes on diverse types of cancer cell lines. Here, we integrated datasets of compound response and gene expression profiles on NCI60 cell lines and constructed a network, revealing the relationship for 801 compounds and 341 gene probes. As examples, obtusol, which shows an exclusive sensitivity on a small number of colon cell lines, is related to a set of gene probes that have unique overexpression in colon cell lines. We also found that the SLC7A11 gene, a direct target of miR-26b, might be a key element in understanding the action of many diverse classes of anticancer compounds. We demonstrated that this network might be useful for studying the mechanisms of varied compound response on diverse cancer cell lines.

The Side Effects and Correlates of OROS-Methylphenidate in the Treatment of Children and Adolescents with ADHD

OBJECTIVES: The aim of this study was to investigate the effect of the clinical and demographic variables such as body weight, dosage, family history of attention-deficit hyperactivity disorder (ADHD), and psychiatric co-morbidity on the side-effects of OROS-Methylphenidate (OROS-MPH), and to evaluate the relationship between drug response and side effect severity. METHODS: A total of 144 children (ages 6-18) with diagnosed ADHD were treated with OROS-MPH. Children were examined at baseline and after 1, 3, 6, 9, and 12 weeks of each treatment condition. The stimulant drug side effect rating scale (SERS), pulse rate, systolic blood pressure, diastolic blood pressure, and electrocardiogram (ECG) were evaluated to assess side effect profiles. Changes in these parameters from baseline were examined and analyzed. RESULTS: Anorexia (30.95%) and insomnia (13.10%) were the most commonly reported side effects during this study. Insomnia and loss of appetite score increased at one week follow-up, but was sustained or decreased as treatment progressed. Small but significant increases in pulse rate and diastolic blood pressure were observed during treatment; however, no clinically meaningful changes in ECG parameters were noted during the study. Low body weight, high dosage of OROS-MPH, and family history of ADHD were associated with cardiovascular side effect. In contrast, there was no significant relationship between OROS-MPH treatment response and the severity of side effect and no difference resulted between the responder and non-responder groups with respect to OROS-MPH dosage in the 12 weeks of follow-up. CONCLUSION: To the best of our knowledge, this study is the first Korean study to investigate comprehensive side effect profiles and their correlates in OROS-MPH treatment for ADHD children. OROS-MPH was well tolerated with no clinically significant side effects during the treatment period. In conclusion, low body weight, high dosage of OROS-MPH, and family history of ADHD could be used as predictive factors in increasing pulse rate and blood pressure.

Comparison between Therapeutic Efficacies of Histone Deacetylase Inhibitors and Established Drug Regimens Against Breast Cancer Cells using the Histoculture Drug Response Assay / 한국유방암학회지

PURPOSE: Histone deacetylase inhibitors (HDACIs) induce accumulation of acetylated histones in nucleosomes, which lead to reactivate gene expression and inhibit the growth and survival of tumor cells. This study evaluated the efficacy of HDACIs in breast cancer cells in comparison with other established drug regimens. METHODS: Drug responses of tumor samples from mastectomy specimens of 78 breast cancer patients were evaluated using the histoculture drug response assay (HDRA). Tumor inhibition rates (IRs) of established drug regimens such as doxorubicin, cyclophosphamide, doxorubicin with cyclophosphamide (AC), paclitaxel, docetaxel and doxorubicin with docetaxel (AT), as well as those of three HDACIs (SAHA, PXD101, and a novel compound CG-2) were evaluate. RESULTS: The percentages of chemosensitive tumors (chemoresponsiveness) were 26.9-60.3% with established regimens and 61.5-73.1% with HDACIs when the cutoff value for inhibition rate was set at 30%. Breast cancer cells appeared to be more chemoresponsive to HDACIs than to established drug regimens. Chemoresponsiveness to AT was the highest among the established drug regimens. A combination regimen offered higher activity than did a single drug (doxorubicin vs AT; p<0.001). HER2/Neu-overexpressing breast cancers were chemosensitive to SAHA and AT (p=0.031 and 0.04, respectively). CONCLUSION: Our findings show that breast cancer cells were sensitive to HDACIs, with therapeutic efficacies comparable to those of established drug regimens. Specific biological markers such as HER2/Neu could be assessed for effectiveness as HDACIs chemosensitivity markers in further clinical trials.

Farmacogenética de inibidores seletivos de recaptação de serotonina: uma revisão: [revisão] / Pharmacogenetics of selective serotonine reuptake inhibitors: a review: [revision]

A variabilidade da resposta aos medicamentos se deve em grande parte a fatores genéticos, e essa variabilidade afeta os efeitos terapêuticos e as reações adversas, de forma que a mesma dose de um medicamento pode ser benéfica para um paciente mas ineficaz para outro. Os fármacos conhecidos como inibidores seletivos de recaptação de serotonina (ISRSs) pertencem a uma classe de medicamentos utilizados para o tratamento de uma série de patologias relacionadas com a serotonina, especialmente a depressão. O objetivo deste trabalho é reunir os dados presentes na literatura sobre a associação de genes candidatos com a resposta a ISRSs, fornecendo assim um panorama sobre o estado atual de conhecimento sobre o assunto. A resposta ao tratamento com ISRSs depende da variabilidade de genes codificantes de proteínas envolvidas com o papel da serotonina no cérebro. Com os avanços conquistados a partir do Projeto Genoma Humano, foi possível detectar essas variações, e várias delas mostraram ter importância farmacogenética. Portanto, alguns dos genes relacionados à farmacogenética dos ISRSs já são conhecidos, o que torna clara a necessidade de maiores investigações prospectivas para determinar a real utilidade desse conhecimento na prática clínica, com relação à possibilidade da determinação da dose adequada do fármaco correto para cada paciente, prática que vem sendo denominada de "medicina personalizada".

A large proportion of the variability in drug response is due to genetic factors, and this variability affects therapeutic effects and adverse reactions, so that the same dosage of a drug can be beneficial to some patients, but ineffective to others. The drugs known as selective serotonin reuptake inhibitors (SSRI) belong to a pharmacological class used in the management of a number of diseases related to serotonin, especially depression. The aim of this paper is to collect data from the literature about the association of candidate genes with response to SSRI, providing an overview on the current knowledge of this subject. The effect of SSRI treatment depends on the variability in genes coding proteins involved with the role of serotonin in the brain. The new data from the Human Genome Project allowed detection of these variations, and several of them proved to have pharmacogenetic importance. Therefore, some of the genes related to SSRI pharmacogenetics are already known. This reinforces the need of larger prospective investigations to determine the real use of this knowledge in clinical practice as to the possibility of determining the right dosage, and the right drug to each patient, a practice that has been called "personalized medicine".

Can the Histoculture Drug Response Assay Predict the Clinical Results of Chemotherapy in Breast Cancer? / 한국유방암학회지

PURPOSE: The behavior of invasive carcinomas in human can be very varied with different individual responses to chemotherapy. Individualization is crucial to the optimization of chemotherapy. Therefore, the prediction of a tumor's sensitivity to anticancer agents has been the subject of intensive investigation. In order to investigate the pathobiology of breast cancer, it is necessary to maintain or recreate the characteristics of the three-dimensional architecture of the tissues in culture. In this study, we have evaluated the relationship between the Histoculture Drug Response Assay (HDRA) assessment and chemotherapy responses in breast cancer patients. METHODS: Tumor specimens from 30 patients with breast cancer were evaluated using the HDRA. Tumor tissues were cultured on gelfoam sponge gel in 24-well plates, followed by treatment with a variety of chemotherapeutic agents. All treatments were conducted in triplicate. The sensitivity of a chemotherapy regimen was defined as a tumor inhibition rate (IR) in excess of 30%. Neoadjuvant or palliative chemotherapy for patients, using anthracycline or taxane, was conducted on the basis of the established protocols. The responses to treatments were compared with the results of the HDRA. RESULTS: The mean IR for the combinations of doxorubicin and docetaxel and for FAC and AC were 48, 45, and 36%, respectively. The above partial rate of response to chemotherapy was 81.1%. The sensitivity and specificity of the HDRA assessment, with a 30% inhibition rate, were 81.5 and 66.7%, respectively. The positive and negative response prediction values were 91.7 and 44.4%, respectively. The responses to treatments and the results of the HDRA assessment were not correlated with the expressions of the hormonal receptor or c-erbB2. CONCLUSION: In cases in which the inhibition rate is in excess of 30%, the HDRA assessment yielded a high positive response prediction value. The sensitivity to chemotherapy, as determined by the HDRA, appears to be a good guide for selection in breast cancer patients. Thus the results presented herein should be integrated into future research on the subject.

Can the Histoculture Drug Response Assay Predict the Clinical Results of Chemotherapy in Breast Cancer? / 한국유방암학회지

PURPOSE: The behavior of invasive carcinomas in human can be very varied with different individual responses to chemotherapy. Individualization is crucial to the optimization of chemotherapy. Therefore, the prediction of a tumor's sensitivity to anticancer agents has been the subject of intensive investigation. In order to investigate the pathobiology of breast cancer, it is necessary to maintain or recreate the characteristics of the three-dimensional architecture of the tissues in culture. In this study, we have evaluated the relationship between the Histoculture Drug Response Assay (HDRA) assessment and chemotherapy responses in breast cancer patients. METHODS: Tumor specimens from 30 patients with breast cancer were evaluated using the HDRA. Tumor tissues were cultured on gelfoam sponge gel in 24-well plates, followed by treatment with a variety of chemotherapeutic agents. All treatments were conducted in triplicate. The sensitivity of a chemotherapy regimen was defined as a tumor inhibition rate (IR) in excess of 30%. Neoadjuvant or palliative chemotherapy for patients, using anthracycline or taxane, was conducted on the basis of the established protocols. The responses to treatments were compared with the results of the HDRA. RESULTS: The mean IR for the combinations of doxorubicin and docetaxel and for FAC and AC were 48, 45, and 36%, respectively. The above partial rate of response to chemotherapy was 81.1%. The sensitivity and specificity of the HDRA assessment, with a 30% inhibition rate, were 81.5 and 66.7%, respectively. The positive and negative response prediction values were 91.7 and 44.4%, respectively. The responses to treatments and the results of the HDRA assessment were not correlated with the expressions of the hormonal receptor or c-erbB2. CONCLUSION: In cases in which the inhibition rate is in excess of 30%, the HDRA assessment yielded a high positive response prediction value. The sensitivity to chemotherapy, as determined by the HDRA, appears to be a good guide for selection in breast cancer patients. Thus the results presented herein should be integrated into future research on the subject.

Histoculture Drug Response Assay in Colorectal Cancer Specimen

PURPOSE: For decades, systemic medical treatment for colorectal cancer has been limited almost entirely to 5- fluorouracil (5-FU). In cases of advanced colorectal cancer, the response rate to standard 5-FU regimen was lower than 20%. Recently, new drugs that have another action mechanism have been introduced-irinotecan, oxaliplatin, raltitrexed, capecitabine, etc. Clinicians have to choose the appropriate drug for advanced cases. Until recently, choice of chemotherapeutic agents was based on the experience of clinicians, or on retrospective or prospective clinical trial reports. In this study, we performed HDRA (histoculture drug response assay) to assess the effectiveness of chemotherapeutic agents in colorectal cancer. METHODS: Tumor specimens of 33 colorectal cancers were collected in 15 ml tubes containing PBS buffer. Tissues were minced using an autoclaved knife and histocultured on collagen sponge gel matrix, followed by treatment with 5-FU, 5-FU & leucovorin, oxaliplatin, oxaliplatin & 5-FU, irinotecan, or irinotecan & 5-FU. After 48 hours, cell viability was assessed by MTT assay. The inhibition rate of each drug was calculated for relative survival. Cases of drug responsibility below 30% were regarded as drug resistant cases. RESULTS: Thirty cases were tested. Three cases had synchronous lesion. Thirty-three tissues were evaluated using HDRA. Seventeen cases (53.3%) were rectal cancer. The initial 6 cases were tested using a single agent the other 27 cases were tested using combined agents. The regimen showing the best responses was oxaliplatin with 5-FU (8/26 cases, 30.8%). Seven cases were regarded as chemoresistant cases because they showed low IR below 30% for all agents. Synchronous lesions showed similar drug responses. CONCLUSION: HDRA is relatively simple and easily applicable to in vitro study to determine the appropriate chemotherapeutic agents. Further study is necessary to assess the effectiveness including tumor recurrence and survival.

Advances in pharmacogenetics of anti-Parkinson's drugs treatment / 中国药理学通报

Parkinson's disease(PD)is a neurodegenerative disease that predominantly affects the elderly.Dopamine mimicking drug is the mainstay in the treatment of Parkinson's disease.However,there is a large of interindividual variability in response to anti-Parkinson's disease drugs.It is thought that genetic variability in dopamine system genes is one of the important factors in determining interindividual variability in drug response.There are a lot of studies focused on the relationship between the risk of Parkinson's disease and genetic variations in domestic,while it is a lack of the pharmacogenetics study on Parkinson's disease.This review summarizes the relationship between the polymorphism of genes encoding dopamine transporter,dopamine-metabolizing enzymes and dopamine receptors and Parkinson's disease treatment.

Pharmacoepigenetics and interindividual variations in drug response / 中国药理学通报

With the development of pharmacogenetics and pharmacogenomics,pharmacoepigenetics potentially offers another level of explanation for interindividual variations in drug response that cannot be accounted for on the basis of genetic polymorphisms.Many genes encoding enzymes,drug transporters,transcription factors,drug targets,and nuclear receptors are under epigenetic control,which has implications in the context of interindividual variations in drug response as well as drug resistance during cancer treatment.In this overview,we summarize the newest advancement in this field.

Basic Principles of Drug Interaction

There is nothing that is harmless ; the dose alone decides that something is no poison(Paracelsus. 1493-1541). So, in a point of view to maximize the therapeutic efficacy of drug therapy in a was that minimize the drug toxicity, the knowledges of the drug-interactions as well as the pharmacokinetic and pharmacodynamic principles of every therapeutic drug used in the medical clinic cannot be emphasized too much. Many drug interactions can be predicted if the pharmacokinetic properties, pharmacodynamic mechanisms of action of the interacting drugs are known and most adverse interactions can be avoided. In this paper, the clinical importance, classification, and general principles of clinical drug-interactions are presentated with a few explanatory examples.