Investigating the Association Between Type 2 Diabetes Mellitus and Pathological Responses Among Breast Cancer Patients Receiving Neoadjuvant Chemotherapy.

INTRODUCTION: The relationship between type 2 diabetes mellitus (T2DM) and pathological responses after neoadjuvant chemotherapy (NACT) is controversial. In this study, we aim to determine the association of pathological responses in breast cancer women with T2DM after receiving NACT. METHODS: Medical records of breast cancer women with T2DM who received NACT from January 2016 to January 2021 at the medical center in the Gujranwala Institute of Nuclear Medicine and Radiotherapy, Pakistan, were identified and retrieved retrospectively. Variables, including pathological responses, diabetes status, and other clinical data, were collected. Patients were grouped as diabetic and nondiabetic based on the doctor's diagnosis or the diabetic's medication history recorded upon the breast cancer diagnosis. Factors influencing the pathological complete response (pCR) were determined using multivariate logistic regression utilizing IBM SPSS Statistics (version 20). RESULTS: A total of 1372 patient files who received NACT and breast cancer surgery from January 2016 to January 2021 were selected. Out of 1372 breast cancer women receiving NACT, 345 (25.1%) had pre-existing diabetes, while 1027 (74.85%) were without pre-existing diabetes. The most common molecular subtypes of breast cancer were luminal A and B. Two hundred fifty-eight patients (18.8%) had a pCR after receiving NACT. The pCR in diabetic patients was 3.9%, and in nondiabetes, 14.9%. Most women had a pathological partial response (pPR) after the NACT 672 (48.9%). The pPR in diabetic patients was 11.0%, and in nondiabetic patients, it was 38.0%. In nondiabetics, the odds of achieving pPR increase more than pathological no response after the NACT with odd ratio: 1.71 (95% confidence interval: 1.24-2.37). The probability of pCR in patients with luminal B was 1.67 times higher than that in patients with triple-negative breast cancer with odd ratio: 1.67, 95% confidence interval (1.00-2.79), P = 0.05. CONCLUSIONS: The results of the study show that T2DM may have an adverse impact on pCR and pPR following NACT and surgery. Further investigation is needed to explore how changes in blood glucose levels over time impact pathological responses.

Hand-foot syndrome in cancer patients on capecitabine: examining prevalence, impacts, and associated risk factors at a cancer centre in Malaysia.

INTRODUCTION: Hand-foot syndrome (HFS) significantly impacts quality of life in cancer patients undergoing capecitabine treatment. This study assessed capecitabine-associated HFS prevalence, its impacts on chemotherapy treatment, and identified risk factors in multiracial Malaysian patients. METHODS: We included adult cancer patients receiving capecitabine at Sarawak General Hospital for at least two cycles from April 1, 2021 to June 30, 2022. HFS rates, time to HFS, and proportions of HFS-related treatment modifications were determined. Characteristics between patients with and without HFS were compared and multivariable logistic regression was used to identify risk factors for all-grade HFS and grade ≥2. RESULTS: Among 369 patients, 185 (50.1%) developed HFS, with 14.6% experiencing grade ≥2 and 21.6% (40/185) underwent treatment modifications. Risk factors for all-grade HFS include older age (OR 1.03 95%CI 1.01, 1.06), prior chemotherapy (OR 2.09 95%CI 1.22, 3.58), higher capecitabine dose (OR 2.96 95%CI 1.62, 5.38), prolonged treatment (OR 1.36 95%CI 1.21, 1.51), folic acid intake (OR 3.27 95%CI 1.45, 7.35) and lower neutrophil count (OR 0.77 95%CI 0.66, 0.89). For HFS grade ≥2, older age (OR 1.04 95%CI 1.01, 1.08), female sex (OR 2.10 95%CI 1.05, 4.18), Chinese race (OR 2.10 95%CI 1.06, 4.18), and higher capecitabine dose (OR 2.62 95%CI 1.28, 5.35) are significant risk factors. Use of calcium channel blockers were associated with reduced risks of all-grade HFS (OR 0.27, 95%CI 0.12, 0.60) and grade ≥2 (OR 0.21 95%CI 0.06, 0.78). CONCLUSION: This study provides real-world data on capecitabine-induced HFS in Malaysian patients and identifies risk factors that may offer insights into its understanding and management.

Qualitative assessment of knowledge, attitude and practice of oncologists about precision medicine in cancer patients- study from Lahore, Pakistan.

BACKGROUND: Precision medicine (PM) is in great progressive stages in the West and allows healthcare practitioners (HCPs) to give treatment according to the patient's genetic findings, physiological and environmental characteristics. PM is a relatively new treatment approach in Pakistan Therefore, it is important to investigate the level of awareness, attitude, and challenges faced by oncology physicians while practicing PM for various therapies, especially cancer treatment. OBJECTIVES: The present study aims to explore the level of awareness, attitude, and practice of PM in Pakistan along with the challenges faced by the oncologists for the treatment of cancer using the PM approach. METHODS: Phenomenology-based qualitative approach was used. Face-to-face in-depth interviews were conducted using the purposive sampling approach among oncologists in Lahore, Pakistan. The data were analyzed using thematic content analysis to identify themes and sub-themes. RESULTS: Out of 14 physicians interviewed 11 were aware of PM. They were keen on training to hone their skills and agreed on providing PM. Oncologists believed PM was expensive and given to affluent patients only. Other impeding factors include cost, lack of knowledge, and drug unavailability. CONCLUSIONS: Despite basic knowledge and will to practice, resource and cost constraints were marked as significant barriers. Additional training programs and inclusion into the curriculum may help to pave the way to PM implementation in the future. In addition, health authorities and policymakers need to ensure a cheaper PM treatment can be made available for all cancer patients.

Attitude and perception of pharmacists and healthcare professionals about the criteria used in drug formulary selection in the United Arab Emirates.

BACKGROUND: There is lack of both resources and expertise explains the limited extent to which pharmacoeconomic evidence is used in formulary decision-making. OBJECTIVES: The present study aims to assess attitude and perceptions toward the criteria used to select formulary drugs among UAE healthcare organizations. METHODS: A descriptive cross-sectional study was conducted amongst the licensed physicians in all specialties, all pharmacists and other healthcare professionals with a minimum of 3 month experience those registered with Ministry of health and prevention and those working in the private sector in the UAE. Participants are sent an email containing a validated web-based electronic link to access the questionnaire. The questionnaire composed of two sections is used to assess the healthcare professionals' attitude and perceptions regarding the criteria used to select formulary drugs. Data analysis were done using SPSS Version 24. RESULTS: A total of 866 respondents participated in the study and completed the whole questionnaire. The average attitude score about the criteria used in drug formulary selection was 84.5% with a 95% confidence interval (CI) of [83.9%, 85.4%]. Of the total participants, 27 (3.1%) had poor attitude about the criteria used in drug formulary selection, 240 (27.7%) had moderate attitude and 599 (69.2%) had good attitude. The results of statistical modeling showed that education level, area of expertise and age were jointly highly associated with attitude about the criteria used in drug formulary selection. CONCLUSIONS: The study revealed that pharmacists and Healthcare professionals had a good attitude about the criteria used in drug formulary selection in the United Arab Emirates. This study purposed to provide Emirate pharmacy and therapeutics policy makers with a clear criterion of best practice related to methodological recommendations to help in increasing the utilization and implementation of pharmacoeconomic evidence in the drug formulary selection process.

Knowledge, attitude and perception of community pharmacists towards pharmacogenomics services in northern Nigeria: a cross-sectional study.

OBJECTIVES: To evaluate knowledge, attitude and perception of community pharmacists towards pharmacogenomics services. METHODS: A cross-sectional study was conducted among community pharmacists in two cities in Northern Nigeria using a self-administered, validated and pre-tested questionnaire. The data were collected from December 2021 to February 2022 and were analysed using both descriptive and inferential analyses. RESULTS: A total of 161 completed questionnaires were included in this study (response rate was 61.9%). Most of the respondents were males (59.0%). Only 25.5% had previous pharmacogenomics training but 90.1% indicated an interest in attending pharmacogenomics training in the future. Overall, respondents had moderate knowledge of pharmacogenomics with higher knowledge score found among those who had previous pharmacogenomics training (11.9 ± 1.7 vs 10.5 ± 2.4; p = 0.001), and those with postgraduate qualification (11.7 ± 1.9 vs 10.7 ± 2.3; p = 0.028). The mean attitude score was 6.8 ± 2.0 out of 10.0 indicating a good attitude towards pharmacogenomics services. Those with previous training (8.1 ± 1.7 vs 6.2 ± 1.9; p < 0.001) and those with postgraduate qualification (7.2 ± 2.3 vs 6.6 ± 1.9; p = 0.042) had better attitude towards pharmacogenomics services. The median perception score was 34.0 out of 45.0, indicating a positive perception towards pharmacogenomics. There was a better perception among those with previous pharmacogenomics training (40.0 [21-45] vs 34.0 [0-45]; p = 0.002) and those with postgraduate qualifications (39.0 [0-45] vs 34.0 [21-45]; p = 0.010). Barriers to the implementation of pharmacogenomics included lack of knowledge (89.4%), lack of guidelines (87.5%) and lack of reimbursement (81.4%). CONCLUSION: Community pharmacists have a moderate knowledge, a good attitude and a positive perception towards pharmacogenomics services. Those with previous pharmacogenomics training and those with postgraduate qualifications had better knowledge, attitude and perception towards pharmacogenomics services. Lack of knowledge, lack of guidelines and lack of reimbursement were the major barriers to the implementation of pharmacogenomics services in community pharmacies in Nigeria. Pharmacogenomics should be included in pharmacy training curricula to prepare pharmacists for the provision of pharmacogenomics services. Development of local guidelines and a robust reimbursement plan for pharmacogenomics services is recommended.

Time-Dissociated Pharmacokinetic Pharmacodynamic Model of Cyclosporine Among Malaysian Renal Transplant Recipients.

BACKGROUND: Cyclosporine is an essential component of many immunosuppressive regimens. However, its pharmacokinetic and pharmacodynamic (PKPD) modeling has not been widely investigated. This study aims to develop a time-dissociated PKPD model of cyclosporine in renal transplant patients. METHODS: Medical records of renal transplant patients at Penang General Hospital were retrospectively analyzed. A time-dissociated PKPD model with covariate effects was developed using NONMEM to evaluate renal graft function response, quantified as estimated glomerular filtration rate (eGFR), toward the cyclosporine cumulative exposure (area under the concentration-time curve). The final model was integrated into a tool to predict the potential outcome. Individual eGFR predictions were evaluated based on the clinical response recorded as acute rejection/nephrotoxicity events. RESULTS: A total of 1256 eGFR readings with 2473 drug concentrations were obtained from 107 renal transplant patients receiving cyclosporine. An Emax drug effect with a linear drug toxicity model best described the data. The baseline renal graft level (E0), maximum effect (Emax), area under the concentration-time curve achieving 50% of the maximum effect, and nephrotoxicity slope were estimated as 12.9 mL·min-1·1.73 m-2, 50.7 mL·min-1·1.73 m-2, 1740 ng·h·mL-1, and 0.00033, respectively. The hemoglobin level was identified as a significant covariate affecting the E0. The model discerned acute rejection from nephrotoxicity in 19/24 cases. CONCLUSIONS: A time-dissociated PKPD model successfully described a large number of observations and was used to develop an online tool to predict renal graft response. This may help discern early rejection from nephrotoxicity, especially for patients unwilling to undergo a biopsy or those waiting for biopsy results.

Genetic Determinants in HLA and Cytochrome P450 Genes in the Risk of Aromatic Antiepileptic-Induced Severe Cutaneous Adverse Reactions.

Adverse drug reaction (ADR) is a pressing health problem, and one of the main reasons for treatment failure with antiepileptic drugs. This has become apparent in the event of severe cutaneous adverse reactions (SCARs), which can be life-threatening. In this review, four hypotheses were identified to describe how the immune system is triggered in the development of SCARs, which predominantly involve the human leukocyte antigen (HLA) proteins. Several genetic variations in HLA genes have been shown to be strongly associated with the susceptibility to developing SCARs when prescribed carbamazepine or phenytoin. These genetic variations were also shown to be prevalent in certain populations. Apart from the HLA genes, other genes proposed to affect the risk of SCARs are genes encoding for CYP450 drug-metabolising enzymes, which are involved in the pharmacokinetics of offending drugs. Genetic variants in CYP2C9 and CYPC19 enzymes were also suggested to modulate the risk of SCARs in some populations. This review summarizes the literature on the manifestation and aetiology of antiepileptic-induced SCARs, updates on pharmacogenetic markers associated with this reaction and the implementation of pre-emptive testing as a preventive strategy for SCARs.

Population Pharmacokinetic Modeling of Cyclosporine Among Malaysian Renal Transplant Patients: An Evaluation of Methods to Handle Missing Doses in Conventional Drug-Monitoring Data.

Cyclosporine is a primary drug in transplant immunosuppression regimens. It has a narrow therapeutic index and variable pharmacokinetic behavior. This study aimed to develop a population pharmacokinetic model of cyclosporine in Malaysian renal transplant recipients as well as to evaluate the performances of different methodsfor handling missing doses. A total of 2804 concentrationts predose and 2 hours after doses were collected retrospectively from 113 renal transplant patients on cyclosporine in Penang General Hospital. Model structure and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling software. Missing doses were handled using different methods to evaluate their performance. Covariate analysis was performed using stepwise forward addition (P < .05) followed by backward elimination (P < .001). Prediction-corrected visual predictive check and sampling-importance resampling methods were used to validate the final model. A 1-compartment model with first-order absorption and elimination best fitted the data. All methods to handle missing doses performed well with the missing dose method being superior to other methods and thus was applied in the final model. Cyclosporine clearance (CL/F) was estimated as 15.1 L/h, and volume of distribution (V/F) was 108 L. Postoperative time, sex, and calcium channel blockers were identified as significant covariates on CL/F, whereas sex and cholesterol level were identified as significant covariates on V/F. This is the first population pharmacokinetic model developed in Malaysian renal transplant patients using a large sample with an evaluation of different methods to handle missing doses in less informative conventional therapeutic drug-monitoring data.

Statins-related peripheral neuropathy among diabetic patients.

BACKGROUND: Peripheral neuropathy (PN) is a complaint with often unidentified reasons. Some medicines, including statins therapy, are anticipated to be amongst the reasons for PN. AIMS: This study intended to assess the association of peripheral neuropathy with statins therapy amongst Type 2 diabetic patients. METHODS: At Penang General Hospital, 757 cases were categorized into two groups (564 with statins therapy and 193 without statins therapy). The diagnosis of PN was investigated retrospectively for a period of 10 years (2006-2016). Confounding risk factors as age, diabetes period, hypertension, glycemic control, other co-morbidity, and prescriptions were matched. RESULTS: About 129 (22.9%) cases from 564 statins users had PN. Only 30 (15.5%) subjects had PN from 193 statins non-users. Chi-square test showed a significant variance among statins treatment cohort and statin-free cohort in the occurrence of PN (P-value: 0.001). Spearman's investigation presented a positive correlation (r: 0.078, p-value: 0.031) among statins use and PN prevalence. Binary logistic regression was statistically significant for statins therapy as a predictor of peripheral neuropathy incidence (r2: 0.006, p-value: 0.027) amid diabetic patients. The relative risk of peripheral neuropathy connected with statins therapy is (RR: 1.47, 95% CI: 1.02-2.11). The excess relative risk is 47.1%. While the absolute risk (AR) is 7.3% and the number needed to harm (NNH) is 14. CONCLUSIONS: The study indicated a positive association between peripheral neuropathy and statins utilization. Peripheral neuropathy was higher amongst statins users than the statins-free group.

Southeast Asian Pharmacogenomics Research Network (SEAPharm): Current Status and Perspectives.

Pharmacogenomics (PGx) is increasingly being recognized as a potential tool for improving the efficacy and safety of drug therapy. Therefore, several efforts have been undertaken globally to facilitate the implementation process of PGx into routine clinical practice. Part of these efforts include the formation of PGx working groups working on PGx research, synthesis, and dissemination of PGx data and creation of PGx implementation strategies. In Asia, the Southeast Asian Pharmacogenomics Research Network (SEAPharm) is established to enable and strengthen PGx research among the various PGx communities within but not limited to countries in SEA; with the ultimate goal to support PGx implementation in the region. From the perspective of SEAPharm member countries, there are several key elements essential for PGx implementation at the national level. They include pharmacovigilance database, PGx research, health economics research, dedicated laboratory to support PGx testing for both research and clinical use, structured PGx education, and supportive national health policy. The status of these essential elements is presented here to provide a broad picture of the readiness for PGx implementation among the SEAPharm member countries, and to strengthen the PGx research network and practice in this region.

The statins effects on HbA1c control among diabetic patients: An umbrella review of systematic reviews and meta-analyses of observational studies and clinical trials.

Statins have impacts on the metabolism of glucose that might influence the progress of diabetes in non-diabetics or affect glycemic control in patients with existing diabetes. Experimental proof has been contradictory about whether some statins display beneficial properties while others indicate harmful impressions. Some systematic reviews of statins had stated conflicting findings on the concern of glucose metabolism. The current study investigates the published systematic reviews and meta-analyses to combine their results and give a clear situation regarding the influence of statins therapy on glycated hemoglobin (HbA1c). This study has valuable strength points; long follow-up period and big sample size.

The effects of glycemic control on morbidity and survival among diabetic patients.

AIMS: The study intended to investigate the impact of controlled glycemia on morbidity and estimated 10-year survival (ES-10Y). METHODS: A cross-sectional investigation was conducted at General Penang Hospital, Malaysia. Demographic criteria and laboratory tests of patients were investigated. Controlled glycemia (CG) was recognized as glycated hemoglobin (HbA1c) ≤7% depending on American Diabetes Association guidelines 2018. Charlson Comorbidity Index (CCI) was used to estimate the confounding influence of co-morbidities and predict ES-10Y. Data was managed by IBM-SPSS 23.0. RESULTS: A total of 400 cases categorized to (44.25%) patients with CG, and (55.75%) cases had uncontrolled glycemia (UCG). HbA1c mean in CG and UCG group was (6.8 ±â€¯0.9 vs 9.5 ±â€¯1.6, P-value: 0.001). Fasting blood glucose was (7 ±â€¯2.3 vs. 9.9 ±â€¯4.3, P-value: 0.001) in CG and UCG group. CCI was (3.38 ±â€¯2.38 vs. 4.42 ±â€¯2.70, P-value: 0.001) and, ES-10Y was (62% vs 46.2%, p-value: 0.001) in CG vs. UCG respectively. Spearman test indicates a negative correlation between CG and CCI (r: 0.19, p-value: 0.001). Logistic regression confirmed HbA1c as a significant predictor of CCI (r2: 0.036, P-value: 0.001). CG has a positive correlation with survival (r: 0.16, P-value: 0.001) and logistic regression of survival (r2: 0.26, P-value: 0.001). CONCLUSIONS: More than one-half of the investigated persons had UCG. Controlled HbA1c was associated with lower co-morbidities and higher ES-10Y.

Evaluation of statins impacts on cognitive function among diabetic patients.

AIMS: The study was intended to evaluate the association of cognitive impairment with statins therapy among diabetic outpatients. METHODS: Mini-Addenbrooke's Cognitive Examination (M-ACE) was conducted for 280 cases in a cross-sectional study at Hospital Pulau Pinang. M-ACE score is 30, and the cut-off score for mild cognitive impairment is ≤ 21 and ≤ 16 for dementia. RESULTS: The cognitive impairment was distributed among 59 (55.1%) patients with mild cognitive impairment and 48 (44.9%) patients with dementia. From 177 patients using statins, about 80 (45.2%) cases had cognitive impairment. While from 103 statins non-users, only 27 (26.2%) had cognitive impairment. The relative risk of cognitive impairment associated with statins use in diabetic patients is (RR: 1.72, 95% CI: 1.2-2.48) and the excess relative risk is 72.4%. The absolute risk is 19%, and the number needed to harm is 6. Spearman's test indicated a positive association between statins usage and cognitive impairment incidence (r: 0.188, p-value: 0.002). However, Spearman's test showed a non-significant correlation amongst statins and dementia incidence (P-value: 0.587, RR: 1.16, 95% CI: 0.67-2.02). CONCLUSIONS: Statins therapy has a higher association with cognitive impairment risk than statins-free treatment; however, there is no association between statin use and dementia incidence among diabetic patients.

Prescribing statins among patients with type 2 diabetes: The clinical gap between the guidelines and practice.

BACKGROUND: Statins are recommended for cardiovascular protection for people with diabetes (high-risk groups). This study aimed to evaluate the gap between the guidelines of statin utilization and clinical practice among outpatients with type 2 diabetes regarding the patient's age and gender, to assess if this preventive drug is being satisfactorily utilized or not. MATERIALS AND METHODS: In this cross-sectional study, patients aged <40 or >75 years, pregnant patients, and patients with type 1 diabetes, human immunodeficiency virus, or liver cirrhosis were excluded. Demographics, laboratory parameters, and prevalence of exposure to statin therapy were evaluated. This study was guided by the 2013 American College of Cardiology/American Heart Association cholesterol guidelines. IBM SPSS software was used for data management. RESULTS: The study cohort involved 576 patients, with age being 58.3 ± 8.9 years. There were 50.5% of females and 49.5% of males. Overall 81.1% of patients aged 58.8 ± 8.8 years were statin users and 18.9% of patients aged 56.2 ± 9 years were statin nonusers. About 83.2% of females and 78.9% of males were prescribed statins. Statin medications included simvastatin 79.2%, atorvastatin 11.6%, lovastatin 5.8%, rosuvastatin 2.1%, and pravastatin 1.3%. Statin users' and nonusers' adherence was 56.5%, and 41.3% (P = 0.004), respectively. The adherence to medication plan of females and males was 55.7% and 51.6%, respectively (P = 0.004). CONCLUSION: Patients with diabetes who are at high risk of cardiovascular events, exposure to statin treatment is significantly less than perfect position both in females and males. Nearly one-fifth of the patients with type 2 diabetes are not using statins despite therapeutic necessities.

Pharmacometabolomics analysis of plasma to phenotype clopidogrel high on treatment platelets reactivity in coronary artery disease patients.

Dual antiplatelet therapy (DAPT) of clopidogrel and aspirin is crucial for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, some patients may endure clopidogrel high on treatment platelets reactivity (HTPR) which may cause thromboembolic events. Clopidogrel HTPR is multifactorial with some genetic and non-genetic factors contributing to it. We aimed to use nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis of plasma to investigate this multifactorial and identify metabolic phenotypes and pathways associated with clopidogrel HTPR. Blood samples were collected from 71 CAD patients planned for interventional angiographic procedure (IAP) before the administration of clopidogrel 600 mg loading dose (LD) and 6 h after the LD. Platelets function testing was done 6 h post-LD using VerifyNow® P2Y12 assay. Pre-dose and post-dose plasma samples were analysed using 1H NMR. Multivariate statistical analysis was used to indicate the discriminating metabolites. Two metabotypes, each with 34 metabolites (pre-dose and post-dose) were associated with clopidogrel HTPR. Pathway analysis of these metabotypes revealed that aminoacyl-tRNA biosynthesis, nitrogen metabolism and glycine-serine-threonine metabolism are the most perturbed metabolic pathways associated with clopidogrel HTPR. Furthermore, the identified biomarkers indicated that clopidogrel HTPR is multifactorial where the metabolic phenotypes of insulin resistance, type two diabetes mellitus, obesity, gut-microbiota and heart failure are associated with it. Pharmacometabolomics analysis of plasma revealed new insights on the implicated metabolic pathways and the predisposing factors of clopidogrel HTPR.

1H NMR based pharmacometabolomics analysis of urine identifies metabolic phenotype of clopidogrel high on treatment platelets reactivity in coronary artery disease patients.

Clopidogrel high on treatment platelets reactivity (HTPR) has burdened achieving optimum therapeutic outcome. Although there are known genetic and non-genetic factors associated with clopidogrel HTPR, which explain in part clopidogrel HTPR, yet, great portion remains unknown, often hindering personalizing antiplatelet therapy. Nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis is useful technique to phenotype drug response. We investigated using 1H NMR analysis to phenotype clopidogrel HTPR in urine. Urine samples were collected from 71 coronary artery disease (CAD) patients who were planned for interventional angiographic procedure prior to taking 600mg clopidogrel loading dose (LD) and 6h post LD. Patients' platelets function testing was assessed with the VerifyNow® P2Y12 assay at 6h after LD. Urine samples were analysed using 1H NMR. Multivariate statistical analysis was used to identify metabolites associated with clopidogrel HTPR. In pre-dose samples, 16 metabolites were associated with clopidogrel HTPR. However, 18 metabolites were associated with clopidogrel HTPR in post-dose samples. The pathway analysis of the identified biomarkers reflected that multifactorial conditions are associated with clopidogrel HTPR. It also revealed the implicated role of gut microbiota in clopidogrel HTPR. Pharmacometabolomics not only discovered novel biomarkers of clopidogrel HTPR but also revealed implicated pathways and conditions.

Dynamic methylation and expression of Oct4 in early neural stem cells.

Neural stem cells are a multipotent population of tissue-specific stem cells with a broad but limited differentiation potential. However, recent studies have shown that over-expression of the pluripotency gene, Oct4, alone is sufficient to initiate a process by which these can form 'induced pluripotent stem cells' (iPS cells) with the same broad potential as embryonic stem cells. This led us to examine the expression of Oct4 in endogenous neural stem cells, as data regarding its expression in neural stem cells in vivo are contradictory and incomplete. In this study we have therefore analysed the expression of Oct4 and other genes associated with pluripotency throughout development of the mouse CNS and in neural stem cells grown in vitro. We find that Oct4 is still expressed in the CNS by E8.5, but that this expression declines rapidly until it is undetectable by E15.5. This decline is coincident with the gradual methylation of the Oct4 promoter and proximal enhancer. Immunostaining suggests that the Oct4 protein is predominantly cytoplasmic in location. We also found that neural stem cells from all ages expressed the pluripotency associated genes, Sox2, c-Myc, Klf4 and Nanog. These data provide an explanation for the varying behaviour of cells from the early neuroepithelium at different stages of development. The expression of these genes also provides an indication of why Oct4 alone is sufficient to induce iPS formation in neural stem cells at later stages.