Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. METHODS: Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naïve tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. RESULTS: Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (aldehyde dehydrogenase 1 family member A1 [ALDH1A1] inhibitor) exhibited synergism with nanoparticle albumin-bound-paclitaxel in the organoid model for the stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in the stem-like and metabolism subtypes. The poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis not only reproduced the 3 subtypes but also showed heterogeneity in iCC. CONCLUSIONS: This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.

Safety evaluation of oral calcitonin-gene-related peptide receptor antagonists in patients with acute migraine: a systematic review and meta-analysis.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) receptor antagonists have been suggested as novel treatments for acute migraine. This study aimed to use meta-analysis to compare the safety and tolerability of five existing oral CGRP receptor antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) with that of a placebo or triptans against acute migraine. METHODS: Five prominent databases were searched to identify randomized controlled trials on this topic. The primary safety outcomes of interest were any adverse events (AEs) and treatment-related adverse events (TRAEs), and secondary outcomes were individual events, namely diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting. RESULTS: Fifteen studies met the eligibility criteria and were examined in detail. Although, compared to placebo, oral CGRP receptor antagonists significantly increased the incidence of any AEs (risk ratio [RR] = 1.15; 95% confidence interval [CI] = 1.07-1.23), there was no difference in the incidence of TRAEs (RR = 1.18; 95% CI = 1.00-1.38). Moreover, CGRP receptor antagonists were safer than triptans with respect to primary safety outcomes, such as any AEs (RR = 0.78; 95% CI = 0.63-0.98) and TRAEs (RR = 0.68; 95% CI = 0.58-0.79). CONCLUSION: Despite oral CGRP receptor antagonists posing a significantly higher risk of AEs when compared to placebo, CGRP receptor antagonists have a favorable safety profile compared to triptans. Our findings inform strategies to enhance safety and tolerability in the treatment of acute migraine.

The relationships between systemic cytokine profiles and inflammatory markers in colorectal cancer and the prognostic significance of these parameters.

BACKGROUND: Immunomodulatory cytokines and systemic inflammatory markers are important during cancer development and progression. This study investigated the association and prognostic impact of systemic cytokine profiles and inflammatory markers in colorectal cancer (CRC). METHODS: Interleukin (IL)-1ß, IL-6, IL-8, IL-9, IL-10, tumour necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) serum levels were measured using multiplex bead assays in CRC patients. Data on systemic inflammatory markers, such as the modified Glasgow prognostic score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI) and fibrinogen, were collected. Survival analysis was performed to identify factors associated with progression-free survival (PFS) and overall survival (OS). RESULTS: There were moderate-to-strong correlations within serum cytokines, as well as within systemic inflammatory markers, whereas the associations between serum cytokines and systemic inflammatory markers were generally weak. IL-8 and the LMR were independent significant prognostic factors for PFS and OS. The low IL-8 and high LMR group had the best survival (both PFS and OS) of all groups. CONCLUSIONS: Systemic cytokine profiles and inflammatory markers have relatively weak intergroup correlations. A composite classification of systemic cytokine profiles and inflammatory markers has an enhanced prognostic value in CRC.

Domperidone prescribing patterns in pediatric patients before and after safety warning in South Korea.

OBJECTIVE: In 2014, the Korean Ministry of Food and Drug Safety (MFDS) issued a safety warning to carefully consider adverse cardiac effects when prescribing domperidone for children. We conducted this study to compare the trends of domperidone prescription in pediatrics before and after the MFDS safety warning. MATERIALS: This study included patients < 18 years old who used national health insurance services within the year 2011 and the year 2016, sampled from Health Insurance Review Agency data. METHODS: We analyzed domperidone prescribing patterns including prescribed daily dosage, maximum period of continuous prescription, and number and types of co-prescribed medications and compared two different years pre and post safety warning. RESULTS: A total of 16,614 pediatric patients (1.74%) received domperidone prescriptions in 2011, and 11,317 patients (1.23%) in 2016. The probability of receiving at least one prescription in 2016 has been reduced by 30% compared to 2011. Gastritis was the most common indication in both years. The number of prescriptions containing a maximum daily dosage of over 30 mg was significantly lower in 2016. In the same time period, the number of cases with a maximum continuous prescription period of more than 7 days significantly decreased (p < 0.001). In addition, from 2011 to 2016, comorbid diseases of domperidone-treated patients were similar, but the number of co-prescriptions of interacting medication to domperidone decreased (p < 0.001). CONCLUSION: After the 2014 safety letter was released, the pattern of prescribing domperidone in pediatrics has enhanced drug safety for children in terms of frequency of prescriptions, maximum duration of domperidone use, and the prescription of drugs interacting with domperidone.

Application of an Inter-Species Extrapolation Method for the Prediction of Drug Interactions between Propolis and Duloxetine in Humans.

Duloxetine (DLX) is a potent drug investigated for the treatment of depression and urinary incontinence. DLX is extensively metabolized in the liver by two P450 isozymes, CYP2D6 and CYP1A2. Propolis (PPL) is one of the popular functional foods known to have effects on activities of CYPs, including CYP1A2. Due to the high probability of using DLX and PPL simultaneously, the present study was designed to investigate the potent effect of PPL on pharmacokinetics (PKs) of DLX after co-administration in humans. A PK study was first conducted in 18 rats (n = 6/group), in which the plasma concentration of DLX and its major metabolite 4-hydroxy duloxetine (4-HD) with or without administration of PPL was recorded. Population PKs and potential effects of PPL were then analyzed using NONMEM software. Lastly, these results were extrapolated from rats to humans using the allometric scaling and the liver blood flow method. PPL (15,000 mg/day) exerts a statistically significant increase in DLX exposures at steady state, with a 20.2% and 24.6% increase in DLX C m a x , s s and the same 28.0% increase in DLX A U C s s when DLX (40 or 60 mg) was administered once or twice daily, respectively. In conclusion, safety issues are required to be attended to when individuals simultaneously use DLX and PPL at high doses, and the possibility of interactions between DLX and PPL might be noted.

Label-free quantitative proteomic analysis of human periodontal ligament stem cells by high-resolution mass spectrometry.

BACKGROUND AND OBJECTIVES: Proteome analysis of periodontal ligament stem cells (PDLSCs) could be used to study the function of PDL tissue. We used a label-free quantitative proteomic technique to investigate differentially expressed proteins (DEPs) in human PDLSCs (hPDLSCs) compared to human bone marrow mesenchymal stem cells (hBMSCs) and identify proteins specific to hPDLSCs. MATERIAL AND METHODS: hPDLSCs (n = 3) and hBMSCs (n = 3) were cultured and harvested for protein extraction and trypsin digestion. The proteomes of both cell types were analyzed by nano-liquid chromatography/tandem mass spectrometry. DEPs in hPDLSCs compared to hBMSCs were detected by label-free quantification and evaluated through signal transduction pathway and gene ontology (GO) analysis. RESULTS: In total, 690 and 771 proteins were identified from hPDLSCs and hBMSCs, of which 561 proteins were in common and 124 DEPs were found between hPDLSCs and hBMSCs. Fifty-eight proteins were expressed at significantly higher levels in hPDLSCs, whereas 66 proteins were expressed at lower levels compared to hBMSCs. The more highly expressed proteins were associated with translation and initiating protein synthesis, and lower expressed proteins were related to cell aging and metabolic processes. Proteins unique to hPDLSCs and hBMSCs were associated with translation and metabolic processes, respectively. CONCLUSION: Our results demonstrate evidence of distinct differences in protein expression between hPDLSCs and hBMSCs by using label-free quantitative proteomic analysis which was the first attempt in this field. DEPs included previously reported hPDLSC marker proteins and novel marker candidates, such as microtubule-associated protein, CTP synthase 1 and stathmin, which could be the markers for developing periodontal disease diagnostics and therapies.

Effects of FGF21-secreting adipose-derived stem cells in thioacetamide-induced hepatic fibrosis.

Mesenchymal stem cells (MSCs) have been investigated to treat liver diseases, but the efficiency of MSCs to treat chronic liver diseases is conflicting. FGF21 can reduce inflammation and fibrosis. We established FGF21-secreting adipose derived stem cells (FGF21_ADSCs) to enhance the effects of ADSCs and transplanted them into thioacetamide (TAA)-induced liver fibrosis mice via the tail vein. Transplantation of FGF21_ADSCs significantly improved liver fibrosis by decreasing serum hyaluronic acid and reducing the expression of fibrosis-related factors such as α-smooth muscle actin (α-SMA), collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) compared with the Empty_ADSCs by inhibition of p-JNK, NF-κB and p-Smad2/3 signalling. α-lactoalbumin (LA) and lactotransferrin (LTF), secretory factors produced from FGF21_ADSCs inhibited TGF-ß1-induced expression of α-SMA and collagen in LX-2 cells. These results suggest that transplantation of FGF21_ADSCs inhibited liver fibrosis more effectively than Empty_ADSCs, possibly via secretion of α-LA and LTF.

Effectiveness of febuxostat in patients with allopurinol-refractory hyperuricemic chronic kidney disease
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OBJECTIVE: As uncontrolled hyperuricemia has been associated with an increased risk of cardiovascular disease and the progression of chronic kidney disease (CKD), management of serum uric acid levels is important. The aim of this study was to evaluate the effectiveness of febuxostat in regulating uncontrolled hyperuricemia in patients with renal dysfunction. MATERIALS AND METHODS: We included patients with CKD and persistent uncontrolled hyperuricemia despite treatment with allopurinol. The primary outcome of the study, which was the overall response rate of febuxostat, was defined as the proportion of patients that achieved a serum uric acid level < 7.0 mg/dL. The secondary outcomes included the change in renal function and factors that might influence treatment outcomes. The safety outcome was evaluated based on the incidence of adverse reactions. RESULTS: A total of 111 patients who switched medication to febuxostat were included. Febuxostat treatment significantly lowered serum uric acid level and the response rates were above 70% at all the time points for 1 year. Febuxostat-treated patients demonstrated no significant change in renal function during the study period. A history of gout attack decreased the response rate of febuxostat (odds ratio (OR): 3.13, 95% confidence interval (CI): 1.08 - 9.06), whereas low-dose aspirin use significantly increased response rate (OR: 0.29, 95% CI: 0.09 - 0.92) in the first month. No patients experienced any severe adverse events. CONCLUSIONS: Febuxostat effectively lowered serum uric acid levels and was well tolerated in patients with CKD and allopurinol-refractory hyperuricemia.
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Performance comparison of first-order conditional estimation with interaction and Bayesian estimation methods for estimating the population parameters and its distribution from data sets with a low number of subjects.

BACKGROUND: Exploratory preclinical, as well as clinical trials, may involve a small number of patients, making it difficult to calculate and analyze the pharmacokinetic (PK) parameters, especially if the PK parameters show very high inter-individual variability (IIV). In this study, the performance of a classical first-order conditional estimation with interaction (FOCE-I) and expectation maximization (EM)-based Markov chain Monte Carlo Bayesian (BAYES) estimation methods were compared for estimating the population parameters and its distribution from data sets having a low number of subjects. METHODS: In this study, 100 data sets were simulated with eight sampling points for each subject and with six different levels of IIV (5%, 10%, 20%, 30%, 50%, and 80%) in their PK parameter distribution. A stochastic simulation and estimation (SSE) study was performed to simultaneously simulate data sets and estimate the parameters using four different methods: FOCE-I only, BAYES(C) (FOCE-I and BAYES composite method), BAYES(F) (BAYES with all true initial parameters and fixed ω 2 ), and BAYES only. Relative root mean squared error (rRMSE) and relative estimation error (REE) were used to analyze the differences between true and estimated values. A case study was performed with a clinical data of theophylline available in NONMEM distribution media. NONMEM software assisted by Pirana, PsN, and Xpose was used to estimate population PK parameters, and R program was used to analyze and plot the results. RESULTS: The rRMSE and REE values of all parameter (fixed effect and random effect) estimates showed that all four methods performed equally at the lower IIV levels, while the FOCE-I method performed better than other EM-based methods at higher IIV levels (greater than 30%). In general, estimates of random-effect parameters showed significant bias and imprecision, irrespective of the estimation method used and the level of IIV. Similar performance of the estimation methods was observed with theophylline dataset. CONCLUSIONS: The classical FOCE-I method appeared to estimate the PK parameters more reliably than the BAYES method when using a simple model and data containing only a few subjects. EM-based estimation methods can be considered for adapting to the specific needs of a modeling project at later steps of modeling.

Prioritization of diseases for the development of a pharmaceutical care service model in South Korea using the analytic hierarchy process
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OBJECTIVE: Drug therapy plays a critical role in most chronic diseases. Effectiveness of pharmaceutical care services in the improvement of clinical, social, or economic outcomes has been scientifically proven through numerous studies. In South Korea, to optimize and standardize pharmaceutical care for patients with chronic metabolic diseases, the development of a pharmaceutical care service model is needed. MATERIALS: To determine the priority of diseases in developing pharmaceutical care service models, analytic hierarchny process (AHP)analysis was used. A survey questionnaire standardized with detailed evaluation areas and an index, to ensure sufficient understanding and identical standards of evaluators, was designed. It was prepared for pair-wise comparisons of individual criteria of candidate diseases. METHODS: Medical specialists and pharmacists who have clinical experience and expertise in chronic metabolic diseases or at least 10 years of experience in pharmacy practice were recruited. They responded to a survey consisting of nine sections by using the pair-wise comparison method. RESULTS: A total of seven candidate diseases were selected for prioritization. Diabetes mellitus was given the highest score of 0.2695, cardiovascular disease (0.2598) being the next, followed by chronic kidney disease (0.2000), and cerebrovascular diseases (0.1087). The criteria were weighted as follows: disease characteristics (0.4964), patient-oriented care (0.3649), and improvement in services (0.1386). CONCLUSION: Diabetes, cardiovascular diseases, and chronic kidney disease were found to have high priority in developing a pharmaceutical care service model in South Korea. In the future, further research for the development and application of pharmaceutical care services models for different types of diseases is required.
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Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

OBJECTIVES: To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS: Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD: The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS: Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION: Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.

Influence of initial angiotensin receptor blockers on treatment persistence in uncomplicated hypertension: A nation-wide population-based study.

We identified 55 504 uncomplicated, treatment-naïve hypertensive patients who started angiotensin II receptor blockers (ARBs) in 2012 from national claims data. The proportion of patients remaining on any hypertension treatment at 12 months and the adherence rate were similar between the losartan cohort (66.82% and 68.25%) and the nonlosartan ARB cohort (67.48% and 69.01%). After adjusting for confounding factors, there was no difference in persistence (aHR 0.98, 95% confidence interval (CI) 0.95-1.01) on hypertension treatment between losartan and nonlosartan ARB cohort. Post hoc analysis showed that patients initially prescribed eprosartan, irbesartan (both, aHR 1.33), and telmisartan (aHR 1.11) were more likely to discontinue the initial drug, whereas valsartan initiators (aHR 0.96) were less likely compared with losartan initiators.

Copy number variability analysis of pharmacogenes in patients with lymphoma, leukemia, hepatocellular, and lung carcinoma using The Cancer Genome Atlas data.

OBJECTIVE: Individual differences in drug efficacy and toxicity remain an important clinical concern. We investigated copy number variation (CNV) frequencies for pharmacogenes using The Cancer Genome Atlas dataset. MATERIALS AND METHODS: One hundred and fifty-two pharmacogenes were selected from liver hepatocellular carcinoma, lung squamous cell carcinoma (LUSC), acute myeloid leukemia, and lymphoid neoplasm diffuse large B-cell lymphoma (DLBL). The germ line and somatic CNV frequencies were analyzed. RESULTS: We found CNVs with more than 1% frequency in drug-metabolizing enzymes including CYP2A6, CYP2D6, GSTP1, CYP2E1, GSTM1, GSTT1, and SULT1A1, drug transporters such as SLC19A1 and SLC28A1, and targets such as FHIT in normal tissue or blood. GSTM1 had the highest frequency for gene gain (45.45, 39.18, 31.01, and 34.77%, respectively) and for gene loss (18.18, 29.38, 20.89, and 26.68%, respectively) in DLBL, acute myeloid leukemia, liver hepatocellular carcinoma, and LUSC. P2RY12 and P2RY1 had the highest frequency for gene gain in LUSC (26.95 and 26.68%, respectively) whereas ABCB1 and ABL2 had the highest frequency for gene gain in DLBL (27.27%) in cancer tissue or blood. CONCLUSION: Germ line and somatic CNVs of pharmacogenes may play a role in determining individual variations in drug responses. Inclusion of CNVs in pharmacogenetic variations holds promise as biomarkers that can increase the benefits and reduce the risks of drug therapy on an individual level.

Evaluation of Fibroblast Growth Factor Receptor 2 Expression, Heterogeneity and Clinical Significance in Gastric Cancer.

BACKGROUND: We aimed to evaluate the protein and mRNA expression of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer (GC). METHODS: A tissue microarray containing 362 surgically resected GC tissues and 135 matched metastatic lymph nodes was evaluated using FGFR2b IHC and FGFR2 ISH. FGFR2 fluorescence ISH was also performed in 188 cases. RESULTS: All FGFR2-amplified cases (5 of 188) showed FGFR2b protein and FGFR2 mRNA overexpression (p < 0.001), and FGFR2 amplification was not identified in FGFR2b IHC- and FGFR2 mRNA ISH-negative cases. Kaplan-Meier survival analysis revealed that FGFR2b protein and FGFR2 mRNA overexpression was significantly associated with a poor overall survival (p < 0.001 and p = 0.012, respectively), and multivariate analyses showed that FGFR2 mRNA overexpression was an independent biomarker of a poor overall survival. Intratumoral heterogeneity of FGFR2b protein and FGFR2 mRNA overexpression was observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2b and FGFR2 expression results between primary and matched metastatic lymph nodes were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) cases, respectively. CONCLUSIONS: Intratumoral heterogeneity and discordant FGFR2b expression in primary tumors and metastatic lymph nodes are common in GC.

Population pharmacokinetics of cyclosporine in hematopoietic stem cell transplant patients: consideration of genetic polymorphisms.

BACKGROUND: Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce. OBJECTIVE: The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data. METHODS: A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program. RESULTS: A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA. CONCLUSIONS: In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study.

Prognostic implication of TSC1 and mTOR expression in gastric carcinoma.

BACKGROUND: Gastric adenocarcinoma is the sixth most common and third most lethal cancer in the world. Except for HER2-targeted therapy, targeted agents against specific molecules participating in gastric carcinogenesis, including those in the mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathway have not been proved to be effective. However, some studies have suggested that dysfunction of TSC1 may augment mTOR inhibitor activity. METHODS: We studied p-mTOR and TSC1 status by immunohistochemical analysis of gastric carcinoma samples using a tissue microarray method and expression values adopted from The Cancer Genome Atlas. RESULTS: High p-mTOR and low TSC1 expression status is associated with adverse clinicopathologic parameters. Patients with high p-mTOR levels showed poor survival. Patients with low TSC1 levels showed unfavorable survival status in the overall patients group. The combination of p-mTOR status and TSC1 status provided more strong survival information than using each parameter alone. CONCLUSIONS: In gastric cancer, high p-mTOR expression level is a statistically significant parameter in multivariate and Kaplan-Meier analyses (log-rank test). In addition to p-mTOR, TSC1 expression provided additional information to predict survival. We therefore suggest that evaluation of both p-mTOR and TSC1 status may be helpful in clinical trials related to mTOR inhibitors.

DNA damage response-related proteins in gastric cancer: ATM, Chk2 and p53 expression and their prognostic value.

OBJECTIVES: The aims of this study were to assess expressions of the DNA damage response (DDR)-related proteins and to investigate their clinical significances in gastric carcinoma. METHODS: Two independent cohorts, a training set (n=524) and validation set (n=394), of gastric cancer patients were enrolled. Ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (Chk2), and p53 expressions were examined by immunohistochemistry using tissue microarray. RESULTS: ATM loss, Chk2 loss, and p53 positivity were observed in 21.8, 14.1, and 36.1% of the training set, and in 17.3, 12.2, and 35.8% of the validation set, respectively. In the training set, the aberrant expressions of ATM, Chk2, or p53 were significantly associated with an advanced TNM stage and poor disease-specific survival. This association was verified in the validation set. Chk2 positivity and p53 negativity were significantly related to a prolonged disease-specific survival. Also, patients with nonaberrant expressional levels of all 3 DDR-related proteins had a more favorable outcome than others. Multivariate analyses showed that Chk2 loss and at least 1 aberrant DDR-related protein remained as independent prognostic factors of poor disease-specific survival. CONCLUSIONS: This study elucidated the prognostic implications of DDR-related proteins, and suggests that their aberrant expressions play critical roles in the development and progression of gastric cancer.

Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients.

PURPOSE: Enteric-coated mycophenolate sodium (EC-MPS) is effective and safe in preventing rejection after transplantation and is mainly transported by ABCs and OATPs and metabolized by UGTs. The genetic polymorphisms affect the inter-individual variation in drug disposition and elimination. The aims of this study were to develop a population pharmacokinetic (PK) model and to evaluate the influence of genetic and clinical factors on the PK of mycophenolic acid (MPA) in Korean renal transplant recipients. METHODS: Population analysis of EC-MPS was performed using non-linear mixed effects modeling (NONMEM). After clinical and genetic factors were evaluated using a stepwise covariate method, we selected clinically relevant covariates considering covariate effects. The final model was validated by bootstrap and visual predictive check. At last, we performed the model-based simulations in order to explore an optimal dose to achieve target area under the curve (AUC) in hypothetical scenarios. RESULTS: From 166 plasma concentrations (n=34), a time-lagged two-compartment with a flip-flop model best describes the PK of MPA. The covariate analysis identified lower creatinine clearance (CLcr) and SLCO1B1 variant genotype were correlated with lower MPA clearance, on the contrary, UGT1A9 variant had decreased distribution of MPA, contributing to lower absorption. When considering to UGT1A9, SLCO1B1 genotypes, and renal function, the new recommended dose of 540 mg twice daily resulted in a higher success of achieving the target AUC0-12h in the 30-60 mg.h/L. CONCLUSIONS: CLcr, UGT1A9 and SLCO1B1 genotypes seem to be promising parameters to predict the pharmacokinetics with flip-flop phenomenon of EC-MPS in transplant recipient having stable renal function. This model on clinical practice may help prevent overexposure and achieve a proper AUC in the Korean population.

Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis.

STUDY OBJECTIVES: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. METHODS: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. RESULTS: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. CONCLUSION: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.

The Application of Knowledge-Based Clinical Decision Support Systems to Detect Antibiotic Allergy.

Prevention of drug allergies is important for patient safety. The objective of this study was to evaluate the outcomes of antibiotic allergy-checking clinical decision support system (CDSS), K-CDSTM. A retrospective chart review study was performed in 29 hospitals and antibiotic allergy alerts data were collected from May to August 2022. A total of 15,535 allergy alert cases from 1586 patients were reviewed. The most frequently prescribed antibiotics were cephalosporins (48.5%), and there were more alerts of potential cross-reactivity between beta-lactam antibiotics than between antibiotics with the same ingredients or of the same class. Regarding allergy symptoms, dermatological disorders were the most common (38.8%), followed by gastrointestinal disorders (28.4%). The 714 cases (4.5%) of immune system disorders included 222 cases of anaphylaxis and 61 cases of severe cutaneous adverse reactions. Alerts for severe symptoms were reported in 6.4% of all cases. This study confirmed that K-CDS can effectively detect antibiotic allergies and prevent the prescription of potentially allergy-causing antibiotics among patients with a history of antibiotic allergies. If K-CDS is expanded to medical institutions nationwide in the future, it can prevent an increase in allergy recurrence related to drug prescriptions through cloud-based allergy detection CDSSs.