Evaluation of Medication Adherence Among Prevalent Users in Hypertension, Dyslipidemia, and Diabetes Using Health Insurance Claims: A Population-Based Cohort Study in Japan.

PURPOSE: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined. METHODS: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression. RESULTS: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications. CONCLUSION: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.

Lymphoscintigraphy Findings are Associated with Outcome in Children with Chylothorax After Cardiac Surgery.

Postoperative chylothorax in patients with congenital heart diseases (CHD) results in poor outcomes if anatomical and functional abnormalities of the lymphatic system are present. While these abnormalities are typically diagnosed by intranodal lymphangiography and dynamic contrast magnetic resonance lymphangiography, the usefulness of lymphoscintigraphy in these patients has not been evaluated. Between January 2019 and December 2021, 28 lymphoscintigraphies were performed in our institution for investigating prolonged pleural effusion after cardiac surgery. The images were assessed by three board-certified pediatric cardiologists retrospectively to determine the likelihood of a central lymphatic flow disorder. The likelihood was scored (range 1-3) based on structural abnormalities and congestive flow in the lymphatic system. Those scores were summed and the likelihood was categorized as low to intermediate (< 8 points) or high (8 or 9 points). Median age at lymphoscintigraphy was 129 days (IQR, 41-412 days), it was performed at a median of 22 days (IQR, 17-43) after surgery, and median score was 6 points (IQR, 4-7.5). Kendall's coefficient of concordance (0.867; p < 0.05) indicated high inter-rater reliability. Overall survival at 6 months after surgery was 92.5% in the low-to-intermediate group but 68.6% in the high group (p < 0.05), and duration of postoperative thoracic drainage was 27 and 58 days, respectively (p < 0.05). Lymphatic abnormalities detected by lymphoscintigraphy were associated with poorer outcomes. Lymphoscintigraphy was thought to be useful in assessing anatomic and functional lymphatic abnormalities, despite its minimal invasiveness.

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

Normal Ventricular and Regional Blood Flow Volumes and Native T1 Values in Healthy Japanese Children Obtained from Comprehensive Cardiovascular Magnetic Resonance Imaging.

Age-related mean and reference ranges for ventricular volumes and mass, regional blood flow measurements, and T1 values using cardiovascular magnetic resonance (CMR) imaging are yet to be established for the pediatric population. Especially in infants and toddlers, no consistent flow volume sets or T1 values have been reported. The purpose of this study was to determine the relevant normal values.Twenty-three children (aged 0.1-15.3 years) without cardiovascular diseases were included. Comprehensive CMR imaging including cine, 2-dimensional phase-contrast, and native T1 mapping, were performed. Ventricular volumes and masses, 11 sets of regional blood flow volumes, and myocardial and liver T1 values were measured. All intraclass correlation coefficient values were > 0.94, except for the right ventricular mass (0.744), myocardial (0.868) and liver T1 values (0.895), reflecting good to excellent agreement between rates.Regression analysis showed an exponential relationship between body surface area (BSA) and ventricular volumes, mass, and regional blood flow volumes (normal value = a*BSAb). Left ventricular myocardial T1 values were regressed on linear regression with age (normal value = -7.39*age + 1091), and hepatic T1 values were regressed on a quadratic function of age (normal value = 0.923*age2 -18.012*age + 613).Comparison of the 2 different methods for the same physical quantities by Bland-Altman plot showed no difference except that the right ventricular stroke volume was 1.5 mL larger than the main pulmonary trunk flow volume.This study provides the normal values for comprehensive CMR imaging in Japanese children.

Congenital portosystemic venous shunt associated with 22q11.2 deletion syndrome: a case report.

BACKGROUND: 22q11.2 deletion syndrome (22qDS) is the most common chromosomal microdeletion syndrome and is associated with a high rate of congenital heart disease (CHD) and neurodevelopmental abnormalities. Congenital portosystemic venous shunts (CPSS) are rare developmental abnormalities of the portal venous system. The clinical manifestations of CPSS are varied, and some patients have CHD or genetic chromosomal abnormalities, but their relationship remains unknown. We report the first case of CPSS associated with 22qDS. CASE PRESENTATION: A newborn boy referred to our institution was diagnosed with 22qDS due to characteristic facial features and complications of tetralogy of Fallot. A subsequent newborn screening test indicated hypergalactosemia and high blood levels of ammonia and bile acids. Upon closer examination, these abnormalities were found to be caused by the CPSS. Abdominal contrast-enhanced computed tomography and angiography confirmed that abnormal blood vessels ascended from the splenic vein and short-circuited to the left renal vein. Intracardiac repair for CHD was performed at 1 year of age, followed by transcatheter occlusion of the CPSS using a multilayer device (vascular plug) and detachable coil at 2 years of age. After treatment, the abnormal blood parameters promptly normalized. CONCLUSIONS: As the blood flow of CPSS bypasses the liver, the levels of galactose, bile acids, and ammonia in the systemic veins can increase. Some patients with CPSS have CHD, and these toxic substances may cause liver and lung lesions as well as portosystemic encephalopathy (PSE). Several genetic chromosomal abnormalities, including 22qDS, and CPSS have similar symptoms, and neurodevelopmental abnormalities, particularly those caused by PSE, may be difficult to diagnose. Blood tests, such as newborn screening, and abdominal imaging are useful in the early diagnosis of CPSS.

Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography-Photodiode array detection.

BACKGROUND: Dasatinib, nilotinib, and bosutinib, second-generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third-generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography-tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high-performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs. METHODS: Calibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid-phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system. RESULTS: The calibration ranges were 2-500 ng/ml for dasatinib, 100-5000 ng/ml for nilotinib, and 10-500 ng/ml for bosutinib and ponatinib. Intra-day and inter-day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%-96.0%, 80.7%-86.1%, 91.6%-99.0%, and 86.4%-92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively. CONCLUSION: To the best of our knowledge, this is the first report of an HPLC-PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.

Integrated Multi-Omics Analysis Reveals Differential Effects of Fructo-Oligosaccharides (FOS) Supplementation on the Human Gut Ecosystem.

Changes in the gut ecosystem, including the microbiome and the metabolome, and the host immune system after fructo-oligosaccharide (FOS) supplementation were evaluated. The supplementation of FOS showed large inter-individual variability in the absolute numbers of fecal bacteria and an increase in Bifidobacterium. The fecal metabolome analysis revealed individual variability in fructose utilization in response to FOS supplementation. In addition, immunoglobulin A(IgA) tended to increase upon FOS intake, and peripheral blood monocytes significantly decreased upon FOS intake and kept decreasing in the post-FOS phase. Further analysis using a metagenomic approach showed that the differences could be at least in part due to the differences in gene expressions of enzymes that are involved in the fructose metabolism pathway. While the study showed individual differences in the expected health benefits of FOS supplementation, the accumulation of "personalized" knowledge of the gut ecosystem with its genetic expression may enable effective instructions on prebiotic consumption to optimize health benefits for individuals in the future.

Pharmacologic therapy with flecainide for asymptomatic Wolff-Parkinson-White syndrome in an infant with severe left ventricular dyssynchrony.

Some asymptomatic patients with Wolff-Parkinson-White syndrome have severe left ventricular dyssynchrony and dysfunction. We describe a patient who was given a diagnosis of Wolff-Parkinson-White syndrome in infancy and had a complete response to pharmacologic therapy with flecainide. Our findings suggest that flecainide is a suitable resynchronisation therapy for such infants.

Forced expression of S100A10 reduces sensitivity to oxaliplatin in colorectal cancer cells.

BACKGROUND: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. Our recent proteomics studies have demonstrated that intracellular protein expression levels of S100A10 are significantly correlated with the sensitivity of colorectal cancer (CRC) cells to L-OHP, but not 5-FU, suggesting that S100A10 is a candidate predictive marker for the response to L-OHP. In this study, we investigated whether S100A10 is involved in L-OHP sensitivity or not. RESULTS: Forced expression of S100A10 in COLO-320 CRC cells significantly increased the 50% inhibitory concentration (IC50) for L-OHP (P = 0.003), but did not change that for 5-FU, indicating that S100A10 is more specific to L-OHP than 5-FU. Silencing of the S100A10 gene showed no apparent effect on sensitivity to L-OHP in HT29 cells. Silencing of the annexin A2 (a binding partner of S100A10) gene alone downregulated both annexin A2 and S100A10 protein levels, with no change in S100A10 gene expression. However, original levels of intact S100A10 protein in CRC cells positively correlated with S100A10 mRNA levels (P = 0.002, R = 0.91). CONCLUSIONS: The present results have shown that protein expression of S100A10 was associated with resistance to L-OHP, but not 5-FU, supporting the hypothesis that S100A10 expression may predict L-OHP sensitivity. Thus, our present study provides basic findings to support that S100A10 expression can be used as a predictive marker for tumor sensitivity to L-OHP.

[Considering Medical Professionalism from the Standpoint of Pharmacy Education].

Worldwide interest in teaching medical professionalism has increased drastically over the past two decades and is recognized as an important core competency. It is also essential in pharmacy education. However, there is no single definition of medical professionalism owing to its multifaceted nature, leading to difficulty in understanding it. The foundational concept of professionalism are the social contract and accountability, which describe the relationship between the profession and the society which it serves. Profession must understand expectations from the society, which is trustworthy, assures competence, and devoted to the public good for the contract based on their mutual trust. In "teaching," three basic educational actions ("setting expectations," "providing experiences," and "evaluating outcomes") are required. There are two learning goals of professionalism education: the minimum goal of not doing unprofessional acts and the aspirational goal of pursuing a higher level of interiorized professionalism which leads to the professional identity formation. The true professionals are "reflective practitioners," who have the ability to manage ambiguous problems using their interiorized professionalism in complicated situations. Therefore, reflection is one of the central concepts of professionalism education. The Professionalism Mini-Evaluation Exercise (P-MEX), an observational tool to evaluate medical professionalism, has some favorable aspects; the Japanese version is available and is a guide to specific actions for professionalism through its items, although some cautions must be exercised when using it. Considering that teaching professionalism includes not only formal but informal and hidden curricula, all of the staff in the educational environments should consider professionalism education by understanding professionalism.

Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum ß-lactamase producing Enterobacterales (ESBL-E).

STUDY OBJECTIVE: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended-spectrum ß-lactamase producing enterobacterales (ESBL-E) and investigate optimal dosing regimens for not undergoing hemodialysis (non-HD) and undergoing hemodialysis (HD) patients. DESIGN: Prospective observational study. PATIENTS: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022. MEASUREMENTS: Total and Unbound CMZ concentration was measured by high-performance liquid chromatography (HPLC) with solid-phase extraction and ultrafiltration. SETTING: Determining the CMZ dosing regimen involved modified creatinine clearance (CLCR ) with measured body weight (BW) using the Cockcroft-Gault equation. For non-HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre-HD), and 1 and 3 h after starting HD and post-HD. All blood samples were collected at steady-state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non-HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule. MAIN RESULTS: CMZ measurement methods were established. A model analysis of unbound PK in 37 non-HD patients incorporated creatinine clearance (CLCR ) using the Cockcroft-Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non-HD patients with an ESBL-E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CLCR of 60 mL/min required administration of 2 g every 6 h (1- and 3-h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL-E MIC of 4 mg/L. CONCLUSIONS: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL-E-infected patients.

Ingenol mebutate inhibits the growth of pancreatic cancer cells in vitro via STING with an efficacy comparable to that of clinically used anticancer agents.

Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays. In addition, we aimed to identify novel biomolecules that may be involved in the mechanism of action of IM using RNA sequencing, western blotting, and inhibition assays. The IC50 values after 72 h of exposure to IM and SN-38, drugs to which the Panc-1 cells are most sensitive among the tested anticancer agents, were 43.1 ± 16.8 nM and 165 ± 37 nM, respectively. IM showed a cytostatic effect equal to or greater than that of the clinically used pancreatic cancer therapeutic drugs. RNA sequencing and protein expression analysis revealed that expression of stimulator of interferon genes (STING) increased at low IM concentration, whereas cell viability decreased. Co-exposure of IM and STING inhibitor, H-151, to Panc-1 or MIA PaCa-2 cell lines canceled the growth-inhibitory effects of IM alone. In conclusion, IM may have an efficacy comparable to that of existing pancreatic cancer therapeutic agents on the less drug-sensitive Panc-1 cell line and the immune-related molecule STING plays a role in the mechanism of action of IM.

Patient prognosis and prediction model for taking Kampo formulas in dysmenorrhea: An observational study.

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population.

The propionate-GPR41 axis in infancy protects from subsequent bronchial asthma onset.

Evidence has accumulated that gut microbiota and its metabolites, in particular the short-chain fatty acid propionate, are significant contributors to the pathogenesis of a variety of diseases. However, little is known regarding its impact on pediatric bronchial asthma, one of the most common allergic diseases in childhood. This study aimed to elucidate whether, and if so how, intestinal propionate during lactation is involved in the development of bronchial asthma. We found that propionate intake through breast milk during the lactation period resulted in a significant reduction of airway inflammation in the offspring in a murine house dust mite-induced asthma model. Moreover, GPR41 was the propionate receptor involved in suppressing this asthmatic phenotype, likely through the upregulation of Toll-like receptors. In translational studies in a human birth cohort, we found that fecal propionate was decreased one month after birth in the group that later developed bronchial asthma. These findings indicate an important role for propionate in regulating immune function to prevent the pathogenesis of bronchial asthma in childhood.

Flavin Adenine Dinucleotide-Related Adverse Event Necessitating Cardiopulmonary Resuscitation in an Infant.

Mitochondrial rescue drugs, such as vitamin B2, are a treatment modality which can be considered in unexplained cases of cardiac arrest or impaired consciousness in which mitochondrial diseases are considered in the differential. Although case reports exist of children developing a drop in their blood pressure following administration of intravenous flavin adenine dinucleotide (FAD) sodium as vitamin B2, we present the first reported case of a child requiring cardiopulmonary resuscitation (CPR) following FAD sodium infusion for severe bradycardia and hypotension. Intravenous infusion of FAD sodium should be administered as slowly as possible, with careful monitoring of blood pressure and heart rate.

Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum.

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 µL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5-125.0 ng/mL for afatinib, 2.5-125.0 ng/mL for dacomitinib, 4.0-800.0 ng/mL for osimertinib, 1.0-125.0 ng/mL for AZ5104, and 2.5-125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of N-Arylated Heliamine Analogues.

Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme. This report describes the first case of screening of N-arylated heliamine derivatives to develop novel MAO-B selective inhibitors that can be synthesized concisely by microwave-assisted Pd nanoparticle-catalyzed Buchwald-Hartwig amination. We discovered that the derivatives 4h, 4i, and 4j display inhibitory activity against MAO-B with IC50 values of 1.55, 13.5, and 5.08 µM, respectively.

S100A10 protein expression is associated with oxaliplatin sensitivity in human colorectal cancer cells.

BACKGROUND: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. The objective of our study was to find candidate protein markers for tumor sensitivity to L-OHP from intracellular proteins of human colorectal cancer (CRC) cell lines. We performed expression difference mapping (EDM) analysis of whole cell lysates from 11 human CRC cell lines with different sensitivities to L-OHP by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), and identified a candidate protein by liquid chromatography/mass spectrometry ion trap time-of-flight (LCMS-IT-TOF). RESULTS: Of the qualified mass peaks obtained by EDM analysis, 41 proteins were differentially expressed in 11 human colorectal cancer cell lines. Among these proteins, the peak intensity of 11.1 kDa protein was strongly correlated with the L-OHP sensitivity (50% inhibitory concentrations) (P < 0.001, R2 = 0.80). We identified this protein as Protein S100-A10 (S100A10) by MS/MS ion search using LCMS-IT-TOF. We verified its differential expression and the correlation between S100A10 protein expression levels in drug-untreated CRC cells and their L-OHP sensitivities by Western blot analyses. In addition, S100A10 protein expression levels were not correlated with sensitivity to 5-fluorouracil, suggesting that S100A10 is more specific to L-OHP than to 5-fluorouracil in CRC cells. S100A10 was detected in cell culture supernatant, suggesting secretion out of cells. CONCLUSIONS: By proteomic approaches including SELDI technology, we have demonstrated that intracellular S100A10 protein expression levels in drug-untreated CRC cells differ according to cell lines and are significantly correlated with sensitivity of CRC cells to L-OHP exposure. Our findings provide a new clue to searching predictive markers of the response to L-OHP, suggesting that S100A10 is expected to be one of the candidate protein markers.

Design, Synthesis, and Monoamine Oxidase Inhibitory Activity of (+)-Cinchonaminone and Its Simplified Derivatives.

The absolute structure of an indole alkaloid (+)-cinchonaminone by total synthesis of both (+)-cinchonaminone and its enantiomer was determined. The main focus of the study was the enantioselective synthesis of both enantiomers of a chiral cis-3,4-disubstituted piperidine. We also evaluated monoamine oxidase (MAO) inhibitory activities of these enantiomers. Furthermore, its structurally simplified derivatives were synthesized that did not have any chiral center. Two of these derivatives showed stronger MAO inhibitory activities than that of (+)-cinchonaminone.

Prognostic Value of Baseline Medications Plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer: A Retrospective Study.

BACKGROUND: Nivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting. METHODS: We conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression ß coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes. RESULTS: In total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1-2), and poor (scores 3-6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07-2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed. CONCLUSIONS: The findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.