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Tanezumab is a monoclonal antibody against nerve growth factor (NGF). We investigated tanezumab pharmacokinetic (PK)‐NGF relationships and predicted the extent of systemic free NGF suppression with target‐mediated drug disposition (TMDD) modeling using data from three pivotal phase III interventional studies (NCT02697773, NCT02709486, and NCT02528188) in patients with osteoarthritis. Patients received tanezumab 2.5 mg or 5 mg every 8 weeks (q8w) subcutaneously. A TMDD model using a previously established population PK model was used to describe plasma tanezumab and serum total NGF concentration data, and simulations were performed to predict "unobserved" free NGF versus time profiles and dose–response relationships for free NGF. A total of 2992 patients had available data for plasma tanezumab or serum total NGF concentrations and were included in the analysis; 706 of these had data for both tanezumab and total NGF concentrations. The model generally performed well to predict observed total NGF concentrations up to ~24 weeks after each dose. Simulations suggested free NGF concentration would be suppressed by ~75% (median) near the peak of tanezumab concentration and by less than 5% (median) around the trough tanezumab concentration with a tanezumab 2.5 mg q8w regimen. Free NGF concentration was predicted to return to baseline level at ~8 weeks (95% prediction interval: 5–16 weeks) after the last tanezumab dose. This model adequately described plasma tanezumab and serum total NGF concentrations following s.c. administration of tanezumab 2.5 or 5 mg q8w, allowed prediction of relative change in systemic free NGF following s.c. administration of tanezumab. [ABSTRACT FROM AUTHOR]

Transcatheter edge-to-edge repair (TEER) of the mitral valve has become an established therapy for certain patients with mitral regurgitation. However, little is known about the association between institutional volume variations and long-term outcomes using a large-scale database. Our study aimed to describe the institutional variations of TEER and also investigate its association with 180-day readmission rates. We conducted a retrospective cohort study of TEER performed in the US from the 2019 Nationwide Readmission Database. We divided the patients according to the tertiles based on volume of TEER (Q1 [lowest]-Q3 [highest]) and evaluated the association with 180-day readmission rates. A total of 4922 patients (mean age 76.8 ± 10.4 years, and 54.5% male) who underwent TEER at 250 institutions were included in the analyses. There was substantial variation in the number of TEER performed annually across institutions (median 25.0 [11.6–52.5] cases). Readmission within 6-months following TEER was 37.0%, mainly due to heart failure. Higher institutional volume was associated with a reduced incidence of 180-day readmissions (HR of Q3 0.68 95%CI 0.50–0.93, vs Q1; p = 0.016). This association was more prominent in non-elective cases (HR of Q3 0.50 95%CI 0.31–0.81, vs Q1; p = 0.005). Using a nationally representative contemporary database, our study found substantial institutional variation in volume of TEER cases. Higher institutional volume was associated with a decreased risk of 180-day readmission rate, particularly in non-elective cases. Our study suggests the importance of highly skilled heart teams when treating patients who need urgent transcatheter intervention for mitral regurgitation. • There was a substantial institutional variation in volume of transcatheter edge-to-edge repair. • Higher institutional volume was associated with a decreased risk of 180-day readmission rate. • This association was mostly observed in non-elective cases. • Our study suggests the importance of highly skilled heart teams of transcatheter edge-to-edge repair. [ABSTRACT FROM AUTHOR]

Contemporary guidelines emphasize the importance of risk stratification in improving the quality of care for patients undergoing percutaneous coronary intervention (PCI). We aimed to investigate whether adding information from a procedure-based academic registry to administrative claims data would improve the performance of risk prediction model. We combined two nationally representative administrative and clinical databases. The study cohort comprised 43,095 patients; 18,719 and 23, 525 with acute [ACS] and chronic [CCS] coronary syndrome, respectively. Each population was randomly divided into the logistic regression model (derivation cohort, 80%) and model validation (validation cohort, 20%) groups. The performances of the following models were compared using C-statistics: (1) variables restricted to baseline claims data (model #1), (2) clinical registry data (model #2), and (3) expanded to both claims and clinical registry data (model #3). The primary outcomes were in-hospital mortality and bleeding. The primary outcomes occurred in 3.7% (in-hospital mortality)/5.0% (bleeding) of patients with ACS and 0.21%/0.95% of CCS patients. For each event, the model performance was 0.65 (95% confidence interval [CI], 0.60–0.69) /0.67 (0.63–0.71) in ACS and 0.52 (0.35–0.76) /0.62 (0.54–0.70) for CCS patients in model #1, 0.83 (0.80–0.87) /0.77 (0.74–0.81) in ACS and 0.76 (0.60–0.92) /0.67 (0.59–0.75) in CCS for model #2, and 0.83 (0.79–0.86) /0.78 (0.75–0.81) in ACS and 0.76 (0.61–0.92) /0.67 (0.58–0.74) in CCS for model #3. Combining clinical information from the academic registry with claims databases improved its performance in predicting adverse events. • The claims + registry-based risk models outperformed claims-based only risk models in PCI population. • Severity information such as cardiogenic shock only in the registry would be required for further risk stratification. • Combining claims and registries provide clinically relevant stratification schemes. [ABSTRACT FROM AUTHOR]

Recent trials on novel heart failure (HF) treatments (angiotensin receptor-neprilysin inhibitor, sodium-glucose cotransporter 2 inhibitor, and ivabradine) emphasize the use of conventional medical therapy (angiotensin-converting enzyme inhibitors, beta-blockers [BB], and mineral corticosteroid receptor antagonists). We aimed to evaluate the prescription rate of conventional medical therapy and its association with long-term outcomes in patients eligible for recent trials. We examined 1295 consecutive patients with HF with reduced ejection fraction (HFrEF) from a multicenter registry (WET-HF registry). We assessed conventional medical therapy implementation among patients meeting the PARADIGM-HF/DAPA-HF and SHIFT enrollment criteria. We also examined the association between conventional medical therapy use and long-term outcomes within each enrollment criterion. Overall, 62.2% and 35.3% of HFrEF patients met the enrollment criteria of the PARADIGM-HF/DAPA-HF and SHIFT trials. Only 33.9% and 31.9% received full conventional medical therapy within each patient subset. Notably, 84.2% of patients who met the SHIFT enrollment criteria were on BB, and only 23.0% and 4.4% were on ≥50% or the full recommended dose, respectively. Implementation of full conventional medical therapy use was associated with lower 2-year mortality and HF readmission rates in the PARADIGM-HF/ DAPA-HF eligible group (HR 0.68, 95% CI 0.50–0.92). The use of BB at ≥50% of the recommended dose was associated with lower 2-year mortality and HF readmission rates in the SHIFT-eligible group (HR 0.50, 95% CI 0.30–0.84). Conventional medical therapy was underutilized among patients eligible for novel trials within a Japanese HF registry. Further efforts to optimize conventional medical therapy are needed. • Recent novel heart failure (HF) trials recommended the use of conventional medical therapy in the enrollment criteria. • 62.2% and 35.3% of the patients met the enrollment criteria of the PARADIGM-HF/DAPA-HF and the SHIFT trials. • conventional medical therapy was underutilized (~30%) among patients eligible for novel HF trials. • Use of conventional medical therapy was associated with lower rates of 2-year mortality and HF readmission. • Optimizing conventional medical therapy remains a crucial step in improving the outcomes of HF patients. [ABSTRACT FROM AUTHOR]

Aims: Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. Methods: Data from 10 studies of IV or SC tanezumab (2.5–20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2‐compartment model with linear and nonlinear elimination (based on prior analysis of pre‐2015 IV osteoarthritis studies) was expanded to include other pre‐2015 studies. In Step 2, post‐2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment‐emergent anti‐drug antibodies (TE ADA). Results: SC bioavailability was estimated at 62–76%. The key disposition parameters CL, Vc, Vp and KM were estimated to be 0.133 L d−1, 2.6 L, 1.77 L and 31.2 μg L−1, respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9–11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5–10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4–8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6–7%). Conclusion: Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK. [ABSTRACT FROM AUTHOR]

Acute renal failure requiring dialysis after heart transplantation remains a significant clinical issue because of its increasing incidence. We aimed to investigate its time trends, clinical predictors, and long-term outcomes. Adult heart transplantation recipients registered in the United Network for Organ Sharing registry between 2009 and 2020 were identified. The patients were grouped according to the requirement for dialysis in the postoperative heart transplantation period. The independent risk predictors were identified, and the association between post-heart transplantation renal failure requiring dialysis and long-term mortality accounting for re-transplantation was investigated. A total of 28,170 patients were included in the study, of which 3,371 (12%) required dialysis immediately post-heart transplantation. The incidence increased from 7.9% to 13.9% during the study period. Longer ischemic time, serum creatinine at transplantation >1.2 mg/dL, prior cardiac surgery, higher recipient body mass index, support of mechanical ventilation or extracorporeal membrane oxygenation, and history of congenital heart disease or restrictive/hypertrophic cardiomyopathy were its predictors (all p < 0.05). Patients on posttransplant dialysis had a higher risk of all-cause mortality (adjusted hazard ratio [aHR]: 5.2, 95% CI: 4.7-5.7, p < 0.001), 30 day mortality (aHR: 7.7, 95% CI: 6.3-9.6, p < 0.001) and 1 year mortality (aHR: 7.5, 95% CI: 6.6-8.6, p < 0.001). Post-transplant dialysis was associated with a risk of treated rejection at 1 year. Acute renal failure requiring dialysis after heart transplantation is associated with significantly worse 30 day and long-term mortalities, and thus, early identification of high-risk patients is crucial to prevent severe renal complications. [ABSTRACT FROM AUTHOR]

Background: Balancing the effects of dual antiplatelet therapy (DAPT) in the era of potent P2Y12 inhibitors has become a cornerstone of acute coronary syndrome (ACS) management. Recent randomized controlled trials (RCTs) have investigated DAPT de-escalation to decrease the risk of bleeding outcomes.Objectives: The aim of this study was to compare the efficacy and safety outcomes of various DAPT strategies in patients with ACS, including de-escalation from a potent P2Y12 inhibitor to clopidogrel or low-dose prasugrel.Methods: MEDLINE and EMBASE were searched through January 2021 for RCTs investigating the efficacy and safety of DAPT in patients with ACS, and a network meta-analysis was conducted. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, and stroke. The primary bleeding outcome was trial-defined major or minor bleeding.Results: Our search identified 15 eligible RCTs, including 55,798 patients with ACS. De-escalation therapy was associated with reduced risk of primary bleeding outcomes (HR: 0.48 [95% CI: 0.30-0.77] vs clopidogrel; HR: 0.32 [95% CI: 0.20-0.52] vs ticagrelor; HR: 0.36 [95% CI: 0.24-0.55] vs standard-dose prasugrel; and HR: 0.40 [95% CI: 0.22-0.75] vs low-dose prasugrel) without negatively affecting primary efficacy outcomes. There were no significant differences in ischemic or bleeding outcomes between de-escalation to clopidogrel or low-dose prasugrel.Conclusions: Compared with other established uses of DAPT, de-escalation was the most effective strategy for ACS treatment, resulting in fewer bleeding events without increasing ischemic events. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this analysis was to characterize the relationship between tofacitinib dose and efficacy, as measured by American College of Rheumatology (ACR) response rates, and to compare this between Japanese and Western patients with RA. Efficacy data were pooled from 2 double‐blind, dose‐ranging phase 2 studies of tofacitinib monotherapy 1‐15 mg twice daily in patients with RA with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs). NCT00550446 was carried out in mostly Western patients and NCT00687193 in Japanese patients. ACR20, ACR50, and ACR70 response rates in week 12 were analyzed using maximum drug effect (Emax) models on the logit domain. Both studies showed a dose‐response for each end point, supporting the efficacy of tofacitinib in patients with inadequate response to DMARDs. Study‐specific differences in Emax were noted, whereas potency (dose providing half the maximum effect [ED50]) was similar across studies. After adjustment for study differences in Emax by calculating the fractions of the maximum placebo‐adjusted proportion of ACR responses, the estimated locations for the 5‐ and 10‐mg twice‐daily doses on the dose‐response curves were similar for the 2 patient populations: ACR20, ACR50, andACR70 mean fractional responses for 5 and 10 mg twice daily were 0.78, 0.43, 0.32 and 0.90, 0.69, and 0.56, respectively, for the Japanese study and 0.54, 0.41, and 0.22 and 0.73, 0.61, and 0.40, respectively, for the Western study. This analysis therefore supports the rationale for the same dosing regimen in Japanese patients as in Western patients from an efficacy perspective. [ABSTRACT FROM AUTHOR]

Patient-reported quality of life (PRQL) is a primary therapeutic target for patients with chronic heart failure (HF) and is associated with long-term prognosis. However, its utility in hospitalized HF (HHF) patients in the acute setting remains unclear. We aimed to assess the utility of PRQL (the Kansas City Cardiomyopathy Questionnaire [KCCQ]) in HHF patients and its association with long-term prognosis as well as with the clinical risk score (Get With The Guidelines-Heart Failure [GWTG-HF] risk score). PRQL was evaluated using the KCCQ in consecutive 114 HHF patients. Its association with the composite outcome of all-cause mortality or HF readmission within the first year after discharge was analyzed. Furthermore, its distribution by the clinical risk score (GWTG-HF) was evaluated using Pearson's correlation coefficient. The median KCCQ was 34.9, but was widely distributed (interquartile range 23.7–56.8). After adjustment for known prognostic indicators, the KCCQ was not an independent predictor of the composite outcome within the first year (group with high vs. low KCCQ scores: hazard ratio, 0.67; 95% confidence interval 0.26–1.71). There was no significant correlation between the KCCQ and the GWTG-HF risk score. In conclusion, PRQL during the acute phase of HF was significantly impaired and also varied widely, irrespective of patient characteristics or severity. PRQL assessment and risk prediction for HHF patients in the acute setting seemed to provide two distinct types of information for health care providers. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to characterize pharmacokinetics (PK) of PF‐04236921, a novel anti‐interleukin‐6 monoclonal antibody, and its pharmacokinetic/pharmacodynamic (PK/PD) relationship on serum C‐reactive protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn's disease (CD). Methods: Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from two phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study and a Phase 2 SLE study were included. Results: A two‐compartment model with first order absorption and linear elimination and a mechanism‐based indirect response model adequately described the PK and PK/PD relationships, respectively. Central compartment volume of distribution (Vc) positively correlated with body weight. Clearance (CL) negatively correlated with baseline albumin concentration and positively correlated with baseline CRP and creatinine clearance, and was slightly lower in females. After correcting for covariates, CL in CD subjects was approximately 60% higher than other populations. Maximum inhibition of PF‐04236921 on CRP production (Imax) negatively correlated with baseline albumin. Imax positively correlated with baseline CRP and the relationship was captured as a covariance structure in the PK/PD model. Conclusion: Integrated population PK and PK/PD models of PF‐04236921 have been developed using pooled data from healthy subjects and autoimmune patients. The current model enables simulation of PF‐04236921 PK and PD profiles under various dosing regimens and patient populations and should facilitate future clinical study of PF‐04236921 and other anti‐interleukin‐6 monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Aims The aims of this study were to develop a population pharmacokinetic ( PK) model of ampicillin and sulbactam, to identify patient characteristics influencing the PK, and to explore the relationship between dose regimen and degree of renal impairment with exposure and time above minimum inhibitory concentration ( MIC). Methods This analysis was performed on PK data for ampicillin and sulbactam and MIC data from a clinical trial in Japanese patients with community acquired pneumonia. Simulations were performed to investigate the effects of different dosing intervals on exposure and time above MIC in various degrees of renal impairment. Results The plasma concentrations from 47 patients were adequately described by a two compartment model with simultaneous fit of ampicillin and sulbactam PK data, where creatinine clearance on clearance and body weight on volume in the peripheral compartment were identified as covariates for both drugs. Creatinine clearance contributed to reducing inter-individual variability of clearance by 16%. Mean clearance (inter-individual variability) for ampicillin and sulbactam was estimated to be 10.7 l h−1 (14.8%) and 10.4 l h−1 (15.2%), respectively. The time above MIC for each pathogen was generally > 50% of the treatment period. Simulations for exposure and time above MIC supported currently recommended dose adjustments. Conclusions This study provided a PK model for ampicillin and sulbactam, the time above MICs for identified pathogens and associated simulation results. These findings provide useful information and augment evidence for the established dosage regimens in patients with various degrees of renal impairment. [ABSTRACT FROM AUTHOR]

• Pregabalin has been approved in many countries for partial-onset seizures, generalized anxiety disorder and a wide variety of pain disorders. • Although pharmacokinetic studies have demonstrated that pregabalin apparent clearance is correlated with estimated creatinine clearance, quantitatively accurate estimation of this relationship is warranted for establishing clinical usage of this drug. • A population pharmacokinetic model was developed from 14 pregabalin clinical trials using the first-order conditional estimation method, where a one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. • Based on the developed model, pregabalin systemic exposure in patients with lower renal function (30 ≤ estimated creatinine clearance [CL] <60 ml min) is expected to be similar to exposure in patients with normal renal function (CL≥60) administered twice the dose. • This study indicated that the systemic exposure of pregabalin could be adjusted with reference to the estimated proportional relationship between pregabalin apparent clearance and CL regardless of the disease. Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters. This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy ( n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM. A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/ F) was proportional to estimated creatinine clearance (CL). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy. The developed model identified CL and ideal body weight as clinically influential covariates on CL/ F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug. [ABSTRACT FROM AUTHOR]

A method for decomposing dye by spraying water solution of dye into nonequilibrium plasma in gas phase was investigated using a pulsed-corona discharge reactor. The corona reactor consists of a discharge wire and a cylindrical electrode. The water solution of indigo carmine with a concentration of 20 mg/L was sprayed into the reactor from a showerhead. The sprayed water solution was circulated into the reactor. The dependence of the discharging power injected into the reactor on the decomposition rates of chromogenic and unsaturated bonds in indigo carmine was investigated. Indigo blue was decolored by 1-mm circulation with the discharging power of 8.6 W. The nuclear magnetic resonance spectrometry showed that indigo carmine was decomposed completely by, 60-mm treatment. The chromogenic and unsaturated bonds were almost decomposed at 9 and 360 J/mg, respectively. As the discharging power increased, the decomposition rates of both bonds in indigo carmine increased. The decomposition rates of the chromogenic bond showed equal values in equal discharging power regardless of the difference of discharge repetition rate and charging voltage of the capacitor. In contrast, the higher repetitive pulses were more effective for the decomposition of the unsaturated bond rather than the magnitude of charging voltage in equal discharging power. [ABSTRACT FROM AUTHOR]

Toxicity resulting from retained contrast media may cause adverse cardiovascular outcomes (e.g., heart failure and cardiogenic shock) for dialysis patients. However, the association between the administered contrast volume and outcomes of dialysis patients after percutaneous coronary intervention (PCI) has not been sufficiently investigated. We evaluated 953 consecutive dialysis patients (age, 67.9 ± 9.9 years; 30.1% with acute coronary syndrome) who underwent PCI between September 2008 and March 2019. Patients were divided into two groups: those with a contrast volume ≥ 200 ml and those with a contrast volume < 200 ml. The cutoff was 200 ml because 100 ml increment of contrast volume is known to raise the risk of acute kidney injury, and 200 ml is more than the average volume used at most PCI centers. The primary endpoint was a composite of in-hospital death, post-PCI cardiogenic shock and post-PCI heart failure. A multivariable logistic regression model and smooth spline curve were constructed to assess the association between contrast volume and the primary endpoint. The median contrast volume was 157 ml (interquartile range, 115–210 ml). The overall primary endpoint incidence was 6.8% (N = 65). A contrast volume ≥ 200 ml was associated with a higher risk of the primary endpoint (odds ratio 2.91; 95% confidence interval 1.42–6.05; P = 0.004). The smooth spline curve demonstrated a linear relationship between the contrast volume and primary endpoint. In conclusions, the contrast volume was associated with adverse in-hospital outcomes of dialysis patients undergoing PCI. Attention should be focused on the contrast volume used for dialysis patients undergoing PCI. [ABSTRACT FROM AUTHOR]

Objectives To assess the applicability of Electronic Frailty Index (eFI) and Hospital Frailty Risk Score (HFRS) algorithms to Japanese administrative claims data and to evaluate their association with long-term outcomes. Study Design and Setting A cohort study using a regional government administrative healthcare and long-term care (LTC) claims database in Japan 2014–18. Participants Plan enrollees aged ≥50 years. Methods We applied the two algorithms to the cohort and assessed the scores' distributions alongside enrollees' 4-year mortality and initiation of government-supported LTC. Using Cox regression and Fine–Gray models, we evaluated the association between frailty scores and outcomes as well as the models' discriminatory ability. Results Among 827,744 enrollees, 42.8% were categorised by eFI as fit, 31.2% mild, 17.5% moderate and 8.5% severe. For HFRS, 73.0% were low, 24.3% intermediate and 2.7% high risk; 35 of 36 predictors for eFI, and 92 of 109 codes originally used for HFRS were available in the Japanese system. Relative to the lowest frailty group, the highest frailty group had hazard ratios [95% confidence interval (CI)] of 2.09 (1.98–2.21) for mortality and 2.45 (2.28–2.63) for LTC for eFI; those for HFRS were 3.79 (3.56–4.03) and 3.31 (2.87–3.82), respectively. The area under the receiver operating characteristics curves for the unadjusted model at 48 months was 0.68 for death and 0.68 for LTC for eFI, and 0.73 and 0.70, respectively, for HFRS. Conclusions The frailty algorithms were applicable to the Japanese system and could contribute to the identifications of enrollees at risk of long-term mortality or LTC use. [ABSTRACT FROM AUTHOR]

Background: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer.Methods: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α1-microglobulin, β2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment.Results: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline.Conclusions: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies. [ABSTRACT FROM AUTHOR]

Objective: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. Methods: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. Results: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5–59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2–5.4) and 10.4 months (95% CI, 8.1–14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%).Conclusions: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with Anaplastic lymphoma kinase (ALK)-positive lung cancer after progression of ALK-tyrosine kinase inhibitor have limited treatment options. This study shows clinical efficacy of the combination of alectinib and bevacizumab with acceptable toxicity in patients with ALK-positive lung cancer after ALK-TKI failure. Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients. [ABSTRACT FROM AUTHOR]

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer. [ABSTRACT FROM AUTHOR]

The specific mechanisms how lung cancer cells harboring epidermal growth factor receptor (EGFR) activating mutations can survive treatment with EGFR-tyrosine kinase inhibitors (TKIs) until they eventually acquire treatment-resistance genetic mutations are unclear. The phenotypic diversity of cancer cells caused by genetic or epigenetic alterations (intratumor heterogeneity) confers treatment failure and may foster tumor evolution through Darwinian selection. Recently, we found DDX3X as the protein that was preferentially expressed in murine melanoma with cancer stem cell (CSC)-like phenotypes by proteome analysis. In this study, we transfected PC9, human lung cancer cells harboring EGFR exon19 deletion, with cDNA encoding DDX3X and found that DDX3X, an ATP-dependent RNA helicase, induced CSC-like phenotypes and the epithelial-mesenchymal transition (EMT) accompanied with loss of sensitivity to EGFR-TKI. DDX3X expression was associated with upregulation of Sox2 and increase of cancer cells exhibiting CSC-like phenotypes, such as anchorage-independent proliferation, strong expression of CD44, and aldehyde dehydrogenase (ALDH). The EMT with switching from E-cadherin to N-cadherin was also facilitated by DDX3X. Either ligand-independent or ligand-induced EGFR phosphorylation was inhibited in lung cancer cells that strongly expressed DDX3X. Lack of EGFR signal addiction resulted in resistance to EGFR-TKI. Moreover, we found a small nonadherent subpopulation that strongly expressed DDX3X accompanied by the same stem cell-like properties and the EMT in parental PC9 cells. The unique subpopulation lacked EGFR signaling and was highly resistant to EGFR-TKI. In conclusion, our data indicate that DDX3X may play a critical role for inducing phenotypic diversity, and that treatment targeting DDX3X may overcome primary resistance to EGFR-TKI resulting from intratumor heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Variety of information relating between genome and the pathological findings in disease will yield a wealth of clues to discover new function, the role of genes and pathways, and future medicine. In addition to molecular information such as gene expression and genome copy number, detailed clinical information is essential for such systematic omics analysis. Results: In order to provide a basic platform to realize a future medicine based on the integration of molecular and clinico-pathological information of disease, we have developed an integrated clinical omics database (iCOD) in which comprehensive disease information of the patients is collected, including not only molecular omics data such as CGH (Comparative Genomic Hybridization) and gene expression profiles but also comprehensive clinical information such as clinical manifestations, medical images (CT, X-ray, ultrasounds, etc), laboratory tests, drug histories, pathological findings and even life-style/environmental information. The iCOD is developed to combine the molecular and clinico-pathological information of the patients to provide the holistic understanding of the disease. Furthermore, we developed several kinds of integrated view maps of disease in the iCOD, which summarize the comprehensive patient data to provide the information for the interrelation between the molecular omics data and clinico-pathological findings as well as estimation for the disease pathways, such as three layerlinked disease map, disease pathway map, and pathome-genome map. Conclusions: With these utilities, our iCOD aims to contribute to provide the omics basis of the disease as well as to promote the pathway-directed disease view. The iCOD database is available online, containing 140 patient cases of hepatocellular carcinoma, with raw data of each case as supplemental data set to download. The iCOD and supplemental data can be accessed at http://omics.tmd.ac.jp/icod_pub_eng [ABSTRACT FROM AUTHOR]

Aims/Introduction: Increased incidence of hospitalization for heart failure (HHF) among patients with diabetes is increasingly being reported. We investigated the incidence of adverse cardiovascular events including HHF among patients with type 2 diabetes mellitus, and the potential clinical improvement with sodium–glucose cotransporter 2 inhibitors (SGLT2i) using a contemporary administrative claims database from a large governmental district of Japan. Materials and Methods: We included initiators of any oral glucose‐lowering drugs between 2013 and 2018. We estimated the 5‐year cumulative incidence of hospitalization for HF, myocardial infarction and stroke, treating death as a competing risk. We evaluated the possible impact of introducing SGLT2i to the potential recipients of the drug, using the inclusion criteria from Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA‐REG OUTCOME) and Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE‐TIMI 58) trials, assuming the same risk reduction as theirs. Results: Among 23,340 drug initiators (54.0% men, and 6.4% aged >85 years), the 5‐year cumulative incidence was 5.4% (95% confidence interval 4.9–5.9%) for HHF, 1.9% (95% confidence interval 1.7–2.2%) for myocardial infarction admission and 6.1% (95% confidence interval 5.7–6.6%) for stroke admission. Among 6,192 patients with laboratory test data, 651 (10.5%) and 2,680 (43.3%) patients met the EMPA‐REG‐like and DECLARE‐like criteria, respectively. The 5‐year cumulative incidence among the 2,849 patients meeting either of the criteria was estimated to decrease from 97.1 to 75.6 events through 75% adoption of SGLT2i. Conclusions: The incidence of HHF was similar to that of stroke. A significant portion of our cohort met the inclusion criteria for major randomized clinical trials for SGLT2i, and estimated reduction in the HHF events was substantial. [ABSTRACT FROM AUTHOR]

Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) induced by anti‐programmed‐cell death‐1 (PD‐1) and anti‐PD‐ligand 1 (PD‐L1) is potentially life‐threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune‐related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti‐PD‐1/PD‐L1 therapies, the association between radiologic features and clinical outcomes remains unclear. Methods: Patients with advanced non‐small‐cell lung cancer who were treated with 1st to 3rd line anti‐PD‐1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. Results: A total of 231 patients who received anti‐PD‐1 therapy were enrolled. Thirty‐one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2‐NE) versus not reached (95% CI: 13.2‐NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. Conclusions: This study demonstrated that patients who developed GGO exhibited worse outcomes among non‐small‐cell lung cancer patients receiving anti‐PD‐1 therapies. [ABSTRACT FROM AUTHOR]

Background: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) in EGFR‐mutant non‐small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR‐mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR‐TKIs in patients with EGFR‐mutant NSCLC with newly diagnosed brain metastases. Methods: We retrospectively analyzed the data of EGFR‐mutant NSCLC patients with CNS metastases who received EGFR‐TKIs as a first‐line therapy. Results: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR‐TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3–9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1–30.1). The overall response rate of the CNS was 37%. The median CNS progression‐free survival (PFS) was 13.2 months (95% CI: 10.0–16.2). Brain radiotherapy prior to EGFR‐TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS‐PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. Conclusion: EGFR‐TKI showed a favorable effect for EGFR‐mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS‐PFS were observed with upfront brain radiotherapy. [ABSTRACT FROM AUTHOR]

The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo—expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo—expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo—expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects. [ABSTRACT FROM AUTHOR]

Background: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI.Methods: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level.Results: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI.Conclusions: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that most solid malignancies consist of heterogeneous tumor cells and that a relatively small subpopulation, which shares biological features with stem cells, survives through potentially lethal stresses such as chemotherapy and radiation treatment. Since the survival of this subpopulation of cancer stem cells (CSC) plays a critical role in recurrence, it must be eradicated in order to cure cancer. We previously reported that vaccination with CD133 murine melanoma cells exhibiting biological CSC features induced CSC-specific effector T cells. These were capable of eradicating CD133 tumor cells in vivo, thereby curing the parental tumor. In the current study, we indicated that DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) is an immunogenic protein preferentially expressed in CD133 tumor cells. Vaccination with DDX3X primed specific T cells, resulting in protective and therapeutic antitumor immunity. The DDX3X-primed CD4 T cells produced CD133 tumor-specific IFNγ and IL-17 and mediated potent antitumor therapeutic efficacy. DDX3X is expressed in various human cancer cells, including lung, colon, and breast cancer cells. These results suggest that anti-DDX3X immunotherapy is a promising treatment option in efforts to eradicate CSC in the clinical setting. [ABSTRACT FROM AUTHOR]

Voriconazole (VFEND) is a triazole antifungal agent which inhibits the biosynthesis of ergosterol, a fungal cell membrane component. In Japan, voriconazole has become a commonly used antimicrobial in off-label use for pediatric patients. The aims of this report were to provide information about voriconazole pharmacokinetics (PK) in Japanese pediatric and adolescent patients, and to explore relationships between the PK, administered dose, and laboratory test results. In total, data from 24 pediatric or adolescent patients (18 males and 6 females) were used for the analysis. For the measurement of plasma voriconazole concentrations, 103 blood samples were collected from the 24 patients. As a whole, median plasma voriconazole concentrations following intravenous and oral administrations were comparable, and the trough plasma concentrations at steady state ( C) increased with increasing voriconazole doses (mg/kg). However, no systematic trend was observed between C and laboratory test results. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC) and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an "omics" study by integrating many kinds of analysis into a single comprehensive investigation. In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers. Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC. This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC. Materials and methods: Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro-dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language. Result: We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene expression analysis, together with the clinical information, suggested UGT2B28, LOC440995, CXCL6, SULT1B1, RALBP1, TYMS, RAB12, RNMT, ARHGDIB, S1000A2, ABHD2, OIT3 and ABHD12 as genes that are possibly associated with CRC. Some of these genes have already been reported as being related to CRC. TYMS has been reported as being associated with resistance to the anti-cancer drug 5-fluorouracil, and we observed a copy number increase for this gene. RALBP1, ARHGDIB and S100A2 have been reported as oncogenes, and we observed copy number increases in each. ARHGDIB has been reported as a metastasis-related gene, and our data also showed copy number increases of this gene in cases with metastasis. Conclusion: The combination of CNA analysis and gene expression analysis was a more effective method for finding genes associated with the clinicopathological classification of CRC than either analysis alone. Using this combination of methods, we were able to detect genes that have already been associated with CRC. We also identified additional candidate genes that may be new markers or targets for this form of cancer. [ABSTRACT FROM AUTHOR]

The administration of beta-blockers is challenging and their efficacy is unclear in heart failure (HF) patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the association of beta-blockers with mortality in such patients. This multicenter observational cohort study included hospitalized HF patients with a left ventricular ejection fraction <50% and evaluated them retrospectively. COPD was diagnosed based on medical records and/or the clinical judgment of each investigator. The study endpoints were two-year all-cause, cardiac, and non-cardiac mortality. This study included 83 patients with COPD and 1760 patients without. Two-year all-cause, cardiac, and non-cardiac mortality were observed in 315 (17%), 149 (8%), and 166 (9%) patients, respectively. Beta-blockers were associated with lower all-cause mortality regardless of COPD (COPD: hazard ratio [HR] 0.39, 95% CI 0.16–0.98, p = 0.044; non-COPD: HR 0.62, 95% CI 0.46–0.83, p = 0.001). This association in HF patients with COPD persisted after multivariate analysis and inverse probability weighting and was due to lower non-cardiac mortality (HR 0.40, 95% CI 0.14–1.18. p = 0.098), not cardiac mortality (HR 0.37, 95% CI 0.07–2.01, p = 0.248). Beta-blockers were associated with lower all-cause mortality in HF patients with COPD due to lower non-cardiac mortality. This may reflect selection biases in beta-blocker prescription. [ABSTRACT FROM AUTHOR]

Autism, characterized by profound impairment in social interactions and communicative skills, is the most common neurodevelopmental disorder, and its underlying molecular mechanisms remain unknown. Ca2+-dependent activator protein for secretion 2 (CADPS2; also known as CAPS2) mediates the exocytosis of dense-core vesicles, and the human CADPS2 is located within the autism susceptibility locus 1 on chromosome 7q. Here we show that Cadps2-knockout mice not only have impaired brain-derived neurotrophic factor release but also show autistic-like cellular and behavioral phenotypes. Moreover, we found an aberrant alternatively spliced CADPS2 mRNA that lacks exon 3 in some autistic patients. Exon 3 was shown to encode the dynactin 1–binding domain and affect axonal CADPS2 protein distribution. Our results suggest that a disturbance in CADPS2-mediated neurotrophin release contributes to autism susceptibility. [ABSTRACT FROM AUTHOR]

We examined human bone marrow mesenchymal stem cells by applying real-time quantitative polymerase chain reaction (PCR) (RT-PCR) technology and electron-microscopic techniques. Our RT-PCR demonstrated that the values of peroxisome proliferation-activated receptor γ2 (PPARγ2) and lipoprotein lipase (LPL) mRNA dramatically increased according to adipogenic stimulation. The expressions of both PPARγ2 and LPL mRNA were significantly reduced (P<0.01) and almost disappeared after stimulation had ceased. The expressions of both genes, however, increased again by stimulation even though the cells were in a dedifferentiated state for a month. In the ultrastructural study, over 80% of the cells proceeded into morphologically well-developed adipocytes at the 12th day of induction/maintenance which were packed with lipid droplets and clusters. In the next process these lipid products were excreted from the cell bodies and the peripheral small parts containing numerous droplets were torn from the greater parts, which stuck tightly to each other and adhered to culture dishes. Adipocytes were not detected in the culture media during the final stage. The total cell number was equal to and over 90% of the cells dedifferentiated into fibroblast-like stem cells during the final maintenance period of 1 month. Furthermore the dedifferentiated cells quickly differentiated again into adipocytes by stimulation even if they were quiescent for 1 month. Thus we conclude that mesenchymal stem cells have strong reversibility from both the genetic and morphological points of view. [ABSTRACT FROM AUTHOR]

In the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, an early invasive strategy did not decrease mortality compared to a conservative strategy for stable ischemic heart disease (SIHD) patients with moderate-to-severe ischemia, and the role of revascularization would be revised. However, the applicability and potential influence of this trial in daily practice remains unclear. Our objective was to assess the eligibility and representativeness of the ISCHEMIA trial on the patients with percutaneous coronary intervention (PCI). From a multicenter registry, we extracted a consecutive 13,223 SIHD patients with PCI (baseline cohort). We applied ISCHEMIA eligibility criteria and compared the baseline characteristics between the eligible patients and the actual study participants (randomized controlled trial (RCT) patients). In 3463 patients with follow-up information (follow-up cohort), the 2 year composite of major adverse cardiac events was evaluated between the eligible patients and RCT patients, as well as eligible and non-eligible patients in the registry. In the baseline cohort, 77.3% of SIHD patients with moderate-to-severe ischemia were eligible for the ISCHEMIA. They were comparable with RCT patients for baseline characteristics and outcomes unlike the non-eligible patients. In conclusion, the trial results seem applicable for the majority of PCI patients with moderate-to-severe ischemia except for the non-eligible patients. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention has become the standard of care, particularly in patients with acute coronary syndrome (ACS). Current clinical guidelines recommend novel P2Y12 inhibitors (e.g., prasugrel or ticagrelor) in addition to aspirin based on the results of representative randomized controlled trials conducted predominantly in Western countries. These agents were superior to clopidogrel in reducing the composite ischemic events, with a trade-off of the increased bleeding events. However, multiple differences exist between East Asian and Western patients, especially with respect to their physique, thrombogenicity, hemorrhagic diathesis, and on-treatment platelet reactivity. Recent studies from East Asian countries (e.g., Japan or South Korea) have consistently demonstrated that use of novel P2Y12 inhibitors is associated with a higher risk of bleeding events than use of clopidogrel, despite borderline statistical difference in the incidence of composite ischemic events. Additionally, multiple studies have shown that the optimal duration of DAPT may be shorter in East Asian than Western patients. This review summarizes clinical studies of antithrombotic strategies in East Asian patients with ACS. Understanding these differences in antithrombotic strategies including DAPT and their impacts on clinical outcomes will aid in selection of the optimal tailored antithrombotic therapy for patients with ACS. [ABSTRACT FROM AUTHOR]