The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy ...of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer.
We did a randomised, multicentre, double-blind, placebo-controlled, phase 2–3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 SOX or oral capecitabine 1000 mg/m2 CAPOX, twice daily on days 1–14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing.
Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7–14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44–14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97–9·40) in the placebo plus chemotherapy group (hazard ratio HR 0·68; 98·51% CI 0·51–0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1–29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67–20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18–19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75–1·08; p=0·26). The most common treatment-related grade 3–4 adverse events were neutrophil count decreased (71 20% of 359 patients in the nivolumab plus chemotherapy group vs 57 16% of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 9% vs 33 9%). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 5% vs ten 3%). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease).
Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients.
Ono Pharmaceutical and Bristol-Myers Squibb.
To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of zolpidem (10 mg) was ...administered to 15 male and 15 female healthy subjects. Blood samples were collected up to 12 h post-dose to determine plasma zolpidem concentrations. Pharmacokinetic parameters were obtained using non-compartmental analysis. Digit symbol substitution test, choice reaction time, and visual analog scale of sleepiness were used to evaluate pharmacodynamics. We measured CYP3A4 activity using 4β-hydroxycholesterol, an endogenous metabolite. Mean maximum plasma concentration and area under the plasma concentration-time curve were higher for females than for males (9.9% and 32.5%, respectively); other pharmacokinetic parameters showed no significant differences. Pharmacodynamic scores for females showed delayed recovery compared with that for males. CYP3A4 activity was higher in females than in males (p = 0.030). There was no serious adverse event, and adverse event incidence was not different between the sexes. Zolpidem exposure was about 30% higher in females than in males. Delayed pharmacodynamic score recovery in females could be related to higher zolpidem concentrations. Although apparent clearance was lower in females, systemic clearance might not be the cause of the different exposures to zolpidem.
Precise monitoring of neurotransmitters, such as dopamine (DA), is critical for understanding brain function and treating neurological disorders since dysregulation of DA implicates in a range of ...disorders, including Parkinson's disease (PD), schizophrenia, and addiction. This study proposes a multi‐deformable double‐sided (MDD) DA‐sensing probe with the three‐electrode system in all‐in‐one form for reliable real‐time monitoring of DA dynamics by integrating working, reference, and counter electrodes on a single probe. The proposed probe achieves high DA sensitivity and selectivity in virtue of enzyme immobilization on the 3D nanostructures grown on working electrode. Also, the serpentine design is employed for the electrodes to withstand in various deformations by achieving high stretchability and manage the stress induced on the probe. Experimental and computational analysis demonstrates an effective reduction in induced‐stress on the electrodes. The MDD DA‐sensing probe is implanted into the brain with success to enable real‐time, in vivo monitoring of DA levels in rodents. Furthermore, DA dynamic changes are monitored before and after treatment with L‐DOPA in hemi‐PD mice. This extremely deformable implantable probe has the potential for use in the study and treatment of neurodegenerative diseases, providing reliable monitoring of DA dynamics with minimal damage to brain tissue.
A multi‐deformable double‐sided (MDD) probe facilitates real‐time dopamine monitoring in the brain. The all‐in‐one probe integrates working, reference, and counter electrodes, achieving high sensitivity and selectivity through enzyme immobilization on ZnO Nanorods. Its serpentine design ensures stretchability and stress management. Successful rodent implantation enables reliable in‐vivo monitoring of dopamine dynamics, including assessing L‐DOPA treatment effects in hemi‐PD mice.
This study examines how the corporate philanthropy decisions of group-affiliated firms in Korea (Chaebol firms) are made. Based on the attention-based view, we argue that when corporate decision ...makers at group-affiliated firms focus their attention more (less) on internal markets than external stakeholders because of the firm’s high (low) reliance on intragroup transactions, the firm will decrease (increase) its level of corporate philanthropy. We further argue that the relationship will be stronger when governance mechanisms focus on the instrumental value of corporate philanthropy. Using a panel sample of group-affiliated firms in Korea from 2011 to 2015, we find that as intragroup sales increase, the level of corporate philanthropy decreases, and such a negative relationship is stronger when outside director representation and foreign investor ownership are high. Our study suggests that internal dependence and corporate governance mechanisms jointly affect the level of corporate philanthropy at firms in a business group. Thus, this study contributes to the literature on corporate philanthropy, business group, and corporate governance.
Early detection of faults in rotating machinery systems is crucial in preventing system failure, increasing safety, and reducing maintenance costs. Current methods of fault detection suffer from the ...lack of efficient feature extraction method, the need for designating a threshold producing minimal false alarm rates, and the need for expert domain knowledge, which is costly. In this paper, we propose a novel data-driven health division method based on convolutional neural networks using a graphical representation of time series data, called a nested scatter plot. The proposed method trains the model with a small amount of labeled data and does not require a threshold value to predict the health state of rotary machines. Notwithstanding the lack of datasets that show the ground truth of health stages, our experiments with two open datasets of run-to-failure bearing demonstrated that our method is able to detect the early symptoms of bearing wear earlier and more efficiently than other threshold-based health indicator methods.
This study developed a Deep Neural Network (DNN) based distributed hydrologic model for an urban watershed in Republic of Korea. The developed model is composed of multiple Long Short-Term Memory ...(LSTM) hidden units connected by a fully connected layer. To examine the study area using the developed model, time series of 10-minute radar-gauge composite precipitation data and 10-minute temperature data at 239 model grid cells with 1km resolution were used as inputs to simulate 10-minute watershed flow discharge as an output. The model performed well for the calibration period (2013-2016) and validation period (2017-2019), with Nash-Sutcliffe Efficiency coefficient values being 0.99 and 0.67, respectively. Further in-depth analyses were performed to derive the following conclusions: (1) the map of runoff-precipitation ratios produced using the developed DNN model resembled imperviousness ratio map of the study area from the land cover data, revealing that the DNN successfully deep-learned the precipitation partitioning processes only with the input and output data without depending on any priori information about hydrology; (2) the model successfully reproduced the soil moisture dependent runoff process, an essential prerequisite of continuous hydrologic models; (3) each LSTM unit has different temporal sensitivity to the precipitation stimulus, with fast-response LSTM units having greater output weight factors near the watershed outlet, which implies that the developed model has a mechanism to separately consider the hydrological components with distinct response time such as direct runoff and the groundwater-driven baseflow.
Patients with mitral stenosis and atrial fibrillation (AF) require anticoagulation for stroke prevention. Thus far, all studies on direct oral anticoagulants (DOACs) have excluded patients with ...moderate to severe mitral stenosis.
The aim of this study was to validate the efficacy of DOACs in patients with mitral stenosis.
The study population was enrolled from the Health Insurance Review and Assessment Service (HIRA) database in the Republic of Korea, and it included patients who were diagnosed with mitral stenosis and AF and either were prescribed DOACs for off-label use or received conventional treatment with warfarin. The primary efficacy endpoint was ischemic strokes or systemic embolisms, and the safety outcome was intracranial hemorrhage.
A total of 2,230 patients (mean age 69.7 ± 10.5 years; 682 30.6% males) were included in the present study. Thromboembolic events occurred at a rate of 2.22%/year in the DOAC group, and 4.19%/year in the warfarin group (adjusted hazard ratio for DOAC: 0.28; 95% confidence interval: 0.18 to 0.45). Intracranial hemorrhage occurred in 0.49% of the DOAC group and 0.93% of the warfarin group (adjusted hazard ratio for DOAC: 0.53; 95% confidence interval: 0.22 to 1.26).
In patients with AF accompanied with mitral stenosis, DOAC use is promising and hypothesis generating in preventing thromboembolism. Our results need to be replicated in a randomized trial.
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Since the increment of the threat to public health caused by foodborne pathogens, researches have been widely studied on developing the miniaturized detection system for the on-site pathogen ...detection. In the study, we focused on the development of portable, robust, and disposable film-based polymerase chain reaction (PCR) chip containing a multiplex chamber for simultaneous gene amplification. In order to simply fabricate and operate a film-based PCR chip, different kinds of PCR chambers were designed and fabricated using polyethylene terephthalate (PET) and polyvinyl chloride (PVC) adhesive film, in comparison with commercial PCR, which employs a stereotyped system at a bench-top scale. No reagent leakage was confirmed during the PCR thermal cycling using the film PCR chip, which indicates that the film PCR chip is structurally stable for rapid heat cycling for DNA amplification. Owing to use of the thin film to fabricate the PCR chip, we are able to realize fast thermal transfer from the heat block that leads to short PCR amplification time. Moreover, using the film PCR chip, we could even amplify the target pathogen with 10 CFU mL
. The artificially infected milk with various concentration of
was successfully amplified on a single film PCR chip. On the basis of the reliable results, the developed film PCR chip could be a useful tool as a POCT device to detect foodborne pathogens via genetic analysis.
The drone‐based inspection process on power transmission lines needs to be automated due to the large scale of power facilities and the limited line of sight available to drone pilots. Through the ...task environment analysis, however, it was found that the steel tower structure and energized AC power conductors may cause GPS signal distortion and magnetic interference with a drone's geomagnetic sensor, respectively. These factors could seriously affect the drone's autopilot flight, at worst leading to a crash. To enable drone inspections to be performed in a safe and efficient manner, this paper presents the entire process of operating an autopilot inspection drone on the basis of GPS and GIS information in a hazardous ultrahigh voltage environment, and its application results in the field. This process includes how to measure GPS co‐ordinates of steel towers and how to generate an autopilot flight path. More specifically, the paper examines the potential problems that may occur when drones are applied to areas located in mountains and rivers where humans cannot inspect power lines due to a lack of accessibility, and proposes effective solutions to these practical issues.
Background and Purpose
We recently reported that AAV1‐Rheb(S16H) transduction could protect hippocampal neurons through the induction of brain‐derived neurotrophic factor (BDNF) in the rat ...hippocampus in vivo. It is still unclear how neuronal BDNF produced by AAV1‐Rheb(S16H) transduction induces neuroprotective effects in the hippocampus and whether its up‐regulation contributes to the enhance of a neuroprotective system in the adult brain.
Experimental Approach
To determine the presence of a neuroprotective system in the hippocampus of patients with Alzheimer's disease (AD), we examined the levels of glial fibrillary acidic protein, BDNF and ciliary neurotrophic factor (CNTF) and their receptors, tropomyocin receptor kinase B (TrkB) and CNTF receptor α(CNTFRα), in the hippocampus of AD patients. We also determined whether AAV1‐Rheb(S16H) transduction stimulates astroglial activation and whether reactive astrocytes contribute to neuroprotection in models of hippocampal neurotoxicity in vivo and in vitro.
Key Results
AD patients may have a potential neuroprotective system, demonstrated by increased levels of full‐length TrkB and CNTFRα in the hippocampus. Further AAV1‐Rheb(S16H) transduction induced sustained increases in the levels of full‐length TrkB and CNTFRα in reactive astrocytes and hippocampal neurons. Moreover, neuronal BDNF produced by Rheb(S16H) transduction of hippocampal neurons induced reactive astrocytes, resulting in CNTF production through the activation of astrocytic TrkB and the up‐regulation of neuronal BDNF and astrocytic CNTF which had synergistic effects on the survival of hippocampal neurons in vivo.
Conclusions and Implications
The results demonstrated that Rheb(S16H) transduction of hippocampal neurons could strengthen the neuroprotective system and this intensified system may have a therapeutic value against neurodegeneration in the adult brain.
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