In general, in thermoelectric materials the electrical conductivity σ and thermal conductivity κ are related and thus cannot be controlled independently. Previously, to maximize the thermoelectric ...figure of merit in state-of-the-art materials, differences in relative scaling between σ and κ as dimensions are reduced to approach the nanoscale were utilized. Here we present an approach to thermoelectric materials using tin disulfide, SnS2, nanosheets that demonstrated a negative correlation between σ and κ. In other words, as the thickness of SnS2 decreased, σ increased whereas κ decreased. This approach leads to a thermoelectric figure of merit increase to 0.13 at 300 K, a factor ∼1,000 times greater than previously reported bulk single-crystal SnS2. The Seebeck coefficient obtained for our two-dimensional SnS2 nanosheets was 34.7 mV K(-1) for 16-nm-thick samples at 300 K.
: To quantify the effects of midline-related landmark identification on midline deviation measurements in posteroanterior (PA) cephalograms using a cascaded convolutional neural network (CNN).
: A ...total of 2,903 PA cephalogram images obtained from 9 university hospitals were divided into training, internal validation, and test sets (n = 2,150, 376, and 377). As the gold standard, 2 orthodontic professors marked the bilateral landmarks, including the frontozygomatic suture point and latero-orbitale (LO), and the midline landmarks, including the crista galli, anterior nasal spine (ANS), upper dental midpoint (UDM), lower dental midpoint (LDM), and menton (Me). For the test, Examiner-1 and Examiner-2 (3-year and 1-year orthodontic residents) and the Cascaded-CNN models marked the landmarks. After point-to-point errors of landmark identification, the successful detection rate (SDR) and distance and direction of the midline landmark deviation from the midsagittal line (ANS-mid, UDM-mid, LDM-mid, and Me-mid) were measured, and statistical analysis was performed.
: The cascaded-CNN algorithm showed a clinically acceptable level of point-to-point error (1.26 mm vs. 1.57 mm in Examiner-1 and 1.75 mm in Examiner-2). The average SDR within the 2 mm range was 83.2%, with high accuracy at the LO (right, 96.9%; left, 97.1%), and UDM (96.9%). The absolute measurement errors were less than 1 mm for ANS-mid, UDM-mid, and LDM-mid compared with the gold standard.
: The cascaded-CNN model may be considered an effective tool for the auto-identification of midline landmarks and quantification of midline deviation in PA cephalograms of adult patients, regardless of variations in the image acquisition method.
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found ...that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
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•Aβ induces metabolic reprogramming of microglia from OXPHOS to glycolysis•Metabolic reprogramming of microglia is dependent on the mTOR-HIF-1α pathway•Chronic exposure to Aβ induces metabolic defects of microglia•Metabolic boosting with IFN-γ restores immunological function of microglia
Baik et al. report that amyloid-β acutely triggers microglial activation and metabolic reprogramming from OXPHOS to glycolysis. However, chronic exposure to amyloid-β induces overall metabolic defects in microglia in a model of Alzheimer's disease. Treatment with IFN-γ restores glycolytic metabolism and immunological function of microglia, suggesting that modulation of microglial metabolism may be a potential therapeutic strategy.
Mesenchymal stem cell (MSC) is a promising tool for the therapy of immune disorders. However, their efficacy and mechanisms in treating allergic skin disorders are less verified. We sought to ...investigate the therapeutic efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) against murine atopic dermatitis (AD) and to explore distinct mechanisms that regulate their efficacy. AD was induced in mice by the topical application of Dermatophagoides farinae. Naïve or activated-hUCB-MSCs were administered to mice, and clinical severity was determined. The subcutaneous administration of nucleotide-binding oligomerization domain 2 (NOD2)-activated hUCB-MSCs exhibited prominent protective effects against AD, and suppressed the infiltration and degranulation of mast cells (MCs). A β-hexosaminidase assay was performed to evaluate the effect of hUCB-MSCs on MC degranulation. NOD2-activated MSCs reduced the MC degranulation via NOD2-cyclooxygenase-2 signaling. In contrast to bone marrow-derived MSCs, hUCB-MSCs exerted a cell-to-cell contact-independent suppressive effect on MC degranulation through the higher production of prostaglandin E2 (PGE2 ). Additionally, transforming growth factor (TGF)-β1 production from hUCB-MSCs in response to interleukin-4 contributed to the attenuation of MC degranulation by downregulating FcεRI expression in MCs. In conclusion, the subcutaneous application of NOD2-activated hUCB-MSCs can efficiently ameliorate AD, and MSC-derived PGE2 and TGF-β1 are required for the inhibition of MC degranulation.
Coronavirus disease 2019 (COVID-19) has strained healthcare systems worldwide. Predicting COVID-19 severity could optimize resource allocation, like oxygen devices and intensive care. If machine ...learning model could forecast the severity of COVID-19 patients, hospital resource allocation would be more comfortable. This study evaluated machine learning models using electronic records from 3,996 COVID-19 patients to forecast mild, moderate, or severe disease up to 2 days in advance. A deep neural network (DNN) model achieved 91.8% accuracy, 0.96 AUROC, and 0.90 AUPRC for 2-day predictions, regardless of disease phase. Tree-based models like random forest achieved slightly better metrics (random forest: 94.1% of accuracy, 0.98 AUROC, 0.95 AUPRC; Gradient boost: 94.1% of accuracy, 0.98 AUROC, 0.94 AUPRC), prioritizing treatment factors like steroid use. However, the DNN relied more on fixed patient factors like demographics and symptoms in aspect to SHAP value importance. Since treatment patterns vary between hospitals, the DNN may be more generalizable than tree-based models (random forest, gradient boost model). The results demonstrate accurate short-term forecasting of COVID-19 severity using routine clinical data. DNN models may balance predictive performance and generalizability better than other methods. Severity predictions by machine learning model could facilitate resource planning, like ICU arrangement and oxygen devices.
Though cornin is known to induce angiogenic, cardioprotective, and apoptotic effects, the apoptotic mechanism of this iridoid monoglucoside is not fully understood in prostate cancer cells to date. ...To elucidate the antitumor mechanism of cornin, cytotoxicity assay, cell cycle analysis, Western blotting, RT‐qPCR, RNA interference, immunofluorescence, immunoprecipitation, reactive oxygen species (ROS) measurement, and inhibitor assay were applied in this work. Cornin exerted cytotoxicity, increased sub‐G1 population, and cleaved PARP and caspase3 in LNCaP cells more than in DU145 cells. Consistently, cornin suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3) and disrupted the colocalization of STAT3 and androgen receptor (AR) in LNCaP and DU145 cells, along with suppression of AR, prostate‐specific antigen (PSA), and 5α‐reductase in LNCaP cells. Furthermore, cornin increased ROS production and the level of miR‐193a‐5p, while ROS inhibitor N‐acetylcysteine disturbed the ability of cornin to attenuate the expression of AR, p‐STAT3, PSA, pro‐PARP, and pro‐caspase3 in LNCaP cells. Notably, miR‐193a‐5p mimics the enhanced apoptotic effect of cornin, while miR‐193a‐5p inhibitor reverses the ability of cornin to abrogate AR, PSA, and STAT3 in LNCaP cells. Our findings suggest that ROS production and the disturbed crosstalk between STAT3 and AR by microRNA‐193a‐5p are critically involved in the apoptotic effect of cornin in prostate cancer cells.
Silver (Ag) metal‐based structures are promising building blocks for next‐generation photonics and electronics owing to their unique characteristics, such as high reflectivity, surface plasmonic ...resonance effects, high electrical conductivity, and tunable electron transport mechanisms. However, Ag structures exhibit poor sustainability in terms of device performance because harsh chemicals, particularly S2− ions present in the air, can damage their structures, lowering their optical and electrical properties. Here, the surface chemistry of Ag structures with (3‐mercaptopropyl)trimethoxysilane (MPTS) ligands at room temperature and under ambient conditions is engineered to prevent deterioration of their optical and electrical properties owing to S2− exposure. Regardless of the dimensions of the Ag structures, the MPTS ligands can be applied to each dimension (0D, 1D, and 3D). Consequently, highly sustainable plasmonic effects (Δλ < 2 nm), Fabry–Perot cavity resonance structures (Δλ < 2 nm), reflectors (ΔRReflectance < 0.5%), flexible electrodes (ΔRelectrical < 0.1 Ω), and strain gauge sensors (ΔGF < 1), even in S2− exposing conditions is achieved. This strategy is believed to significantly contribute to environmental pollution reduction by decreasing the volume of electronic waste.
The surface chemistry of Ag structures of different dimensions (0D/1D/3D) with MPTS ligands under benign conditions to prevent the deterioration of the structural, optical, and electrical properties from sulfidation is engineered. This anti‐tarnish technique prevents the loss of plasmonic effects and F–P cavity resonances. It leads to the highly sustainable performance of LED reflectors, conductive paints, flexible electrodes, and wearable strain sensors.
In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable ...gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value.
We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery
surgery) with MSI.
MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio HR, 1.88; 95% CI, 1.28 to 2.76;
< .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73;
= .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).
In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.
Summary Background The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned ...interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. Methods CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II–IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m2 twice daily on days 1–14 plus intravenous oxaliplatin 130 mg/m2 on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov , NCT00411229. Findings We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54–70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio HR 0·58, 95% CI 0·47–0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63–73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47–58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51–0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74–82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64–73) in the observation group. Adverse event data were not collected after the primary analysis. Interpretation Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. Funding F Hoffmann La-Roche and Sanofi.
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