•Everolimus suppressed tumor growth in the NPC PDX model and had an additive antitumor effect with palbociclib.•Everolimus together with autophagy inhibitor, hydroxychloroquine, had additive ...anti-tumor effect on EBV(+) PDX tumor.•High mTOR level was a poor prognostic factor in metastatic NPC.
Nasopharyngeal carcinoma (NPC) is associated with Epstein–Barr virus (EBV) infection. To test preclinical NPC drugs, we established two patient-derived xenograft (PDX) mouse models, EBV-positive PDX-B13 and EBV-negative PDX-Li41, for drug screening.
Based on next generation sequencing (NGS) studies, PDX-B13 had CCND1 copy number (CN) gain but CDKN2A CN loss, whereas PDX-Li41 had CDKN2A and RB1 CN loss, TSC1 (negative regulator of mTOR) frameshift deletion mutation, and increased activation of mTOR, a serine/threonine kinase that governs metabolism, autophagy, and apoptosis. Increased mTOR was also associated with poor NPC prognosis.
Everolimus, an mTOR inhibitor, suppressed tumor growth in the two PDX NPC models and had an additive antitumor effect with palbociclib, a CDK4/6 inhibitor. PDX tumors treated with various drugs or untreated were subjected to RNA sequencing, transcriptome profile analysis, and selective Western blotting to understand the interactions between these drugs and gene expression profiles. Palbociclib also suppressed EB viral nuclear antigen (EBNA1) expression in PDX-B13. Everolimus together with autophagy inhibitor, hydroxychloroquine, had additive anti-tumor effect on PDX-B13 tumor. Immunohistochemistry revealed that high mTOR levels were correlated with poor overall survival in patients with metastatic NPC (N = 90).
High mTOR levels are a poor prognostic factor in NPC, and cell cycle, mTOR and autophagy pathways may serve as therapeutic targets in NPC. In addition, PDX models can be used for efficiently testing potential NPC drugs.
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Antinuclear antibody pattern recognition is vital for autoimmune disease diagnosis but labor-intensive for manual interpretation. To develop an automated pattern recognition system, we established ...machine learning models based on the International Consensus on Antinuclear Antibody Patterns (ICAP) at a competent level, mixed patterns recognition, and evaluated their consistency with human reading.
51,694 human epithelial cells (HEp-2) cell images with patterns assigned by experienced medical technologists collected in a medical center were used to train six machine learning algorithms and were compared by their performance. Next, we choose the best performing model to test the consistency with five experienced readers and two beginners.
The mean F1 score in each classification of the best performing model was 0.86 evaluated by Testing Data 1. For the inter-observer agreement test on Testing Data 2, the average agreement was 0.849 (κ) among five experienced readers, 0.844 between the best performing model and experienced readers, 0.528 between experienced readers and beginners. The results indicate that the proposed model outperformed beginners and achieved an excellent agreement with experienced readers.
This study demonstrated that the developed model could reach an excellent agreement with experienced human readers using machine learning methods.
The decent ductileness, high ionic conductivity, low cost, and versatility over synthesis methods make Li-argyrodite a promising for all-solid-state lithium batteries. However, its serious ...interfacial incompatibility with Li anode, dendrite growth, and intrinsic air instability impedes its practicability. Herein, we report a CuCl dual doped Li-argyrodite sulfide superb-conductor (Li6+3xP1−xCuxS5−xCl1+x) prepared to overcome these issues via ball-mill free synthesis approach. The maximum Li+ conductivity of 4.34 mS cm−1 at room temperature with ultrawide voltage stability up to 8 V vs. Li/Li+ was achieved in Li6.3P0.9Cu0.1S4.9Cl1.1 (LPSC-1) via a both composite and planar electrode system and can suppress dendrite formation at a current density of 3 mA cm−2 at 50 оC. The symmetrical cell cycled at 0.1 and 1 mA cm−2 also demonstrates remarkable reversibility with negligible overpotential alteration for more than 2400 h and 400 h. An ex-situ XPS and AC impedance analysis proved enhanced interfacial compatibility at Li | SE and achieved a critical current density of 3 mA cm−2. More interestingly, incorporating soft acid Cu in LPSC-1 boosts the air stability and suppresses H2S generation by two-folds. The XRD for the LPSC-1 before and after air exposure proves the decrease in the oxophilicity of the sulfide solid electrolyte.
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•Doping soft acid Cu in LPSC boosts the air stability and suppresses H2S generation.•Ultra-high Li metal capability at 0.1 mA cm−2, 1 mA cm−2 and 3 mA cm−2.•Ionic conductivity of 4.34 mS cm−1 at RT with extended voltage stability, 8 V.•Superior dendrite suppression capability with CCD 3 mA cm−2 at 50 оC.•Decrease in oxophilicity with structural stability confirmed via XRD.
: Oral midazolam is the most commonly used sedative premedication agent in pediatric patients. While effective, oral midazolam cannot reduce the incidence of emergence agitation. Oral dexmedetomidine ...may be effective in providing satisfactory sedation and reduce the incidence of emergence agitation, although the results of different randomized controlled trials are conflicting.
: This study enrolled randomized controlled trials (RCTs) examining premedication with oral dexmedetomidine versus oral midazolam in pediatric patients undergoing general anesthesia. PubMed, the Cochrane Library, Embase, and the Web of Science database were searched from their inception until June 2023. The outcomes were the incidence of satisfactory preoperative sedation, satisfactory sedation during separation from parents, satisfactory sedation during anesthesia induction using an anesthesia mask, and the incidence of emergence agitation.
: A total of 9 RCTs comprising 885 patients were analyzed. Our data revealed comparable effects of dexmedetomidine and midazolam with respect to satisfactory preoperative sedation and a satisfactory incidence of sedation during parental separation and mask acceptance before anesthesia induction. Notably, our data revealed that the rate of emergence agitation was significantly lower in pediatric patients receiving dexmedetomidine (
= 162) than in those receiving midazolam (
= 159) (odds ratio = 0.16; 95% confidence interval: 0.06 to 0.44;
< 0.001;
= 35%).
: Data from this meta-analysis revealed comparable effects for premedication with oral dexmedetomidine or oral midazolam with respect to satisfactory sedation; furthermore, premedication with oral dexmedetomidine more effectively mitigated emergence agitation in pediatric patients receiving general anesthesia compared with oral midazolam.
In this work, the supercritical oxygen treatment is proposed to passivate the defects of enhancement-mode p-GaN high-electron mobility transistors. After the treatment, the treated device gets ...enhanced in ON-state current and transconductance without changing the threshold voltage. Thus, the supercritical oxygen may not affect Mg doping concentration of the p-GaN layer, degrading the p-GaN layer after the treatment. The statistical analysis indicates uniformity of devices is improved after the treatment. The gate lag and pulsed <inline-formula> <tex-math notation="LaTeX">\text{I}_{\text {D}} </tex-math></inline-formula>-<inline-formula> <tex-math notation="LaTeX">\text{V}_{\text {D}} </tex-math></inline-formula> measurements are proposed to examine the interface between the passivation layer and the AlGaN layer. The few trapped electrons in defects exhibit the suppression of the charge trapping effect. Based on these results mentioned above, the physical model is proposed to explain the phenomenon. The pristine passivation layer has a number of dangling bonds which capture the electrons and lead to the charge trapping effect. The supercritical oxygen permeates into material matrix, repairing the dangling bonds. Therefore, the technique exhibits potential for power device improvement, enabling effective practical application in the future.
Dysregulation of pericellular proteolysis is strongly implicated in cancer metastasis through alteration of cell invasion and the microenvironment. Matriptase-2 (MT-2) is a membrane-anchored serine ...protease which can suppress prostate cancer (PCa) cell invasion. In this study, we showed that MT-2 was down-regulated in PCa and could suppress PCa cell motility, tumor growth, and metastasis. Using microarray and biochemical analysis, we found that MT-2 shifted TGF-β action towards its tumor suppressor function by repressing epithelial-to-mesenchymal transition (EMT) and promoting Smad2 phosphorylation and nuclear accumulation to upregulate two TGF-β1 downstream effectors (p21 and PAI-1), culminating in hindrance of PCa cell motility and malignant growth. Mechanistically, MT-2 could dramatically up-regulate the expression of nuclear receptor NR4A3 via iron metabolism in PCa cells. MT-2-induced NR4A3 further coactivated Smad2 to activate p21 and PAI-1 expression. In addition, NR4A3 functioned as a suppressor of PCa and mediated MT-2 signaling to inhibit PCa tumorigenesis and metastasis. These results together indicate that NR4A3 sustains MT-2 signaling to suppress PCa cell invasion, tumor growth, and metastasis, and serves as a contextual factor for the TGF-β/Smad2 signaling pathway in favor of tumor suppression via promoting p21 and PAI-1 expression.
Objectives
Left ventricle function directly impacts left atrial (LA) conduit function, and LA conduit strain is associated with exercise intolerance in patients with heart failure with preserved ...ejection fraction (HFpEF). Pulmonary capillary wedge pressure (PCWP) before and during exercise is the current gold standard for diagnosing HFpEF. Post-exercise ΔPCWP can lead to worse long-term outcomes. This study examined the correlation between LA strain and post-exercise ΔPCWP in patients with HFpEF.
Methods
We enrolled 100 subjects, including 74 with HFpEF and 26 with non-cardiac dyspnea, from November 2017 to December 2020. Subjects underwent echocardiography, invasive cardiac catheterization, and expired gas analysis at rest and during exercise. Arterial blood pressure, right atrial pressure, pulmonary artery pressure, and PCWP were recorded during cardiac catheterization. Cardiac output, stroke volume, pulmonary vascular resistance, pulmonary artery compliance, systemic vascular resistance, and LV stroke work were calculated using standard formulas.
Results
Exercise LA conduit strain significantly correlated with both post-exercise ΔPCWP (
r
= − 0.707,
p
< 0.001) and exercise PCWP (
r
= − 0.659;
p
< 0.001). Exercise LA conduit strain differentiated patients who did and did not meet the 2016 European Society of Cardiology HFpEF criteria with an area under the curve of 0.69 (95% confidence interval, 0.548–0.831) using a cutoff value of 14.25, with a sensitivity of 0.64 and a specificity of 0.68.
Conclusions
Exercise LA conduit strain significantly correlates with post-exercise ΔPCWP and has a comparable power to identify patients with HFpEF. Additional studies are warranted to confirm the ability of LA conduit strain to predict long-term outcomes among patients with HFpEF.
Clinical relevance statement
Exercise left atrial conduit strain was highly associated with the difference of post-exercise pulmonary capillary wedge pressure and may indicate increased mortality risk in patients with heart failure with preserved ejection fraction, and also has comparable diagnostic ability.
Key Points
•
Left atrial conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction
.
•
Left atrial conduit strain during exercise can identify patients with heart failure with preserved ejection fraction
.
•
Exercise left atrial conduit strain significantly correlates with the difference of pulmonary capillary wedge pressure during and before exercise which might predict the long-term outcomes of heart failure with preserved ejection fraction patients
.
The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve ...therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, which enables us to perform ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Forty liquid biopsies were collected from HNC patients, and the CTCs were expanded ex vivo using the eSelect system within four weeks. Immunofluorescence staining confirmed that the CTC-derived organoids were positive for EpCAM and negative for CD45. Two illustrative cases present the potential of this strategy for evaluating treatment response. The statistical analysis confirmed that drug sensitivity in CTC-derived organoids was associated with a clinical response. The multivariant logistic regression model predicted that the treatment accuracy of chemotherapy responses achieved 93.75%, and the area under the curves (AUCs) of prediction models was 0.8841 in the whole dataset and 0.9167 in cisplatin specific dataset. In summary, cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, and this can potentially underpin predictive assays to guide HNC treatments.
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