Olink Proteomics for the Identification of Biomarkers for Early Diagnosis of Postmenopausal Osteoporosis.

This investigation aims to employ Olink proteomics in analyzing the distinct serum proteins associated with postmenopausal osteoporosis (PMOP) and identifying prognostic markers for early detection of PMOP via molecular mechanism research on postmenopausal osteoporosis. Postmenopausal women admitted to Beijing Jishuitan Hospital were randomly selected and categorized into three groups based on their dual-energy X-ray absorptiometry (DXA) T-scores: osteoporosis group (n = 24), osteopenia group (n = 20), and normal bone mass group (n = 16). Serum samples from all participants were collected for clinical and bone metabolism marker measurements. Olink proteomics was utilized to identify differentially expressed proteins (DEPs) that are highly associated with postmenopausal osteoporosis. The functional analysis of DEPs was performed using Gene Ontology and Kyto Encyclopedia Genes and Genomes (KEGG). The biological characteristics of these proteins and their correlation with PMOP were subsequently analyzed. ROC curve analysis was performed to identify potential biomarkers with the highest diagnostic accuracy for early stage PMOP. Through Olink proteomics, we identified five DEPs highly associated with PMOP, including two upregulated and three downregulated proteins. TWEAK and CDCP1 markers exhibited the highest area under the curve (0.8188 and 0.8031, respectively). TWEAK and CDCP1 have the potential to serve as biomarkers for early prediction of postmenopausal osteoporosis.

The impact of plan complexity on calculation and measurement-based pre-treatment verifications for sliding-window intensity-modulated radiotherapy.

Background and purpose: In sliding-window intensity-modulated radiotherapy, increased plan modulation often leads to increased plan complexities and dose uncertainties. Dose calculation and/or measurement checks are usually adopted for pre-treatment verification. This study aims to evaluate the relationship among plan complexities, calculated doses and measured doses. Materials and methods: A total of 53 plan complexity metrics (PCMs) were selected, emphasizing small field characteristics and leaf speed/acceleration. Doses were retrieved from two beam-matched treatment devices. The intended dose was computed employing the Anisotropic Analytical Algorithm and validated through Monte Carlo (MC) and Collapsed Cone Convolution (CCC) algorithms. To measure the delivered dose, 3D diode arrays of various geometries, encompassing helical, cross, and oblique cross shapes, were utilized. Their interrelation was assessed via Spearman correlation analysis and principal component linear regression (PCR). Results: The correlation coefficients between calculation-based (CQA) and measurement-based verification quality assurance (MQA) were below 0.53. Most PCMs showed higher correlation rpcm-QA with CQA (max: 0.84) than MQA (max: 0.65). The proportion of rpcm-QA  ≥ 0.5 was the largest in the pelvis compared to head-and-neck and chest-and-abdomen, and the highest rpcm-QA occurred at 1 %/1mm. Some modulation indices for the MLC speed and acceleration were significantly correlated with CQA and MQA. PCR's determination coefficients (R2 ) indicated PCMs had higher accuracy in predicting CQA (max: 0.75) than MQA (max: 0.42). Conclusions: CQA and MQA demonstrated a weak correlation. Compared to MQA, CQA exhibited a stronger correlation with PCMs. Certain PCMs related to MLC movement effectively indicated variations in both quality assurances.

Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α.

In hypoxic and pseudohypoxic rodent models of pulmonary hypertension (PH), hypoxia-inducible factor (HIF) inhibition attenuates disease initiation. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PH in humans, indicating the involvement of other mechanisms. Given the association between endothelial cell dysfunction and PH, the effects of pseudohypoxia and its underlying pathways were investigated in primary human lung endothelial cells. PHD2 silencing or inhibition, while activating HIF2α, induced apoptosis-resistance and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activated AKT and ERK, inhibited JNK, and reduced AIP1 (ASK1-interacting protein 1), all independent of HIF2α. Like PHD2, AIP1 silencing affected these same kinase pathways and produced a similar dysfunctional endothelial cell phenotype, which was partially reversed by AKT inhibition. Consistent with these in vitro findings, AIP1 protein levels in lung endothelial cells were decreased in Tie2-Cre/Phd2 knockout mice compared with wild-type controls. Lung vascular endothelial cells from patients with pulmonary arterial hypertension (PAH) showed IFN/STAT activation. Lung tissue from both SU5416/hypoxia PAH rats and patients with PAH all showed AKT activation and dysregulated AIP1 expression. In conclusion, PHD2 deficiency in lung vascular endothelial cells drives an apoptosis-resistant and inflammatory phenotype, mediated by AKT activation and AIP1 loss independent of HIF signaling. Targeting these pathways, including PHD2, AKT, and AIP1, holds the potential for developing new treatments for endothelial dysfunction in PH.NEW & NOTEWORTHY HIF activation alone does not conclusively lead to human PH, suggesting that HIF-independent signaling may also contribute to hypoxia-induced PH. This study demonstrated that PHD2 silencing-induced pseudohypoxia in human lung endothelial cells suppresses apoptosis and activates STAT, effects that persist despite HIF2α inhibition or knockdown and are attributed to AKT and ERK activation, JNK inhibition, and AIP1 loss. These findings align with observations in lung endothelial cells and tissues from PAH rodent models and patients.

Chronic mitral regurgitation predicts acute heart failure and worse outcomes after endovascular treatment for large vessel occlusion stroke.

BACKGROUND: Valvular diseases are widely recognized as important etiologies for large vessel occlusion stroke (LVO) but their impact on outcomes among patients with LVO receiving endovascular treatment (EVT) are less well delineated. METHODS: This study was a post hoc exploratory analysis of the RESCUE-BT trial, DEVT trial and BASILAR prospective registry. Outcome measures included the modified Rankin Scale (mRS) score at 90 days, symptomatic intracranial hemorrhage, and post-stroke early acute heart failure (EAHF). Chronic significant mitral regurgitation (csMR) was defined as a long-existing mitral regurgitation (MR) with moderate-to-severe MR grade examined by the transthoracic echocardiography. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were obtained by logistic regression models. RESULTS: Among 2011 patients in these three studies, 837 individuals receiving EVT with available information for valvular status were included in this study. In all categories of chronic valvular disorders, only csMR was related to very poor outcomes (mRS 5-6, aOR 2.76 (95% CI 1.59 to 4.78), P<0.001). CsMR (aOR 7.65 (95% CI 4.33 to 13.49), P<0.001) was an independent predictor of post-stroke EAHF. Mediation analysis showed that csMR increased EAHF instead of reocclusion events or venous thrombosis mediated its effects on functional outcome (49.50% (95% CI 24.83% to 90.00%)). Identical results of csMR on clinical outcomes and post-stroke EAHF were detected in novel cohorts constructed by propensity score matching and sensitivity analysis. CONCLUSION: Our study demonstrated that csMR was a mediator of heart-brain interaction associated with poor outcomes of LVO after EVT by increasing the frequency of post-stroke EAHF. Replication of these findings in a larger cohort is warranted.

Effect of three oral pathogens on the TMA-TMAO metabolic pathway.

Background: Trimethylamine-N-oxide (TMAO) is produced by hepatic flavin-containing monooxygenase 3 (FMO3) from trimethylamine (TMA). High TMAO level is a biomarker of cardiovascular diseases and metabolic disorders, and it also affects periodontitis through interactions with the gastrointestinal microbiome. While recent findings indicate that periodontitis may alter systemic TMAO levels, the specific mechanisms linking these changes and particular oral pathogens require further clarification. Methods: In this study, we established a C57BL/6J male mouse model by orally administering Porphyromonas gingivalis (P. gingivalis, Pg), Fusobacterium nucleatum (F. nucleatum, Fn), Streptococcus mutans (S. mutans, Sm) and PBS was used as a control. We conducted LC-MS/MS analysis to quantify the concentrations of TMAO and its precursors in the plasma and cecal contents of mice. The diversity and composition of the gut microbiome were analyzed using 16S rRNA sequencing. TMAO-related lipid metabolism and enzymes in the intestines and liver were assessed by qPCR and ELISA methods. We further explored the effect of Pg on FMO3 expression and lipid molecules in HepG2 cells by stimulating the cells with Pg-LPS in vitro. Results: The three oral pathogenic bacteria were orally administered to the mice for 5 weeks. The Pg group showed a marked increase in plasma TMAO, betaine, and creatinine levels, whereas no significant differences were observed in the gut TMAO level among the four groups. Further analysis showed similar diversity and composition in the gut microbiomes of both the Pg and Fn groups, which were different from the Sm and control groups. The profiles of TMA-TMAO pathway-related genera and gut enzymes were not significantly different among all groups. The Pg group showed significantly higher liver FMO3 levels and elevated lipid factors (IL-6, TG, TC, and NEFA) in contrast to the other groups. In vitro experiments confirmed that stimulation of HepG2 cells with Pg-LPS upregulated the expression of FMO3 and increased the lipid factors TC, TG, and IL-6. Conclusion: This study conclusively demonstrates that Pg, compared to Fn and Sm, plays a critical role in elevating plasma TMAO levels and significantly influences the TMA-TMAO pathway, primarily by modulating the expression of hepatic FMO3 and directly impacting hepatic lipid metabolism.

A conjugate vaccine strategy that induces protective immunity against arecoline.

Betel-quid chewing addiction is the leading cause of oral submucous fibrosis and oral cancer, resulting in significant socio-economic burdens. Vaccination may serve as a promising potential remedy to mitigate the abuse and combat accidental overdose of betel nut. Hapten design is the crucial factor to the development of arecoline vaccine that determines the efficacy of a candidate vaccine. Herein, we reported that two kinds of novel arecoline-based haptens were synthesized and conjugated to Bovine Serum Albumin (BSA) to generate immunogens, which generated antibodies with high affinity for arecoline but reduced binding for guvacoline and no affinity for arecaidine or guvacine. Notably, vaccination with Arec-N-BSA, which via the N-position on the tetrahydropyridine ring (tertiary amine group), led to a higher antibody affinity compared to Arec-CONH-BSA, blunted analgesia and attenuated hypothermia for arecoline.

Pollution characteristics and affecting factors of phthalate esters in agricultural soils in mainland China.

Phthalate esters (PAEs), the most commonly produced and used plasticizers, are widely used in plastic products and agroecosystems, posing risks to agricultural products and human health. However, current research on PAE pollution characteristics in agricultural soils in China is not comprehensive; affecting factors and relationships with microplastics and plasticizer organophosphate esters have not been sufficiently considered. In this study, farmland soil samples were collected with field questionnaires on a national scale across mainland China. The results showed that the detection rate of PAEs was 100% and the Σ16PAEs concentrations were 23.5 - 903 µg/kg. The level of PAEs was highest in the greenhouse, and significantly higher than that in mulched farmland (p < 0.05). The PAE concentration in northwestern China was the lowest among different physical geographic zones. PAEs in farmlands posed a low cancer risk to Chinese people. PAE pollution in farmlands was significantly (p < 0.05) affected by agronomic measures (such as disposal method), environmental factors, and socioeconomic factors. Overall, PAEs were significantly and positively correlated (p < 0.05) with organophosphate esters but not with microplastics. This study aims to provide scientific data for relevant prevention and control policies, as well as actionable recommendations for pollution reduction.

CNN-based multi-modal radiomics analysis of pseudo-CT utilization in MRI-only brain stereotactic radiotherapy: a feasibility study.

BACKGROUND: Pseudo-computed tomography (pCT) quality is a crucial issue in magnetic resonance image (MRI)-only brain stereotactic radiotherapy (SRT), so this study systematically evaluated it from the multi-modal radiomics perspective. METHODS: 34 cases (< 30 cm³) were retrospectively included (2021.9-2022.10). For each case, both CT and MRI scans were performed at simulation, and pCT was generated by a convolutional neural network (CNN) from planning MRI. Conformal arc or volumetric modulated arc technique was used to optimize the dose distribution. The SRT dose was compared between pCT and planning CT with dose volume histogram (DVH) metrics and gamma index. Wilcoxon test and Spearman analysis were used to identify key factors associated with dose deviations. Additionally, original image features were extracted for radiomic analysis. Tumor control probability (TCP) and normal tissue complication probability (NTCP) were employed for efficacy evaluation. RESULTS: There was no significant difference between pCT and planning CT except for radiomics. The mean value of Hounsfield unit of the planning CT was slightly higher than that of pCT. The Gadolinium-based agents in planning MRI could increase DVH metrics deviation slightly. The median local gamma passing rates (1%/1 mm) between planning CTs and pCTs (non-contrast) was 92.6% (range 63.5-99.6%). Also, differences were observed in more than 85% of original radiomic features. The mean absolute deviation in TCP was 0.03%, and the NTCP difference was below 0.02%, except for the normal brain, which had a 0.16% difference. In addition, the number of SRT fractions and lesions, and lesion morphology could influence dose deviation. CONCLUSIONS: This is the first multi-modal radiomics analysis of CNN-based pCT from planning MRI for SRT of small brain lesions, covering dosiomics and radiomics. The findings suggest the potential of pCT in SRT plan design and efficacy prediction, but caution needs to be taken for radiomic analysis.

Zero-Shot Medical Image Translation via Frequency-Guided Diffusion Models.

Recently, the diffusion model has emerged as a superior generative model that can produce high quality and realistic images. However, for medical image translation, the existing diffusion models are deficient in accurately retaining structural information since the structure details of source domain images are lost during the forward diffusion process and cannot be fully recovered through learned reverse diffusion, while the integrity of anatomical structures is extremely important in medical images. For instance, errors in image translation may distort, shift, or even remove structures and tumors, leading to incorrect diagnosis and inadequate treatments. Training and conditioning diffusion models using paired source and target images with matching anatomy can help. However, such paired data are very difficult and costly to obtain, and may also reduce the robustness of the developed model to out-of-distribution testing data. We propose a frequency-guided diffusion model (FGDM) that employs frequency-domain filters to guide the diffusion model for structure-preserving image translation. Based on its design, FGDM allows zero-shot learning, as it can be trained solely on the data from the target domain, and used directly for source-to-target domain translation without any exposure to the source-domain data during training. We evaluated it on three cone-beam CT (CBCT)-to-CT translation tasks for different anatomical sites, and a cross-institutional MR imaging translation task. FGDM outperformed the state-of-the-art methods (GAN-based, VAE-based, and diffusion-based) in metrics of Fréchet Inception Distance (FID), Peak Signal-to-Noise Ratio (PSNR), and Structural Similarity Index Measure (SSIM), showing its significant advantages in zero-shot medical image translation.

A Zinc Oxide Nanowire-Modified Mineralized Collagen Scaffold Promotes Infectious Bone Regeneration.

Bone infection poses a major clinical challenge that can hinder patient recovery and exacerbate postoperative complications. This study has developed a bioactive composite scaffold through the co-assembly and intrafibrillar mineralization of collagen fibrils and zinc oxide (ZnO) nanowires (IMC/ZnO). The IMC/ZnO exhibits bone-like hierarchical structures and enhances capabilities for osteogenesis, antibacterial activity, and bacteria-infected bone healing. During co-cultivation with human bone marrow mesenchymal stem cells (BMMSCs), the IMC/ZnO improves BMMSC adhesion, proliferation, and osteogenic differentiation even under inflammatory conditions. Moreover, it suppresses the activity of Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans by releasing zinc ions within the acidic infectious microenvironment. In vivo, the IMC/ZnO enables near-complete healing of infected bone defects within the intricate oral bacterial milieu, which is attributed to IMC/ZnO orchestrating M2 macrophage polarization, and fostering an osteogenic and anti-inflammatory microenvironment. Overall, these findings demonstrate the promise of the bioactive scaffold IMC/ZnO for treating bacteria-infected bone defects.

Pretreatment patient-specific quality assurance prediction based on 1D complexity metrics and 3D planning dose: classification, gamma passing rates, and DVH metrics.

PURPOSE: Highly modulated radiotherapy plans aim to achieve target conformality and spare organs at risk, but the high complexity of the plan may increase the uncertainty of treatment. Thus, patient-specific quality assurance (PSQA) plays a crucial role in ensuring treatment accuracy and providing clinical guidance. This study aims to propose a prediction model based on complexity metrics and patient planning dose for PSQA results. MATERIALS AND METHODS: Planning dose, measurement-based reconstructed dose and plan complexity metrics of the 687 radiotherapy plans of patients treated in our institution were collected for model establishing. Global gamma passing rate (GPR, 3%/2mm,10% threshold) of 90% was used as QA criterion. Neural architecture models based on Swin-transformer were adapted to process 3D dose and incorporate 1D metrics to predict QA results. The dataset was divided into training (447), validation (90), and testing (150) sets. Evaluation of predictions was performed using mean absolute error (MAE) for GPR, planning target volume (PTV) HI and PTV CI, mean absolute percentage error (MAPE) for PTV D95, PTV D2 and PTV Dmean, and the area under the receiver operating characteristic (ROC) curve (AUC) for classification. Furthermore, we also compare the prediction results with other models based on either only 1D or 3D inputs. RESULTS: In this dataset, 72.8% (500/687) plans passed the pretreatment QA under the criterion. On the testing set, our model achieves the highest performance, with the 1D model slightly surpassing the 3D model. The performance results are as follows (combine, 1D, and 3D transformer): The AUCs are 0.92, 0.88 and 0.86 for QA classification. The MAEs of prediction are 0.039, 0.046, and 0.040 for 3D GPR, 0.018, 0.021, and 0.019 for PTV HI, and 0.075, 0.078, and 0.084 for PTV CI. Specifically, for cases with 3D GPRs greater than 90%, the MAE could achieve 0.020 (combine). The MAPE of prediction is 1.23%, 1.52%, and 1.66% for PTV D95, 2.36%, 2.67%, and 2.45% for PTV D2, and 1.46%, 1.70%, and 1.71% for PTV Dmean. CONCLUSION: The model based on 1D complexity metrics and 3D planning dose could predict pretreatment PSQA results with high accuracy and the complexity metrics play a leading role in the model. Furthermore, dose-volume metric deviations of PTV could be predicted and more clinically valuable information could be provided.

Self-promoted electroactive biomimetic mineralized scaffolds for bacteria-infected bone regeneration.

Infected bone defects are a major challenge in orthopedic treatment. Native bone tissue possesses an endogenous electroactive interface that induces stem cell differentiation and inhibits bacterial adhesion and activity. However, traditional bone substitutes have difficulty in reconstructing the electrical environment of bone. In this study, we develop a self-promoted electroactive mineralized scaffold (sp-EMS) that generates weak currents via spontaneous electrochemical reactions to activate voltage-gated Ca2+ channels, enhance adenosine triphosphate-induced actin remodeling, and ultimately achieve osteogenic differentiation of mesenchymal stem cells by activating the BMP2/Smad5 pathway. Furthermore, we show that the electroactive interface provided by the sp-EMS inhibits bacterial adhesion and activity via electrochemical products and concomitantly generated reactive oxygen species. We find that the osteogenic and antibacterial dual functions of the sp-EMS depend on its self-promoting electrical stimulation. We demonstrate that in vivo, the sp-EMS achieves complete or nearly complete in situ infected bone healing, from a rat calvarial defect model with single bacterial infection, to a rabbit open alveolar bone defect model and a beagle dog vertical bone defect model with the complex oral bacterial microenvironment. This translational study demonstrates that the electroactive bone graft presents a promising therapeutic platform for complex defect repair.

Mobile schwannoma of the lumbar spine: A case report and literature review.

BACKGROUND: Schwannoma is a benign tumor that originates from the cells of nerve sheaths. The occurrence of mobile schwannoma of the lumbar spine is extremely rare, and when clinicians perform spinal explorations in the expected locations, the results are often negative. This report presents a case of mobile schwannoma in the lumbar spine, aiming to remind doctors to consider the possibility of tumor migration during preoperative planning, thereby avoiding secondary harm to the patient. CASE REPORT: A 48-year-old male patient presented with a 2-year history of lower back pain and numbness in both lower extremities, which has progressively worsened over the past 3 months. An Magnetic resonance imaging scan revealed an oval-shaped lesion located in the L2/3 vertebral segment, which migrated to the L3/4 vertebral segment following contrast enhancement. The patient underwent tumor resection surgery, and the diagnosis of schwannoma was confirmed through pathological examination. CONCLUSION: Clinical physicians should increase their understanding of mobile schwannoma of the lumbar spine and utilize imaging techniques to accurately locate the tumor before surgery, in order to avoid unnecessary surgical scope and the risks of additional surgery.

Effect of statin treatment on clinical outcomes in cardioembolic stroke with endovascular thrombectomy.

BACKGROUND: While statins have been widely used in patients with large-artery atherosclerotic stroke, their effectiveness in patients with cardioembolic large vessel occlusion (CE-LVO) undergoing endovascular treatment (EVT) remains unclear. This study aimed to evaluate whether combining statin therapy with EVT could improve clinical outcomes in patients with acute ischemic stroke caused by CE-LVO in the anterior circulation. METHODS: We performed a retrospective screening on patients with CE-LVO in the anterior circulation who underwent EVT in 27 hospitals across China between 2018 and 2021. The primary outcome measure was functional independence, defined as a 90-day modified Rankin Scale (mRS) score of 0 to 2. Safety outcomes included 90-day mortality and symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 510 patients with CE-LVO in the anterior circulation undergoing EVT were included in this study. Of these, 404 (79.2%) patients received statin treatment (statin group), while 106 (20.8%) did not (non-statin group). Statin treatment was significantly associated with improved functional independence (adjusted OR (aOR) 2.072, 95% CI 1.197 to 3.586, P=0.009). Moreover, statin use was associated with a lower rate of 90-day mortality (aOR 0.343, 95% CI 0.197 to 0.596, P<0.001) and a lower rate of sICH (aOR 0.153, 95% CI 0.072 to 0.325, P<0.001). CONCLUSION: Statin treatment was associated with improved clinical outcomes and reduced risks of mortality and sICH in patients with CE-LVO in the anterior circulation undergoing EVT.

Melatonin ameliorates atherosclerosis by suppressing S100a9-mediated vascular inflammation.

Atherosclerosis (AS)-associated cardiovascular diseases are predominant causes of morbidity and mortality worldwide. Melatonin, a circadian hormone with anti-inflammatory activity, may be a novel therapeutic intervention for AS. However, the exact mechanism is unclear. This research intended to investigate the mechanism of melatonin in treating AS. Melatonin (20 mg/kg/d) was intraperitoneally administered in a high-fat diet (HFD)-induced AS model using apolipoprotein E-deficient (ApoE-/-) mice for 12 weeks. Immunohistochemical and immunofluorescence analyses, data-independent acquisition (DIA)-based protein profiling, ingenuity pathway analysis (IPA), and western blotting were employed to investigate the therapeutic effects of melatonin in treating HFD-induced AS. An adeno-associated virus (AAV) vector was further used to confirm the antiatherosclerotic mechanism of melatonin. Melatonin treatment markedly attenuated atherosclerotic lesions, induced stable phenotypic sclerotic plaques, inhibited macrophage infiltration, and suppressed the production of proinflammatory cytokines in ApoE-/- mice with HFD-induced AS. Notably, DIA-based quantitative proteomics together with IPA identified S100a9 as a pivotal mediator in the protective effects of melatonin. Moreover, melatonin significantly suppressed HFD-induced S100a9 expression at both the mRNA and protein levels. The overexpression of S100a9 significantly activated the NF-κB signaling pathway and markedly abolished the antagonistic effect of melatonin on HFD-induced vascular inflammation during atherogenesis. Melatonin exerts a significant antiatherogenic effect by inhibiting S100a9/NF-κB signaling pathway-mediated vascular inflammation. Our findings reveal a novel antiatherosclerotic mechanism of melatonin and underlie its potential clinical use in modulating AS with good availability and affordability.

Efficacy and Quality-of-Life Following Involved Nodal Radiotherapy for Head and Neck Squamous Cell Carcinoma: The INRT-AIR Phase II Clinical Trial.

PURPOSE: Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy, but it is associated with significant dose to normal organs-at-risk (OAR). In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity-modulated radiotherapy. PATIENTS AND METHODS: Patients with newly diagnosed HNSCC of the oropharynx, larynx, and hypopharynx were eligible for enrollment. Each LN was characterized as involved or suspicious based on radiologic criteria and an in-house artificial intelligence (AI)-based classification model. Gross disease received 70 Gray (Gy) in 35 fractions and suspicious LNs were treated with 66.5 Gy, without ENI. The primary endpoint was solitary elective volume recurrence, with secondary endpoints including patterns-of-failure and patient-reported outcomes. RESULTS: Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer. With a median follow-up of 33.4 months, the 2-year risk of solitary elective nodal recurrence was 0%. Gastrostomy tubes were placed in 14 (21%), with median removal after 2.9 months for disease-free patients; no disease-free patient is chronically dependent. Grade I/II dermatitis was seen in 90%/10%. There was no significant decline in composite MD Anderson Dysphagia Index scores after treatment, with means of 89.1 and 92.6 at 12 and 24 months, respectively. CONCLUSIONS: These results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable quality-of-life outcomes. Additional prospective studies are needed to support this promising paradigm before implementation in any nontrial setting.

InSitu Integrated Fabrication for Multi-Interface Stabilized and Highly Durable Polyaniline@Graphene Oxide/Polyether Ether Ketone Special Separation Membranes.

Special separation membranes are widely employed for separation and purification purposes under challenging operating conditions due to their low energy consumption, excellent solvent, and corrosion resistance. However, the development of membranes is limited by corrosion-resistant polymer substrates and precise interfacial separation layers. Herein, polyaniline (PANI) is employed to achieve insitu anchoring of multiple interfaces, resulting in the fabrication of polyaniline@graphene oxide/polyether ether ketone (PANI@GO/PEEK) membranes. Insitu growth of PANI achieves the adequate bonding of the PEEK substrate and GO separation interface, which solves the problem of solution processing of PEEK and the instability of GO layers. By bottom-up confined polymerization of aniline, it could control the pore size of the separation layer, correct defects, and anchor among polymer, nano-separation layer, and nano-sheet. The mechanism of membrane construction within the confined domain and micro-nano structure modulation is further explored. The membranes demonstrate exceptional stability realizing over 90% rejection in 2 m HCl, NaOH, and high temperatures. Additionally, -membranes exhibit remarkable durability after 240 days immersion and 100 h long-term operation, which display the methanol flux of 50.2 L m-2 h-1 and 92% rejection of AF (585 g mol-1 ). This method substantially contributes to special separation membranes by offering a novel strategy.

Semi-crystalline sulfonated poly(ether ketone) proton exchange membranes: The trade-off of facile synthesis and performance.

Improving the performance of proton exchange membranes (PEMs) through the synthesis of sulfonated polymers with elaborate molecular structures has received extensive approval. However, the tedious synthetic process and consequently high costs restrain their possible substitution for Nafion, a classic PEM material. Herein, a series of semi-crystalline sulfonated poly(ether ketone)s with fluorene-based units were prepared via direct copolymerization of commercially available monomers and followed post-sulfonation, namely SPEK-FD-x, where × represents the molar ratio of the fluorene-containing monomer to the employed bisphenol monomers. The entire synthetic pathway was facile without involving hardly accessible materials. Subsequently, various properties of SPEK-FD-x membranes were investigated and further compared with Nafion 117. Due to the formation of the well-defined hydrophilic-hydrophobic microphase separation morphology and the reinforcement of the PEK crystalline regions, the SPEK-FD-x membranes exhibited outstanding proton conductivity, resistance for methanol permeation, as well as dimensional, thermal, oxidative, and mechanical stability. Among them, the overall behavior of the SPEK-FD-25 membrane was comparable to or even greater than that of Nafion 117, most importantly, it also performed decently in both H2/air fuel cells and direct methanol fuel cells. Therefore, with the straightforward synthesis and superior performance, the SPEK-FD-x membranes may serve as a promising alternative to Nafion.

Inflammation and DKK1-induced AKT activation contribute to endothelial dysfunction following NR2F2 loss.

NR2F2 is expressed in endothelial cells (ECs) and Nr2f2 knockout produces lethal cardiovascular defects. In humans, reduced NR2F2 expression is associated with cardiovascular diseases including congenital heart disease and atherosclerosis. Here, NR2F2 silencing in human primary ECs led to inflammation, endothelial-to-mesenchymal transition (EndMT), proliferation, hypermigration, apoptosis-resistance, and increased production of reactive oxygen species. These changes were associated with STAT and AKT activation along with increased production of DKK1. Co-silencing DKK1 and NR2F2 prevented NR2F2-loss-induced STAT and AKT activation and reversed EndMT. Serum DKK1 concentrations were elevated in patients with pulmonary arterial hypertension (PAH) and DKK1 was secreted by ECs in response to in vitro loss of either BMPR2 or CAV1, which are genetic defects associated with the development of PAH. In human primary ECs, NR2F2 suppressed DKK1, whereas its loss conversely induced DKK1 and disrupted endothelial homeostasis, promoting phenotypic abnormalities associated with pathologic vascular remodeling. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating chronic vascular diseases associated with EC dysfunction.NEW & NOTEWORTHY NR2F2 loss in the endothelial lining of blood vessels is associated with cardiovascular disease. Here, NR2F2-silenced human endothelial cells were inflammatory, proliferative, hypermigratory, and apoptosis-resistant with increased oxidant stress and endothelial-to-mesenchymal transition. DKK1 was induced in NR2F2-silenced endothelial cells, while co-silencing NR2F2 and DKK1 prevented NR2F2-loss-associated abnormalities in endothelial signaling and phenotype. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating vascular diseases associated with endothelial dysfunction.

ARMO: automated and reliable multi-objective model for lymph node metastasis prediction in head and neck cancer.

Objective. Accurate diagnosis of lymph node metastasis (LNM) is critical in treatment management for patients with head and neck cancer. Positron emission tomography and computed tomography are routinely used for identifying LNM status. However, for small or less fluorodeoxyglucose (FDG) avid nodes, there are always uncertainties in LNM diagnosis. We are aiming to develop a reliable prediction model is for identifying LNM.Approach. In this study, a new automated and reliable multi-objective learning model (ARMO) is proposed. In ARMO, a multi-objective model is introduced to obtain balanced sensitivity and specificity. Meanwhile, confidence is calibrated by introducing individual reliability, whilst the model uncertainty is estimated by a newly defined overall reliability in ARMO. In the training stage, a Pareto-optimal model set is generated. Then all the Pareto-optimal models are used, and a reliable fusion strategy that introduces individual reliability is developed for calibrating the confidence of each output. The overall reliability is calculated to estimate the model uncertainty for each test sample.Main results. The experimental results demonstrated that ARMO obtained more promising results, which the area under the curve, accuracy, sensitivity and specificity can achieve 0.97, 0.93, 0.88 and 0.94, respectively. Meanwhile, based on calibrated confidence and overall reliability, clinicians could pay particular attention to highly uncertain predictions.Significance. In this study, we developed a unified model that can achieve balanced prediction, confidence calibration and uncertainty estimation simultaneously. The experimental results demonstrated that ARMO can obtain accurate and reliable prediction performance.