The Effects of Tremella fuciformis Polysaccharide on the Physicochemical, Multiscale Structure and Digestive Properties of Cyperus esculentus Starch.

In this study, we have investigated the effects of Tremella fuciformis polysaccharide (TP) on the pasting, rheological, structural and in vitro digestive properties of Cyperus esculentus starch (CS). The results showed that the addition of TP significantly changed the pasting characteristics of CS, increased the pasting temperature and pasting viscosity, inhibited pasting, reduced the exudation of straight-chain starch and was positively correlated with the amount of TP added. The addition of the appropriate amount of TP could increase its apparent viscosity and enhance its viscoelasticity. The composite system of CS/TP exhibited higher short-range ordered structure and solid dense structure, which protected the crystal structure of CS, but was related to the amount of TP added. In addition, the introduction of TP not only decreased the in vitro digestion rate of CS and increased the content of slow-digestible starch (SDS) and resistant starch (RS), but also reduced the degree of digestion. Correlation studies established that TP could improve the viscoelasticity, relative crystallinity and short-range order of the CS/TP composite gel, maintain the integrity of the starch granule and crystalline structure, reduce the degree of starch pasting and strengthen the gel network structure of CS, which could help to lower the digestibility of CS.

Adsorption Properties of Dissolved Gas Molecules in Transformer Oil on the ReSe2 Monolayer: A DFT Study.

Based on density functional theory, the adsorption behavior of seven typical dissolved gas molecules (CO, CO2, H2, CH4, C2H2, C2H4, and C2H6) and H2O molecule on the ReSe2 monolayer was systematically investigated. The interactions between the ReSe2 monolayer and eight gas molecules were investigated by calculating the adsorption energies, charge transfer, density of states (DOS), and deformation charge density (DCD) for eight different adsorption systems. The gas sensitivity of the ReSe2 monolayer toward these gases was studied using frontier molecular orbital theory and work function analysis. The results demonstrate that compared to other gas molecules, the ReSe2 monolayer exhibits a stronger interaction with CO with an adsorption energy of -1.49 eV. It also displays excellent sensitivity and selectivity toward CO making it a promising candidate for CO gas sensing applications. We aspire that this research will offer theoretical guidance for the development of ReSe2-based gas sensors and contribute to state monitoring technology in oil-immersed power equipment.

Colistin monotherapy or combination for the treatment of bloodstream infection caused by Klebsiella pneumoniae: a systematic review and meta-analysis.

BACKGROUND: Bloodstream infection of Klebsiella pneumoniae (BSI-KP) were associated with increased mortality. Klebsiella pneumoniae was tested to susceptible to colistin by E-test and broth microdilution method in clinical laboratory. This study aimed to assess the efficacy of colistin versus tigecycline, carbapenem monotherapy and combination in the treatment of BSI-KP. METHODS: Electronic databases such as PubMed, Web of Science and Embase were searched. The last search was in November 24th, 2022, addressing the colistin, carbapenems and tigecycline monotherapy and combination treatments in patients with BSI-KP. The primary outcomes were 30-day or 28-day mortality. OR where available with 95% CI were pooled in random-effects meta-analysis. RESULTS: Following the outlined search strategy, a total of 658 articles were identified from the initial database searching. Six studies, 17 comparisons were included. However, they all were observational design, lacking high-quality randomized controlled trials (RCTs). Moderate or low-quality evidences suggested that colistin monotherapy was associated with an OR = 1.35 (95% CI = 0.62-2.97, P = 0.45, Tau2 = 0.00, I2 = 0%) compared with tigecycline monotherapy, OR = 0.81 (95% CI = 0.27-2.45, P = 0.71, Tau2 = 0.00, I2 = 0%) compared with carbapenem monotherapy. Compared with combination with tigecycline or carbapenem, Colistin monotherapy resulted in OR of 3.07 (95% CI = 1.34-7.04, P = 0.008, Tau2 = 0.00, I2 = 0%) and 0.98 (95%CI = 0.29-3.31, P = 0.98, Tau2 = 0.00, I2 = 0% ), respectively. CONCLUSIONS: Colistin, carbapenem and tigecycline monotherapy showed similar treatment effects in patients who suffered from BSI-KP. Compared with colistin monotherapy, colistin combined tigecycline therapy might play the synergism effects. TRIAL REGISTRATION: retrospectively registered.

The Mh-miR393a-TIR1 module regulates Alternaria alternata resistance of Malus hupehensis mainly by modulating the auxin signaling.

miRNAs govern gene expression and regulate plant defense. Alternaria alternata is a destructive fungal pathogen that damages apple. The wild apple germplasm Malus hupehensis is highly resistant to leaf spot disease caused by this fungus. Herein, we elucidated the regulatory and functional role of miR393a in apple resistance against A. alternata by targeting Transport Inhibitor Response 1. Mature miR393 accumulation in infected M. hupehensis increased owing to the transcriptional activation of MIR393a, determined to be a positive regulator of A. alternata resistance to either 'Orin' calli or 'Gala' leaves. 5' RLM-RACE and co-transformation assays showed that the target of miR393a was MhTIR1, a gene encoding a putative F-box auxin receptor that compromised apple immunity. RNA-seq analysis of transgenic calli revealed that MhTIR1 upregulated auxin signaling gene transcript levels and influenced phytohormone pathways and plant-pathogen interactions. miR393a compromised the sensitivity of several auxin-signaling genes to A. alternata infection, whereas MhTIR1 had the opposite effect. Using exogenous indole-3-acetic acid or the auxin synthesis inhibitor L-AOPP, we clarified that auxin enhances apple susceptibility to this pathogen. miR393a promotes SA biosynthesis and impedes pathogen-triggered ROS bursts by repressing TIR1-mediated auxin signaling. We uncovered the mechanism underlying the miR393a-TIR1 module, which interferes with apple defense against A. alternata by modulating the auxin signaling pathway.

FBG-based three-dimensional micro-force sensor with axial force sensitivity-enhancing and temperature compensation for micro-forceps.

During retinal microsurgery, excessive interaction force between surgical instruments and intraocular tissue can cause serious accidents such as tissue injury, irreversible retinal damage, and even vision loss. It is essential to accurately sense the micro tool-tissue interaction force, especially for the Ophthalmic Microsurgery Robot. In this study, a fiber Bragg grating (FBG) three-dimensional (3-D) micro-force sensor for micro-forceps is proposed, which is integrated with the drive module as an end-effector and can be conveniently mounted onto the ophthalmic surgical robot. An innovative axial force sensitivity-enhancing structure is proposed based on the principles of flexure-hinge and flexible levers to overcome the low sensitivity of axial force measurement. A dual-grating temperature compensation method is adopted for axial force measurement, which considers the differential temperature sensitivity of the two FBGs. Three FBGs are arranged along the circumference of the guide tube in this study to measure transverse forces and compensate for effects caused by changes in temperature. The experimental results demonstrate that the micro-forceps designed in this study achieved a resolution of 0.13 mN for transverse force and 0.30 mN for axial force. The temperature compensation experiments show that the 3-D micro-force sensor can simultaneously compensate for temperature effects in axial and transverse force measurement.

Three-dimensional force detection and decoupling of a fiber grating sensor for a humanoid prosthetic hand.

A fiber Bragg grating (FBG) based three-dimensional (3D) force sensor for a humanoid prosthetic hand is designed, which can precisely detect 3D force and compensate for ambient temperature. FBG was encapsulated in polydimethylsiloxane (PDMS) for force sensitization and immobilization, and the structural parameters of the sensor were optimized by using finite element simulation, so that its sensitivity to 3D force is enhanced. In the meantime, the calibration experiments for normal force fZ, shear force fX/fY, and temperature were conducted, and the 3D force data were decoupled using the least square (LS) and backpropagation (BP) neural networks decoupling methods, so that an overall decoupling error is 0.038. The results show that the sensor has a simple structure, high sensitivity, high linearity, good creep resistance, and rapid decoupling, providing a successful design for the 3D force detection of a humanoid prosthetic hand.

Tiger Nut Oil-Based Oil Gel: Preparation, Characterization, and Storage Stability.

In this study, Tiger nut (Cyperus esculentus L.) oil-based oleogels were prepared using the emulsion template method with whey protein (WPI; 0.5-2.5% (w/v) and Xanthan gum (XG; 0.1-0.5% (w/v). The microstructure of the oleogels obtained from the high internal phase emulsion (HIPE) and an emulsion after further shearing were observed using an optical microscope and laser confocal microscopy. A series of rheological tests were conducted to evaluate the effect of WPI and XG concentrations on the strength of the emulsion and oleogel. The texture, oil holding capacity, and oxidative stability of oleogels were characterized. The results showed that XG alone could not form oleogel, while the concentration of WPI had more effect than XG. When WPI was at a fixed concentration, the viscoelasticity of HIPE increased with the addition of XG. This was due to the complexation of WPI and XG, forming a stable gel network between the tight emulsion droplets and thus giving it a higher viscoelasticity. With an increase in WPI concentration, the stability and viscoelasticity of the emulsion were increased, and the oil-holding capacity and gel strength of the oleogels were enhanced. Moreover, the addition of XG could significantly enhance the stability and viscoelasticity of the emulsion (p < 0.05), and an increase in the concentration had a positive effect on it. The oleogels showed high gel strength (G' > 15,000 Pa) and good thixotropic recovery when the XG concentration was higher than 0.3% (w/v). WPI (2.0%) and XG (>0.3%) could be used to obtain HIPE with good physicochemical and viscoelastic properties, which in turn lead to oleogels with minimal oil loss, viscoelastic and thixotropic recovery, and temperature stability. Compared with tiger nut oil-based oleogel, tiger nut oil contained more polyunsaturated fatty acids, which were more easily decomposed through oxidation during storage and had lower oxidation stability. This study provides a reference for the preparation of oleogels from food-approved polymers and provides additional theoretical support for their potential application as solid fat substitutes.

Traceability Research on Dendrobium devonianum Based on SWATHtoMRM.

SWATHtoMRM technology was used in this experiment to further identify and trace the sources of Dendrobium devonianum and Dendrobium officinale produced in the same area using TOF and MS-MRM. After the conversion of the R package of SWATHtoMRM, 191 MRM pairs of positive ions and 96 pairs of negative ions were obtained. Dendrobium devonianum and Dendrobium officinale can be separated very well using the PCA and PLS-DA analysis of MRM ion pairs; this shows that there are obvious differences in chemical composition between Dendrobium devonianum and Dendrobium officinale, which clearly proves that the pseudotargeted metabolomics method based on SWATHtoMRM can be used for traceability identification research. A total of 146 characteristic compounds were obtained, with 20 characteristic compounds in Dendrobium devonianum. The enrichment pathways of the characteristic compounds were mainly concentrated in lipids and atherosclerosis, chagas disease, fluid shear stress and atherosclerosis, proteoglycans in cancer, the IL-17 signaling pathway, the sphingolipid signaling pathway, diabetic cardiomyopathy, arginine and proline metabolism, etc., among which the lipid and atherosclerosis pathways were more enriched, and 11 characteristic compounds affected the expression levels of IL-1, TNFα, CD36, IL-1ß, etc. These can be used as a reference for research on variety improvement and active substance accumulation in Dendrobium devonianum and Dendrobium officinale.

Ag-Doped MoSe2/ZnO Heterojunctions: A Highly Responsive Gas-Sensitive Material for Selective Detection of NO Based on DFT Study.

In this work, the adsorption and sensing behavior of Ag-doped MoSe2/ZnO heterojunctions for H2, CH4, CO2, NO, CO, and C2H4 have been studied based on density functional theory (DFT). In gas adsorption analysis, the adsorption energy, adsorption distance, transfer charge, total electron density, density of states (DOS), energy band structure, frontier molecular orbital, and work function (WF) of each gas has been calculated. Furthermore, the reusability and stability of the Ag-doped MoSe2/ZnO heterojunctions have also been studied. The results showed that Ag-doped MoSe2/ZnO heterojunctions have great potential to be a candidate of highly selective and responsive gas sensors for NO detection with excellent reusability and stability.

Adsorption and controlled release performances of flavor compounds by rice bran insoluble dietary fiber improved through steam explosion method.

In this study, steam explosion was employed as a modification process for rice bran insoluble dietary fiber (RBIDF) to improve the flavor adsorption and controlled release capacities of RBIDF. Results showed that the flavor adsorption ability of RBIDF was effectively improved due to the unfolding structure, increased specific surface area and pore volume and exposure of more functional groups after steam explosion treatment. The mechanism of the flavor adsorption behavior of modified RBIDF was preliminarily explored using adsorption kinetics and isotherms combined with SEM and DSC analysis. Results showed that the Langmuir isotherm model and pseudo-second-order kinetic model yielded the best fit to the adsorption data, indicating monolayer adsorption of flavor onto the modified RBIDF, and the adsorption was mainly driven by chemisorption process. The flavor release profile of modified RBIDF was investigated by HS-SPME/GC-MS and E-nose. After long-time storage, the flavor compounds were retained at a higher concentration in the modified RBIDF compared with the untreated RBIDF, indicating that the steam explosion treatment prolonged the retention time and enhanced the retention and controlled release capacities of RBIDF for flavor compounds. This study provides indications for potential applications of steam explosion-modified RBIDF as a novel flavor delivery system and functional ingredient.

SOD mineralized zeolitic imidazole framework-8 for the treatment of chemotherapy-related acute kidney injury.

Acute kidney injury (AKI), a prevalent and fatal adverse event, seriously affects cancer patients undergoing chemotherapy. The most important pathological mechanism of AKI is oxidative stress from reactive oxygen species (ROS). Currently, ROS scavenging is a promising strategy to manage the risk of chemotherapy-induced AKI. Herein, we successfully synthesized SOD@ZIF-8 nanoparticles by biomimetic mineralization, which were taken up by cells and could improve cell viability by limiting oxidative stress damage, as found in in vitro studies. Moreover, SOD@ZIF-8 nanoparticles exhibit broad-spectrum antioxidant properties in addition to significant renal accumulation in AKI mice, preventing clinically related cisplatin-induced AKI in murine models. AKI alleviation in the model was validated by measuring blood serum, staining kidney tissue, and related biomarkers. SOD@ZIF-8 nanoparticle therapeutic efficiency exceeds NAC, a small molecular antioxidant functioning through free radical scavenging. The results suggest SOD@ZIF-8 nanoparticles as a potential therapeutic option for AKI and other ROS-related disorders.

Metabolite of chiral cycloxaprid in solvent and in the raw of Puer tea.

Cycloxaprid (CYC) with a chiral oxabridged cis- structure contains a pair of enantiomers. Enantioselective degradation, transformation and metabolite of CYC was performed in different solvents under light and raw Puer tea processing. The results showed that cycloxaprid enantiomers in acetonitrile and acetone was stable over 17 day, however the transformation of 1S, 2R-(-)-cycloxaprid or 1R, 2S-(-)-cycloxaprid was founded in methanol. The fastest degradation of cycloxaprid occurred in acetone under light, the metabolites were founded with retention times (TR) at 34.83, 15.78 min, which mainly was via the reduce reaction of NO2 to NO, and rearrange reaction to tetrahydropyran. Degradation pathways were via the cleavage of the oxabridge seven member ring and the whole C ring. However, the degradation pathway under raw Puer tea processing was via the cleavage of whole C ring and the cleavage of oxabridge seven member ring and reducing NO2, then it underwent an elimination of nitromethylene and rearrange reaction. This pathway of Puer tea processing was firstly founded.

Performance assessment of variant UNet-based deep-learning dose engines for MR-Linac-based prostate IMRT plans.

Objective. UNet-based deep-learning (DL) architectures are promising dose engines for traditional linear accelerator (Linac) models. Current UNet-based engines, however, were designed differently with various strategies, making it challenging to fairly compare the results from different studies. The objective of this study is to thoroughly evaluate the performance of UNet-based models on magnetic-resonance (MR)-Linac-based intensity-modulated radiation therapy (IMRT) dose calculations.Approach. The UNet-based models, including the standard-UNet, cascaded-UNet, dense-dilated-UNet, residual-UNet, HD-UNet, and attention-aware-UNet, were implemented. The model input is patient CT and IMRT field dose in water, and the output is patient dose calculated by DL model. The reference dose was calculated by the Monaco Monte Carlo module. Twenty training and ten test cases of prostate patients were included. The accuracy of the DL-calculated doses was measured using gamma analysis, and the calculation efficiency was evaluated by inference time.Results. All the studied models effectively corrected low-accuracy doses in water to high-accuracy patient doses in a magnetic field. The gamma passing rates between reference and DL-calculated doses were over 86% (1%/1 mm), 98% (2%/2 mm), and 99% (3%/3 mm) for all the models. The inference times ranged from 0.03 (graphics processing unit) to 7.5 (central processing unit) seconds. Each model demonstrated different strengths in calculation accuracy and efficiency; Res-UNet achieved the highest accuracy, HD-UNet offered high accuracy with the fewest parameters but the longest inference, dense-dilated-UNet was consistently accurate regardless of model levels, standard-UNet had the shortest inference but relatively lower accuracy, and the others showed average performance. Therefore, the best-performing model would depend on the specific clinical needs and available computational resources.Significance. The feasibility of using common UNet-based models for MR-Linac-based dose calculations has been explored in this study. By using the same model input type, patient training data, and computing environment, a fair assessment of the models' performance was present.

Improving the identification and diagnostic efficiency of Metagenomic Next-Generation Sequencing for mycobacterial granuloma on postoperative formalin-fixed paraffin-embedded specimens.

OBJECTIVE: Metagenomic Next-Generation Sequencing (mNGS) has been validated to have an important role in the diagnosis of mycobacterium infection. The study aimed to further explore the mycobacteria identification ability of mNGS on formalin-fixed paraffin-embedded（FFPE）tissues from postoperative specimens. METHODS: Patients who underwent surgical biopsy or resection for clarifying the diagnosis and whose initial postoperative pathology indicated granulomatous lesions were included. Fresh tissues were sent for mycobacterium culture and Xpert MTB/RIF (Xpert) to establish the diagnosis. FFPE specimens were sent for mNGS and molecular pathology，the diagnostic values were compared between the two methods. RESULTS: A total of 65 cases with definite diagnoses were finally included in the study. 31 cases were confirmed as mycobacterium granuloma using the fresh specimen etiology as diagnostic criteria. The overall sensitivity and specificity of mNGS on FFPE specimens in the diagnosis of mycobacterium granuloma were 100% and 88.24%, respectively. In 19 cases diagnosed as tuberculous granulomas, the sensitivity (100% vs47.37%) and negative predictive value (NPV, 100%vs 82.14%) of mNGS were both significantly higher than that of molecular pathology on the FFPE section（both p 0.00）while the positive predictive value (PPV) and specificity were not significantly different. In 12 cases diagnosed as Non-tuberculous mycobacterium (NTM）granuloma, the sensitivity of mNGS was also significantly higher than that of molecular pathology on FFPE section (100% vs 66.67%, p 0.00) while the specificity, PPV and NPV were all not significantly different. CONCLUSIONS: The mNGS could be used for one-time detection of pathogens on FFPE sections with high sensitivity. It could be recommended as a supplementary method for the identification of pathogenic bacteria in the diagnosis of postoperative granuloma lesions.

The evaluation of the nutritional quality of common wild edible fungi in Yunnan Province.

There are huge resource reserves of wild edible fungi richer in their varieties in Yunnan Province which is located on plateau of low latitude and possesses unique various climate environments and bigger vegetative cover ratios. Moreover, nutrients and flavor substances in the same or various species of wild edible fungi differ greatly with the influence on different components from habitats and geographic areas. So, 5 common wild edible fungi were collected from different areas in Yunnan Province, and several findings were made from this research. Above all, through the evaluation of amino acids, these 5 fungi met the criteria for ideal protein by WHO/FAO, and the nutritional value of protein was ranked as matsutake > truffle > collybia albuminosa > bolete > chanterelle. Next, after the analysis of taste activity values, the ranking of taste was bolete > collybia albuminosa > truffle > matsutake > chanterelle. Subsequently, the ranking of characters was truffle > collybia albuminosa >bolete > matsutake > chanterelle through principal component analysis. Finally, truffle could be completely divided by Fisher discrimination analysis with a bigger difference from others, main in ash, protein, sugar, and polysaccharide, meanwhile, truffle and bolete could be completely divided by orthogonal projections to latent structures discrimination analysis, main in protein, crude fiber, fat, and amino acid. So, there was a more conspicuous difference in nutrients among fungi, through which nutrients combined with multivariate statistics analysis made possible the correct differentiation of small range categories in wild edible fungi, and the correct classification of small range of them could effectively be realized.

Brain Organoid Computing for Artificial Intelligence.

Brain-inspired hardware emulates the structure and working principles of a biological brain and may address the hardware bottleneck for fast-growing artificial intelligence (AI). Current brain-inspired silicon chips are promising but still limit their power to fully mimic brain function for AI computing. Here, we develop Brainoware , living AI hardware that harnesses the computation power of 3D biological neural networks in a brain organoid. Brain-like 3D in vitro cultures compute by receiving and sending information via a multielectrode array. Applying spatiotemporal electrical stimulation, this approach not only exhibits nonlinear dynamics and fading memory properties but also learns from training data. Further experiments demonstrate real-world applications in solving non-linear equations. This approach may provide new insights into AI hardware.

The efficacy of neoadjuvant EGFR-TKI therapy combined with radical surgery for stage IIIB lung adenocarcinoma harboring EGFR mutations: A retrospective analysis based on single center.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could provide survival benefits for locally advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). However, the role of radical surgery for EGFR-TKI treated stage IIIB EGFRm NSCLC remains controversial. This study attempted to assess the feasibility of neoadjuvant EGFR-TKI followed by radical surgery for stage IIIB EGFRm NSCLC. Patients and Methods: Between 2013 and 2020, EGFRm lung adenocarcinoma (LUAD) patients in clinical stage IIIB undergoing neoadjuvant EGFR-TKI followed by surgery (T-S-Arm) and EGFR-TKI alone (T-Arm) were reviewed retrospectively in Shanghai Pulmonary Hospital (SPH). The chi-square test, Student's t-test or Fisher's exact test was performed for analysis of baseline characteristics. Progression-free survival (PFS) was estimated using the Kaplan-Meier analysis. Multivariate Cox regression analysis was used to identify independent predictors of progression. Results: A total of 43 patients were divided into T-S-Arm (n = 21) and T-Arm (n = 22). Patients were well-balanced between the two arms. The majority of patients were female (n = 25, 58.1%), non-smokers (n = 35, 81.4%), first-generation of EGFR-TKI treatment (n = 39, 90.7%), and exon 19 deletions (19-DEL) (n = 26, 60.5%). The median diagnostic age was 63.0 years [interquartile range (IQR), 54.0-67.5 years). At the cut-off date with June 30th 2022, median follow-up time was 28 months (IQR, 20-39 months). Neoadjuvant EGFR-TKI treatment followed by radical surgery could significantly improve the median PFS compared with patients underwent EGFR-TKI alone (23.0 months vs 14.5 months, P = 0.002). Multivariate Cox regression analysis demonstrated that radical surgery (T-S-Arm vs. T-Arm, HR: 0.406; 95% CI: 0.207-0.793, P = 0.027) was the only independent predictor for disease progression. The stratified analysis demonstrated patients with N2 disease could benefit from radical surgery (HR, 0.258; 95% CI, 0.107-0.618), especially for patients harboring L858R mutation (HR, 0.188; 95% CI, 0.059-0.604). Conclusions: For stage IIIB EGFRm NSCLC patients, the prognosis might be improved by neoadjuvant EGFR-TKI followed by radical surgery versus EGFR-TKI alone, especially for those with N2 disease and harboring L858R mutation.

Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial.

BACKGROUND: This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC). METHODS: Patient eligibility mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. RESULTS: In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). CONCLUSIONS: Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. TRIAL REGISTRATION: ChiCTR1900024014, June 22, 2019.

An ultra-fast deep-learning-based dose engine for prostate VMAT via knowledge distillation framework with limited patient data.

Objective. Deep-learning (DL)-based dose engines have been developed to alleviate the intrinsic compromise between the calculation accuracy and efficiency of the traditional dose calculation algorithms. However, current DL-based engines typically possess high computational complexity and require powerful computing devices. Therefore, to mitigate their computational burdens and broaden their applicability to a clinical setting where resource-limited devices are available, we proposed a compact dose engine via knowledge distillation (KD) framework that offers an ultra-fast calculation speed with high accuracy for prostate Volumetric Modulated Arc Therapy (VMAT).Approach. The KD framework contains two sub-models: a large pre-trained teacher and a small to-be-trained student. The student receives knowledge transferred from the teacher for better generalization. The trained student serves as the final engine for dose calculation. The model input is patient computed tomography and VMAT dose in water, and the output is DL-calculated patient dose. The ground-truth \dose was computed by the Monte Carlo module of the Monaco treatment planning system. Twenty and ten prostate cases were included for model training and assessment, respectively. The model's performance (teacher/student/student-only) was evaluated by Gamma analysis and inference efficiency.Main results. The dosimetric comparisons (input/DL-calculated/ground-truth doses) suggest that the proposed engine can effectively convert low-accuracy doses in water to high-accuracy patient doses. The Gamma passing rate (2%/2 mm, 10% threshold) between the DL-calculated and ground-truth doses was 98.64 ± 0.62% (teacher), 98.13 ± 0.76% (student), and 96.95 ± 1.02% (student-only). The inference time was 16 milliseconds (teacher) and 11 milliseconds (student/student-only) using a graphics processing unit device, while it was 936 milliseconds (teacher) and 374 milliseconds (student/student-only) using a central processing unit device.Significance. With the KD framework, a compact dose engine can achieve comparable accuracy to that of a larger one. Its compact size reduces the computational burdens and computing device requirements, and thus such an engine can be more clinically applicable.

Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: Anti-PD-1(L1) therapies are less efficacious in patients with EGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood. METHODS: The characteristics of T cells in EGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples. In vitro restimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic EGFRL858R mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism in vivo. RESULTS: EGFR-mutated tumors showed a lack of CD8+T cell infiltration and impaired CD8+T cell cytotoxic function. The incompetent CD8+T cells in EGFR-mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8+T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in EGFR-mutated tumors. IL-10 induced hallmarks of CD8+T cells immunity in CD39-dependent manner. Using autochthonous EGFR L858R-driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in EGFR-mutated lung tumors. CONCLUSIONS: Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8+T cells, fewer phenotypically cytotoxic and exhausted CD39+CD8+T cells in EGFR-mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment in EGFR-mutated tumors.