Microbiological Rapid On-Site Evaluation for Pulmonary Infectious Diseases.

The prompt initiation of empirical anti-infective therapy is crucial in patients presenting with unexplained pulmonary infection. Although imaging acquisition is relatively straightforward in clinical practice, its lack of specificity often necessitates additional time-consuming tests such as sputum culture, bronchoalveolar-lavage fluid culture, or genetic sequencing to identify the underlying etiology of the disease accurately. Moreover, the limited efficacy of empirical anti-infective treatment may contribute to antibiotic misuse. Recent advancements in interpreting microbial background on rapid on-site evaluation (ROSE) slides have enabled clinicians to promptly obtain samples through bronchoscopy (e.g., alveolar lavage, mucosal brushing, tissue clamp), facilitating bedside staining and interpretation that provides essential microbial background information. Consequently, this establishes a foundation for developing targeted anti-infection treatment and individualized drug therapy plans. With a better understanding of which pathogens are causing infections in real-time, physicians can avoid unnecessary broad-spectrum antibiotics contributing to antibiotic resistance. Establishing a rapid and standardized M-ROSE workflow within respiratory medicine departments or intensive care units will greatly assist physicians in formulating accurate treatment strategies for patients, which holds significant clinical implications.

Brassinosteroid regulates stomatal development in etiolated cotyledons via transcription factors BZR1 and BES1.

Brassinosteroids (BRs) are phytohormones that regulate stomatal development BRASSINAZOLE RESISTANT 1. In this study, we report that BR represses stomatal development in etiolated Arabidopsis (Arabidopsis thaliana) cotyledons via transcription factors BRASSINAZOLE RESISTANT 1 (BZR1) and bri1-EMS SUPPRESSOR1 (BES1), which directly target MITOGEN-ACTIVATED PROTEIN KINASE KINASE 9 (MKK9) and FAMA, two important genes for stomatal development. BZR1/BES1 bind MKK9 and FAMA promoters in vitro and in vivo, and mutation of the BZR1/BES1 binding motif in MKK9/FAMA promoters abolishes their transcription regulation by BZR1/BES1 in plants. Expression of a constitutively active MKK9 (MKK9DD) suppressed overproduction of stomata induced by BR deficiency, while expression of a constitutively inactive MKK9 (MKK9KR) induced high-density stomata in bzr1-1D. In addition, bzr-h, a sextuple mutant of the BZR1 family of proteins, produced overabundant stomata, and the dominant bzr1-1D and bes1-D mutants effectively suppressed the stomata-overproducing phenotype of brassinosteroid insensitive 1-116 (bri1-116) and brassinosteroid insensitive 2-1 (bin2-1). In conclusion, our results revealed important roles of BZR1/BES1 in stomatal development, and their transcriptional regulation of MKK9 and FAMA expression may contribute to BR-regulated stomatal development in etiolated Arabidopsis cotyledons.

From NAFLD to MASLD: When metabolic comorbidity matters.

INTRODUCTION AND OBJECTIVES: In a recent development, a cohort of hepatologists has proposed altering the nomenclature of non-alcoholic fatty liver disease (NAFLD) to metabolic-associated steatotic liver disease (MASLD), accompanied by modified diagnostic criteria. Our objective was to investigate the effect of the revised definition on identifying significant hepatic fibrosis. PATIENTS AND METHODS: From Jan 2009 to Dec 2022, a total of 428 patients with biopsy-proven hepatic steatosis were diagnosed with NAFLD. Patients were classified into subgroups according to MASLD and Cryptogenic-SLD diagnostic criteria. The clinical pathological features were compared between these two groups. Risk factors for significant fibrosis were analysed in the MASLD group. In total, 329 (76.9 %) patients were diagnosed with MASLD, and 99 (23.1 %) were diagnosed with Cryptogenic-SLD. RESULTS: Those with MASLD exhibited a higher degree of disease severity regarding histology features than Cryptogenic-SLD. The prevalence of significant fibrosis increased from 13 % to 26.6 % for one and two criteria present to 42.5 % for meeting three or more cardiometabolic risk factor (CMRF) criteria (p = 0.001). ALB (aOR:0.94,95 %CI:0.90-1.00; p = 0.030), lower levels of PLT (aOR:0.99, 95 %CI:0.99-1.00; p < 0.001), and more metabolic comorbidities (aOR:1.42,95 %CI:1.14-1.78; p = 0.012) were independent risk factors of significant fibrosis in MASLD. CONCLUSIONS: The new nomenclature of MASLD and SLD is more applicable to identifying significant fibrosis than NAFLD. Patients with three or more cardiometabolic risk factors are at higher risk of fibrosis.

Analysis of clinical characteristics and imagological features of the aortic dissection patients with negative D-dimer results.

Background: D-dimer (DD) is a vital biomarker to rule out the diagnosis of aortic dissection (AD). However, the DD level in some patients with AD is not high in clinical practice, which often leads to missed diagnosis; therefore, understanding the characteristics of patients with AD and negative DD is of great clinical value. Methods: From May 2015 to October 2020, 286 patients with AD who visited the first medical contact (FMC) within 24 h of symptom onset and were hospitalized in the Xiamen Cardiovascular Hospital of Xiamen University were enrolled in this study. Clinical characteristics and outcomes of patients were assessed. Results: Among them, 13 cases (approximately 4.5%) had negative DD results. Compared to patients with positive DD results, patients with negative DD results had significantly higher platelet counts and lower aortic dissection detection risk scores (ADD-RS). The imagological analysis showed that patients with AD and negative DD had lower extension scores and milder damage to the mesenteric artery and three branches of the aortic arch. Furthermore, the results of the multivariable analysis showed that white blood cell count (WBC) [odds ratio (OR): 1.379, P = 0.028], FMC (OR: 0.904, P = 0.028), and extension score (OR: 1.623, P = 0.046) were associated with negative DD result. Conclusions: Patients with AD and negative DD results had longer FMC and lower WBC. Imaging showed a smaller tear extension range and less damage to the mesenteric artery and three branches of the aortic arch. A negative DD result could not completely rule out AD even if the ADD-RS was zero.

Phylogenetic analysis, morphological studies, element profiling, and muscarine detection reveal a new toxic Inosperma (Inocybaceae, Agaricales) species from tropical China.

Tropical Asian collections of Inosperma are usually poisonous mushrooms that have caused many poisoning incidents. However, the species diversity and the toxic mechanisms of these Inosperma species are still unclear. In this study, we describe the discovery of Inosperma wuzhishanense sp. nov. from Wuzhishan City, Hainan Province, tropical China. The new species was identified based on morphological and multi-locus (ITS, nrLSU, and RPB2) phylogenetic analyses. The new species is characterized by its reddish-brown pileus, fibrillose stipes with finely protruding fibrils, rather crowded lamellae, smooth and ellipsoid basidiospores, and mostly clavate, thin-walled cheilocystidia. The new species is phylogenetically nested in the Old World tropical clade 2 and is sister to the tropical Indian taxa I. akirnum. Detailed descriptions, color photos of the new species, and comparisons with its closely related species are provided. Additionally, the muscarine content of the new species was analyzed by ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). The muscarine contents ranged from 4,359.79 ± 83.87 mg/kg to 7,114.03 ± 76.55 mg/kg, 2,748.37 ± 106.85 mg/kg to 4,491.35 ± 467.21 mg/kg, and 2,301.36 ± 83.52 mg/kg to 2,775.90 ± 205.624 mg/kg in the stipe, pileus, and lamellae, respectively. The elemental composition and concentration were determined using inductively coupled plasma-mass spectrometry (ICP-MS). A total of 24 elements were detected. Among the heavy metals detected, arsenic showed the highest level of toxicity with a concentration of 36.76 ± 0.43 mg/kg.

A Novel Fluorescence Sensor for Iodide Detection Based on the 1,3-Diaryl Pyrazole Unit with AIE and Mechanochromic Fluorescence Behavior.

A D-A type of luminophore, TPA-CDP, was designed and synthesized by using triphenylamine (TPA) as D (electron donor), 1,3-diaryl pyrazole with cyano groups (CDP) as A (electron acceptor) and employing a cyanovinyl segment as a recognition group. Firstly, TPA-CDP demonstrates effective fluorescence quenching as a sensor for I- by the nucleophilic addition reaction of the cyanovinyl segment with a high level of sensitivity, selectivity and a low determination limit of 4.43 µM. Interestingly, TPA-CDP exhibited an AIE phenomenon with the fw value reaching 50%. In addition, TPA-CDP displayed distinct mechanochromic fluorescence behavior with 70 nm red shift, which was observed over four repeated cycles. Furthermore, the mechanochromic fluorescence behavior of TPA-CDP, as observed in powder XRD experiments, was found to be associated with the morphological transition from a crystalline state to an amorphous state. These results confirm the significant potential of CDP as a powerful electron-deficient component in the creation of D-A-type mechanochromic fluorescence materials and biosensors for detecting I-.

Dynamic cytokines signature predicts survival outcome from severe Immune-related hepatitis with PD-1/PD-L1 blockade in lung cancer.

BACKGROUND: Immune-related adverse events (irAEs), particularly immune-related hepatitis (IRH) is a potentially serious complication of immune checkpoint inhibitor (ICI) therapy. This retrospective cohort study investigated potential prognostic and predictive biomarkers for IRH. METHOD: This study included 37 patients with advanced lung cancer who received ICIs and were divided into two groups: ≥Grade 3 (G3)-IRH group (n = 17) and without irAE (no-irAE) group (n = 20). Blood samples collected at three different time points and pre-treatment tumor biopsy samples were analyzed using multi-omics assays. RESULTS: The IL-1B RNA expression was significantly increased (limma, fold = 1.94) in the ≥ G3-IRH group than the no-irAE group. Compared with no-irAE group, ≥G3-IRH group had higher monocyte and eosinophil infiltration and lower macrophage infiltration, particularly macrophage M2. Transcriptomics analyses of pre-treatment tumor samples revealed significant upregulation of various inflammation-related genes in the ≥ G3-IRH group (False discovery rate < 0.05). Moreover, various proinflammatory cytokines and chemokines were significantly lower in the plasma of the ≥ G3-IRH group than in the no-irAE group. Subgroup analyses of the ≥ G3-IRH group revealed that plasma IL-1A was significantly higher among those whose IRH resolved than those who had IRH-related death. Patients who died had a greater increase in immune score and Euclidean distance from the baseline to the seventh day of IRH onset, with a dramatic increase in Euclidean distance after immunosuppression, suggesting overstimulated immune status. CONCLUSION: Our study demonstrated the association between IL-1B overexpression and IRH susceptibility. Immune score and Euclidean distance of inflammatory cytokines may provide predictive value on the survival outcome from ≥ G3 IRH.

Sucrose Esters and Beeswax Synergize to Improve the Stability and Viscoelasticity of Water-in-Oil Emulsions.

W/O emulsions are commonly used to prepare stable low-fat products, but their poor stability limits widespread applications. In this study, sucrose ester (SE) and beeswax were utilized to prepare an oil dispersion system in rapeseed oil, which was used as the external oil phase to further synergistically construct the W/O emulsion systems. The results show that spherical and fine crystals are formed under the synergistic effect of SE and BW (1.5 SE:0.5 BW). In this state, a dense interfacial crystal layer was easily formed, preventing droplet aggregation, leading to droplet size reduction (1-2 µm) and tight packing, improving viscoelasticity and resistance to deformation, and increasing the recovery rate (52.26%). The long-term stability of W/O emulsions containing up to 60 wt% water was found to be more than 30 days. The increase in the aqueous phase led to droplet aggregation, which increased the viscosity (from 400 Pa·s to 2500 Pa·s), improved the structural strength of the emulsion, and increased the width of the linear viscoelastic region (from 1% strain to 5% strain). These findings provide some technical support for the further development of stable low-fat products.

Straw mulch improves soil carbon and nitrogen cycle by mediating microbial community structure and function in the maize field.

This study was conducted to investigate the capability of the microbial community characteristics and soil variables to promote carbon and nitrogen cycles in maize fields under straw mulch. We covered the surface soil of the maize field with different amounts of wheat straw (0 kg/ha, 2,250 kg/ha, and 4,500 kg/ha) and used 16S rRNA and ITS sequencing, Biology ECO-plate, traditional enzymology, TOC analyzer, and HPLC to measure bacterial and fungal community composition and functions, characteristics of microbial carbon source metabolism, carbon and nitrogen fraction, enzyme activity, and organic acid content in the maize rhizosphere and non-rhizosphere. The results indicated that short-term straw mulch insignificantly affected the alpha diversity of bacterial and fungal communities whereas significantly influenced their beta diversity. The results of functional prediction revealed that straw mulch considerably boosted the relative abundances of bacteria belonging to chemoheterotrophy, aerobic chemoheterotrophy, ureolysis, and nitrogen fixation and inhibited fermentation and nitrate reduction in maize rhizosphere soil. These processes primarily drove the C and N cycles in soil. Straw mulch also improved fungal saprotrophs by raising the proportion of Chaetomiaceae and Chaetosphaeriaceae. The Biology ECO-plate results illustrated that straw mulch weakened the metabolism capacity of microbial labile carbon resources. As a result, the labile C and N fractions were raised under straw mulch. Our results also showed that straw mulch primarily regulated the microbial community structure in rhizosphere soil by significantly decreasing Firmicutes and Ascomycota relative abundance while increasing Basidiomycota. The fungal community structure is more than bacterial for affecting soil microbial biomass carbon, readily oxidizable organic carbon, dissolved organic carbon, available nitrogen, ammonium, and nitrate directly and indirectly through malic acid content and cellulase, protease, and amylase activity. Overall, our findings imply that straw mulch might influence the bacterial and fungal community structures, thereby boosting the production of labile C and N components and accelerating the C and N cycle in maize fields.

Biochemical characterization and molecular modification of a zearalenone hydrolyzing enzyme Zhd11D from Phialophora attinorum.

ZEN lactone hydrolase (ZHD) can hydrolyze zearalenone (ZEN) to less or non-toxic product, providing an environment-friendly way for food or feeds-containing ZENs detoxification. Here, a newly identified ZHD from Phialophora attinorum, annotated as Zhd11D, was characterized to exhibit highest activity against ZEN at pH 8.0 and 35 â„ƒ with a specific activity of 304.7 U/mg, which was far higher than most of the reported ZHDs. A nonspecific protein engineering method was introduced through fusing a segment of amphiphilic short peptide S1 at the N-terminus of Zhd11D, resulting in both improved activity (1.5-fold) and thermostability (2-fold at 40 â„ƒ). Biochemical analysis demonstrated that self-aggregation caused by intermolecular interactions between S1 contributed to the improvement of the enzymatic properties of Zhd11D. Additionally, S1-Zhd11D showed a higher hydrolysis rate of ZEN than Zhd11D in peanut oil.

Repurposing of rilpivirine for preventing platelet ß3 integrin-dependent thrombosis by targeting c-Src active autophosphorylation.

BACKGROUND: HIV-infected individuals are known to be at higher risk for thrombotic cardiovascular disease (CVD), which may also be differentially affected by components of anti-HIV drugs. To identify the effects of a series of FDA-approved anti-HIV drugs on platelet aggregation in humans, focusing on the novel pharmacological effects of rilpivirine (RPV), a reverse transcriptase inhibitor, on platelet function both in vitro and in vivo and the mechanisms involved. METHODS AND RESULTS: In vitro studies showed that RPV was the only anti-HIV reagent that consistently and efficiently inhibited aggregation elicited by different agonists, exocytosis, morphological extension on fibrinogen, and clot retraction. Treatment of mice with RPV significantly prevented thrombus formation in FeCl3-injured mesenteric vessels, postcava with stenosis surgery, and ADP -induced pulmonary embolism models without defects in platelet viability, tail bleeding, and coagulation activities. RPV also improved cardiac performance in mice with post-ischemic reperfusion. A mechanistic study revealed that RPV preferentially attenuated fibrinogen-stimulated Tyr773 phosphorylation of ß3-integrin by inhibiting Tyr419 autophosphorylation of c-Src. Molecular docking and surface plasmon resonance analyses showed that RPV can bind directly to c-Src. Further mutational analysis showed that the Phe427 residue of c-Src is critical for RPV interaction, suggesting a novel interaction site for targeting c-Src to block ß3-integrin outside-in signaling. CONCLUSION: These results demonstrated that RPV was able to prevent the progression of thrombotic CVDs by interrupting ß3-integrin-mediated outside-in signaling via inhibiting c-Src activation without hemorrhagic side effects, highlighting RPV as a promising reagent for the prevention and therapy of thrombotic CVDs.

Coconut shell biochar application in liquid-solid microextraction of triazine herbicides from multi-media environmental samples.

A rapid, fast, widely applicable liquid-solid microextraction and purification method of triazine herbicides (TRZHs) in muti-media samples using salting-out assisted liquid-liquid extraction (SALLE) combined with self-assembled monolithic spin columns-solid phase micro extraction (MSC-SPME) was developed. Environmentally friendly coconut shell biochar (CSB) was used as the adsorbents of MSC-SPME. Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was the separation and determination method. The adsorption kinetics and isotherms were investigated to indicate the interaction between CSB and TRZHs. Several parameters influencing the liquid-solid microextraction efficiency, such as sample pH, salting-out solution volume and pH, sample loading speed, elution speed, elution ratio and volume of eluent were systematically investigated with the aid of orthogonal design. The whole extraction process was operated within 10 min. Under the optimum extraction and determination conditions, good linearities for three TRZHs were obtained in a range of 0.10-200.00 ng mL-1, with linear coefficients (R2) greater than 0.999. The limits of detection (LODs) and limits of quantification (LOQs) were in the range of 6.99-11.00 ng L-1 and 23.33-36.68 ng L-1, respectively. The recoveries of the three TRZHs in multi-media environmental samples were ranged from 69.00% to 124.72%, with relative standard deviations (RSDs) lower than 0.43%. This SALLE-MSC-SPME-UPLC-MS/MS method was successfully applied to the determination of TRZHs in environmental and food samples and exhibited the advantages of high efficiency and sensitivity, low cost, and environmental friendliness. Compared with the methods published before, CSB-MSC was green, rapid, easy-operated, and reduced the whole cost of the experiment; SALLE combined MSC-SPME eliminated the matrix references effectively; what's more, the SALLE-MSC-SPME-UPLC-MS/MS method could be applied to various sample without complicated sample pretreatment procedure.

Improving the specific activity and stability of alkaline pectinase PEL3 through SpyTag/SpyCatcher cyclization.

OBJECTIVES: PEL3, an alkaline pectinase, exhibited the highest activity among documented alkaline pectate lyases reported in our early study. Unfortunately, undesired thermal stability hampering its industrial application. The purpose of this study is to enhance the performance of wild-type PEL3 (W-PEL3) based on SpyTag/SpyCatcher-mediated cyclization. RESULTS: The cyclized PEL3 (C-PEL3) was observed to fold correctly and generate a spatial conformation in a head-to-tail manner in E. coli. C-PEL3 exhibited comparable optimum pH and temperature to those of W-PEL3. Moreover, the catalytic activity of C-PEL3 increased by 23% compared to W-PEL3, and the kcat/Km of C-PEL3 was 1.5-fold greater than that of the W-PEL3. Importantly, C-PEL3 showed improved stability compared to W-PEL3. Firstly, C-PEL3 displayed a 65% increase in residual activity after treatment at 55 °C for 30 min. Secondly, C-PEL3 was prone to resist heat-induced protein aggregation. Thirdly, C-PEL3 exhibited metal ion stability. Circular dichroism analysis revealed that C-PEL3 was more capable of maintaining its secondary structures than W-PEL3 upon heat treatment. CONCLUSIONS: C-PEL3, the initial example of a circular pectinase through SpyTag/SpyCatcher cyclization, exhibits superior performance and represents a highly encouraging contender for industrial utilization.

[Acupoint injection ameliorates Th1/Th2 imbalance through Toll-like receptor 4/activator protein-1 signal pathway and improves inflammatory response in rats with allergic rhinitis].

OBJECTIVE: To observe the effect of acupoint injection on serum T helper (Th)1/Th2 related cytokines, and the expression levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and activator protein-1 (AP-1) of nasal mucosa in allergic rhinitis (AR) rats, so as to explore its mechanism underlying improvement of AR. METHODS: Thirty-two SD rats were randomly divided into normal, model, non-acupoint injection and acupoint injection groups (n=8 in each group). The AR model was established by ovalbumin sensitization. In the acupoint injection group, "Yintang" (GV24+) and bilateral "Yingxiang" (LI20) were selected for injection of mixture solution of dexamethasone and lidocaine (0.05 mL/acupoint), once every 4 days for a total of 4 times. The non-acupoints, located at the midpoint between the "Houhai" and "Huantiao" (GB30) on the bilateral hips and the sites 5 cm inferior to the axillary were injected with the same dose of mixture solution as that in the acupoint injection group. The AR severity was assessed by cumulative quantification scoring methods (including the numbers of nose-catching and sneezes, and the amount of nasal secretions in 30 min). The pathological changes of nasal mucosa were observed by HE staining. The contents of immunoglobulin E (IgE), interleukin (IL)-4 and interferon (IFN)-γ in serum were detected by ELISA. The expressions of TLR4 and MyD88 in nasal mucosa was detected by immunofluorescence. The expression of AP-1 in nasal mucosa was detected by Western blot. RESULTS: Following modeling, the AR symptom score, serum IgE and IL-4 contents and expression of TLR4, MyD88 and AP-1 of nasal mucosa were significantly increased in the model group than those in the normal group (P<0.01), while the serum IFN-γ content was significantly decreased (P<0.01). Compared with the model group and non-acupoint injection group, the AR symptom score, the serum contents of IgE and IL-4 and the expressions of TLR4, MyD88 and AP-1 in nasal mucosa were significantly decreased in the acupoint injection group (P<0.01, P<0.05), while the serum IFN-γ content was significantly increased (P<0.01). H.E. staining of the nasal mucosa showed that most of the epithelium fell off, the lamina propria vessels expanded, the glands proliferated, and eosinophils and lymphocytes infiltrated in the model and non-acupoint injection groups, and those were significantly improved in the acupoint injection group. CONCLUSION: Acupoint injection can effectively improve allergic inflammation of the nose in AR rats, which may be related with its function in inhibiting the abnormal activation of TLR4/AP-1 signaling pathway and regulating the imbalance of Th1/Th2.

Integrative transcriptomic and proteomic analyses reveal a positive role of BES1 in salt tolerance in Arabidopsis.

Introduction: Salt stress is a major environmental factor limiting plant growth and development. Previous studies have indicated that the steroidal hormones-brassinosteroids (BRs) are important regulators of plant responses to salt stress. However, the underlying molecular mechanisms have not been fully understood. Methods: (1) Phenotypic analysis of bes1-D, BES1-RNAi and their wild-type (Col-0) under salt treatments with different concentrations of NaCl. (2) Transcriptomic and proteomic profiling of BES1-regulated genes and proteins under salt treatment; (3) qRT-PCR validation of selected BES1-regulated genes under salt stress; (4) Transient transcriptional assay of BES1 regulation on its putative target genes in Arabidopsis protoplasts; (5) Electrophoresis Mobility Shift Assay (EMSA) of BES1 binding with its potential target genes. Results and Discussion: Phenotypic analysis indicated that bes1-D, a gain-of-function mutant of the BR-regulated transcription factor BES1 in Arabidopsis showed better salt tolerance than the wild-type plant, while a BES1 RNA interference (BES1-RNAi) line was more sensitive to salt stress. Global gene expression profiling and time series clustering analyses identified a total of 1,170 genes whose expression was boosted in bes1-D under salt stress. Further GO enrichment and gene functional network analyses identified several key modules that are regulated by BES1 and most sensitive to salt stress perturbations, including stress response, response to ABA and ROS, flavonoid biosynthesis and transmembrane transport. A comparative proteomic analysis performed under the same stress conditions supported the results from the transcriptome analysis. In addition, transient gene transcription assays in Arabidopsis protoplasts and in vitro DNA binding assays verified that BES1 regulates the expression of some ion transporter genes directly and indirectly. Taken together, our results support a positive role of BES1 in plant salt tolerance.

Copy number variations mediate major pathological response to induction chemo-immunotherapy in unresectable stage IIIA-IIIB lung cancer.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Despite this, evidence supporting optimal management of certain stages remains a topic of debate. In this retrospective study we examine the efficacy and safety, as well as exploring the biomarkers of neoadjuvant induction immuno-chemotherapy, in Chinese patients with unresectable stage III NSCLC. METHODS: Patients with unresectable stage III NSCLC who were identified as driver mutation-negative and who received neoadjuvant chemo-immunotherapy were enrolled from three Chinese hospitals between Jan. 17, 2019, and Jan.17, 2022. Perioperative outcomes and survival data were collected. Retrospective biomarker exploration was performed in available baseline tumor samples and surgical specimens. RESULTS: 94 patients were enrolled and received chemo-immunotherapy as neoadjuvant treatment. 80 patients had squamous cell carcinoma, and 26 had stage IIIB disease. Surgery conversion rate was 74.4%, R0 resection rate was 98.4%. Of 64 patients who underwent surgery, major pathological response (MPR) rate was 65.6% and pathologic complete response (pCR) rate was 42.2%. 73% of patients with N2 disease demonstrated down-staging to N0. Treatment-related adverse events (TRAEs) occurred in 43 patients (45.7%) with anemia was the most common. The Grade ≥ 3 TRAEs rate was 3.2% (3/94). A significant association between copy number variation (CNV) ploidy was also found. CONCLUSION: The combination treatment of immuno-chemotherapy for unresectable stage III NSCLC is not only effective but also has a favourable safety profile. For the first time we provide evidence that CNV status may be a predictive biomarker of MPR.

MMP9-Responsive Graphene Oxide Quantum Dot-Based Nano-in-Micro Drug Delivery System for Combinatorial Therapy of Choroidal Neovascularization.

Age-related macular degeneration (AMD), especially wet AMD with choroidal neovascularization (CNV), commonly causes blindness in older patients and disruption of the choroid followed by second-wave injuries, including chronic inflammation, oxidative stress, and excessive matrix metalloproteinase 9 (MMP9) expression. Increased macrophage infiltrate in parallel with microglial activation and MMP9 overexpression on CNV lesions is shown to contribute to the inflammatory process and then enhance pathological ocular angiogenesis. Graphene oxide quantum dots (GOQDs), as natural antioxidants, exert anti-inflammatory effects and minocycline is a specific macrophage/microglial inhibitor that can suppress both macrophage/microglial activation and MMP9 activity. Herein, an MMP9-responsive GOQD-based minocycline-loaded nano-in-micro drug delivery system (C18PGM) is developed by chemically bonding GOQDs to an octadecyl-modified peptide sequence (C18-GVFHQTVS, C18P) that can be specifically cleaved by MMP9. Using a laser-induced CNV mouse model, the prepared C18PGM shows significant MMP9 inhibitory activity and anti-inflammatory action followed by antiangiogenic effects. Moreover, C18PGM combined with antivascular endothelial growth factor antibody bevacizumab markedly increases the antiangiogenesis effect by interfering with the "inflammation-MMP9-angiogenesis" cascade. The prepared C18PGM shows a good safety profile and no obvious ophthalmic or systemic side effects. The results taken together suggest that C18PGM is an effective and novel strategy for combinatorial therapy of CNV.

The valuable role of dynamic 18F FDG PET/CT-derived kinetic parameter Ki in patients with nasopharyngeal carcinoma prior to radiotherapy: A prospective study.

BACKGROUND AND PURPOSE: Dynamic positron emission tomography/computed tomography (PET/CT) served the potential role of characterizing malignant foci. The main objective of this prospective study was to explore the advantage of dynamic PET/CT imaging in characterizing nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Patients with probable head and neck disease underwent a local dynamic PET/CT scan followed by a whole-body static scan. Patlak analysis was used to generate parametric influx rate constant (Ki) images from 48 frames obtained from a dynamic PET/CT scan. By delineating the volumes-of-interest (VOIs) of: primary tumor (PT), lymph node (LN), and normal nasopharyngeal tissues (N), we acquired the corresponding Ki mean and SUVmean of each site respectively to perform the quantitative statistical analysis. RESULTS: Qualified images of 71 patients with newly diagnosed NPC and 8 without nasopharyngeal malignant lesions were finally included. We found the correlations between Ki mean-PT and critical clinical features, including clinical stage (r = 0.368), T category (r = 0.643) and EBV-DNA copy status (r = 0.351), and Ki mean-PT differed within the group. SUVmean-PT showed correlations with clinical stage (r = 0.280) and T category (r = 0.472), but could hardly differ systematically within group of clinical features except T category. Ki mean-LN offered the positive correlations with N category (r = 0.294), M category (r = 0.238) and EBV-DNA copy status (r = 0.446), and differed within the group. In addition, Ki mean represented a sensitivity of 94.4 % and a specificity of 100 %, in distinguishing NPC from the non-NPC, when the cut-off was defined as 0.0106. When the cut-off of SUV being defined as 2.03, the sensitivity and specificity were both 100 %. CONCLUSION: Our research confirmed Ki compared favorably to SUV in characterizing NPC and found that Ki can serve as an effective imaging marker of NPC.

Erratum: GCN5 participates in KLF4-VEGFA feedback to promote endometrial angiogenesis.

[This corrects the article DOI: 10.1016/j.isci.2022.104509.].