Radical bromination-induced ipso cyclization-ortho cyclization sequence of N-hydroxylethyl-N-arylpropiolamides.

A facile procedure is reported for the synthesis of various 2-bromo-1-phenyl-5,6-dihydro-3H,7aH-benzo[b]pyrrolo[2,1-c][1,4]oxazin-3-ones via a radical bromination-induced ipso cyclization-ortho cyclization sequence of N-arylpropiolamides in the presence of TBAB and oxone. The radical cyclization sequence involves a radical bromo α-addition into the alkyne, ipso-cyclization, and ortho-trapping of the spirocyclic intermediate.

MiR-30a sensitized lung cancer against neoadjuvant chemotherapy by depressing autophagy.

OBJECTIVE: This study was aimed at exploring whether miR-30a enhanced sensitivity of non-small-cell lung cancer (NSCLC) cells against neoadjuvant chemotherapy through an autophagy-dependent way. METHODS: We totally recruited 304 NSCLC patients who have underwent chemotherapy, as well as 185 NSCLC patients who did not receive chemotherapy. NSCLC cell lines (i.e. H1299 and H460) were also purchased, and they were transfected by miR-30a mimic/inhibitor. Furthermore, cisplatin (DDP)/pemetrexed (PEM) resistance of NSCLC cells was assessed utilizing MTT assay, and autophagic proteins isolated from NSCLC tissues and cells were quantitated by western blotting. RESULTS: Lowly expressed miR-30a was reflective of lymph node metastasis, advanced TNM stage and poor 5-year survival among NSCLC patients treated by neoadjuvant chemotherapy (i.e. combined treatment of DDP and PEM) (P < 0.05). Moreover, DDP combined with PEM attenuated viability and proliferation, but, on the contrary, promoted autophagy of H1299 and H460 cell lines (P < 0.05). However, miR-30a undermined resistance of NSCLC cells against DDP and PEM (P < 0.05), and it suppressed DDP/PEM-induced autophagy and promoted DDP/PEM-triggered apoptosis of NSCLC cells (P < 0.05). CONCLUSIONS: Intentionally elevating miR-30a expression was conducive to improving NSCLC prognosis after neoadjuvant chemotherapy, for its depressing drug-caused autophagy and resistance.

Antimicrobial peptide CAMA-syn expressed in pulmonary epithelium by recombination adenovirus inhibited the growth of intracellular bacteria.

BACKGROUND: Intracellular bacteria, especially Mycobacterium tuberculosis, are important pathogenic microorganisms that endanger human health. Purified and synthesized cecropin A-magainin 2 (CAMA-syn) can exhibit a higher antibacterial activity and lower cytotoxicity. To enhance such antimicrobial potential, it would be desirable to deliver CAMA-syn expressed in lung epithelial cells by an adenovirus vector using gene therapy. METHODS: A549 cells in vitro and lung epithelial cells in vivo were used to express CAMA-syn by transducing recombinant adenovirus Ad-SPC-CAMA/GFP, and the expression of CAMA-syn was determined by a reverse transcriptase-polymerase reaction (RT-PCR) and immunofluorescence. The antimicrobial activity in cells was investigated by colony-forming rate and growth curve. Forty Kunming mice of a Bacillus Calmette-Guerin (BCG) infection animal model were randomly divided into three groups: adenoviruses delivery of Ad-SPC-CAMA/GFP, Ad-CMV-CAMA/GFP and empty-virus Ad-CMV-GFP. The expression of CAMA-syn in mice was confirmed by RT-PCR and immunofluorescence. After tracheal injection of adenoviral vector for 3 days, lungs from the mouse model were extracted and homogenized for detection of colony-forming efficiency. RESULTS: CAMA-syn expressed in lung epithelial cells A549 conferred antimicrobial activity against a series of bacteria, including Salmonella abortusovis and BCG. The results obtained in vivo showed that the colony-forming rate of Ad-SPC-CAMA/GFP (74.54%) and Ad-CMV-CAMA/GFP (62.31%) transduced into mice was significantly lower than that of the control group. CONCLUSIONS: Lung epithelial-specific expression of antimicrobial peptide CAMA-syn mediated by adenovirus suppressed the growth of intracellular bacteria, providing a promising approach for the control of refractory intracellular infection.

Ultrasensitive high-performance liquid chromatography determination of tetracycline antibiotics and their 4-epimer derivatives based on dual effect of methanesulfonic acid.

In reversed-phase liquid chromatography, tetracycline antibiotics yield broad and asymmetrical peaks, as a result of their ionic interaction with the anionic free silanol groups and metal ion present in the silica-based stationary phases (commonly derivatized with C18 groups). These frequently encountered difficulties were absolutely eliminated based on dual effect when methanesulfonic acid was employed as an eluent additive. The study revealed that the performance of methanesulfonic acid to minimize the "silanol effect" is mainly explained by both direct neutralization of the anionic silanol sites and electrostatic attraction with analytes. Based on these dual action mechanisms, an ultrasensitive method has been successfully developed for the simultaneous determination of tetracycline antibiotics and their derivatives (minocycline, oxytetracycline, tetracycline, chlortetracycline, metacycline, doxycycline, 4-epitetracycline, and 4-epichlortetracycline) in bovine milk with convenient ultraviolet detection within 15 min. Under the optimal conditions, the calibration curves showed good linearity (r2  > 0.999) for all analytes in the range of 1∼200 ng/mL with the instrument limits of detection as low as 0.3 ng/mL. The study sheds new light on suitable additives to analyze basic compounds with the advantage of good compatibility with MS detection.

Selective and sensitive determination of tetracyclines by HPLC with chemiluminescence detection based on a cerium(IV)-methoxylated cypridina luciferin analogue system.

A novel approach for the simultaneous and selective analysis of chlortetracycline, doxycycline, 4-epichlortetracycline, oxytetracycline, metacycline, and tetracycline by high-performance liquid chromatography coupled with sensitive post-column chemiluminescence reaction was set up. Six tetracyclines were separated through a simple and effective isocratic procedure using a mixture of acetonitrile and 3.5 mM methanesulfonic acid. After that, intensive chemiluminescence signals were produced by the reaction between cerium(IV) and methoxylated cypridina luciferin analogues system in the presence of tetracyclines. Under the appropriate experimental conditions, the developed method was evaluated by testing of linearity, limits of detection, precision, and accuracy. The limit of detection was from 2 to 10 nM and relative standard deviation of intraday precision was below 9%. The developed high-performance liquid chromatography with chemiluminescence method has been performed for the with trace analysis of tetracycline antibiotic residues in milk samples with satisfactory results.

Determination of bromate via the chemiluminescence generated in the sulfite and carbon quantum dot system.

The authors describe a chemiluminescence (CL)-based assay for the determination of bromate. The method is based on the use of a solution of carbon quantum dots (CQDs) and sulfite. Strong CL (peak at 490 nm) is observed when bromate is injected into the solution. The CL increases linearly in the 0.3 to 10 µmol L-1 bromate concentration range, giving a 0.1 µmol L-1 limit of detection (at an S/N ratio of 3). A possible CL mechanism is suggested that involves a redox reaction between the CQDs, bromate and sulfite in the acidic medium. This leads to the formation of hole-injected and electron-injected CQDs. Radiative recombination of oxidant-injected holes and electrons in the CQDs accounts for the occurrence of CL. This mechanism contradicts the previous assumption that the transfer of energy occurs from SO2* to the CQDs. Although nitrite may interfere in the determination of bromate, its effect can be eliminated by adding sulfamic acid. The assay is sensitive and represents a new tool for the determination of bromate, which is a carcinogen. Graphical abstract Under acidic condition, carbon quantum dots (CQDs) can react with sulfite and bromate transforming to hole-injected CQDs (CQDs•-) and electron-injected CQDs (CQDs•+), respectively. Thereafter, strong chemiluminescence (490 nm) aroused from the radiative electron-hole annihilation between CQDs•- and CQDs•+.

Aggregated gold nanoparticles rich in electromagnetic field "hotspots" for surface enhanced Raman scattering.

A simple method for one-step synthesis of aggregated gold nanoparticles (a-AuNPs) using single-layer carbon dots (s-CDs) as the capping agents has been proposed. The obtained a-AuNPs are mainly composed of several spherical AuNPs of 20-25 nm sized, which aggregate to form nanogaps of ∼1 nm. Furthermore, the obtained a-AuNPs produce a strong localized surface plasmon resonance (LSPR) absorption band centered at around 640 nm, which is quite close to the wavelength of the commonly used 633 nm laser in surface enhanced Raman scattering (SERS). Thus, under the irradiation of 633 nm laser, a lot of electromagnetic field "hot spots" are formed at around the nanogaps, and strong SERS activity is achieved. The obtained a-AuNPs are dropped on tin-foil wafers to fabricate SERS substrates, which show the advantages of high sensitivity, fast response, good repeatability and satisfactory stability. On the basis, a sensitive SERS sensor is developed to detect malachite green in aquaculture water, with a low detection limit of 1 × 10-9 mol/L.

Rapid detection of tebuconazole based on hydrogel SERS chips.

Tebuconazole is one of the most commonly used fungicides in agricultural production, that has the merits of highly effectiveness, broad spectrum and systemic function. Excessive tebuconazole may pose a great threat to human and animal health. Traditional detection techniques for tebuconazole usually have limitations such as expensive equipment, poor antibody stability, and time-consuming procedures. Herein, a sensitive sensor is developed for the rapid detection of tebuconazole based on hydrogel surface-enhanced Raman scattering (SERS) chips. Aggregated Ag nanoparticles (a-AgNPs) with tunable localized surface plasmon resonance (LSPR) wavelength are in-situ synthesized in polyvinyl alcohol (PVA) solution for preparing hydrogel SERS chips. Three hydrogel SERS chips are obtained to match the three commonly used laser wavelengths. On the basis, a match laser wavelength is selected according to the energy levels of tebuconazole and the Fermi level of a-AgNPs to gain a strong chemical enhancement. At the same time, the chip with a corresponding LSPR wavelength to the laser is applied to obtain a strong electromagnetic enhancement. Thus, highly sensitive SERS signal of tebuconazole is obtained. Furthermore, the obtained hydrogel SERS chips have good repeatability, outstanding reproducibility and strong anti-interference ability, and show outstanding reliability in practical applications. As a result, the SERS chips offer a reliable and convenient platform for the quick detection of tebuconazole in foods. The detection limit is as low as 1 ppb, and the recoveries is distributed in the range of 94.66-106.70 %. This work would promote greatly the application of SERS in small molecule detection.

Efficacy and safety of thoracic radiotherapy for extensive stage small cell lung cancer after immunotherapy in real world.

The immunotherapy combined chemotherapy has been the standard treatment strategy for extensive-stage small lung cancer (ES-SCLC). The CREST trial reported consolidative thoracic radiotherapy (cTRT) improved overall survival (OS) for ES-SCLC with intrathoracic residual after chemotherapy. In this study, patients with ES-SCLC who received immunotherapy were assigned to receive either TRT or no TRT. TRT significantly improved progression-free survival (PFS), local recurrence-free survival (LRFS) and OS with well tolerated toxicity. Further sub-cohort analysis, TRT significantly improved LRFS in patients with oligo-metastasis and without liver metastasis.

Impact of the immune molecular profile of the tumor microenvironment on the prognosis of NSCLC.

The present study aimed to clarify the association between macrophages, tumor neo-vessels and programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment and the clinicopathological features of patients with non-small cell lung cancer (NSCLC), and to explore the prognostic factors of stromal features in NSCLC. To determine this, tissue microarrays containing samples of 92 patients with NSCLC were studied using immunohistochemistry and immunofluorescence. The quantitative data demonstrated that in tumor islets, the number of CD68+ and CD206+ tumor-associated macrophages (TAMs) was 8-348 (median, 131) and 2-220 (median, 52), respectively (P<0.001). In tumor stroma, the number of CD68+ and CD206+ TAMs was 23-412 (median, 169) and 7-358 (median, 81), respectively (P<0.001). The number of CD68+ TAMs in each location of the tumor islets and tumor stroma was significantly higher than that of CD206+ TAMs, and they were significantly correlated (P<0.0001). The quantitative density of CD105 and PD-L1 in tumor tissues was 19-368 (median, 156) and 9-493 (median, 103), respectively. Survival analysis revealed that a high density of CD68+ TAMs in tumor stroma and islets and a high density of CD206+ TAMs and PD-L1 in tumor stroma were associated with worse prognosis (both P<0.05). Collectively, the survival analysis demonstrated that the high-density group was related to a worse prognosis regardless of combined neo-vessels and PD-L1 expression with the CD68+ TAMs in tumor islets and stroma, or CD206+ TAMs in tumor islets and stroma. To the best of our knowledge, the present study was the first to provide a multi-component combined prognostic survival analysis of different types of macrophages in different regions with tumor neo-vessels and PD-L1, which demonstrated the importance of macrophages in tumor stroma.

Triple­negative breast cancer cells that survive ionizing radiation exhibit an Axl­dependent aggressive radioresistant phenotype.

This study aimed to investigate the aggressive behavior of triple-negative breast cancer (TNBC) cells that had survived ionizing radiation and explore the potential targets of TNBC combination treatment. Consistent with the previous literature, Axl was highly expressed in TNBC and closely associated with the degree of malignancy based on immunohistochemical staining. Using a gradient irradiation method, the ionizing radiation-resistant mouse TNBC cell line 4T-1/IRR was established. It was found that Axl expression was upregulated in 4T-1/IRR cells. After irradiation by X-ray, the cell viability and colony formation ability of 4T-1/IRR cells were significantly increased when compared with the 4T-1 cells. Combined radiotherapy with Axl inhibition by treatment with R428 and small interfering RNA lentivirus targeting Axl infection significantly reduced cell viability, colony formation ability, DNA double-stranded break repair, and the invasive and migratory ability of 4T-1/IRR cells. In vivo, the small animal radiation research platform was applied to precisely administer radiotherapy of the tumor-bearing mice. R428 treatment combined with 6 Gy X-ray significantly inhibited the growth of 4T-1/IRR cells-derived xenograft tumors in the BALB/c mouse. The results of western blotting showed that the critical molecular mechanism involved in the radioresistance of TNBC cells was the PI3K/Akt/mTOR signaling pathway induced by Axl activation. Thus, it is hypothesized that targeted Axl therapy combined with radiotherapy may have significant potential for the treatment of TNBC.

Externally Heated Diamond ANvil Cell Experimentation (EH-DANCE) for studying materials and processes under extreme conditions.

Externally heated diamond anvil cells provide a stable and uniform thermal environment, making them a versatile device to simultaneously generate high-pressure and high-temperature conditions in various fields of research, such as condensed matter physics, materials science, chemistry, and geosciences. The present study features the Externally Heated Diamond ANvil Cell Experimentation (EH-DANCE) system, a versatile configuration consisting of a diamond anvil cell with a customized microheater for stable resistive heating, bidirectional pressure control facilitated by compression and decompression membranes, and a water-cooled enclosure suitable for vacuum and controlled atmospheres. This integrated system excels with its precise control of both pressure and temperature for mineral and materials science research under extreme conditions. We showcase the capabilities of the system through its successful application in the investigation of the melting temperature and thermal equation of state of high-pressure ice-VII at temperatures up to 1400 K. The system was also used to measure the elastic properties of solid ice-VII and liquid H2O using Brillouin scattering and Raman spectra of carbonates using Raman spectroscopy, highlighting the potential of the EH-DANCE system in high-pressure research.

Neuroglobin Facilitates Neuronal Oxygenation through Tropic Migration under Hypoxia or Anemia in Rat: How Does the Brain Breathe?

The discovery of neuroglobin (Ngb), a brain- or neuron-specific member of the hemoglobin family, has revolutionized our understanding of brain oxygen metabolism. Currently, how Ngb plays such a role remains far from clear. Here, we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia. We found that Ngb was present in, co-localized to, and co-migrated with mitochondria in the cell body and neurites of neurons. Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane (CM) or cell surface in living neurons, and this was accompanied by the mitochondria. In vivo, hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio. Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase (SDH) and ATPase activity in neuronal N2a cells. Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia. Mutation of Ngb at its oxygen-binding site (His64) significantly increased SDH activity and reduced ATPase activity in N2a cells. Taken together, Ngb was physically and functionally linked to mitochondria. In response to an insufficient oxygen supply, Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation. This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.

Clinical and molecular characteristics of kinase domain duplications across diverse cancer types in the Chinese population.

BACKGROUND: Kinase domain duplications (KDDs) have recently been recognized as oncogenic mutations and possible association with drug resistance in cancers. METHOD: Here, targeted sequencing was performed with the tumor tissue and/or plasma from 65 cancer patients with KDDs. RESULT: Intact KDDs were identified in approximately 0.1% of the total population across multiple cancer types. EGFR KDD was first identified in colorectal cancer and breast cancer, whereas FGFR2 KDD was first identified in gastric cancer. Tumors with EGFR KDD displayed lower concurrent TP53 gene alterations (p = 0.03) and slightly higher chromosome instability (p = 0.27) compared to tumors with non-EGFR-KDDs. Immune pathway analysis further revealed the enrichment of the cytokine receptors pathway (93%) in the KDD carriers. Hyperprogression-related gene mutations were identified in four cases. CONCLUSION: Collectively, our data revealed the genomic features of KDD alterations in a multi-cancer cohort, providing more information for the potential treatment application in the KDD carriers.

An Immune-Related Gene Signature for Predicting Neoadjuvant Chemoradiotherapy Efficacy in Rectal Carcinoma.

Background: Locally advanced rectal cancers (LARC) show a highly variable response to neoadjuvant chemoradiotherapy (nCRT), and the impact of the tumor immune response in this process is poorly understood. This study aimed to characterize the immune-related gene expression profiles (GEP), pathways, and cell types associated with response or resistance to neoadjuvant chemoradiotherapy. Methods: The transcriptomic and clinical data of Rectal carcinoma from the Gene Expression Omnibus database and Immune-related genes (IRGs) from ImmPort were downloaded to identify the differentially expressed immune-related genes (DEIRGs) between responder and non-responder to neoadjuvant chemoradiotherapy. Gene set enrichment analyses were performed to uncover significantly enriched GO terms and KEGG pathways. Immune cell infiltration was estimated from RNA-sequencing data using ImmuCellAI. Afterward, we constructed an immune-related gene-based predictive model (IRGPM) by Support Vector Machine and validated it in an external cohort. Result: A 15-gene signature (HLA-DPB1, HLA-DQA1, CXCL9, CXCL10, TAP2, INHBB, BMP2, CD74, IL33, CCL11, CXCL11, DEFB1, HLA-DPA1, CCN3, STAT1) was identified as DEIRGs and found to be significantly associated with nCRT outcomes. Gene set enrichment analyses indicated that the 15 genes play active roles in inflammation-related biological processes. In addition, ImmuCellAI revealed that CD4 naive T cells, Tex, Th1 were significantly up-regulated (p=0.035, p=0.02, p=0.0086, respectively), while Tfh were significantly down-regulated (p=0.015) in responder subgroup. Finally, a novel predictive model was developed by SVM based on DEIRGs with an AUC of 80% (internal validation) and 73.5% (external validation). Conclusion: Our team conducted a genomic study of the relationship between gene expression profile and response to nCRT in LARC. Our data suggested that the DEIRGs signature could help predict the efficacy of nCRT. And a DEIRGs-based SVM model was developed to monitor the outcomes of nCRT in LARC.

Iron/photoredox dual catalysis for acyl nitrene-based C-O bond formation towards phthalides.

This paper describes iron/photoredox dual-catalyzed acyl nitrene formation and the use of acyl nitrene in constructing various C-O bonds towards phthalides. The developed reaction starts from N-methoxyl-2-alkylbenzamides. Mechanism surveys suggest the reaction involves iron nitrene-based hydrogen atom abstraction (HAA), radical-polar crossover and O-nucleophilic SN1. Distinctively, the often-reported radical rebound in previous publications is not observed. The reaction represents the first example on acyl nitrene-based synthesis of phthalides. Moreover, it also serves as a supplement for the synthesis of marketed medicines such as 3-butylphthalides (NBP), thalidomide, Pomalyst and Otezia.

Photoredox/Iron Dual-Catalyzed Insertion of Acyl Nitrenes into C-H Bonds.

In this work, the use of N-acyloxybenzamides as efficient acyl nitrene precursors under photoredox/iron dual catalysis is reported. The resulting acyl nitrenes could be captured by various types of C-H bonds and S- or P-containing molecules. Mechanism investigations suggested that the formation of the acyl nitrene from the N-acyloxybenzamide occurs by a photoredox process, and it is believed that in this redox process oxidative N-H bond cleavage of the N-acyloxybenzamide occurs prior to reductive N-O bond cleavage of the N-acyloxybenzamide.

Efficacy and safety evaluation of neoadjuvant immunotherapy plus chemotherapy for resectable non-small cell lung cancer in real world.

Objectives: The combination of immunotherapy and chemotherapy has shown great efficacy in stage IV non-small cell lung cancer (NSCLC) and is now widely used in clinical treatment strategy. This study retrospectively analyzed the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy for resectable NSCLC in real world. Methods: We retrospectively analyzed patients with NSCLC who received neoadjuvant immunotherapy plus chemotherapy and underwent complete tumor resection in Zhejiang Cancer Hospital between January 2019 and January 2021. Tumor staging was based on the eighth TNM classification system of the American Joint Committee on Cancer staging criteria. The safety and toxicity (including operative and postoperative complications) and the efficacy [including objective response rate (ORR), disease control rate (DCR), tumor major pathological remission (MPR), and pathological complete response (pCR)] were evaluated. Results: In total, 368 patients with NSCLC were administered with neoadjuvant immunotherapy. Of them, 211 patients were included in this retrospective study. Most patients had stage II-III disease, with 75 (35.5%) and 88 (41.7%) patients diagnosed with clinical stages IIB and IIIA, respectively. A total of 206 patients (97.6%) received at least two doses of neoadjuvant immunotherapy plus chemotherapy. In addition, 121 patients (57.3%) have achieved MPR, and 80 patients (37.9%) have achieved pCR, with ORR at 69.2% and DCR at 97.7%. Treatment-related adverse events occurred in 46.4% of patients, and the incidence rate of grade 3 or 4 treatment-related adverse events was 13.3% (13/98). Moreover, adverse events of any grade of surgical complication occurred in 15.6% of patients. One-year disease-free survival was 80.6% (170/211). Conclusions: Neoadjuvant immunotherapy plus chemotherapy has significant efficacy with a high pCR and tolerable adverse effects for patients with resectable stage II-III NSCLC in real world.

Qiguiyin Decoction Improves Multidrug-Resistant Pseudomonas aeruginosa Infection in Rats by Regulating Inflammatory Cytokines and the TLR4/MyD88/NF-κB Signaling Pathway.

Pseudomonas aeruginosa (PA), a Gram-negative bacterium, has a high detection rate in hospital-acquired infections. Recently, the frequent appearance of multidrug-resistant (MDR) PA strain with high morbidity and mortality rates has aggravated the difficulty in treating infectious diseases. Due to its multiple resistance mechanisms, the commonly used antibiotics have gradually become less effective. Qiguiyin decoction (QGYD) is a clinically experienced prescription of Chinese herbal medicine, and its combined application with antibiotics has been confirmed to be effective in the clinical treatment of MDR PA infection, which could be a promising strategy for the treatment of drug-resistant bacterial infections. However, the mechanism of QGYD restoring antibiotics susceptibility to MDR PA remains unclear. In the present study, we investigated the effects of QGYD and levofloxacin (LEV) singly or in combination on MDR PA-induced pneumonia rat models. Further analysis was carried out in the serum differential expression profiles of inflammatory cytokines by cytokine antibody array. Besides, the lung TLR4/MyD88/NF-κB signaling pathway was detected by RT-qPCR. Our results showed that based on the treatment of MDR PA-infected rat model with LEV, the combination of QGYD improved the general state and immune organ index. Furthermore, it moderately increased the expressions of proinflammatory cytokines including IL-1ß, IL-6, and TNF-α in the early stage of infection and decreased their release rapidly in the later stage, while regulated the same phase change of anti-inflammatory cytokine IL-10. In addition, the adhesion molecule ICAM-1 was significantly downregulated after QGYD combined with LEV treatment. Moreover, the mRNA expressions of TLR4, MyD88, NF-κB, and ICAM-1 were significantly downregulated. These results indicated that the mechanism of QGYD restoring LEV susceptibility to MDR PA was related to its regulation of inflammatory cytokines and the TLR4/MyD88/NF-κB signaling pathway, which provides theoretical support for the clinical application of QGYD combined with LEV therapy to MDR PA infection.

A combined predictive model based on radiomics features and clinical factors for disease progression in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy.

Purpose: To accurately assess disease progression after Stereotactic Ablative Radiotherapy (SABR) of early-stage Non-Small Cell Lung Cancer (NSCLC), a combined predictive model based on pre-treatment CT radiomics features and clinical factors was established. Methods: This study retrospectively analyzed the data of 96 patients with early-stage NSCLC treated with SABR. Clinical factors included general information (e.g. gender, age, KPS, Charlson score, lung function, smoking status), pre-treatment lesion status (e.g. diameter, location, pathological type, T stage), radiation parameters (biological effective dose, BED), the type of peritumoral radiation-induced lung injury (RILI). Independent risk factors were screened by logistic regression analysis. Radiomics features were extracted from pre-treatment CT. The minimum Redundancy Maximum Relevance (mRMR) and the Least Absolute Shrinkage and Selection Operator (LASSO) were adopted for the dimensionality reduction and feature selection. According to the weight coefficient of the features, the Radscore was calculated, and the radiomics model was constructed. Multiple logistic regression analysis was applied to establish the combined model based on radiomics features and clinical factors. Receiver Operating Characteristic (ROC) curve, DeLong test, Hosmer-Lemeshow test, and Decision Curve Analysis (DCA) were used to evaluate the model's diagnostic efficiency and clinical practicability. Results: With the median follow-up of 59.1 months, 29 patients developed progression and 67 remained good controlled within two years. Among the clinical factors, the type of peritumoral RILI was the only independent risk factor for progression (P< 0.05). Eleven features were selected from 1781 features to construct a radiomics model. For predicting disease progression after SABR, the Area Under the Curve (AUC) of training and validation cohorts in the radiomics model was 0.88 (95%CI 0.80-0.96) and 0.80 (95%CI 0.62-0.98), and AUC of training and validation cohorts in the combined model were 0.88 (95%CI 0.81-0.96) and 0.81 (95%CI 0.62-0.99). Both the radiomics and the combined models have good prediction efficiency in the training and validation cohorts. Still, DeLong test shows that there is no difference between them. Conclusions: Compared with the clinical model, the radiomics model and the combined model can better predict the disease progression of early-stage NSCLC after SABR, which might contribute to individualized follow-up plans and treatment strategies.