OBJECTIVES: The emergence and outbreak of carbapenem-resistant Pseudomonas aeruginosa (CRPA) are a major global public threat. we aimed to characterize the genome of drug-resistant and virulent genes in an extremely drug-resistant Pseudomonas aeruginosa strain to understand its antimicrobial resistance trends and pathogenicity. METHODS: An XDR Pseudomonas aeruginosa strain was isolated in China from a patient with severe pneumonia. Antimicrobial susceptibility testing, genome sequencing and phylogenetic analysis was performed. Predictions were fulfilled using curated bioinformatics tools. RESULTS: The assembly of the strain (CRPA190) comprised 76 contigs with a total length of 7 009 318 bp. CRPA190 belongs to sequence type 1791 (ST1791) and the O11 serogroup. Nine prophage regions, three CRISPR arrays, and two Cas clusters were identified. However, no plasmids were predicted. Antibiotic susceptibility tests showed that CRPA190 was resistant to all the tested antibiotics, including carbapenem, polymyxin B and ceftazidime-avibactam. Forty antimicrobial resistance genes were predicted in CRPA190, including several carbapenemase genes such as blaPDC-142, blaPME-1, blaNDM-1 and blaOXA-902. The isolate was predicted to be pathogenic and possess strong biofilm-forming ability. It harbors virulence genes that are associated with an arsenal of virulence determinants involved in adherence, motility, exotoxins, exoenzymes, immune modulation, biofilms, nutritional/metabolic factors and effector delivery systems. CONCLUSION: These findings enhance our understanding of the resistance and pathogenicity of the ST1791 Pseudomonas aeruginosa strain which is unique in China and provide a broader perspective on the global epidemiological landscape, suggesting the emergence of P. aeruginosa ST1971, which requires control measures to limit its dissemination.
In this study, the effect of hydrothermal treatment with different temperatures (120-180⯰C) on the rheological properties of xanthan gum was evaluated. When the temperature of hydrothermal treatment was relatively low (120⯰C), the rheological properties of the hydrothermally treated xanthan gum was similar to the untreated xanthan gum (pseudoplastic and solid-like/gel-like behavior). However, as the temperature of hydrothermal treatment was higher, the rheological properties of the hydrothermally treated xanthan gum changed greatly (e.g., a wider range of Newtonian plateaus in flow curves, existence of a critical frequency between the storage modulus (G') and the loss modulus (G") in the dynamic viscoelasticity measurement, variation of complex viscosity). Although the hydrothermal treatment showed little influence on the functional groups of xanthan gum, it altered the micromorphology of xanthan gum from uneven and rough lump-like to thinner and smoother flake-like. In addition, higher concentration (2â¯%) of hydrothermally treated xanthan gum made its viscosity close to that of the untreated xanthan gum (1â¯%). Besides, hydrothermal treatment also affected the effect of temperature and salt (CaCl2) adding on the rheological properties of xanthan gum. Overall, this study can provide some useful information on the rheological properties of xanthan gum after hydrothermal treatment.
Background: After femoral oncological knee arthroplasty, some patients suffer from rotating axis fracture, which significantly impacts the life span of the rotating hinge knee (RHK) prosthesis. This research aimed to analyze the biomechanical response of anatomical gastrocnemius reconstruction and assess whether it could reduce the risk of rotating axis breakage by finite element (FE) analysis. Methods: A femur-prosthesis-tibia FE model was established using the data from CT scans. The mechanical properties of the RHK implant were quantitatively compared before and after gastrocnemius reconstruction at 6 angles: 10°, 20°, 30°, 40°, 50°, and 60°. Results: Our results showed that gastrocnemius reconstruction effectively altered the stress distribution around the rotating axis, considerably relieving the stress in the fracture-prone region. In addition, the peak stress in the rotating axis, bending axis, prosthesis stem, and femoral condyles decreased variably. Conclusion: In distal femoral resection knee arthroplasty, the rebuilding of gastrocnemius substantially improved the stress distribution within the prosthesis, thereby having the potential to reduce the risk of prosthetic fracture and prolong the overall durability of the prosthesis.
Bio-based epoxy resins have received significant attention in terms of concerns regarding carbon emission. Epoxidized soybean oil (ESO) derived from sustainable feedstock has been widely used to blend with traditional diglycidyl ether of bisphenol-A (DGEBA) to replace some of the petroleum-based components. In this work, molecular dynamics (MD) simulations were applied to track the network formation and predict the performance of methyl hexahydrophthalic anhydride (MHHPA)-cured ESO/DGEBA blend systems. The effects of ESO content and cross-linking degree on the mass density, volumetric shrinkage, glass transition temperature (Tg), coefficient of thermal expansion (CTE), Young's modulus, yield strength, and Poisson's ratio of the epoxy resin were systematically investigated. The results show that systems with high ESO content achieve gelation at low cross-linking degree. The Tg value, Young's modulus, and yield strength increase with the increase in cross-linking degree, but the CTE at the glassy state and Poisson's ratio decrease. The comparison results between the simulated and experimental data demonstrated that the MD simulations can accurately predict the thermal and mechanical properties of ESO-based thermosets. This study gains insight into the variation in thermo-mechanical properties of anhydride-cured ESO/DGEBA-based epoxy resins during the cross-linking process and provides a rational strategy for optimizing bio-based epoxy resins.
Fatty acids from cooking fumes and hypochlorous acid (HOCl) released from indoor cleaning adversely affect respiratory health, but the molecular-level mechanism remains unclear. Here, the effect of cooking oil fumes [palmitic acid (PA), oleic acid (OA), and linoleic acid (LA)] on lung model phospholipid (POPG) hydrochlorination mediated by HOCl at the air-water interface of the hanged droplets was investigated. Interfacial hydrochlorination of POPG was impeded by OA and LA, while that of POPG was facilitated by PA. The effect on POPG hydrochlorination increased with the decrease in oil fume concentration. A potential mechanism with respect to the chain length of these oil fumes, regardless of their saturation, was proposed. PA with a short carbon chain looses the POPG packing and leads to the exposure of the C=C double bonds of POPG, whereas OA and LA with a long carbon chain hinder HOCl from reaching the C=C bonds of POPG. These results for short chain and low concentration dependence suggest that the decay of oil fumes or the conversion of short-chain species by indoor interfacial chemistry might be adverse to lung health. These results provide insights into the relationship between indoor multicomponent pollutants and the respiratory system.
Air Pollution, Indoor , Fatty Acids , Fatty Acids/chemistry , Hypochlorous Acid/chemistry , Cooking , Phospholipids/chemistry
Glycidic esters represent pivotal constituents in synthetic chemistry, offering enhanced versatility for tailoring toward a diverse array of molecular targets in comparison with simple epoxides. While considerable progress has been made in the asymmetric synthesis of trans- and trisubstituted glycidic esters, achieving enantioselective preparation of cis-glycidic esters has remained a long-standing challenge. Here, we demonstrate a selectivity-predictable modular platform for the asymmetric synthesis of cis-glycidic esters via a novel dinuclear (salen)titanium(III)-catalyzed radical-type kinetic resolution (KR) approach. This radical KR protocol operates under mild conditions and demonstrates a wide substrate scope, facilitating the synthesis of alkyl- and aryl-substituted cis-glycidic esters with high levels of regioselectivity and enantioselectivity, along with hydroxy ester byproducts representing synthetically valuable motifs as well. This study presents a unique exploration of radical-type KR applied to epoxides, effectively overcoming the steric challenges inherent in conventional nucleophilic-type methodologies typically employed in epoxide chemistry.
OBJECTIVES: Stiff shoulder, including primary and secondary types, poses diagnostic challenges due to vague definitions and criteria. This study evaluates the diagnostic potential of ultrasound-measured axillary recess (AR) thickness in shoulder stiffness. DESIGNS: In this cross-sectional study, 35 patients with unilateral shoulder stiffness were assessed. AR thickness was measured using high-resolution ultrasound. Parameters like passive range of motion (PROM), Numerical Rating Scale (NRS), and Constant-Murley (CM) score were evaluated to find correlations with AR thickness. RESULTS: The average age was 50.7 years, and mean BMI was 22.7. AR thickness in stiff shoulders (average 3.19 mm) was significantly higher than in unaffected shoulders (average 1.93 mm, p < 0.001). A cutoff of 3.0 mm for AR thickness yielded 73.3% sensitivity and 84.6% specificity for primary stiffness; 2.6 mm cutoff resulted in 57.9% sensitivity and 88.2% specificity for secondary stiffness. Significant correlations were found between AR thickness and PROM, especially in shoulder external rotation and extension. CONCLUSION: AR thickness measured by ultrasound might serve as a valuable diagnostic and evaluation parameter in shoulder stiffness.
Cell-free DNA (cfDNA) has been found to be elevated in patients with schizophrenia (SZ), potentially derived from activated apoptosis, but the underlying mechanisms remain unknown. Moreover, whether the concentrations of cfDNA are altered with disease stage has not been investigated, which limits its clinical application as an auxiliary diagnostic marker for SZ. Using an improved fluorescence correlation spectroscopy (FCS) method that does not require DNA extraction, we measured the molar concentrations of cfDNA in plasma samples of 191 patients with SZ, 78 patients with mood disorders (MD) and 65 healthy controls (HC). We also analyzed the cfDNA composition from either the nucleus or mitochondria, oxidation markers and biochemical indexes to explore the potential mechanistic associations of the increased cfDNA levels. We found that in SZ patients, the cfDNA levels were significantly increased (P = 0.003) regardless of the different disease stages or antipsychotic medication use. Furthermore, qPCR revealed that cell-free nuclear DNA (cf-nDNA) (P = 0.041) but not cell-free mitochondrial DNA (cf-mtDNA) was elevated in SZ patients. Moreover, decreased SOD activity in SZ patients (P = 0.005) was negatively correlated with cfDNA levels (P = 0.047), and fasting blood glucose was positively correlated with cfDNA levels in SZ patients (P = 0.013). Our study provides evidence to support that the elevated cfDNA may be a convenient, effective and stable trait indicator of SZ. Further analysis showed that it mainly came from nucleus, suggesting increased apoptosis, and potentially related to oxidative stress and high blood glucose levels in patients.
Chrysanthemi indic Flos (CIF) has been commonly consumed for the treatment of inflammation and related skin diseases. However, the potential bioactive components responsible for its anti-inflammatory and sensitive skin (SS) improvement activities, and the correlated mechanisms of action still remain unknown. In this work, it was firstly found that the CIF extract (CIFE) displayed arrestive free radical scavenging activity on DPPH and ABTS radicals, with no significant difference with positive control Trolox (p > 0.05). Then, compared to the negative group, CIFE markedly decreased the productions of the pro-inflammatory cytokines (IL-1ß, IL-6, PEG2, TNF-α, IFN-γ, NO) in LPS induced RAW264.7 cells in a dose-dependent manner (p < 0.01). Besides, CIFE strongly inhibited the COX-2 and hyaluronidase (HAase) with the IC50 values of 1.06 ± 0.01 µg/mL and 12.22 ± 0.39 µg/mL, indicating higher inhibitory effect than positive control of aspirin of 6.33 ± 0.05 µg/mL (p < 0.01), and comparable inhibitory effect with indometacin of 0.60 ± 0.03 µg/mL, and ascorbic acid of 11.03 ± 0.41 µg/mL (p > 0.05), respectively. Furthermore, kinetic assays with Lineweaver-Burk plot (Michaelis Menten equation) suggested that CIFE reversibly inhibited the COX-2 and HAase, with a mixed characteristics of competitive and non-competitive inhibition. Thereafter, multi-target affinity ultrafiltration liquid chromatography-mass spectrometry (UF-LC/MS) method was employed to fast fish out the potential COX-2 and HAase in CIFE. Herein, 13 components showed various affinity binding degrees to the COX-2 and HAase, while those components with relative binding affinity (RBA) value higher than 3.0, such as linarin and chlorogenic acid isomers, were deemed to be the most bioactive components for the anti-inflammatory and SS improvement activities of CIFE. Finally, the interaction mechanism, including binding energy, inhibition constant, docking sites, and the key amino acids involved in hydrogen bonds between the potential ligands and COX-2/HAase were simulated and confirmed with the molecule docking analysis. In summary, this study showcased the prominent anti-inflammatory and SS improvement activities of CIF, which would provide further insights on this functional medicinal plant to be a natural anti-SS remedy.
Intercropping has been recommended as a beneficial cropping practice for improving soil characteristic and tea quality. However, there is limited research on the effects of intercropping fruit trees on soil chemical properties, soil aggregate structure, and tea quality components. In this study, intercropping fruit trees, specifically loquats and citrus, had a significant impact on the total available nutrients, AMN, and AP in soil. During spring and autumn seasons, the soil large-macroaggregates (>2 mm) proportion increased by 5.93% and 19.03%, as well as 29.23% and 19.14%, respectively, when intercropping loquats and citrus. Similarly, intercropping waxberry resulted in a highest small-macroaggregates (0.25 mm-2 mm) proportion at 54.89% and 77.32%. Soil aggregate stability parameters of the R0.25, MWD, and GMD were generally considered better soil aggregate stability indicators, and significantly improved in intercropping systems. Intercropping waxberry with higher values for those aggregate stability parameters and lower D values, showed a better soil aggregate distribution, while intercropping loquats and citrus at higher levels of AMN and AP in different soil aggregate sizes. As the soil aggregate sizes increased, the AMN and AP contents gradually decreased. Furthermore, the enhanced levels of amino acids were observed under loquat, waxberry, and citrus intercropping in spring, which increased by 27.98%, 27.35%, and 26.21%, respectively. The contents of tea polyphenol and caffeine were lower under loquat and citrus intercropping in spring. These findings indicated that intercropping fruit trees, specifically loquat and citrus, have immense potential in promoting the green and sustainable development of tea plantations.
Soil , Soil/chemistry , Citrus/growth & development , Camellia sinensis/growth & development , Trees/growth & development , Tea , Fruit/growth & development , Agriculture/methods , Crop Production/methods
Primary Biliary Cholangitis (PBC) and Autoimmune Hepatitis (AIH) are autoimmune diseases that target hepatocytes and bile duct cells, respectively. Despite their shared autoimmune nature, the differences in immunologic characteristics between them remain largely unexplored. This study seeks to elucidate the unique immunological profiles of PBC and AIH, and to identify key differences. We comprehensively analyzed various T-cell subsets and their receptor expression in a cohort of 45 patients, including 27 PBC and 18 AIH cases. Both diseases exhibited T cell exhaustion and senescence along with a surge in inflammatory cytokines. Significantly increased CD38+HLA-DR+CD8+T cell populations were observed in both diseases. AIH was characterized by an upregulation of CD8+TEMRA, CD4+TEM, and CD4+TEMRA cells, and a concurrent reduction in Treg cells. In contrast, PBC displayed a pronounced presence of Tfh cells and a contraction of CD4-CD8-T cell populations. Correlation analysis revealed that NKP46+NK frequency was closely tied to ALT and AST levels, and TIGIT expression on T cells was associated with GLB level in AIH. In PBC, there is a significant correlation between Tfh cells and ALP levels. Moreover, the identified immune landscapes in both diseases strongly related to disease severity. Through logistic regression analysis, γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies emerged as distinct markers capable of differentiating PBC from AIH. In conclusion, our analyses reveal that PBC and AIH share similarities and differences regarding to immune profiles. And γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies are potential noninvasive immunological markers that can differentiate PBC from AIH.
OBJECTIVE: This study aimed to establish a nomogram-based assessment for predicting the risk of hyponatremia after spinal cord injury (SCI). DESIGN: The study is a retrospective single-center study. PARTICIPANTS: SCI patients hospitalized in the First Affiliated Hospital of Guangxi Medical University. SETTING: The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China. METHODS: We performed a retrospective clinical study to collect SCI patients hospitalized in the First Affiliated Hospital of Guangxi Medical University from 2016 to 2020. Based on their clinical scores, the SCI patients were grouped as either hyponatremic or non-hyponatremic, SCI patients in 2016-2019 were identified as the training set, and patients in 2020 were identified as the test set. A nomogram was generated, the calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to validate the model. RESULTS: A total of 895 SCI patients were retrieved. After excluding patients with incomplete data, 883 patients were finally included in this study and used to construct the nomograms. The indicators used in the nomogram included sex, completeness of SCI, pneumonia, urinary tract infection, fever, constipation, white blood cell (WBC), albumin and serum Ca2+. These indices were determined by the least absolute shrinkage and selection operator (LASSO) regression analysis. The C-index of the model was 0.81, the area under the curve (AUC) of the training set was 0.82(Cl:0.79-0.85), and the validation set was 0.79(Cl:0.73-0.85). CONCLUSIONS: Nomogram has good predictive ability, sex, completeness of SCI, pneumonia, urinary tract infection, fever, constipation, WBC, albumin and serum Ca2+ were predictors of hyponatremia after SCI.
Takeaway food has become a prominent component of the diet in urban areas of China, especially for young people. Although dietary intake is a major pathway to contaminants for human exposure, studies on emerging organophosphite antioxidants (OPAs) and organophosphate esters (OPEs) in food are scarce. Here, we investigated four OPAs and 19 OPEs in takeaway foods (n = 99) and paired takeaway food packaging (n = 50) in China. AO168=O (mean: 14.9 ng/g ww), TPPO (mean: 1.05 ng/g ww), and TCIPP (mean: 0.579 ng/g ww) were dominant in the takeaway food. Some OPEs had significant correlations in takeaway food. Emerging OPAs and OPEs in takeaway food varied significantly depending on the packaging materials and food types. AO168 and AO168=O were widespread in the paired takeaway food packaging. The migration efficiencies of emerging OPAs and OPEs were low in takeaway food packaged in aluminum foil. Although the actual contamination of emerging OPAs and OPEs in takeaway food significantly differed from those of in food simulants migrated from paired takeaway food packaging, the results imply that food itself and takeaway food packaging are potential contamination sources of emerging OPAs and OPEs in takeaway food. The average estimated dietary intakes of emerging OPAs and OPEs were 465 ng/kg body weight (bw)/day and 91.9 ng/kg bw/day, respectively. The exposure risk of emerging OPAs and OPEs through takeaway food intake is low in China.
Forkhead box protein 1 (FOXP1) serves as a tumour promoter or suppressor depending on different cancers, but its effect in oesophageal squamous cell carcinoma has not been fully elucidated. This study investigated the role of FOXP1 in oesophageal squamous cell carcinoma through bioinformatics analysis and experimental verification. We determined through public databases that FOXP1 expresses low in oesophageal squamous cell carcinoma compared with normal tissues, while high expression of FOXP1 indicates a better prognosis. We identified potential target genes regulated by FOXP1, and explored the potential biological processes and signalling pathways involved in FOXP1 in oesophageal squamous cell carcinoma through GO and KEGG enrichment, gene co-expression analysis, and protein interaction network construction. We also analysed the correlation between FOXP1 and tumour immune infiltration levels. We further validated the inhibitory effect of FOXP1 on the proliferation of oesophageal squamous cell carcinoma cells through CCK-8, colony formation and subcutaneous tumour formation assays. This study revealed the anticarcinogenic effect of FOXP1 in oesophageal squamous cell carcinoma, which may serve as a novel biological target for the treatment of tumour.
Cell Proliferation , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Forkhead Transcription Factors , Gene Expression Regulation, Neoplastic , Repressor Proteins , Humans , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Cell Line, Tumor , Animals , Repressor Proteins/metabolism , Repressor Proteins/genetics , Computational Biology/methods , Mice , Prognosis , Protein Interaction Maps/genetics , Signal Transduction , Gene Regulatory Networks , Mice, Nude
Tris(2,4-di-tert-butylphenyl) phosphite (AO168), an organophosphite antioxidant, can be oxidized to tris(2,4-di-tert-butylphenyl) phosphate (AO168 = O) during the production, processing, and application of plastics. AO168 = O can be further transformed to bis(2,4-di-tert-butylphenyl) phosphate and 2,4-di-tert-butylphenol. Here, we discovered the contamination of AO168 and its transformation products in dairy products for the first time. More samples contained AO168 (mean concentration: 8.78 ng/g wet weight [ww]), bis(2,4-di-tert-butylphenyl) phosphate (mean:11.1 ng/g ww) and 2,4-di-tert-butylphenol (mean: 46.8 ng/g ww) than AO168 = O (mean: 40.2 ng/g ww). The concentrations of AO168 and its transformation products were significantly correlated, and differed with the packaging material and storage conditions of the product. Estimated daily intakes (EDIs) of AO168 and its transformation products were calculated. Although the overall dietary risks were below one, transformation products accounted for 96.7% of the total hazard quotients. The high-exposure EDIs of total AO168 were above the threshold of toxicological concern (300 ng/kg bw/day), and deserve continual monitoring.
Dairy Products , Food Contamination , Phosphites , Food Contamination/analysis , Humans , Phosphites/analysis , Phosphites/chemistry , Dairy Products/analysis , Dietary Exposure/analysis , Animals , Food Packaging/instrumentation , Organophosphorus Compounds/analysis , Organophosphorus Compounds/chemistry
Introduction: A retrospective study based on sentinel surveillance was conducted in 10 provincial-level administrative divisions (PLADs) in China to enhance the understanding of the epidemiological characteristics of human parainfluenza viruses (HPIVs). Methods: From January 2019 to June 2023, respiratory specimens were collected from individuals with acute respiratory infections (ARIs) and screened for four HPIVs serotypes and other common respiratory viruses using multiplex real-time polymerase chain reaction (PCR). This study analyzed the association of HPIVs infections with seasonal patterns, geographical distribution, demographic profiles, clinical features, and co-infection status. Results: During the study period, a total of 12,866 ARIs were included. The overall detection rate of HPIVs was 6.15%, varying from 5.04% in 2022 to 9.70% in 2020. The median age of HPIVs-infected patients was 3 years. HPIV2 was more prevalent among individuals aged 5-17 years (42.57%), while HPIV4 was more common in those over 65 years (12.24%). HPIV3 (54.16%) and HPIV1 (27.18%) were the predominant serotypes, and their prevalence exhibited significant seasonal fluctuations post- coronavirus disease 2019 (COVID-19) pandemic. The peak of HPIV3 shifted three months later in 2020 compared to 2019 and returned to a summer peak thereafter. Two peaks of HPIV1 were observed in 2021 following the peak of HPIV3. Additionally, co-infections were frequent in HPIVs cases (overall rate: 22.12%), with human rhinovirus being the most common co-infecting virus. Conclusions: The prevalence of HPIVs in China was predominantly due to HPIV3 and HPIV1, and their seasonal patterns were altered by pandemic restrictions. Hence, continuous surveillance of HPIVs is essential.
Antimicrobial nanomaterials frequently induce inflammatory reactions within lung tissues and prompt apoptosis in lung cells, yielding a paradox due to the inherent anti-inflammatory character of apoptosis. This paradox accentuates the elusive nature of the signaling cascade underlying nanoparticle (NP)-induced pulmonary inflammation. In this study, we unveil the pivotal role of nano-microflora interactions, serving as the crucial instigator in the signaling axis of NP-induced lung inflammation. Employing pulmonary microflora-deficient mice, we provide compelling evidence that a representative antimicrobial nanomaterial, silver (Ag) NPs, triggers substantial motility impairment, disrupts quorum sensing, and incites DNA leakage from pulmonary microflora. Subsequently, the liberated DNA molecules recruit caspase-1, precipitating the release of proinflammatory cytokines and activating N-terminal gasdermin D (GSDMD) to initiate pyroptosis in macrophages. This pyroptotic cascade culminates in the emergence of severe pulmonary inflammation. Our exploration establishes a comprehensive mechanistic axis that interlinks the antimicrobial activity of Ag NPs, perturbations in pulmonary microflora, bacterial DNA release, macrophage pyroptosis, and consequent lung inflammation, which helps to gain an in-depth understanding of the toxic effects triggered by environmental NPs.
BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.
Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.
Carcinoma, Endometrioid , Endometrial Hyperplasia , Endometrial Neoplasms , Fertility Preservation , Proteogenomics , Humans , Female , Progestins/therapeutic use , Antineoplastic Agents, Hormonal , Endometrial Hyperplasia/drug therapy , Fertility Preservation/methods , Retrospective Studies , Carcinoma, Endometrioid/drug therapy , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/pathology , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology
Objective: This study aimed to create a predictive model based on machine learning to identify the risk for tracheobronchial tuberculosis (TBTB) occurring alongside Mycoplasma pneumoniae pneumonia in pediatric patients. Methods: Clinical data from 212 pediatric patients were examined in this retrospective analysis. This cohort included 42 individuals diagnosed with TBTB and Mycoplasma pneumoniae pneumonia (combined group) and 170 patients diagnosed with lobar pneumonia alone (pneumonia group). Three predictive models, namely XGBoost, decision tree, and logistic regression, were constructed, and their performances were assessed using the receiver's operating characteristic (ROC) curve, precision-recall curve (PR), and decision curve analysis (DCA). The dataset was divided into a 7:3 ratio to test the first and second groups, utilizing them to validate the XGBoost model and to construct the nomogram model. Results: The XGBoost highlighted eight significant signatures, while the decision tree and logistic regression models identified six and five signatures, respectively. The ROC analysis revealed an area under the curve (AUC) of 0.996 for XGBoost, significantly outperforming the other models (p < 0.05). Similarly, the PR curve demonstrated the superior predictive capability of XGBoost. DCA further confirmed that XGBoost offered the highest AIC (43.226), the highest average net benefit (0.764), and the best model fit. Validation efforts confirmed the robustness of the findings, with the validation groups 1 and 2 showing ROC and PR curves with AUC of 0.997, indicating a high net benefit. The nomogram model was shown to possess significant clinical value. Conclusion: Compared to machine learning approaches, the XGBoost model demonstrated superior predictive efficacy in identifying pediatric patients at risk of concurrent TBTB and Mycoplasma pneumoniae pneumonia. The model's identification of critical signatures provides valuable insights into the pathogenesis of these conditions.
Pneumonia, Mycoplasma , Tuberculosis , Humans , Child , Retrospective Studies , Mycoplasma pneumoniae , Pneumonia, Mycoplasma/complications , Area Under Curve
