Evaluation of the novel International Association for the Study of Lung Cancer grading system in adenocarcinoma with spread through air space.

Background: The International Association for the Study of Lung Cancer (IASLC) pathology panel has proposed a new grading system for invasive lung adenocarcinoma (LADC). This study aims to validate this novel grading system for invasive LADC using propensity score matching (PSM), with a specific focus on patients exhibiting spread through air space (STAS). Methods: We retrospectively analyzed the clinicopathologic features of a large cohort of 910 non-mucinous LADCs with STAS from 2017 to 2020 and classified them according to the novel grading system. We applied PSM to adjust for potential confounders between the grading groups. Kaplan-Meier and Cox proportional hazards models were adopted for prognostic evaluation. Results: The results showed that the IASLC grading system (grades 2 and 3) stratified well in terms of recurrence-free survival (RFS) and overall survival (OS) (P=0.02 and P=0.02, respectively) after matching, with Grade 3 being an independent predictor of RFS [hazard ratio (HR), 1.533; P=0.02] and OS (HR, 2.765; P=0.02) in multivariable models. The concordance index (C-index) and area under the curve (AUC) of the IASLC system were 0.719 and 0.754 for recurrence and 0.844 and 0.891 for death, respectively. In addition, anaplastic lymphoma kinase (ALK) fusion and tumor protein p53 (TP53) mutations were detected more frequently in grade 3 tumors, while epidermal growth factor receptor (EGFR) mutations were more prevalent in grade 2 tumors. The IASLC grade did not predict the benefit of adjuvant chemotherapy (ACT). Conclusions: This study suggests that the new IASLC grading system is a valuable prognostic tool for patients with STAS-positive LADC.

Predictive value of fine fibrillatory wave for declining eGFR in patients with persistent atrial fibrillation: Long-term follow-up study.

BACKGROUND: Renal dysfunction has been identified as a risk factor for both stroke and bleeding events in atrial fibrillation (AF) patients, yet the mechanisms remain unclear. We examines the connection between fine fibrillatory wave and estimated glomerular filtration rate (eGFR) decline, alongside chronic kidney disease (CKD). METHODS: Persistent AF patients admitted to Jinan University's First Affiliated Hospital from January 2019 to June 2023 were enrolled. Kaplan-Meier analysis explored kidney endpoints for coarse and fine fibrillatory wave. A multivariate Cox model estimated adjusted hazard ratios (HR) and 95 % confidence intervals (95 % CI) to determine the correlation between fine fibrillatory wave and eGFR decline, as well as CKD. RESULTS: Of the 3521 AF patients, 229 were ultimately included in the analysis of this study. The median age of these patients was 75 years, with 58 % being male. The median follow-up time was 23 months, and the mean eGFR was 70 ± 19 mL/min/1.73 m2. Multivariate COX regression analysis revealed fine fibrillatory wave (HR = 8.311, 95 % CI 3.418-20.211, p < 0.001) as an independent risk factor associated with a ≥ 30 % decline in eGFR. Among 166 AF patients with eGFR >60 mL/min/1.73 m2, 40 cases (24 %) experienced a decline to <60 mL/min/1.73 m2. In comparison to coarse fibrillatory wave, the risk of fine fibrillatory wave causing eGFR decline to <60 mL/min/1.73 m2 was approximately 4.6 times higher (HR = 4.645, 95 % CI 2.127-10.142, p<0.001). CONCLUSIONS: Fine fibrillatory wave was independently associated with the risk of eGFR decline ≥30 % and eGFR decline to <60 mL/min/1.73 m2.

Hollow dodecahedral Zn0.3Cd0.7S@NiCo-mixed metal oxide p-n heterojunction with high-efficiency photocatalytic hydrogen production activity.

The growing demand for clean and sustainable energy has driven extensive research into efficient photocatalysts for hydrogen production. However, many semiconductor photocatalysts in this field still face the challenges such as wide band gap, limited visible light absorption, and inefficient separation and transport of photoinduced charges. In this study, nickel-cobalt layered double hydroxide (NiCo-LDH) was synthesized using an "etch-and-grow" method with zeolitic imidazolate framework-67 (ZIF-67) as a sacrificial template, followed by high-temperature calcination to produce nickel-cobalt mixed metal oxide (NiCo-MMO). Zn0.3Cd0.7S quantum dots were used to modify NiCo-MMO resulting in a hollow dodecahedral Zn0.3Cd0.7S@NiCo-MMO composite photocatalyst. In hydrogen production performance test, the optimized Zn0.3Cd0.7S@NiCo-MMO exhibited excellent performance (8177.5 µmol·g-1·h-1) and demonstrated good cycling stability. The hollow dodecahedral structure of the Zn0.3Cd0.7S@NiCo-MMO enhanced the light trapping ability and provided large surface area. The p-n heterojunction formed within Zn0.3Cd0.7S@NiCo-MMO accelerated carrier separation and transfer, effectively inhibited the recombination of photogenerated electrons and holes, and significantly improved the hydrogen production activity.

SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

Association between echocardiographic features, troponin levels, and survival time in hospitalized COVID-19 patients with cardiovascular events.

Introduction: This study aims to explore the predictive roles of echocardiographic parameters and biomarkers in determining outcomes among hospitalized COVID-19 patients experiencing cardiovascular events. Methods: A retrospective cohort study was conducted involving 49 COVID-19 patients who encountered cardiovascular events during hospitalization and underwent echocardiography. Our findings revealed notable associations between echocardiographic parameters and survival time. Results: A decrease in left ventricular ejection fraction (LVEF) of 10% was linked to a 20% reduction in survival time (TR: 0.80, 95% CI: 0.67 - 0.96, p = .017). Similarly, an increase in left ventricular (LV) volume by 10 mL was associated with a 9% decrease in survival time (TR: 0.91, 95% CI: 0.84 - 0.98, p = .011). Moreover, an increase in left atrial (LA) volume by 10 mL corresponded to an 8% decrease in survival time (TR: 0.92, 95% CI: 0.86 - 0.99, p = .026). Additionally, each 1 cm increase in right ventricular (RV) diameter was linked to a 22% reduction in survival time (TR: 0.78, 95% CI: 0.61 - 0.99, p = .043). Furthermore, a 10 mL increase in right atrial (RA) volume was associated with a 12% decrease in survival time (TR: 0.88, 95% CI: 0.78 - 0.98, p = .017). Notably, a tenfold rise in troponin levels was linked to a 33% decrease in survival time (TR: 0.67, 95% CI: 0.48 - 0.93, p = .014). Conclusions: Our study emphasizes the significant associations between various echocardiographic parameters and troponin levels with reduced survival time among COVID-19 patients experiencing cardiovascular events. These findings highlight the potential utility of echocardiography and troponin assessment in predicting outcomes and guiding management strategies in this patient population.

Prominent response to savolitinib monotherapy in high-grade fetal adenocarcinoma with MET amplification and concurrent brain metastasis: a case report.

Background: Mesenchymal-epithelial transition (MET) represents a potential therapeutic target in various cancers, with amplification of the MET gene identified in a subset of patients with pulmonary adenocarcinomas. However, MET gene amplification is rarely observed in high-grade fetal adenocarcinoma (H-FLAC). Case Description: Here we present a novel case of a patient diagnosed with stage IV H-FLAC harboring MET amplifications and treated with savolitinib. The 69-year-old male patient, who presented with a primary complaint of cough and white sputum, had a history of hypertension for over 10 years and a 45-year smoking history. The patient received savolitinib monotherapy treatment due to brain metastases. Despite the omission of radiotherapy for asymptomatic brain metastases, a notable response to savolitinib therapy was observed, with a partial response (PR) achieved after 4 weeks and a reduction in the brain tumor. At the time of the submission of this report, the patient received over 24 weeks of savolitinib treatment, and was maintained PR. The patient was still undergoing treatment. This highlights the potential clinical benefits of targeted therapy against MET amplification in H-FLAC. Conclusions: H-FLAC harboring MET amplification and brain metastasis is rare. Treatment with savolitinib monotherapy resulted in a PR, providing preliminary insights to the efficacy of savolitinib for H-FLAC with MET amplification.

Single-Cell Transcriptome Analysis Reveals 2 Subtypes of Tumor Cells of Sclerosing Pneumocytoma With Distinct Molecular Features and Clinical Implications.

Pulmonary sclerosing pneumocytoma (PSP) is a rare, distinctive benign lung adenoma of pneumocyte origin. Despite its rarity, the tumor's unique cellular morphology has sparked ongoing debates regarding the origin of its constituent cells. This study aimed to elucidate the molecular features of PSP tumor cells and enhance our understanding of the cellular processes contributing to PSP formation and biological behavior. Tissue samples from PSP and corresponding normal lung tissues (n = 4) were collected. We employed single-cell RNA sequencing and microarray-based spatial transcriptomic analyses to identify cell types and investigate their transcriptomes, with a focus on transcription factors, enriched gene expression, and single-cell trajectory evaluations. Our analysis identified 2 types of tumor cells: mesenchymal-epithelial dual-phenotype (MEDP) cells and a distinct subpopulation of type II alveolar epithelial cells exhibiting characteristics slightly reminiscent of type I alveolar epithelial cells (AT2Cs) corresponding to histologic round stromal cells and surface cuboidal cells, respectively. MEDP cells displayed weak alveolar epithelial differentiation but strong collagen production capabilities, as indicated by the expression of both TTF-1 and vimentin. These cells played a pivotal role in forming the solid and sclerotic areas of PSP. Moreover, MEDP cells exhibited a pronounced propensity for epithelial-mesenchymal transition, suggesting a greater potential for metastasis compared with AT2Cs. The capillary endothelial cells of PSP displayed notable diversity. Overall, this study provides, for the first time, a comprehensive mapping of the single-cell transcriptome profile of PSP. Our findings delineate 2 distinct subtypes of tumor cells, MEDP cells and AT2Cs, each with its own biological characteristics and spatial distribution. A deeper understanding of these cell types promises insights into the histology and biological behaviors of this rare tumor.

Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer (RATICAL): a nationwide multicenter retrospective study.

BACKGROUND: Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement. This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC. METHODS: In this real-world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)-VENTANA-D5F3. The positive ALK gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well. RESULTS: The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC-VENTANA-D5F3 revealed an intra-hospital consistency rate of 98.2% (879/895) and an inter-hospital consistency rate of 99.2% (646/651). IHC-VENTANA-D5F3 was used in 53.6%, real-time polymerase chain reaction (RT-PCR) in 25.4%, next-generation sequencing (NGS) in 18.3%, and fluorescence in-situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT-PCR. The overall ALK gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of > 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all P < 0.05). CONCLUSIONS: This study highlights the real-world variability and challenges of ALK test in advanced NSCLC, demonstrating a predominant use of IHC-VENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.

Novel molecular subtypes of METex14 non-small cell lung cancer with distinct biological and clinical significance.

Not all MET exon 14 skipping (METex14) NSCLC patients benefited from MET inhibitors. We hypothesized an inter-tumoral heterogeneity in METex14 NSCLC. Investigations at genomic and transcriptomic level were conducted in METex14 NSCLC samples from stage I-III and recurrent/metastatic patients as discovery and validation cohort. Four molecular subtypes were discovered. MET-Driven subtype, with the worst prognosis, displayed MET overexpression, enrichment of MET-related pathways, and higher infiltration of fibroblast and regulatory T cells. Immune-Activated subtype having the most idea long-term survival, had higher tertiary lymphoid structures, spatial co-option of PD-L1+ cancer cells, and GZMK+ CD8+ T cell. FGFR- and Bypass-Activated subtypes displayed FGFR2 overexpression and enrichments of multiple oncogenic pathways respectively. In the validation cohort, patients with MET-Driven subtype had better response to MET inhibitors than those with MET overexpression. Thus, molecular subtypes of METex14 NSCLC with distinct biological and clinical significance may indicate more precise therapeutic strategies for METex14 NSCLC patients.

Global burden of atrial fibrillation/atrial flutter and its attributable risk factors from 1990 to 2021.

AIMS: To devise effective preventive measures, a profound understanding of the evolving patterns and trends in atrial fibrillation (AF) and atrial flutter (AFL) burdens is pivotal. Our study was designed to quantify the burden and delineate the risk factors associated with AF and AFL across 204 countries and territories spanning 1990-2021. METHODS AND RESULTS: Data pertaining to AF and AFL were sourced from the Global Burden of Disease Study 2021. The burden of AF/AFL was evaluated using metrics such as incidence, disability-adjusted life years (DALYs), deaths, and their corresponding age-standardized rates (ASRs), stratified by age, sex, socio-demographic index (SDI), and human development index (HDI). The estimated annual percentage change was employed to quantify changes in ASRs. Population attributable fractions were calculated to determine the proportional contributions of major risk factors to age-standardized AF/AFL deaths. This analysis encompassed the period from 1990 to 2021. Globally, in 2021, there were 4.48 million incident cases [95% uncertainty interval (UI): 3.61-5.70], 8.36 million DALYs (95% UI: 6.97-10.13) and 0.34 million deaths (95% UI: 0.29-0.37) attributed to AF/AFL. The AF/AFL burden in 2021, as well as its trends from 1990 to 2021, displayed substantial variations based on gender, SDI quintiles, and geographical regions. High systolic blood pressure emerged as the leading contributor to age-standardized AF/AFL incidence, prevalence, death, and DALY rate globally among all potential risk factors, followed closely by high body mass index. CONCLUSION: Our study underscores the enduring significance of AF/AFL as a prominent public health concern worldwide, marked by profound regional and national variations. Despite the substantial potential for prevention and management of AF/AFL, there is a pressing imperative to adopt more cost-effective strategies and interventions to target modifiable risk factors, particularly in areas where the burden of AF/AFL is high or escalating.

Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma.

Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.

Associations between specific volatile organic chemical exposures and cardiovascular disease risks: insights from NHANES.

Introduction: An increasing body of research has demonstrated a correlation between pollutants from the environment and the development of cardiovascular diseases (CVD). However, the impact of volatile organic chemicals (VOC) on CVD remains unknown and needs further investigation. Objectives: This study assessed whether exposure to VOC was associated with CVD in the general population. Methods: A cross-sectional analysis was conducted utilizing data from five survey cycles (2005-2006, 2011-2012, 2013-2014, 2015-2016, and 2017-2018) of the National Health and Nutrition Examination Survey (NHANES) program. We analyzed the association between urinary VOC metabolites (VOCs) and participants by multiple logistic regression models, further Bayesian Kernel Machine Regression (BKMR) models and Weighted Quantile Sum (WQS) regression were performed for mixture exposure analysis. Results: Total VOCs were found to be positively linked with CVD in multivariable-adjusted models (p for trend = 0.025), independent of established CVD risk variables, such as hypertension, diabetes, drinking and smoking, and total cholesterol levels. Compared with the reference quartile of total VOCs levels, the multivariable-adjusted odds ratios in increasing quartiles were 1.01 [95% confidence interval (CI): 0.78-1.31], 1.26 (95% CI: 1.05-1.21) and 1.75 (95% CI: 1.36-1.64) for total CVD. Similar positive associations were found when considering individual VOCs, including AAMA, CEMA, CYMA, 2HPMA, 3HPMA, IPM3 and MHBMA3 (acrolein, acrylamide, acrylonitrile, propylene oxide, isoprene, and 1,3-butadiene). In BKMR analysis, the overall effect of a mixture is significantly related to VOCs when all chemicals reach or exceed the 75th percentile. Moreover, in the WQS models, the most influential VOCs were found to be CEMA (40.30%), DHBMA (21.00%), and AMCC (19.70%). Conclusion: The results of our study indicated that VOC was all found to have a significant association with CVD when comparing results from different models. These findings hold significant potential for public health implications and offer valuable insights for future research directions.

EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

Different clinical characteristics and outcomes of adult hospitalized SARS-CoV-2 pneumonia patients complicated by cardiovascular events during the first, delta and omicron waves of COVID-19.

Background: The effects of SARS-CoV-2 have varied between significant waves of hospitalization. Research question: Are cardiovascular complications different among the first, delta and omicron waves of hospitalized COVID-19 pneumonia patients? Study design and methods: This was a multi-centre retrospective study of patients hospitalized with SARS-CoV-2 pneumonia: 632 were hospitalized during the first wave (March-July 2020), 1013 during the delta wave (September 2020-March 2021), and 323 during the omicron wave (January 2022-July 2022). Patients were stratified by wave and occurrence of cardiovascular events. Results: Among all hospitalized patients with cardiovascular events, patients in the omicron wave were younger (62.4 ± 14 years) than patients in the first wave (67.4 ± 7.8 years) and the delta wave (66.9 ± 12.6 years) and had a higher proportion of non-Hispanic White people than in the first wave (78.6% vs. 61.7%). For COVID-19 patients who suffered from cardiovascular events, the omicron wave patients had significantly higher neutrophil/lymphocyte ratio, white blood cell and platelet counts when compared to the first wave. Omicron wave patients had significantly lower albumin and B-type natriuretic peptide levels (only 5.8% of the first wave and 14.6% of the delta wave) when compared to either the first wave or delta wave patients. In COVID-19 patients who suffered cardiovascular events during hospitalization, mortality rate in the omicron wave (26.8%) was significantly lower than the first wave (48.3%), time to mortality for non-survivors of COVID-19 patients who suffered cardiovascular events was significantly longer in the omicron wave (median 16 days) than in the first wave (median 10 days). Conclusions: Younger and white patients were affected with cardiovascular complications more often by the omicron variant. Despite higher neutrophil/lymphocyte ratio and WBC counts, the omicron patients with cardiovascular events showed lower heart injuries, lower mortality and longer time to mortality for non-survivors when compared to the first and delta waves.

Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations.

Background: For patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients. Methods: We reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS). Results: Of the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016). Conclusion: For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

Peroxygenase-Enabled Reductive Kinetic Resolution for the Enantioenrichment of Organoperoxides.

Enantiomerically pure organoperoxides serve as valuable precursors in organic transformations. Herein, we present the first examples of unspecific peroxygenase catalyzed kinetic resolution of racemic organoperoxides through asymmetric reduction. Through meticulous investigation of the reaction conditions, it is shown that the unspecific peroxygenase from Agrocybe aegerita (AaeUPO) exhibits robust catalytic activity in the kinetic resolution reactions of the model substrate with turnover numbers up to 60000 and turnover frequency of 5.6 s-1. Various aralkyl organoperoxides were successfully resolved by AaeUPO, achieving excellent enantioselectivities (e.g., up to 99 % ee for the (S)-organoperoxide products). Additionally, we screened commercial peroxygenase variants to obtain the organoperoxides with complementary chirality, with one mutant yielding the (R)-products. While unspecific peroxygenases have been extensively demonstrated as a powerful oxidative catalysts, this study highlights their usefulness in catalyzing the reduction of organoperoxides and providing versatile chiral synthons.

Development of a double antibody sandwich ELISA method for the quantitative detection of serum C-reactive protein based on nanobody.

In this study, we successfully developed a nanobody-based double antibody sandwich ELISA kit for the detection of clinical serum C-reactive protein (CRP) by using two novel CRP specific nanobodies. The developed method exhibited a linear detection range of approximately 6-200 ng/mL, with a detection limit of 1 ng/mL. Furthermore, the method demonstrated excellent specificity, as there was no cross-reactivity with interfering substances such as total bilirubin and hemoglobin and so on. To assess reproducibility, independent measurements of the samples were conducted under experimental conditions, resulting in intra- and inter-batch coefficients of variation below 10% and a recovery rate of 93%-102%. These results indicate robust reproducibility of the method. To evaluate the performance of the developed kit, we collected 90 clinical samples for correlation analysis with commercial kits. The results showed a high correlation coefficient value (R2) of 0.98, indicating accurate concordance between the developed and commercial kits. In conclusion, our study successfully developed a nanobody-based double antibody sandwich ELISA kit to detect clinical serum CRP. The utilization of nanobodies represents a significant advancement in the field of CRP immunoassay development. The developed kit demonstrates excellent performance characteristics and holds promise for clinical applications.

Melt-quenched glass formation of a family of metal-carboxylate frameworks.

Metal-organic framework (MOF) glasses are an emerging class of glasses which complement traditional inorganic, organic and metallic counterparts due to their hybrid nature. Although a few zeolitic imidazolate frameworks have been made into glasses, how to melt and quench the largest subclass of MOFs, metal carboxylate frameworks, into glasses remains challenging. Here, we develop a strategy by grafting the zwitterions on the carboxylate ligands and incorporating organic acids in the framework channels to enable the glass formation. The charge delocalization of zwitterion-acid subsystem and the densely filled channels facilitate the coordination bonding mismatch and thus reduce the melting temperature. Following melt-quenching realizes the glass formation of a family of carboxylate MOFs (UiO-67, UiO-68 and DUT-5), which are usually believed to be un-meltable. Our work opens up an avenue for melt-quenching porous molecular solids into glasses.

Proteomic characterization of esophageal squamous cell carcinoma response to immunotherapy reveals potential therapeutic strategy and predictive biomarkers.

Immunotherapy is the first-line therapy for esophageal squamous cell carcinoma (ESCC), yet many patients do not respond due to drug resistance and the lack of reliable predictive markers. We collected 73 ESCC patients (including discovery cohort and validation cohort) without immune thrombocytopenia and undergoing anti-PD1 immunotherapy. Proteomic and phosphoproteomic analysis of 73 ESCC treatment-naive samples by mass spectrometry-based label-free quantification were applied to explore the potential resistant and sensitive mechanisms, and identify predictive markers of ESCC immunotherapy. Comparative analysis found the pathways related to immune and mitochondrial functions were associated with ESCC immunotherapy sensitivity; while platelet activation bioprocess showed negative correlation with CD8+ T cells and related to ESCC immunotherapy non-sensitivity. Finally, we identified 10 ESCC immunotherapy predictive biomarkers with high accuracy (≥ 0.90) to predict the immunotherapeutic response, which was validated in the independent cohort.