Peptide-based allosteric inhibitor targets TNFR1 conformationally active region and disables receptor-ligand signaling complex.

Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a pivotal role in mediating TNF induced downstream signaling and regulating inflammatory response. Recent studies have suggested that TNFR1 activation involves conformational rearrangements of preligand assembled receptor dimers and targeting receptor conformational dynamics is a viable strategy to modulate TNFR1 signaling. Here, we used a combination of biophysical, biochemical, and cellular assays, as well as molecular dynamics simulation to show that an anti-inflammatory peptide (FKCRRWQWRMKK), which we termed FKC, inhibits TNFR1 activation allosterically by altering the conformational states of the receptor dimer without blocking receptor-ligand interaction or disrupting receptor dimerization. We also demonstrated the efficacy of FKC by showing that the peptide inhibits TNFR1 signaling in HEK293 cells and attenuates inflammation in mice with intraperitoneal TNF injection. Mechanistically, we found that FKC binds to TNFR1 cysteine-rich domains (CRD2/3) and perturbs the conformational dynamics required for receptor activation. Importantly, FKC increases the frequency in the opening of both CRD2/3 and CRD4 in the receptor dimer, as well as induces a conformational opening in the cytosolic regions of the receptor. This results in an inhibitory conformational state that impedes the recruitment of downstream signaling molecules. Together, these data provide evidence on the feasibility of targeting TNFR1 conformationally active region and open new avenues for receptor-specific inhibition of TNFR1 signaling.

Quantum nonlinear effect in a dissipatively coupled optomechanical system.

A full-quantum approach is used to study the quantum nonlinear properties of a compound Michelson-Sagnac interferometer optomechanical system. By deriving the effective Hamiltonian, we find that the reduced system exhibits a Kerr nonlinear term with a complex coefficient, entirely induced by the dissipative and dispersive couplings. Unexpectedly, the nonlinearities resulting from the dissipative coupling possess non-Hermitian Hamiltonian-like properties preserving the quantum nature of the dispersive coupling beyond the traditional system dissipation. This protective mechanism allows the system to exhibit strong quantum nonlinear effects when the detuning (the compound cavity detuning Δc and the auxiliary cavity detuning Δe) and the tunneling coupling strength (J) of two cavities satisfy the relation J2 = ΔcΔe. Moreover, the additive effects of dispersive and dissipative couplings can produce strong anti-bunching effects, which exist in both strong and weak coupling conditions. Our work may provide a new way to study and produce strong quantum nonlinear effects in dissipatively coupled optomechanical systems.

Xylarkarynone A and B: Two Bioactive Eremophilane Sesquiterpenes from Xylaria sp. HHY-2.

A new compound xylarkarynone A (1), a first reported natural product compound xylarkarynone B (2) and eight known compounds (3-10) were isolated from Xylaria sp. HHY-2. Their structures were elucidated by spectroscopic methods, DP4+ probability analyses and electronic circular dichroism (ECD) calculations. The bioactivities of isolated compounds were assayed. Compound 1 exhibited obvious activity against A549 cells with an IC50 value of 6.12±0.28 µM. Additionally, compound 1 showed moderate antifungal activities against Plectosphaerella cucumerina and Aspergillus niger with minimum inhibitory concentrations (MICs) of both 16 µg/mL, which was at the same grade with positive control nystatin. Most compounds exhibited varying degrees of inhibitory activity against P. cucumerina, indicating that Xylaria sp. has potential as inhibitors against P. cucumerina.

Dietary pattern and risk of hyperuricemia: an updated systematic review and meta-analysis of observational studies.

Objectives: The associations of posteriori dietary patterns with the risk of hyperuricemia (HUA) are contradictory. Several fair-quality observational studies with inconsistent results have been published following a prior review. Herein, we carried out an updated systematic review and meta-analysis to quantitatively analyze the aforementioned relationships. Methods: Our analysis protocol has been registered with PROSPEPO (Number: CRD42022376745). English publications were searched in Embase, PubMed, and Web of Science from inception to January 1, 2024. Summary odds ratio (OR) and 95% confidence intervals (CIs) were calculated by a random-effects model. We also conducted subgroup, sensitivity, and meta-regression analyses and publication bias assessments. Results: Thirteen studies with a total of 163,192 participants were included in the current meta-analysis. Our finding revealed that the plant-based pattern was linked with a 17% decreased risk of HUA (OR = 0.83, 95%CI = 0.72-0.94, I2 = 72.9%, n = 10). There was no evidence of publication bias in the present analysis. The results of subgroup analyses were generally consistent with the main findings. In meta-regression analyses, no evidence of heterogeneity was detected in the subgroups. Furthermore, our analyses indicated that the animal-based food pattern (OR = 1.36, 95%CI = 1.25-1.47, I2 = 26.7%, n = 11) and sweet food pattern (OR = 1.24, 95%CI = 1.06-1.46, I2 = 0, n = 2) was related to an increased risk of HUA. Conclusion: The plant-based pattern is inversely correlated with HUA risk, whereas animal-based food patterns and sweet food patterns are positively correlated with HUA risk.

Modifiable risk factors of immediate and long-term outcomes in the operable and inoperable with left-sided infective endocarditis.

Objectives: To evaluate the outcomes of left-sided infective endocarditis that can be operated on and cannot be operated on, and to focus on modifiable risk factors for immediate and long-term mortality. Methods: This study retrospectively investigated patients with left-sided infective endocarditis who occurred in our medical center between January 2006 and November 2022. Results: 48 in-hospital deaths occurred (5.8 %, 48/832). We identified time from symptoms to admission and symptomatic neurological complications to be risk factors for multiple organ failure upon admission. Time from symptoms to admission and vegetation size in group of isolated medical treatment were significantly shorter than those in the group of heart operation. We also found that preoperative neurological complications, annulus destruction, levels of serum creatinine at 24 and 48 h post heart operation, and perivalvular leakage are risk factors for in-hospital mortality post heart operation. With 148 µmol/L as a cutoff level, the diagnostic sensitivity and specificity of serum creatinine level 48 h post surgery for in-hospital mortality post cardiac surgery are 100 % and 81.6 %, respectively. We found that vegetation size, ICU stay, postoperative serum creatinine at 48 h, left ventricular end diastolic size postoperative, and red blood cell transfusion were associated with all-time mortality. Conclusions: Early diagnosis and treatment, improvement of surgical techniques, good protection for heart, kidney and blood and close follow-up are advocated to conduce to better immediate and long-term outcomes of the operable and inoperable with left-sided infective endocarditis.

Homogeneous Non-Metallocene Group 4 Metals Ligated with [N,N] Bidentate Ligand(s) for Olefin Polymerization.

The development of catalysts has significantly advanced the progress of polyolefin materials. In particular, group 4 (Ti, Zr, Hf) non-metallocene catalysts ligated with [N,N] bidentate ligand(s) have garnered increasing attention in the field of olefin polymerization due to their structurally stability and exceptional polymerization behaviors. Ligands containing nitrogen donors are diverse and at the core of many highly active catalysts. They mainly include amidine, guanidinato, diamine, and various N-heterocyclic ligands, which can be used to obtain a series of new polyolefin materials, such as ultrahigh molecular weight polyethylene (UHWMPE), olefin copolymers (ethylene/norbornene and ethylene/α-olefin) with high incorporations, and high isotactic or syndiotactic polypropylene after coordination with group 4 metals and activation by cocatalysts. Herein, we focus on the advancements and applications of this field over the past two decades, and introduce the catalyst precursors with [N,N] ligand(s), involving the effects of ligand structure, cocatalyst selection, and polymerization conditions on the catalytic activity and polymer properties.

Polysaccharides Analysis of Cell Wall Using Carbohydrate Gel Electrophoresis.

The plant cell wall is rich in polysaccharides with high heterogeneity. Investigating the composition and structure of cell wall polysaccharides is crucial for understanding the functionalities of plant cell walls. Carbohydrate electrophoresis is a sensitive and rapid method to analyze polysaccharides qualitatively and quantitatively. The process includes digesting the polysaccharides with appropriate cleavage enzymes, labeling the reducing ends of the released oligosaccharides with a highly charged fluorophore, and separating the labeled oligosaccharides in a polyacrylamide gel via high-voltage electrophoresis. The generated fluorescence can be calculated as compared to that of oligosaccharide standards. Therefore, this is a convenient method for polysaccharide characterization that can be performed in most laboratories. Here, we introduce the detailed operational steps and precautions, which are helpful for researchers to quickly obtain the structural information of polysaccharides.

Ammonium Tetrakis(pentafluorophenyl)borate: Preparation and Application in Olefin Coordination Polymerization as the Cocatalyst Compound.

Metallocene catalysts have attracted much attention from academia and industry for their excellent catalytic activity in the field of olefin polymerization. Cocatalysts play a key role in metallocene catalytic systems, which can not only affect the overall catalytic activity, but also have an obvious influence on the structure and properties of the polymer. Although methylaluminoxane (MAO) is currently the most widely used cocatalyst, its price increases the production cost of polyolefin materials. Ammonium tetrakis(pentafluorophenyl)borate has shown excellent performance in polymerization, being one of the best substitutes for the traditional cocatalyst MAO. Compared with the main catalyst, whose composition and structure are relatively complex, the research on cocatalyst is very limited. This review mainly introduces the research history, preparation methods, and application progress in polymerization of ammonium tetrakis(pentafluorophenyl)borate, deepening our understanding of the role of cocatalyst in polymerization, with the hope of inspiring brand-new thinking on improving and enhancing the overall performance of catalyst systems.

Van der Waals Schottky Junction Photodetector with Ultrahigh Rectifying Ratio and Switchable Photocurrent Generation.

Metal-semiconductor junctions play an important role in the development of electronic and optoelectronic devices. A Schottky junction photodetector based on two-dimensional (2D) materials is promising for self-powered photodetection with fast response speed and large signal-to-noise ratio. However, it usually suffers from an uncontrolled Schottky barrier due to the Fermi level pinning effect arising from the interface states. In this work, all-2D Schottky junctions with near-ideal Fermi level depinning are realized, attributed to the high-quality interface between 2D semimetals and semiconductors. We further demonstrate asymmetric diodes based on multilayer graphene/MoS2/PtSe2 with a current rectification ratio exceeding 105 and an ideality factor of 1.2. Scanning photocurrent mapping shows that the photocurrent generation mechanism in the heterostructure switches from photovoltaic effect to photogating effect at varying drain biases, indicating both energy conversion and optical sensing are realized in a single device. In the photovoltaic mode, the photodetector is self-powered with a response time smaller than 100 µs under the illumination of a 405 nm laser. In the photogating mode, the photodetector exhibits a high responsivity up to 460 A/W originating from a high photogain. Finally, the photodetector is employed for single-pixel imaging, demonstrating its high-contrast photodetection ability. This work provides insight into the development of high-performance self-powered photodetectors based on 2D Schottky junctions.

CtDNA based molecular residual disease outcompetes carcinoembryonic antigen in predicting postoperative recurrence of non-small cell lung cancer.

Background: Carcinoembryonic antigen (CEA) has been routinely used as a postoperative monitoring biomarker for non-small cell lung cancer (NSCLC). Emergingly, circulating tumor DNA (ctDNA)-molecular residual disease (MRD) detection is a well-established prognostic marker, with better positive predictive value (PPV) and negative predictive value (NPV). However, the actual clinical efficiency of CEA in MRD context remain unknown. Hence, we conducted this study for direct comparison of CEA and MRD. Methods: Two cohorts were analyzed in this study. To investigate the prognostic and predictive value of CEA, we retrospective enrolled NSCLC patient stage IA2-IIIA (8th tumor-node-metastasis staging system) with longitudinal CEA between 2018 and 2019. We also performed a paired comparison of CEA and MRD in our previous published cohort. Survival data were analyzed using the Kaplan-Meier method, and comparisons were performed using the log-rank test. Sensitivity, specificity, PPV and NPV were calculated using the R package "epiR". McNemar's test was used to analyze the paired data. Statistical differences were set at a P value <0.05. Results: In the retrospective cohort, the sensitivity of longitudinal CEA was only 0.49 [95% confidence interval (CI): 0.37-0.60]. Even for patients with progressively elevated CEA levels, 32% of them still remained disease-free, with PPV of 0.68 (0.49-0.83) and NPV of 0.81 (0.77-0.85). Furthermore, we then compared CEA and MRD values in a previously described MRD cohort. As expected, CEA levels could not stratify the risk of recurrence in detectable versus undetectable MRD populations. Conclusions: MRD is superior to CEA in postoperative monitoring. there is insufficient evidence to support its use as postoperative monitoring tumor marker.

Anaerostipes hadrus, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil.

Anaerostipes hadrus (A. hadrus) is a dominant species in the human gut microbiota and considered a beneficial bacterium for producing probiotic butyrate. However, recent studies have suggested that A. hadrus may negatively affect the host through synthesizing fatty acid and metabolizing the anticancer drug 5-fluorouracil, indicating that the impact of A. hadrus is complex and unclear. Therefore, comprehensive genomic studies on A. hadrus need to be performed. We integrated 527 high-quality public A. hadrus genomes and five distinct metagenomic cohorts. We analyzed these data using the approaches of comparative genomics, metagenomics, and protein structure prediction. We also performed validations with culture-based in vitro assays. We constructed the first large-scale pan-genome of A. hadrus (n = 527) and identified 5-fluorouracil metabolism genes as ubiquitous in A. hadrus genomes as butyrate-producing genes. Metagenomic analysis revealed the wide and stable distribution of A. hadrus in healthy individuals, patients with inflammatory bowel disease, and patients with colorectal cancer, with healthy individuals carrying more A. hadrus. The predicted high-quality protein structure indicated that A. hadrus might metabolize 5-fluorouracil by producing bacterial dihydropyrimidine dehydrogenase (encoded by the preTA operon). Through in vitro assays, we validated the short-chain fatty acid production and 5-fluorouracil metabolism abilities of A. hadrus. We observed for the first time that A. hadrus can convert 5-fluorouracil to α-fluoro-ß-ureidopropionic acid, which may result from the combined action of the preTA operon and adjacent hydA (encoding bacterial dihydropyrimidinase). Our results offer novel understandings of A. hadrus, exceptionally functional features, and potential applications. IMPORTANCE: This work provides new insights into the evolutionary relationships, functional characteristics, prevalence, and potential applications of Anaerostipes hadrus.

The circadian clock affects starvation resistance through the pentose phosphate pathway in silkworm, Bombyx mori.

Disruption of the circadian clock can affect starvation resistance, but the molecular mechanism is still unclear. Here, we found that starvation resistance was significantly reduced in the core gene BmPer deficient mutant silkworms (Per-/-), but the mutant's starvation resistance increased with larval age. Under natural physiological conditions, the weight of mutant 5th instar larvae was significantly increased compared to wild type, and the accumulation ability of triglycerides and glycogen in the fat bodies was upregulated. However, under starvation conditions, the weight consumption of mutant larvae was increased and cholesterol utilization was intensified. Transcriptome analysis showed that beta-oxidation was significantly upregulated under starvation conditions, fatty acid synthesis was inhibited, and the expression levels of genes related to mitochondrial function were significantly changed. Further investigations revealed that the redox balance, which is closely related to mitochondrial metabolism, was altered in the fat bodies, the antioxidant level was increased, and the pentose phosphate pathway, the source of reducing power in cells, was activated. Our findings suggest that one of the reasons for the increased energy burden observed in mutants is the need to maintain a more robust redox balance in metabolic tissues. This necessitates the diversion of more glucose into the pentose phosphate pathway to ensure an adequate supply of reducing power.

Computed tomography radiomics study of invasion and instability of lung adenocarcinoma manifesting as ground glass nodule.

Background: Ground-glass nodule (GGN) is the most common manifestation of lung adenocarcinoma on computed tomography (CT). Clinically, the success rate of preoperative diagnosis of GGN by puncture biopsy and other means is still low. The aim of this study is to investigate the clinical and radiomics characteristics of lung adenocarcinoma presenting as GGN on CT images using radiomics analysis methods, establish a radiomics model, and predict the classification of pathological tissue and instability of GGN type lung adenocarcinoma. Methods: This study retrospectively collected 249 patients with 298 GGN lesions who were pathologically confirmed of having lung adenocarcinoma. The images were imported into the Siemens scientific research prototype software to outline the region of interest and extract the radiomics features. Logistic model A (a radiomics model to identify the infiltration of lung adenocarcinoma manifesting as GGNs) was established using features after the dimensionality reduction process. The receiver operating characteristic (ROC) curve of the model on training set and the verification set was drawn, and the area under the curve (AUC) was calculated. Second, a total of 112 lesions were selected from 298 lesions originating from CT images of at least two occasions, and the time between the first CT and the preoperative CT was defined as not less than 90 days. The mass doubling time (MDT) of all lesions was calculated. According to the different MDT diagnostic thresholds instability was predicted. Finally, their AUCs were calculated and compared. Results: There were statistically significant differences in age and lesion location distribution between the "noninvasive" lesion group and the invasive lesion group (P<0.05), but there were no statistically significant differences in sex (P>0.05). Model A had an AUC of 0.89, sensitivity of 0.75, and specificity of 0.86 in the training set and an AUC of 0.87, sensitivity of 0.63, and specificity of 0.90 in the validation set. There was no significant difference statistically in MDT between "noninvasive" lesions and invasive lesions (P>0.05). The AUCs of radiomics models B1, B2 and B3 were 0.89, 0.80, and 0.81, respectively; the sensitivities were 0.71, 0.54, and 0.76, respectively; the specificities were 0.83, 0.77, and 0.60, respectively; and the accuracies were 0.78, 0.65, and 0.69, respectively. Conclusions: There were statistically significant differences in age and location of lesions between the "noninvasive" lesion group and the invasive lesion group. The radiomics model can predict the invasiveness of lung adenocarcinoma manifesting as GGNs. There was no significant difference in MDT between "noninvasive" lesions and invasive lesions. The radiomics model can predict the instability of lung adenocarcinoma manifesting as GGN. When the threshold of MDT was set at 813 days, the model had higher specificity, accuracy, and diagnostic efficiency.

Acidic Nanoparticles Restore Lysosomal Acidification and Rescue Metabolic Dysfunction in Pancreatic ß-Cells under Lipotoxic Conditions.

Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) polyesters, comprising a 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical with diameters of ≈100 nm and have low polydispersity and good stability. Notably, TFSA NPs, which are composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying properties. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets, INS-1 ß-cells under chronic lipotoxic conditions, and pancreatic tissues of high-fat-diet (HFD) mice. Treatment with TFSA NPs restores lysosomal acidification, autophagic function, and mitochondrial activity, thereby improving the pancreatic function in INS-1 cells and HFD mice with lipid overload. Importantly, the administration of TFSA NPs to HFD mice reduces insulin resistance and improves glucose clearance. These findings highlight the therapeutic potential of lysosome-acidifying TFSA NPs for T2D.

Adjuvant Osimertinib in Patients With Stage IB to IIIA EGFR Mutation-Positive NSCLC After Complete Tumor Resection: ADAURA China Subgroup Analysis.

Introduction: In Chinese patients with NSCLC, prevalence of EGFR-mutated (EGFRm) disease is high. In the global phase 3 ADAURA study (NCT02511106), adjuvant osimertinib was found to have a statistically significant and clinically meaningful improvement in disease-free survival (DFS) versus placebo in resected stage IB to IIIA EGFRm NSCLC. We present efficacy and safety data from a subgroup analysis of 159 Chinese patients enrolled in the People's Republic of China from ADAURA. Methods: In ADAURA, patients with completely resected stage IB to IIIA EGFRm (exon 19 deletion/exon 21 L858R) NSCLC were randomized 1:1 to receive osimertinib (80 mg once daily) or placebo for 3 years or until disease recurrence/discontinuation. Adjuvant chemotherapy was permitted before randomization, per physician/patient choice. Primary end point was investigator-assessed DFS in stage II to IIIA disease; secondary end points included DFS in stage IB to IIIA (overall population), overall survival, health-related quality of life (HRQoL), and safety. Results: Of 682 patients enrolled globally, 159 patients in the People's Republic of China were included in this subgroup analysis (osimertinib n = 77; placebo n = 82). Baseline characteristics were balanced across the treatment arms. At data cutoff, stage II to IIIA DFS hazard ratio (HR) was 0.23 (95% confidence interval [CI]: 0.13-0.42; maturity 59%); stage IB to IIIA DFS HR was 0.29 (95% CI: 0.17-0.48; maturity 42%). At 13% maturity (21 deaths), HR for overall survival in the stage IB to IIIA population was 0.51 (95% CI: 0.21-1.20). HRQoL was maintained from baseline, and safety was consistent with the global population. Conclusions: In this population of Chinese patients from ADAURA, adjuvant osimertinib was found to have a clinically meaningful improvement in DFS versus placebo, with maintained HRQoL and a safety profile consistent with the global study population.

Redoxhigh phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma.

Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

Gut commensal Christensenella minuta modulates host metabolism via acylated secondary bile acids.

A strong correlation between gut microbes and host health has been observed in numerous gut metagenomic cohort studies. However, the underlying mechanisms governing host-microbe interactions in the gut remain largely unknown. Here we report that the gut commensal Christensenella minuta modulates host metabolism by generating a previously undescribed class of secondary bile acids with 3-O-acylation substitution that inhibit the intestinal farnesoid X receptor. Administration of C. minuta alleviated features of metabolic disease in high fat diet-induced obese mice associated with a significant increase in these acylated bile acids, which we refer to as 3-O-acyl-cholic acids. Specific knockout of intestinal farnesoid X receptor in mice counteracted the beneficial effects observed in their wild-type counterparts. Finally, we showed that 3-O-acyl-CAs were prevalent in healthy humans but significantly depleted in patients with type 2 diabetes. Our findings indicate a role for C. minuta and acylated bile acids in metabolic diseases.

PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial.

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. Conclusions and Relevance: The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.