Associations between urinary concentrations of benzothiazole, benzotriazole, and their derivatives and lung cancer: A nested case-control study.

Benzothiazole (BTH), benzotriazole (BTR), and their respective derivatives (BTHs and BTRs) are emerging environmental pollutants with widespread human exposure and oncogenic potential. Studies have demonstrated adverse effects of exposure to certain BTHs and BTRs on the respiratory system. However, no study has examined the associations between exposure to BTHs and BTRs and lung cancer risk. We aimed to examine the associations between urinary concentrations of BTHs and BTRs and the risk of lung cancer in the general population from Quzhou, China. We conducted a nested case-control study in an ongoing prospective Quzhou Environmental Exposure and Human Health (QEEHH) cohort, involving 20, 694 participants who provided urine samples during April 2019-July 2020. With monthly follow-up until November 2022, 212 lung cancer cases were recruited and 1:1 matched with healthy controls based on age and sex. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of lung cancer risk associated with urinary BTHs and BTRs concentrations using conditional logistic regression models after controlling for potential covariates. We also examined effect modification by several covariates, including sex, socioeconomic status, smoking status, alcohol consumption, and dietary habit. Creatinine-corrected urinary BTH and 2-hydroxy-benzothiazole (2-OH-BTH) levels were significantly associated with the risk of lung cancer, after adjusting for a variety of covariates. Participants in the highest quartile of BTH had a 95% higher risk of lung cancer, compared with those in the lowest quartile (adjusted OR = 1.95, 95% CI: 1.08-3.49; p for trend = 0.01). Participants with higher levels of urinary 2-OH-BTH had an 83% higher risk of lung cancer than those with lower levels (adjusted OR = 1.83, 95% CI: 1.16-2.88; p for trend = 0.01). Exposure to elevated levels of BTH and 2-OH-BTH may be associated with an increased risk of lung cancer. These associations were not modified by socio-demographic characteristics.

Exosome-encapsulated lncRNA HOTAIRM1 contributes to PM2.5-aggravated COPD airway remodeling by enhancing myofibroblast differentiation.

Emphysema, myofibroblast accumulation and airway remodeling can occur in the lungs due to exposure to atmospheric pollution, especially fine particulate matter (PM2.5), leading to chronic obstructive pulmonary disease (COPD). Specifically, bronchial epithelium-fibroblast communication participates in airway remodeling, which results in COPD. An increasing number of studies are now being conducted on the role of exosome-mediated cell-cell communication in disease pathogenesis. Here, we investigated whether exosomes generated from bronchial epithelial cells could deliver information to normal stromal fibroblasts and provoke cellular responses, resulting in airway obstruction in COPD. We studied the mechanism of exosome-mediated intercellular communication between human bronchial epithelial (HBE) cells and primary lung fibroblasts (pLFs). We found that PM2.5-induced HBE-derived exosomes promoted myofibroblast differentiation in pLFs. Then, the exosomal lncRNA expression profiles derived from PM2.5-treated HBE cells and nontreated HBE cells were investigated using an Agilent Human LncRNA Array. Combining coculture assays and direct exosome treatment, we found that HBE cell-derived exosomal HOTAIRM1 facilitated the myofibroblast differentiation of pLFs. Surprisingly, we discovered that exosomal HOTAIRM1 enhanced pLF proliferation to secrete excessive collagen secretion, leading to airway obstruction by stimulating the TGF-ß/SMAD3 signaling pathway. Significantly, PM2.5 reduced FEV1/FVC and FEV1 and increased the level of serum exosomal HOTAIRM1 in healthy people; moreover, serum exosomal HOTAIRM1 was associated with PM2.5-related reductions in FEV1/FVC and FVC. These findings show that PM2.5 triggers alterations in exosome components and clarify that one of the paracrine mediators of myofibroblast differentiation is bronchial epithelial cell-derived HOTAIRM1, which has the potential to be an effective prevention and therapeutic target for PM2.5-induced COPD.

Pretreatment radiomic biomarker for immunotherapy responder prediction in stage IB-IV NSCLC (LCDigital-IO Study): a multicenter retrospective study.

BACKGROUND: The predictive efficacy of current biomarker of immune checkpoint inhibitors (ICIs) is not sufficient. This study investigated the causality between radiomic biomarkers and immunotherapy response status in patients with stage IB-IV non-small cell lung cancer (NSCLC), including its biological context for ICIs treatment response prediction. METHODS: CT images from 319 patients with pretreatment NSCLC receiving immunotherapy between January 2015 and November 2021 were retrospectively collected and composed a discovery (n=214), independent validation (n=54), and external test cohort (n=51). A set of 851 features was extracted from tumorous and peritumoral volumes of interest (VOIs). The reference standard is the durable clinical benefit (DCB, sustained disease control for more than 6 months assessed via radiological evaluation). The predictive value of combined radiomic signature (CRS) for pathological response was subsequently assessed in another cohort of 98 patients with resectable NSCLC receiving ICIs preoperatively. The association between radiomic features and tumor immune landscape on the online data set (n=60) was also examined. A model combining clinical predictor and radiomic signatures was constructed to improve performance further. RESULTS: CRS discriminated DCB and non-DCB patients well in the training and validation cohorts with an area under the curve (AUC) of 0.82, 95% CI: 0.75 to 0.88, and 0.75, 95% CI: 0.64 to 0.87, respectively. In this study, the predictive value of CRS was better than programmed cell death ligand-1 (PD-L1) expression (AUC of PD-L1 subset: 0.59, 95% CI: 0.50 to 0.69) or clinical model (AUC: 0.66, 95% CI: 0.51 to 0.81). After combining the clinical signature with CRS, the predictive performance improved further with an AUC of 0.837, 0.790 and 0.781 in training, validation and D2 cohorts, respectively. When predicting pathological response, CRS divided patients into a major pathological response (MPR) and non-MPR group (AUC: 0.76, 95% CI: 0.67 to 0.81). Moreover, CRS showed a promising stratification ability on overall survival (HR: 0.49, 95% CI: 0.27 to 0.89; p=0.020) and progression-free survival (HR: 0.43, 95% CI: 0.26 to 0.74; p=0.002). CONCLUSION: By analyzing both tumorous and peritumoral regions of CT images in a radiomic strategy, we developed a non-invasive biomarker for distinguishing responders of ICIs therapy and stratifying their survival outcome efficiently, which may support the clinical decisions on the use of ICIs in advanced as well as patients with resectable NSCLC.

A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy.

The abnormal activation of epidermal growth factor receptor (EGFR) drives the development of non-small cell lung cancer (NSCLC). The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR mutation. However, free osimertinib administration exhibits an inadequate response in vivo, with only ∼3% patients demonstrating a complete clinical response. Consequently, we designed a biomimetic nanoparticle (CMNP@Osi) comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery, thereby supporting a dual-target strategy for enhancing osimertinib efficacy. After intravenous injection, CMNP@Osi accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous targeting. Osimertinib is subsequently released into the cytoplasm, where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC cells. Thus, this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.

An Ultrahighly Pressure Sensitive Electronic Fish Skin for Underwater Wave Sensing.

Underwater flexible sensors have a future for wide application, which is promising for attaching them to underwater creatures to monitor vital signals and biomechanical analysis of their motion and perceive tiny environmental disturbances. However, the pressure waves induced by biological swimming are extremely weak and susceptible to undercurrents, making them difficult to sense. Here, we report an ultrahighly sensitive biomimetic electronic fish skin designed by embedding an artificial pseudocapacitive-based hair cell into a simulated canal neuromast encapsulation structure, in which the artificial hair cell, as the key sensitive unit, is assembled from hybrid film electrodes and polyurethane-acidic electrolyte foam. Such a film is prepared by inter-cross-linking MXene and holey reduced graphene oxide with the assistance of l-cysteine, effectively increasing the interfacial capacitance and alleviating the oxidation issues of MXene. Meanwhile, the acidic foam with high porosity shows great compressibility to adapt to a high-pressure underwater environment. Consequently, the device exhibits ultrahighly sensitivity (maximum sensitivity ∼173688 kPa-1) over a wide range of depths (0-100 m) and remains stable after 10000 repeated tests. As an example case, the device is integrated as a motion monitoring system to identify the minor disturbances triggered by instantaneous postural changes of fish. The electronic fish skin is expected to demonstrate enormous potentials in flow field monitoring, ocean current detecting, and even seismic waves warning.

Combining autophagy and immune characterizations to predict prognosis and therapeutic response in lung adenocarcinoma.

Background: Autophagy, a key regulator of programmed cell death, is critical for maintaining the stability of the intracellular environment. Increasing evidence has revealed the clinical importance of interactions between autophagy and immune status in lung adenocarcinoma. The present study evaluated the potential of autophagy-immune-derived biomarkers to predict prognosis and therapeutic response in patients with lung adenocarcinoma. Methods: Patients from the GSE72094 dataset were randomized 7:3 to a training set and an internal validation set. Three independent cohorts, TCGA, GSE31210, and GSE37745, were used for external verification. Unsupervised hierarchical clustering based on autophagy- and immune-associated genes was used to identify autophagy- and immune-associated molecular patterns, respectively. Significantly prognostic autophagy-immune genes were identified by LASSO analysis and by univariate and multivariate Cox regression analyses. Differences in tumor immune microenvironments, functional pathways, and potential therapeutic responses were investigated to differentiate high-risk and low-risk groups. Results: High autophagy status and high immune status were associated with improved overall survival. Autophagy and immune subtypes were merged into a two-dimensional index to characterize the combined prognostic classifier, with 535 genes defined as autophagy-immune-related differentially expressed genes (DEGs). Four genes (C4BPA, CD300LG, CD96, and S100P) were identified to construct an autophagy-immune-related prognostic risk model. Survival and receiver operating characteristic (ROC) curve analyses showed that this model was significantly prognostic of survival. Patterns of autophagy and immune genes differed in low- and high-risk patients. Enrichment of most immune infiltrating cells was greater, and the expression of crucial immune checkpoint molecules was higher, in the low-risk group. TIDE and immunotherapy clinical cohort analysis predicted that the low-risk group had more potential responders to immunotherapy. GO, KEGG, and GSEA function analysis identified immune- and autophagy-related pathways. Autophagy inducers were observed in patients in the low-risk group, whereas the high-risk group was sensitive to autophagy inhibitors. The expression of the four genes was assessed in clinical specimens and cell lines. Conclusions: The autophagy-immune-based gene signature represents a promising tool for risk stratification in patients with lung adenocarcinoma, guiding individualized targeted therapy or immunotherapy.

Diabetic visceral neuropathy of gastroparesis: Gastric mucosal innervation and clinical significance.

BACKGROUND AND PURPOSE: The pathogenesis of diabetic gastroparesis due to visceral neuropathy involves multidimensional mechanisms with limited exploration of gastric mucosal innervation. This study aimed to examine quantitatively this topic and its relationship with gastroparesis symptoms and gastric emptying in diabetes. METHODS: We prospectively enrolled 22 patients with type 2 diabetes and gastroparesis symptoms and 25 age- and gender-matched healthy controls for comparison. The assessments included: (i) neuropathology with quantification of gastric mucosal innervation density (MID) on endoscopic biopsy; (ii) clinical manifestations based on the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire; and (iii) functional tests of gastric emptying scintigraphy (GES). RESULTS: In patients with diabetes, stomach fullness, bloating and feeling excessively full after meals constituted the most common GCSI symptoms. Seven patients with diabetes (32%) had prolonged gastric emptying patterns. In diabetes, gastric MID was significantly lower in all the regions examined compared with the controls: antrum (294.8 ± 237.0 vs. 644.0 ± 222.0 mm/mm3 ; p < 0.001), body (292.2 ± 239.0 vs. 652.6 ± 260.9 mm/mm3 ; p < 0.001), and fundus (238.0 ± 109.1 vs. 657.2 ± 332.8 mm/mm3 ; p < 0.001). Gastric MID was negatively correlated with gastroparesis symptoms and total scores on the GCSI (p < 0.001). Furthermore, gastric MID in the fundus was negatively correlated with fasting glucose and glycated hemoglobin levels. Gastric emptying variables, including half emptying time and gastric retention, were prolonged in patients with diabetes, and gastric retention at 3 h was correlated with fasting glucose level. CONCLUSION: In diabetes, gastric MID was reduced and GES parameters were prolonged. Both were correlated with gastroparesis symptoms and glycemic control. These findings provide pathology and functional biomarkers for diabetic visceral neuropathy of gastroparesis and underlying pathophysiology.

Sensitive inflammatory biomarkers of acute fine particulate matter exposure among healthy young adults: Findings from a randomized, double-blind crossover trial on air filtration.

The short-term alteration of peripheral cytokines may be an early adverse health effect of PM2.5 exposure and may be further associated with cardiovascular disease. We conducted a randomized, double-blind crossover trial using true or sham air filtration among 54 healthy college students in Beijing to investigate the potential benefits of short-term indoor air filtration and the adverse health effects of time-weighted personal PM2.5 exposure through inflammatory cytokines. The participants randomly received true or sham air filtration intervention for a week, and the treatment was changed after a two-week washout period. Peripheral blood samples were collected after each intervention period to measure 38 inflammatory cytokines. A linear mixed-effects model was applied to estimate the impacts of air purification or a 10 µg/m3 PM2.5 exposure increase on cytokines. Lag effects of PM2.5 exposure were analyzed using single-day and moving average lag models. Air filtration reduced indoor and time-weighted average personal PM2.5 concentrations by 69.0% (from 33.6 to 10.4 µg/m3) and 40.3% (from 40.6 to 24.3 µg/m3), respectively. We observed a significant association of PM2.5 exposure with growth-regulated alpha protein (GRO-α) of -11.3% (95%CI: 17.0%, -5.4%). In the lag models, significant associations between personal PM2.5 exposure and interleukin-1 receptor antagonist (IL-1Ra), monocyte chemotactic protein (MCP-1), and eotaxin were obtained at lag0, while associations with cytokines including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein-1ß (MIP-1ß), IL-4, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were noted at relatively long lagged exposure windows (lag5-lag6). No significant alteration in cytokines was observed under true air filtration intervention. Our study indicates the effectiveness of air filtration on indoor PM2.5 reduction. PM2.5 exposure may decrease GRO-α levels and change different cytokine levels time-varyingly. Further study is still needed to explore the mechanisms of PM2.5 exposure on the inflammatory response.

Association between gaseous air pollutants and biomarkers of systemic inflammation: A systematic review and meta-analysis.

BACKGROUND: Studies have linked gaseous air pollutants to multiple health effects via inflammatory pathways. Several major inflammatory biomarkers, including C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have also been considered as predictors of cardiovascular disease. However, there has been no meta-analysis to evaluate the associations between gaseous air pollutants and these typical biomarkers of inflammation to date. OBJECTIVES: To evaluate the overall associations between short-term and long-term exposures to ambient ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon dioxide (CO) and major inflammatory biomarkers including CRP, fibrinogen, IL-6 and TNF-α. METHODS: A meta-analysis was conducted for publications from PubMed, Web of Science, Scopus and EMBASE databases up to Feb 1st, 2021. RESULTS: The meta-analysis included 38 studies conducted among 210,438 participants. Generally, we only observed significant positive associations between short-term exposures to gaseous air pollutants and inflammatory biomarkers. For a 10 µg/m3 increase in short-term exposure to O3, NO2, and SO2, there were significant increases of 1.05% (95%CI: 0.09%, 2.02%), 1.60% (95%CI: 0.49%, 2.72%), and 10.44% (95%CI: 4.20%, 17.05%) in CRP, respectively. Meanwhile, a 10 µg/m3 increase in NO2 was also associated with a 4.85% (95%CI: 1.10%, 8.73%) increase in TNF-α. Long-term exposures to gaseous air pollutants were not statistically associated with these biomarkers, but the study numbers were relatively small. Subgroup analyses found more apparent associations in studies with better study design, higher quality, and smaller sample size. Meanwhile, the associations also varied across studies conducted in different geographical regions. CONCLUSION: Short-term exposure to gaseous air pollutants is associated with increased levels of circulating inflammatory biomarkers, suggesting that a systemic inflammatory state is activated upon exposure. More studies on long-term exposure to gaseous air pollutants and inflammatory biomarkers are warranted to verify the associations.

Development and validation of a preoperative CT-based radiomic nomogram to predict pathology invasiveness in patients with a solitary pulmonary nodule: a machine learning approach, multicenter, diagnostic study.

OBJECTIVES: To develop and validate a preoperative CT-based nomogram combined with radiomic and clinical-radiological signatures to distinguish preinvasive lesions from pulmonary invasive lesions. METHODS: This was a retrospective, diagnostic study conducted from August 1, 2018, to May 1, 2020, at three centers. Patients with a solitary pulmonary nodule were enrolled in the GDPH center and were divided into two groups (7:3) randomly: development (n = 149) and internal validation (n = 54). The SYSMH center and the ZSLC Center formed an external validation cohort of 170 patients. The least absolute shrinkage and selection operator (LASSO) algorithm and logistic regression analysis were used to feature signatures and transform them into models. RESULTS: The study comprised 373 individuals from three independent centers (female: 225/373, 60.3%; median [IQR] age, 57.0 [48.0-65.0] years). The AUCs for the combined radiomic signature selected from the nodular area and the perinodular area were 0.93, 0.91, and 0.90 in the three cohorts. The nomogram combining the clinical and combined radiomic signatures could accurately predict interstitial invasion in patients with a solitary pulmonary nodule (AUC, 0.94, 0.90, 0.92) in the three cohorts, respectively. The radiomic nomogram outperformed any clinical or radiomic signature in terms of clinical predictive abilities, according to a decision curve analysis and the Akaike information criteria. CONCLUSIONS: This study demonstrated that a nomogram constructed by identified clinical-radiological signatures and combined radiomic signatures has the potential to precisely predict pathology invasiveness. KEY POINTS: • The radiomic signature from the perinodular area has the potential to predict pathology invasiveness of the solitary pulmonary nodule. • The new radiomic nomogram was useful in clinical decision-making associated with personalized surgical intervention and therapeutic regimen selection in patients with early-stage non-small-cell lung cancer.

Preoperative CT-based peritumoral and tumoral radiomic features prediction for tumor spread through air spaces in clinical stage I lung adenocarcinoma.

OBJECTIVES: This study aims to develop and evaluate preoperative CT-based peritumoral and tumoral radiomic features to predict tumor spread through air space (STAS) status in clinical stage I lung adenocarcinoma (LUAD). MATERIALS AND METHODS: From June 2018 to December 2019, a retrospective diagnostic investigation was done. Patients with pathologically confirmed STAS status (N = 256) were eventually enrolled. The development cohort consisted of 191 patients (74.6%) chosen randomly in a 7:3 ratio, whereas the validation group consisted of 65 patients (25.4%). The performance of models was assessed using receiver operating characteristic analysis, accuracy, sensitivity, specificity, negative predictive values, and positive predictive values. RESULTS: The STAS positive status was found in 85 (33.2%) of the 256 patients (female: 53.2%; median [IQR] age: 62.0, [53.0-79.0] years), while the STAS negative status was found in 171 patients (66.8%) (female:50.6%; median [IQR] age: 62.0, [53.0-87.0] years). The combined TRS and PRS-15 mm model had an AUC of 0.854 (95% CI, 0.799-0.909) in the development cohort and 0.870 (95% CI, 0.781-0.958) in the validation cohort, indicating that the tumor radiomic signature (TRS) model and different peritumoral radiomic signature (PRS) models were used to build the optimal gross radiomic signature (GRS) model. The radiomic nomogram achieves superior discriminatory performance than GRS and clinical and radiological signatures (CRS), with an AUC of 0.871 (95% CI, 0.820-0.922) in the development cohort and AUC of 0.869 (95% CI, 0.776-0.961) in the validation cohort. Based on the Akaike information criterion (AIC) and decision curve analysis (DCA), the radiomic nomogram provided greater clinical predictive capacity than clinical or any radiomic signatures alone. CONCLUSION: In conclusion, we discovered that peritumoral characteristics were substantially related to STAS status. This study revealed the unit of radiomic signature and clinical signatures may have a better performance in STAS status.

Identification of Prognostic Model Based on Immune-Related LncRNAs in Stage I-III Non-Small Cell Lung Cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) participate in the regulation of immune response and carcinogenesis, shaping tumor immune microenvironment, which could be utilized in the construction of prognostic signatures for non-small cell lung cancer (NSCLC) as supplements. METHODS: Data of patients with stage I-III NSCLC was downloaded from online databases. The least absolute shrinkage and selection operator was used to construct a lncRNA-based prognostic model. Differences in tumor immune microenvironments and pathways were explored for high-risk and low-risk groups, stratified by the model. We explored the potential association between the model and immunotherapy by the tumor immune dysfunction and exclusion algorithm. RESULTS: Our study extracted 15 immune-related lncRNAs to construct a prognostic model. Survival analysis suggested better survival probability in low-risk group in training and validation cohorts. The combination of tumor, node, and metastasis staging systems with immune-related lncRNA signatures presented higher prognostic efficacy than tumor, node, and metastasis staging systems. Single sample gene set enrichment analysis showed higher infiltration abundance in the low-risk group, including B cells (p<0.001), activated CD8+ T cells (p<0.01), CD4+ T cells (p<0.001), activated dendritic cells (p<0.01), and CD56+ Natural killer cells (p<0.01). Low-risk patients had significantly higher immune scores and estimated scores from the ESTIMATE algorithm. The predicted proportion of responders to immunotherapy was higher in the low-risk group. Critical pathways in the model were enriched in immune response and cytoskeleton. CONCLUSIONS: Our immune-related lncRNA model could describe the immune contexture of tumor microenvironments and facilitate clinical therapeutic strategies by improving the prognostic efficacy of traditional tumor staging systems.

KEAP1/NFE2L2 Mutations of Liquid Biopsy as Prognostic Biomarkers in Patients With Advanced Non-Small Cell Lung Cancer: Results From Two Multicenter, Randomized Clinical Trials.

PURPOSE: The KEAP1-NFE2L2 (Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)) mutations are associated with resistance to chemotherapy or immunotherapy in non-small cell lung cancer (NSCLC). Conversely, it has been reported that NFE2L2 mutations potentiate improved clinical outcome with immunotherapy. However, therapeutic benefits for patients with KEAP1/NFE2L2 mutations remain unclear. The purpose of this study was to investigate the association between KEAP1/NFE2L2 and NSCLC prognosis, and to explore whether immunotherapy can improve prognosis in populations with KEAP1/NFE2L2 mutations. EXPERIMENTAL DESIGN: The impact of KEAP1/NFE2L2 mutations on survival outcomes in NSCLC patients received immunotherapy and chemotherapy was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, POPLAR (n = 211) and OAK (n = 642)). The Cancer Genome Atlas (TCGA) NSCLC cohort (n=998) and an in-house Chinese NSCLC cohort (n=733) was used For the analysis of immune-related markers. RESULTS: Compared with KEAP1/NFE2L2 wild-type, patients with KEAP1/NFE2L2 mutations were significantly associated with poorer overall survival (OS, HR = 1.97, 95% CI 1.48-2.63, P < 0.001) on atezolizumab and docetaxel (HR = 1.66, 95% CI 1.28-2.16, P < 0.001). In KEAP1/NFE2L2 mutant group, there was no significant difference in median OS between atezolizumab and docetaxel (HR 0.74, 95% CI 0.53-1.03, P = 0.07). NFE2L2/KEAP1 mutations were significantly associated with higher TMB values and PD-L1 expression in the OAK/POPLAR and in-house Chinese NSCLC cohorts. GSEA revealed that KEAP1/NFE2L2mutant subgroup was associated with deficient infiltration of CD4+ T cells, NK T cells and natural Treg cells, and lower expression of DNA damage response genes in TCGA NSCLC cohort. CONCLUSIONS: Our study revealed that patients with KEAP1/NFE2L2 mutations have a worse prognosis than wild-type patients, both on immunotherapy and chemotherapy. In addition, in patients with KEAP1/NFE2L2 mutations, immunotherapy did not significantly improve prognosis compared to chemotherapy.

A prospective study of the associations among fine particulate matter, genetic variants, and the risk of colorectal cancer.

BACKGROUND: Fine particulate matter (PM2.5) is suspected to increase the risk of colorectal cancer, but the mechanism remains unknown. We aimed to investigate the association between PM2.5 exposure, genetic variants and colorectal cancer risk in the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening trial. METHODS: We included a prospective cohort of 139,534 cancer-free individuals from 10 United States research centers with over ten years of follow-up. We used a Cox regression model to assess the association between PM2.5 exposure and colorectal cancer incidence by calculating the hazard ratio (HR) and 95% confidence interval (CI) with adjustment for potential confounders. The polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between PM2.5 exposure and genetic variants in regard to colorectal cancer risk. RESULTS: After a median of 10.43 years of follow-up, 1,666 participants had been diagnosed with colorectal cancer. PM2.5 exposure was significantly associated with an increased risk of colorectal cancer (HR = 1.27; 95% CI = 1.17-1.37 per 5 µg/m3 increase). Five independent susceptibility loci reached statistical significance at P < 1.22 × 10-8 in the interaction analysis. Furthermore, a joint interaction was observed between PM2.5 exposure and the PRS based on these five loci with colorectal cancer risk (P = 3.11 × 10-29). The Gene Ontology analysis showed that the vascular endothelial growth factor (VEGF) receptor signaling pathway was involved in the biological process of colorectal cancer. CONCLUSIONS: Our large-scale analysis has shown for the first time that long-term PM2.5 exposure potential increases colorectal cancer risk, which might be modified by genetic variants.

Small fiber pathology in autism and clinical implications.

OBJECTIVE: To investigate small fiber innervation of the skin and its relationships with clinicometry of autism and peripheral afferents for contact heat-evoked potential (CHEP) and psychophysical measures of thermal thresholds. METHODS: We recruited 32 men with autism (26.5 ± 5.9 years) and conducted small fiber assessments of skin biopsy with quantifying intraepidermal nerve fiber (IENF) density, CHEP, quantitative sensory testing, and large fiber physiology of nerve conduction studies. Results were compared with age-matched controls and analyzed with clinical measures of autism. RESULTS: Patients with autism showed a lower IENF density than controls (5.53 ± 2.09 vs 11.13 ± 3.49 fibers/mm, p < 0.0001). The IENF density was reduced in 17 (53.1%) men with autism classified as skin denervation group. On psychophysics, 9 (28%) men with autism had elevated thermal thresholds, and the warm threshold of the big toe was negatively correlated with IENF density (p = 0.0073), indicating functional impairments of small fiber sensory nerves. IENF density was negatively correlated with CHEP amplitude in autism (p = 0.003), in contrast to the pattern of positive correlation in controls, indicating different processing of nociceptive afferent in autism. Clinically, IENF density was related to distinct tactile symptom patterns in the skin denervation vs normal innervation group, respectively. Furthermore, IENF density was associated with autistic symptoms measured by the Autism Spectrum Quotient in a U-shaped model (p = 0.014). CONCLUSIONS: These observations indicated that a substantial portion of individuals with autism had small fiber pathology, which was associated with tactile and autistic symptoms, providing structural and physiologic evidence for the involvement of peripheral sensory nerves in autism.

A cascade dual-targeted nanocarrier for enhanced alectinib delivery to ALK-positive lung cancer.

Alectinib is a highly efficacious inhibitor for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in the clinic; however, serious adverse events (AEs) occurred in 44.0% of patients. Herein, we explored magnetic/TAT dual-targeted nanocarriers as delivery systems for alectinib. Magnetic targeting efficiently enhanced the extravasation of alectinib-loaded nanoparticles from vessels into the tumor tissue, while the TAT targeting reactivated in the tumor tissue significantly improved the tumor cellular uptake of the nanocarrier. As a result, this dual-targeted polymeric nanocarrier exhibited superior therapeutic effects and induced tumor shrinkage in vivo. Meanwhile, this dual-targeted nanocarrier also minimized alectinib-induced hepatotoxicity, providing an efficient strategy to extend the application of alectinib for NSCLC patients.

Citrus Consumption and Risk of Cutaneous Malignant Melanoma in the Women's Health Initiative.

Citrus products are rich sources of furocoumarins, a class of photoactive compounds. Certain furocoumarins combined with ultraviolet radiation can induce skin cancer. We examined the relationship between citrus consumption and cutaneous melanoma risk among 56,205 Caucasian postmenopausal women in the Women's Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by citrus intake level. During a mean follow-up of 15.7 years, 956 incident melanoma cases were documented. In multivariable adjusted models, the HR (95% CI) for melanoma was 1.12 (0.91, 1.37) among the highest citrus consumers (1.5+ servings/day of fruit or juice) versus the lowest (<2 servings/week), 0.95 (0.76, 1.20) among the highest citrus fruit consumers (5+ servings/week) versus non-consumers, and was 1.13 (0.96, 1.32) for the highest citrus juice consumers (1+ servings/day) versus the lowest (<1 serving/week). In stratified analyses, an increased melanoma risk associated with citrus juice intake was observed among women who spent the most time outdoors in summer as adults; the HR for the highest versus lowest intake was 1.22 (1.02, 1.46) (p trend = 0.03). Further research is needed to explore the association of melanoma with citrus juices among women with high sun exposure.

Cardiorespiratory responses to low-level ozone exposure: The inDoor Ozone Study in childrEn (DOSE).

BACKGROUND: Indoor air pollution has emerged as a significant environmental and public health concern in recent years. However, evidence regarding the cardiorespiratory effects of indoor ozone is limited, and the underlying biological mechanisms are unclear, especially in children. Our study aimed to assess the cardiorespiratory responses to indoor ozone exposure in children. METHODS: A repeated-measure study was conducted in 46 middle-school children in Beijing, China. Real-time concentrations of ozone, along with co-pollutants including particulate matter (PM) and black carbon (BC), were monitored in classrooms from Monday to Friday. Three repeated health measurements of cardiorespiratory functions, including ambulatory electrocardiogram (ECG), blood pressure, fractional exhaled nitric oxide (FeNO) and lung function, were performed on each participant. Mixed-effect models were used to evaluate the effects of indoor ozone exposure. RESULTS: The mean (SD) indoor ozone concentration was 8.7 (6.6) ppb during the study period, which was largely below the current guideline and standards. However, even this low-level ozone exposure was associated with reduced cardiac autonomic function and increased heart rate (HR) in children. For instance, per interquartile range (IQR) increase in ozone at 2-hour moving average was associated with -7.8% (95% CI: -9.9%, -5.6%) reduction in standard deviation of all normal-to-normal intervals (SDNN), and 2.6% (95% CI: 1.6%, 3.6%) increment in HR. In addition, the associations were stronger at high BC levels (BC ≥ 3.7 µg/m3). No significant associations were found for airway inflammation and pulmonary function. CONCLUSIONS: Exposure to low-level indoor ozone that is not associated with respiratory effects was significantly related to disturbed cardiac autonomic function and increased HR in children, which suggested a possible mechanism through which ozone may affect cardiovascular health in children, and indicated more protective measures should be taken to alleviate the acute adverse effects of indoor ozone in this susceptible population.

Fruit and vegetable consumption, cigarette smoke, and leukocyte mitochondrial DNA copy number.

Background: Mitochondrial dysfunction is an important component of the aging process and has been implicated in the development of many human diseases. Mitochondrial DNA copy number (mtDNAcn), an indirect biomarker of mitochondrial function, is sensitive to oxidative damage. Few population-based studies have investigated the impact of fruit and vegetable consumption and cigarette smoke (2 major sources of exogenous antioxidants and oxidants) on leukocyte mtDNAcn. Objectives: We investigated the association between fruit and vegetable consumption, cigarette smoke, and leukocyte mtDNAcn based on data from the Nurses' Health Study (NHS). Methods: Data from 2769 disease-free women in the NHS were used to examine the cross-sectional associations between dietary sources of antioxidants, cigarette smoke, and leukocyte mtDNAcn. In vitro cell-based experiments were conducted to support the findings from the population-based study. Results: In the multivariable-adjusted model, both whole-fruit consumption and intake of flavanones (a group of antioxidants abundant in fruit) were positively associated with leukocyte mtDNAcn (P-trend = 0.005 and 0.02, respectively), whereas pack-years of smoking and smoking duration were inversely associated with leukocyte mtDNAcn (P-trend = 0.01 and 0.007, respectively). These findings are supported by in vitro cell-based experiments showing that the administration of naringin, a major flavanone in fruit, led to a substantial increase in mtDNAcn in human leukocytes, whereas exposure to nicotine-derived nitrosamine ketone, a key carcinogenic ingredient of cigarette smoke, resulted in a significant decrease in mtDNAcn of cells (all P < 0.05). Further in vitro studies showed that alterations in leukocyte mtDNAcn were functionally linked to the modulation of mitochondrial biogenesis and function. Conclusions: Fruit consumption and intake of dietary flavanones were associated with increased leukocyte mtDNAcn, whereas cigarette smoking was associated with decreased leukocyte mtDNAcn, which is a promising biomarker for oxidative stress-related health outcomes.

Perfluoroalkyl substances exposure and risk of polycystic ovarian syndrome related infertility in Chinese women.

Perfluoroalkyl substances (PFASs) are a family of synthetic, fluorinated organic compounds. They have been widely used in industrial applications and consumer products and widespread in the environment, wildlife and human. Experimental and epidemiologic evidence suggested that PFASs are capable of interfering with endocrine processes and have potential reproductive and developmental toxicities. Polycystic ovarian syndrome (PCOS), one of the main reasons of female infertility, is a common endocrine disorder in reproductive age women. We performed a case-control study to evaluate associations between PCOS-related infertility and PFASs concentrations in plasma. A total of 180 infertile PCOS-cases and 187 healthy controls were recruited from the Center for Reproductive Medicine of Shandong University. Blood specimens were collected at enrollment and analyzed for ten PFASs using liquid chromatography-tandem mass spectrometry. Multivariable logistic regression procedure was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each PFAS. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were the dominant PFASs in the plasma of participants, with the median concentration of 5.07 ng/mL and 4.05 ng/mL, respectively. The median levels of individual PFAS were not significantly different between PCOS-cases and controls. While adjusted for the potential confounders (age, BMI, household income, education level, employment status, age at menarche, menstrual volume), the plasma concentration of perfluorododecanoic acid (PFDoA), a 12 carbons lengths of perfluorocarboxylic acids, was associated with a significantly increased risk of PCOS-related infertility (medium vs low tertile: OR = 2.36, 95% CI: 1.12, 4.99, P = 0.02; high vs low tertile: OR = 3.04, 95% CI: 1.19, 7.67, P = 0.02), with the P trend 0.01. No significant relationship was observed between PCOS-related infertility and other PFAS analytes in the adjusted model, despite perfluoroundecanoic acid showed a negative association (P trend 0.03). The potential reproductive health effects of PFASs and the underlying mechanisms merit further investigation in the future.