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Seung-Shick Shin,1,* Dae-Hwa Noh,2,* Byungdoo Hwang,2 Jo-Won Lee,2 Sung Lyea Park,2 Sung-Soo Park,1 Bokyung Moon,2 Wun-Jae Kim,3 Sung-Kwon Moon2 1Department of Food Science and Nutrition, Jeju National University, Jeju, South Korea; 2Department of Food and Nutrition, Chung-Ang University, Anseong, South Korea; 3Department of Urology, Chungbuk National University, Cheongju, Chungbuk, South Korea *These authors contributed equally to this work Background: Although the diverse biological properties of nanoparticles have been studied intensively, research into their mechanism of action is relatively rare. In this study, we investigated the molecular mechanisms of the anticancer activity of heterometallic Au@Pt-nanoseeds (NSs) against bladder cancers.Materials and methods: Mode of action of Au@Pt-NSs was investigated through MTT assay, flow cytometry analysis, Western immunoblots, real-time qPCR, wound-healing migration and invasion assays, zymography, and electrophoretic mobility shift assay (EMSA).Results: Treatment with Au@Pt-NSs significantly inhibited the proliferation of EJ cells in a dose-dependent manner by inducing G1 phase cell cycle arrest. Among the regulators associated with the G1 cell cycle phase, CDK2, CDK4, cyclin D1, cyclin E, and p21WAF1 were shown to participate in the inhibitory pathways of Au@Pt-NSs. In addition, treatment with Au@Pt-NSs led to upregulation of phospho-p38 MAPK and downregulation of phospho-AKT in EJ cells. Interestingly, Au@Pt-NSs inhibited the migratory and invasive potential of the cells, which was attributed to the suppression of the enzymatic activity of matrix metalloproteinase-9 (MMP-9). Using MMP-9-specific oligonucleotides, we showed that transcription factors such as NF-κB and Sp-1 were responsible for the MMP-9-mediated metastatic potential of EJ cells.Conclusion: Au@Pt-NSs significantly limited the progression, migration, and invasion of bladder cancer EJ cells. Our data represent a novel insight into developing cisplatin-like chemotherapeutic reagents with fewer side effects and provide useful information on molecular markers to monitor patients under Au@Pt-NSs-based chemotherapy. Keywords: nanoseeds, nanomedicine, bladder cancer, molecular mechanism

Purpose: There are complex and paradoxical patterns in lung cancer incidence by race/ethnicity and gender; compared to non-Hispanic White (NHW) males, non-Hispanic Black (NHB) males smoke fewer cigarettes per day and less frequently but have higher lung cancer rates. Similarly, NHB females are less likely to smoke but have comparable lung cancer rates to NHW females. We use a multistage carcinogenesis model to study the impact of smoking on lung cancer incidence in NHB and NHW individuals in the Multiethnic Cohort Study (MEC)., Methods: The effects of smoking on the rates of lung tumor initiation, promotion, and malignant conversion, and the incidence of lung cancer in NHB versus NHW adults in the MEC were analyzed using the Two-Stage Clonal Expansion (TSCE) model. Maximum likelihood methods were used to estimate model parameters and assess differences by race/ethnicity, gender, and smoking history., Results: Smoking increased promotion and malignant conversion but did not affect tumor initiation. Non-smoking-related initiation, promotion, and malignant conversion and smoking-related promotion and malignant conversion differed by race/ethnicity and gender. Non-smoking-related initiation and malignant conversion were higher in NHB than NHW individuals, whereas promotion was lower in NHB individuals., Conclusion: Findings suggest that while smoking plays an important role in lung cancer risk, background risk not dependent on smoking also plays a significant and under-recognized role in explaining race/ethnicity differences. Ultimately, the resulting TSCE model will inform race/ethnicity-specific lung cancer natural history models to assess the impact of preventive interventions on US lung cancer outcomes and disparities by race/ethnicity., Competing Interests: Declarations Competing Interests The authors declare no competing interests. Ethics Approval This study was approved by the University of Michigan IRB (HUM00195762). Consent to Participate Informed consent was obtained from all MEC study participants., (© 2024. The Author(s).)

Tissue-resident memory T (T RM ) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T RM cell fate remains poorly understood. Here, we show that whereas skin T RM cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T RM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal T RM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated T RM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Since 1982, recombinant insulin has been used as a substitute for pancreatic insulin from animals. However, increasing demand in medical and food industries warrants the development of more efficient production methods. In this study, we aimed to develop a novel and efficient method for insulin production using a yeast secretion system., Methods: Here, insulin C-peptide was replaced with a hydrophilic fusion partner (HL18) containing an affinity tag for the hypersecretion and easy purification of proinsulin. The HL18 fusion partner was then removed by in vitro processing with the Kex2 endoprotease (Kex2p), and authentic insulin was recovered via affinity chromatography. To improve the insulin functions, molecular chaperones of the host strain were reinforced via the constitutive expression of HAC1., Results: The developed method was successfully applied for the expression of cow, pig, and chicken insulins in yeast. Moreover, biological activity of recombinant insulins was confirmed by growth stimulation of cell line., Conclusions: Therefore, replacement of the C-peptide of insulin with the HL18 fusion partner and use of Kex2p for in vitro processing of proinsulin guarantees the economic production of animal insulins in yeast., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The human CTLH/GID (hGID) complex emerged as an important E3 ligase regulating multiple cellular processes, including cell cycle progression and metabolism. However, the range of biological functions controlled by hGID remains unexplored. Here, we used proximity-dependent biotinylation (BioID2) to identify proteins interacting with the hGID complex, among them, substrate candidates that bind GID4 in a pocket-dependent manner. Biochemical and cellular assays revealed that the hGID GID4 E3 ligase binds and ubiquitinates ARHGAP11A, thereby targeting this RhoGAP for proteasomal degradation. Indeed, GID4 depletion or impeding the GID4 substrate binding pocket with the PFI-7 inhibitor stabilizes ARHGAP11A protein amounts, although it carries no functional N-terminal degron. Interestingly, GID4 inactivation impairs cell motility and directed cell movement by increasing ARHGAP11A levels at the cell periphery, where it inactivates RhoA. Together, we identified a wide range of hGID GID4 E3 ligase substrates and uncovered a unique function of the hGID GID4 E3 ligase regulating cell migration by targeting ARHGAP11A., (© 2024 Bagci et al.)

Monzogranite is known for its high surface area and cation exchange capacity, which play a crucial role in ameliorating the challenges by enhancing nutrient adsorption and facilitating nutrient availability during the weaning period. Weaned crossbred piglets (Duroc × Yorkshire × Landrace), initially weighing 5.36 ± 0.26 kg, were allocated into four treatments with 6 replicates each (10 pigs per replicate). The treatments encompassed CON (basal diet), Z0.1 (0.1% monzogranite supplementation in basal diet), Z0.2 (0.2% monzogranite supplementation), and Z0.3 (0.3% monzogranite supplementation). In phase 1, a linear increase in total average daily gain (ADG) was observed across treatment groups, with a concomitant linear increase in ADG and gain-to-feed ratio (G/F). The overall results showed a linear increase in ADG and G/F. A linear decrease in aspartate aminotransferase and lactate dehydrogenase levels was observed across treatment groups. Conversely, no significant differences were noted in the levels of albumin, alkaline phosphatase, alanine aminotransferase, high-density lipoprotein, low-density lipoprotein, total cholesterol, blood urea nitrogen, triglycerides, and gamma-glutamyl transferase among the treatment groups. Faecal scoring indicated a linear reduction in scores at Day 7 among the treatment groups. However, no significant differences were observed at Days 14 and 28. The assessment of immunoglobulins demonstrated a significant increase in both immunoglobulin G and immunoglobulin A levels in the Z0.1 treatment group compared to the CON. In both phase 1 and phase 2, a linear decrease in cortisol levels was evident. In conclusion, a linear increase in total ADG and G/F during phase 1, sustained across both phases, suggests monzogranite potential to enhance growth performance. Moreover, stress mitigation was shown through a consistent linear decrease in cortisol levels across phases. These findings underscore monzogranite multifaceted impact, emphasizing its potential as a dietary supplement to enhance growth, liver health, and stress resilience in weanling pigs., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n  = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel ( CADM3 , NALCN, NLRC5, ZNF792 , and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level ( p  < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5 , NOD2 , and AIM2 . Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

Background: After accounting for smoking history, lung cancer incidence is greater in African Americans than Whites. In the multiethnic cohort, total nicotine equivalents (TNE) are higher in African Americans than Whites at similar reported cigarettes per day. Greater toxicant uptake per cigarette may contribute to the greater lung cancer risk of African Americans., Methods: In a nested case-control lung cancer study within the Southern Community Cohort, smoking-related biomarkers were measured in 259 cases and 503 controls (40% White; 56% African American). TNE, the trans-3-hydroxycotinine/cotinine ratio, 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), mercapturic acid metabolites of volatile organic compounds, phenanthrene metabolites, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid were quantified in urine. Unconditional logistic regression was used to estimate the ORs and 95% confidence intervals (CI) for each biomarker and lung cancer risk., Results: TNE, NNAL, and Cd were higher in cases than controls (adjusted for age, race, sex, body mass index, and cigarettes per day). Among cases, these levels were higher in African Americans compared with Whites. After accounting for age, sex, body mass index, and pack-years, a one-SD increase in log-TNE (OR = 1.30; 95% CI, 1.10-1.54) and log-NNAL (OR = 1.27; 95% CI, 1.03-1.58 with TNE adjustment) was associated with lung cancer risk. In this study, in which NNAL concentration is relatively high, the association for log-TNE was attenuated after adjustment for log-NNAL., Conclusions: Smoking-related biomarkers provide additional information for lung cancer risk in smokers beyond smoking pack-years., Impact: Urinary NNAL, TNE, and Cd concentrations in current smokers, particularly African American smokers, may be useful for predicting lung cancer risk., (©2024 American Association for Cancer Research.)

Importance: Variation in DNA methylation at specific loci estimates biological age, which is associated with morbidity, mortality, and social experiences. Aging estimates known as epigenetic clocks, including the Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), were trained on data predominately from individuals of European ancestry; however, limited research has explored DunedinPACE in underrepresented populations experiencing health disparities., Objective: To investigate associations of neighborhood and individual sociobehavioral factors with biological aging in a racially and ethnically diverse population., Design, Setting, and Participants: This cohort study, part of the Multiethnic Cohort study conducted from May 1993 to September 1996 to examine racial and ethnic disparities in chronic diseases, integrated biospecimen and self-reported data collected between April 2004 and November 2005 from healthy Hawaii residents aged 45 to 76 years. These participants self-identified as of Japanese American, Native Hawaiian, or White racial and ethnic background. Data were analyzed from January 2022 to May 2024., Main Outcomes and Measures: DNA methylation data were generated from monocytes enriched from cryopreserved lymphocytes and used to derive DunedinPACE scores from November 2017 to June 2021. Neighborhood social economic status (NSES) was estimated from 1990 US Census Bureau data to include factors such as educational level, occupation, and income. Individual-level factors analyzed included educational level, body mass index (BMI), physical activity (PA), and diet quality measured by the Healthy Eating Index (HEI). Linear regression analysis of DunedinPACE scores was used to examine their associations with NSES and sociobehavioral variables., Results: A total of 376 participants were included (113 [30.1%] Japanese American, 144 [38.3%] Native Hawaiian, and 119 [31.6%] White; 189 [50.3%] were female). Mean (SE) age was 57.81 (0.38) years. Overall, mean (SE) DunedinPACE scores were significantly higher among females than among males (1.28 [0.01] vs 1.25 [0.01]; P = .005); correlated negatively with NSES (R = -0.09; P = .08), HEI (R = -0.11; P = .03), and educational attainment (R = -0.15; P = .003) and positively with BMI (R = 0.31; P < .001); and varied by race and ethnicity. Native Hawaiian participants exhibited a higher mean (SE) DunedinPACE score (1.31 [0.01]) compared with Japanese American (1.25 [0.01]; P < .001) or White (1.22 [0.01]; P < .001) participants. Controlling for age, sex, HEI, BMI, and NSES, linear regression analyses revealed a negative association between educational level and DunedinPACE score among Japanese American (β, -0.005 [95% CI, -0.013 to 0.002]; P = .03) and Native Hawaiian (β, -0.003 [95% CI, -0.011 to 0.005]; P = .08) participants, yet this association was positive among White participants (β, 0.007; 95% CI, -0.001 to 0.015; P = .09). Moderate to vigorous PA was associated with lower DunedinPACE scores only among Native Hawaiian participants (β, -0.006; 95% CI, -0.011 to -0.001; P = .005), independent of NSES., Conclusions and Relevance: In this study of a racially and ethnically diverse sample of 376 adults, low NSES was associated with a higher rate of biological aging measured by DunedinPACE score, yet individual-level factors such as educational level and physical activity affected this association, which varied by race and ethnicity. These findings support sociobehavioral interventions in addressing health inequities.

Background: A growing literature has reported associations between traffic-related air pollution and breast cancer, however there are fewer investigations into specific ambient agents and any putative risk of breast cancer development, particularly studies occurring in populations residing in higher pollution areas such as Los Angeles., Objectives: To estimate breast cancer risks related to ambient air toxics exposure at residential addresses., Methods: We examined the relationships between ambient air toxics and breast cancer risk in the Multiethnic Cohort among 48,665 California female participants followed for cancer from 2003 through 2013. We obtained exposure data on chemicals acting as endocrine disruptors or mammary gland carcinogens from the National-Scale Air Toxics Assessment. Cox proportional hazards models were used to estimate breast cancer risk per one interquartile range (IQR) increase in air toxics exposure lagged by 5-years. Stratified analyses were conducted by race, ethnicity, and hormone receptor types., Results: Among all women, increased risks of invasive breast cancer were observed with toxicants related to industries [1,1,2,2-tetrachloroethane (hazard ratio [HR] = 4.22, 95% confidence interval [95% CI] 3.18-5.60), ethylene dichloride (HR = 2.81, 95% CI 2.20-3.59), and vinyl chloride (HR = 2.27, 95% CI 1.81, 2.85); these 3 agents were correlated (r2 = 0.45-0.77)]. Agents related to gasoline production or combustion were related to increased breast cancer risk [benzene (HR = 1.32, 95% CI 1.24, 1.41), ethylbenzene (HR = 1.20, 95% CI 1.13-1.28), toluene (HR = 1.29, 95% CI 1.20-1.38), naphthalene (HR = 1.11, 95% CI 1.02-2.22), acrolein (HR = 2.26, 95% CI 1.92, 2.65)]. Higher hazard ratios were observed in African Americans and Whites compared to other racial and ethnic groups (p-heterogeneity <0.05 for traffic-related air toxics, acrolein, and vinyl acetate)., Conclusions: Our findings suggest that specific toxic air pollutants may be associated with increase breast cancer risk., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T RM ) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating T RM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of T RM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of T RM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how T RM cell responses might be durably boosted or dampened for therapeutic gain.

Upper airway collapse and apneas in obstructive sleep apnea (OSA) induce intermittent hypercapnia and hypoxia, eventually contributing to excessive uric acid production. This study aimed to evaluate the association between hyperuricemia and OSA in the general population via analysis of the eighth KNHANES dataset (2019-2021). OSA risk was identified via the STOP-Bang questionnaire, with a score ≥3 indicating high risk. Among 11,981 total participants, 4572 (38.2%) had a high OSA risk. Participants with a high OSA risk had higher uric acid levels compared to those with a low risk (5.5 ± 1.4 mg/dL vs. 4.8 ± 1.2 mg/dL, p < 0.001). Serum uric acid levels were positively correlated with STOP-Bang score (r: 0.317, p < 0.001). Multivariate analysis revealed that hyperuricemia was associated with a high OSA risk after adjusting for confounders (odds ratio: 1.30, 95%CI: 1.11-1.53, p = 0.001). Therefore, serum uric acid levels are significantly higher in those with a high OSA risk and correlate with the risk of OSA. Further, hyperuricemia is an independently associated risk factor for high OSA risk. More research is warranted to evaluate the long-term clinical outcomes of hyperuricemia in OSA and to determine whether treatment targeting hyperuricemia is effective in the clinical course of OSA.

Purpose: One in six incident cancers in the U.S. is a second primary cancer (SPC). Although primary cancers vary considerably by race and ethnicity, little is known about the population-based occurrence of SPC across these groups., Methods: Using Surveillance, Epidemiology, and End Results (SEER) 12 data and relative to the general population, we calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPC among 2,457,756 Hispanics, non-Hispanic Asian American/Pacific Islanders (NHAAPI), non-Hispanic black (NHB), and non-Hispanic whites (NHW) cancer survivors aged 45 years or older when diagnosed with a first primary cancer (FPC) from 1992 to 2015., Results: The risk of second primary bladder cancer after first primary prostate cancer was higher than expected in Hispanic (SIR = 1.18, 95% CI: 1.01-1.38) and NHAAPI (SIR = 1.41, 95% CI: 1.20-1.65) men than NHB and NHW men. Among women with a primary breast cancer, Hispanic, NHAAPI, and NHB women had a nearly 1.5-fold higher risk of a second primary breast cancer, while NHW women had a 6% lower risk. Among men with prostate cancer whose SPC was diagnosed 2 to <12 months, NHB men were at higher risk for colorectal cancer and Hispanic and NHW men for non-Hodgkin's lymphoma. In the same time frame for breast cancer survivors, Hispanic and NHAAPI women were significantly more likely than NHB and NHW women to be diagnosed with a second primary lung cancer., Conclusion: Future studies of SPC should investigate the role of shared etiologies, stage of diagnosis, treatment, and lifestyle factors after cancer survival across different racial and ethnic populations., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Ultrafine particles (UFP) are unregulated air pollutants abundant in aviation exhaust. Emerging evidence suggests that UFPs may impact lung health due to their high surface area-to-mass ratio and deep penetration into airways. This study aimed to assess long-term exposure to airport-related UFPs and lung cancer incidence in a multiethnic population in Los Angeles County., Methods: Within the California Multiethnic Cohort, we examined the association between long-term exposure to airport-related UFPs and lung cancer incidence. Multivariable Cox proportional hazards regression models were used to estimate the effect of UFP exposure on lung cancer incidence. Subgroup analyses by demographics, histology and smoking status were conducted., Results: Airport-related UFP exposure was not associated with lung cancer risk [per one IGR HR, 1.01; 95% confidence interval (CI), 0.97-1.05] overall and across race/ethnicity. A suggestive positive association was observed between a one IQR increase in UFP exposure and lung squamous cell carcinoma (SCC) risk (HR, 1.08; 95% CI, 1.00-1.17) with a Phet for histology = 0.05. Positive associations were observed in 5-year lag analysis for SCC (HR, 1.12; 95% CI, CI, 1.02-1.22) and large cell carcinoma risk (HR, 1.23; 95% CI, 1.01-1.49) with a Phet for histology = 0.01., Conclusions: This large prospective cohort analysis suggests a potential association between airport-related UFP exposure and specific lung histologies. The findings align with research indicating that UFPs found in aviation exhaust may induce inflammatory and oxidative injury leading to SCC., Impact: These results highlight the potential role of airport-related UFP exposure in the development of lung SCC., (©2024 American Association for Cancer Research.)

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10 -8 ). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10 -4 ). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n  = 6; ATA, n  = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

Approximately 10% of smokers will develop lung cancer. Sensitive predictive biomarkers are needed to identify susceptible individuals. 1,3-Butadiene (BD) is among the most abundant tobacco smoke carcinogens. BD is metabolically activated to 3,4-epoxy-1-butene (EB), which is detoxified via the glutathione conjugation/mercapturic acid pathway to form monohydroxybutenyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA). Alternatively, EB can react with guanine nucleobases of DNA to form N7-(1-hydroxyl-3-buten-1-yl) guanine (EB-GII) adducts. We employed isotope dilution LC/ESI-HRMS/MS methodologies to quantify MHBMA, DHBMA, and EB-GII in urine of smokers who developed lung cancer ( N = 260) and matched smoking controls ( N = 259) from the Southern Community Cohort (white and African American). The concentrations of all three biomarkers were significantly higher in smokers that subsequently developed lung cancer as compared to matched smoker controls after adjusting for age, sex, and race/ethnicity ( p < 0.0001 for EB-GII, p < 0.0001 for MHBMA, and p = 0.0007 for DHBMA). The odds ratio (OR) for lung cancer development was 1.63 for MHBMA, 1.37 for DHBMA, and 1.97 for EB-GII, with a higher OR in African American subjects than in whites. The association of urinary EB-GII, MHBMA, and DHBMA with lung cancer status did not remain upon adjustment for total nicotine equivalents. These findings reveal that urinary MHBMA, DHBMA, and EB-GII are directly correlated with the BD dose delivered via smoking and are associated with lung cancer risk.

Background: Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear., Methods: We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis., Results: Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients ( P < 0.001), patients with hypersensitivity pneumonitis ( P = 0.043), and patients with nonspecific interstitial pneumonia ( P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts ( r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues., Conclusion: S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Importance: The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model-based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity., Objective: To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model-a well-established risk prediction model based on a predominantly White population-across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria., Design, Setting, and Participants: In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included., Exposures: The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines., Outcomes: Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer)., Results: Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity-specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%)., Conclusions: The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.

Skin-resident CD8 + T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T RM 1)] and interleukin-17 (IL-17)-producing (T RM 17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T RM 1 and T RM 17 cells navigate divergent trajectories to acquire tissue residency in the skin. T RM 1 cells depend on a T-bet-Hobit-IL-15 axis, whereas T RM 17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in T RM 17 cells parallel to that induced by Hobit in T RM 1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to T RM 17 cell commitment. Accordingly, by targeting this pathway, skin T RM 17 cells can be ablated without compromising their T RM 1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.

Background: Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic flavivirus and the leading cause of pediatric encephalitis in the Asian Pacific region. The transmission cycle primarily involves Culex spp. mosquitoes and Ardeid birds, with domestic pigs ( Sus scrofa domestica ) being the source of infectious viruses for the spillover of JEV from the natural endemic transmission cycle into the human population. Although many studies have concluded that domestic pigs play an important role in the transmission cycle of JEV, and infection of humans, the role of feral pigs in the transmission of JEV remains unclear. Since domestic and feral pigs are the same species, and because feral pig populations in the United States are increasing and expanding geographically, the current study aimed to test the hypothesis that if JEV were introduced into the United States, feral pigs might play a role in the transmission cycle. Materials and Methods: Sinclair miniature pigs, that exhibit the feral phenotype, were intradermally inoculated with JEV genotype Ib. These pigs were derived from crossing miniature domestic pig with four strains of feral pigs and were used since obtaining feral swine was not possible. Results: The Sinclair miniature pigs became viremic and displayed pathological outcomes similar to those observed in domestic swine. Conclusion: Based on these findings, we conclude that in the event of JEV being introduced into the United States, feral pig populations could contribute to establishment and maintenance of a transmission cycle of JEV and could lead to the virus becoming endemic in the United States.

Kex2 protease (Kex2p) is a membrane-bound serine protease responsible for the proteolytic maturation of various secretory proteins by cleaving after dibasic residues in the late Golgi network. In this study, we present an application of Kex2p as an alternative endoprotease for the in vitro processing of recombinant fusion proteins produced by the yeast Saccharomyces cerevisiae . The proteins were expressed with a fusion partner connected by a Kex2p cleavage sequence for enhanced expression and easy purification. To avoid in vivo processing of fusion proteins by Kex2p during secretion and to guarantee efficient removal of the fusion partners by in vitro Kex2p processing, P 1 ', P 2 ', P 4 , and P 3 sites of Kex2p cleavage sites were elaborately manipulated. The general use of Kex2p in recombinant protein production was confirmed using several recombinant proteins.

The novel bacterial strain MBLB1776 T was isolated from marine mud in Uljin, the Republic of Korea. Cells were Gram-positive, spore-forming, non-motile, and non-flagellated rods. Growth was observed at a temperature range of 10-45 °C, pH range of 6.0-8.0, and NaCl concentrations of 0-4% ( w / v ). Phylogenetic analysis of the 16S rRNA gene sequence revealed that MBLB1776 T belonged to the genus Paenibacillus and was closely related to Paenibacillus cavernae C4-5 T (94.83% similarity). Anteiso-C 15:0 , iso-C 16:0 , C 16:0 , and iso-C 15:0 were the predominant fatty acids. Menaquinone 7 was identified as the major isoprenoid quinone. The major polar lipids included diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. Its whole genome was 6.3 Mb in size, with a G+C content of 55.8 mol%. Average nucleotide identity and in silico DNA-DNA hybridization values were below the species delineation threshold. Gene function analysis revealed the presence of a complete C 30 carotenoid biosynthetic pathway. Intriguingly, MBLB1776 T harbored carotenoid pigments, imparting an orange color to whole cells. Based on this comprehensive polyphasic taxonomy, the MBLB1776 T strain represents a novel species within the genus Paenibacillus , for which the name Paenibacillus aurantius sp. nov is proposed. The type strain was MBLB1776 T (=KCTC 43279 T = JCM 34220 T ). This is the first report of a carotenoid-producing Paenibacillus sp.

The flavivirus envelope protein is a class II fusion protein that drives flavivirus-cell membrane fusion. The membrane fusion process is triggered by the conformational change of the E protein from dimer in the virion to trimer, which involves the rearrangement of three domains, EDI, EDII, and EDIII. The movement between EDI and EDII initiates the formation of the E protein trimer. The EDI-EDII hinge region utilizes four motifs to exert the hinge effect at the interdomain region and is crucial for the membrane fusion activity of the E protein. Using West Nile virus (WNV) NY99 strain derived from an infectious clone, we investigated the role of eight flavivirus-conserved hydrophobic residues in the EDI-EDII hinge region in the conformational change of E protein from dimer to trimer and viral entry. Single mutations of the E-A54, E-I130, E-I135, E-I196, and E-Y201 residues affected infectivity. Importantly, the E-A54I and E-Y201P mutations fully attenuated the mouse neuroinvasive phenotype of WNV. The results suggest that multiple flavivirus-conserved hydrophobic residues in the EDI-EDII hinge region play a critical role in the structure-function of the E protein and some contribute to the virulence phenotype of flaviviruses as demonstrated by the attenuation of the mouse neuroinvasive phenotype of WNV. Thus, as a proof of concept, residues in the EDI-EDII hinge region are proposed targets to engineer attenuating mutations for inclusion in the rational design of candidate live-attenuated flavivirus vaccines., (© 2023. The Author(s).)

Tissue-resident memory T (T RM ) cells play a vital role in local immune protection against infection and cancer. The location of T RM cells within peripheral tissues at sites of pathogen invasion allows for the rapid detection and elimination of microbes, making their generation an attractive goal for the development of next-generation vaccines. Here, we discuss differential requirements for CD8 + T RM cell development across tissues with implications for establishing local prophylactic immunity, emphasizing the role of tissue-derived factors, local antigen, and adjuvants on T RM cell generation in the context of vaccination., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

T cells can acquire a broad spectrum of differentiation states following activation. At the extreme ends of this continuum are short-lived cells equipped with effector machinery and more quiescent, long-lived cells with heightened proliferative potential and stem cell-like developmental plasticity. The latter encompass stem-like exhausted T cells and memory T cells, both of which have recently emerged as key determinants of cancer immunity and response to immunotherapy. Here, we discuss key similarities and differences in the regulation and function of stem-like exhausted CD8 +  T cells and memory CD8 + T cells, and consider their context-specific contributions to protective immunity in diverse outcomes of cancer, including tumour escape, long-term control and eradication. Finally, we emphasize how recent advances in the understanding of the molecular regulation of stem-like exhausted T cells and memory T cells are being explored for clinical benefit in cancer immunotherapies such as checkpoint inhibition, adoptive cell therapy and vaccination., (© 2023. Springer Nature Limited.)

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes., Competing Interests: Declaration of interests E.J.W. is an advisor for Danger Bio, Janssen, New Limit, Marengo, Pluto Immunotherapeutics Related Sciences, Rubius Therapeutics, Santa Ana Bio, Synthekine, and Surface Oncology. E.J.W. is a founder of and holds stock in Surface Oncology, Danger Bio, and Arsenal Biosciences. N.J.M. reports consulting fees from Endpoint Health Inc and AstraZeneca and receives funding from Quantum Leap Healthcare Collaborative outside of the published work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Inhaled particles and gases can harm health by promoting chronic inflammation in the body. Few studies have investigated the relationship between outdoor air pollution and inflammation by race and ethnicity, socioeconomic status, and lifestyle risk factors. We examined associations of particulate matter (PM) and other markers of traffic-related air pollution with circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation. CRP was measured from blood samples obtained in 1994-2016 from 7,860 California residents participating in the Multiethnic Cohort (MEC) Study. Exposure to PM (aerodynamic diameter ≤2.5 μm [PM 2.5 ], ≤10 μm [PM 10 ], and between 2.5 and 10 μm [PM 10-2.5 ]), nitrogen oxides (NO x , including nitrogen dioxide [NO 2 ]), carbon monoxide (CO), ground-level ozone (O 3 ), and benzene averaged over one or twelve months before blood draw were estimated based on participants' addresses. Percent change in geometric mean CRP levels and 95% confidence intervals (CI) per standard concentration increase of each pollutant were estimated using multivariable generalized linear regression. Among 4,305 females (55%) and 3,555 males (45%) (mean age 68.1 [SD 7.5] years at blood draw), CRP levels increased with 12-month exposure to PM 10 (11.0%, 95% CI: 4.2%, 18.2% per 10 μg/m 3 ), PM 10-2.5 (12.4%, 95% CI: 1.4%, 24.5% per 10 μg/m 3 ), NO x (10.4%, 95% CI: 2.2%, 19.2% per 50 ppb), and benzene (2.9%, 95% CI: 1.1%, 4.6% per 1 ppb). In subgroup analyses, these associations were observed in Latino participants, those who lived in low socioeconomic neighborhoods, overweight or obese participants, and never or former smokers. No consistent patterns were found for 1-month pollutant exposures. This investigation identified associations of primarily traffic-related air pollutants, including PM, NO x , and benzene, with CRP in a multiethnic population. The diversity of the MEC across demographic, socioeconomic, and lifestyle factors allowed us to explore the generalizability of the effects of air pollution on inflammation across subgroups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Memory CD8 + T cells can be broadly divided into circulating (T CIRCM ) and tissue-resident memory T (T RM ) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of T CIRCM and T RM cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in T CIRCM and T RM cells in solid organs and barrier locations. High-dimensional analyses revealed unappreciated heterogeneity within T CIRCM and T RM cell lineages across nine different organs after either local or systemic murine infection models. Additionally, we demonstrated the relative effectiveness of strategies allowing for the selective ablation of T CIRCM or T RM populations across organs and identified CD55, KLRG1, CXCR6, and CD38 as stable markers for characterizing memory T cell function during inflammation. Together, these data and analytical framework provide an in-depth resource for memory T cell classification in both steady-state and inflammatory conditions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

CD8 + T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8 + T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1 + progenitor Tex cells to more differentiated TCF-1 - Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy., Competing Interests: Declaration of interests E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supports research in the Wherry laboratory. E.J.W. is an advisor for Danger Bio, Janssen, New Limit, Marengo, Pluto Immunotherapeutics Related Sciences, Santa Ana Bio, Synthekine, and Surface Oncology. E.J.W. is a founder of and holds stock in Surface Oncology, Danger Bio, and Arsenal Biosciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Among the diverse platforms of quantum light sources, epitaxially grown semiconductor quantum dots (QDs) are one of the most attractive workhorses for realizing quantum photonic technologies owing to their outstanding brightness and scalability. However, the spatial and spectral randomness of most QDs severely hinders the construction of large-scale photonic platforms. In this work, a methodology is presented to deterministically integrate single QDs with tailor-made photonic structures. A nondestructive luminescence picking method termed as nanoscale-focus pinspot (NFP) is applied using helium-ion microscopy to reduce the luminous QD density while retaining the surrounding medium. A single QD emission is only extracted out of the high-density ensemble QDs. Then the tailor-made photonic structure of a circular Bragg reflector (CBR) is designed and deterministically integrated with the selected QD. Given that the microscopy can image with nanoscale resolution and apply NFP in situ, photonic devices can be deterministically fabricated on target QDs. The extraction efficiency of the NFP-selected QD emission is improved by 25 times after the CBR integration. Since the NFP method only controls the luminescence without destroying the medium, it is applicable to various photonic structures such as photonic waveguides or photonic crystal cavities regardless of materials., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Background: While cigarette smoking is the leading cause of lung cancer, the majority of smokers do not develop the disease over their lifetime. The inter-individual differences in risk among smokers may in part be due to variations in exposure to smoking-related toxicants., Methods: Using data from a subcohort of 2,309 current smokers at the time of urine collection from the Multiethnic Cohort Study, we prospectively evaluated the association of ten urinary biomarkers of smoking-related toxicants [total nicotine equivalents (TNE), a ratio of total trans-3'-hydroxycotinine (3-HCOT)/cotinine (a phenotypic measure of CYP2A6 enzymatic activity), 4-(methylnitrosamino)-1-3-(pyridyl)-1-butanol (NNAL), S-phenylmercapturic acid (SPMA), 3-hydroxypropyl mercapturic acid (3-HPMA), phenanthrene tetraol (PheT), 3-hydroxyphenanthrene (PheOH), the ratio of PheT/PheOH, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid (8-iso-PGF2α)] with lung cancer risk (n = 140 incident lung cancer cases over an average of 13.4 years of follow-up). Lung cancer risk was estimated using Cox proportional hazards models., Results: After adjusting for decade of birth, sex, race/ethnicity, body mass index, self-reported pack-years, creatinine, and urinary TNE (a biomarker of internal smoking dose), a one SD increase in log total 3-HCOT/cotinine (HR, 1.33; 95% CI, 1.06-1.66), 3-HPMA (HR, 1.41; 95% CI, 1.07-1.85), and Cd (HR, 1.45; 95% CI, 1.18-1.79) were each associated with increased lung cancer risk., Conclusions: Our study demonstrates that urinary total 3-HCOT/cotinine, 3-HPMA, and Cd are positively associated with lung cancer risk. These findings warrant replication and consideration as potential biomarkers for smoking-related lung cancer risk., Impact: These biomarkers may provide additional information on lung cancer risk that is not captured by self-reported smoking history or TNE. See related commentary by Etemadi et al., p. 289., (©2022 American Association for Cancer Research.)

Purpose: A subset of asthmatics suffers from persistent airflow limitation, known as remodeled asthma, despite optimal treatment. Typical quantitative scoring methods to evaluate structural changes of airway remodeling on high-resolution computed tomography (HRCT) are time-consuming and laborious. Thus, easier and simpler methods are required in clinical practice. We evaluated the clinical usefulness of a simple, semi-quantitative method based on 8 HRCT parameters by comparing asthmatics with a persistent decline of post-bronchodilator (BD)-FEV1 to those with a BD-FEV1 that normalized over time and evaluated the relationships of the parameters with BD-FEV1., Methods: Asthmatics (n = 59) were grouped into 5 trajectories (Trs) according to the changes of BD-FEV1 over 1 year. After 9-12 months of guideline-based treatment, HRCT parameters including emphysema, bronchiectasis, anthracofibrosis, bronchial wall thickening (BWT), fibrotic bands, mosaic attenuation on inspiration, air-trapping on expiration, and centrilobular nodules were classified as present (1) or absent (0) in 6 zones., Results: The Tr5 group (n = 11) was older and exhibited a persistent decline in BD-FEV1. The Tr5 and Tr4 groups (n = 12), who had a lower baseline BD-FEV1 that normalized over time, had longer durations of asthma, frequent exacerbations, and higher doses of steroid use compared to the Tr1-3 groups (n = 36), who had a normal baseline BD-FEV1. The Tr5 group had higher emphysema and BWT scores than the Tr4 ( P = 8.25E-04 and P = 0.044, respectively). Scores for the other 6 parameters were not significantly different among the Tr groups. BD-FEV1 was inversely correlated with the emphysema and BWT scores in multivariate analysis ( P = 1.70E-04, P = 0.006, respectively)., Conclusions: Emphysema and BWT are associated with airway remodeling in asthmatics. Our simple, semi-quantitative scoring system based on HRCT may be an easy-to-use method for estimating airflow limitation., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2023 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Smoking intensity varies across smokers and is influenced by individual variability in the metabolism of nicotine, the major addictive agent in tobacco. Therefore, lung cancer risk, which varies by racial ethnic group, is influenced by the primary catalyst of nicotine metabolism, cytochrome P450 2A6 (CYP2A6). In smokers, CYP2A6 catalyzes nicotine 5'-oxidation. In vitro , CYP2A6 also catalyzes, to a much lower extent, 2'-oxidation, which leads to the formation of 4-hydroxy-4-(3-pyridyl) butanoic acid (hydroxy acid). The urinary concentration of hydroxy acid has been quantified in only a few small studies of White smokers. To quantitatively assess the importance of nicotine 2'-oxidation in smokers, an LC-MS/MS-based method was developed for the analysis of nicotine and ten metabolites in urine. The concentrations of nicotine and these metabolites were measured in 303 smokers (99 Whites, 99 Native Hawaiians, and 105 Japanese Americans), and the relative metabolism of nicotine by four pathways was determined. Metabolism by these pathways was also compared across quartiles of CYP2A6 activity (measured as the plasma ratio of 3-hydroxycotinine to cotinine). As reported previously and consistent with their average CYP2A6 activity, nicotine 5'-oxidation was highest in Whites and lowest in Japanese Americans. Nicotine N -glucuronidation and N -oxidation increased with decreasing CYP2A6 activity. However, the relative urinary concentration of hydroxy acid (mean, 2.3%; 95% CI, 2.2-2.4%) did not vary by ethnic group or by CYP2A6 activity. In summary, CYP2A6 is not an important catalyst of nicotine 2'-oxidation in smokers, nor does nicotine 2'-oxidation compensate for decreased CYP2A6 activity.

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements., Competing Interests: The authors have declared that no competing interests exit., (Copyright: © 2023 Streicher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)