The effect of treatment package time on locally advanced oral cavity cancer outcomes.

OBJECTIVE(S): To assess the influence of treatment package time (TPT) on overall survival (OS) and event free survival (EFS) in oral cavity cancer (OCC) patients treated with surgery and adjuvant radiation therapy (RT) with or without concurrent chemotherapy (CHT). MATERIALS/METHODS: 354 adult OCC patients treated at a single, high-volume center between 2012-2022 with various pathologic risk features were included. TPT was defined as days from surgery to RT completion. Kaplan-Meier estimates, log-rank p-values, univariable (UVA) and multivariable (MVA) Cox regression analyses were performed to determine the impact of TPT on OS and EFS, and the optimal TPT cutoff. RESULTS: The optimal TPT cutoff was 105 days. TPT < 105 days was significantly associated with improved OS and EFS (p = 0.002 and p = 0.027, respectively) compared to TPT ≥ 105 days. On UVA, factors significantly associated with OS were TPT < 105 days, former/current smoker status, pathologic stage IV, positive perineural invasion (PNI), and extranodal extension (ENE) (all p < 0.05). On MVA for OS, TPT < 105 days, former/current smoker status, pathologic stage IV, and positive PNI (all p < 0.05) remained significant. Factors significantly associated with EFS on UVA were TPT < 105 days, former/current smoker status, pathologic stage IV, positive PNI or ENE, and concurrent CHT (all p < 0.05). On MVA, TPT < 105 days, pathologic stage IV, and positive PNI (all p < 0.05) remained significant. CONCLUSIONS: In a large, homogenous cohort of OCCs, optimal TPT was <105 days, with TPT ≥ 105 days significantly associated with worse OS and EFS. Multidisciplinary coordination should analyze factors potentially contributing to treatment delay.

Disparities Associated with Decision to Undergo Oncologic Surgery: A Prospective Mixed-Methods Analysis.

BACKGROUND: Underrepresented minority patients with surgical malignancies experience disparities in outcomes. The impact of provider-based factors, including communication, trust, and cultural competency, on outcomes is not well understood. This study examines modifiable provider-based barriers to care experienced by patients with surgical malignancies. METHODS: A parallel, prospective, mixed-methods study enrolled patients with lung or gastrointestinal malignancies undergoing surgical consultation. Surveys assessed patients' social needs and patient-physician relationship. Semi-structured interviews ascertained patient experiences and were iteratively analyzed, identifying key themes. RESULTS: The cohort included 24 patients (age 62 years; 63% White and 38% Black/African American). The most common cancers were lung (n = 18, 75%) and gastroesophageal (n = 3, 13%). Survey results indicated that food insecurity (n = 5, 21%), lack of reliable transportation (n = 4, 17%), and housing instability (n = 2, 8%) were common. Lack of trust in their physician (n = 3, 13%) and their physician's treatment recommendation (n = 3, 13%) were identified. Patients reported a lack of empathy (n = 3, 13%), lack of cultural competence (n = 3, 13%), and inadequate communication (n = 2, 8%) from physicians. Qualitative analysis identified five major themes regarding the decision to undergo surgery: communication, trust, health literacy, patient fears, and decision-making strategies. Five patients (21%) declined the recommended surgery and were more likely Black (100% vs. 21%), lower income (100% vs. 16%), and reported poor patient-physician relationship (40% vs. 5%; all p < 0.05). CONCLUSIONS: Factors associated with declining recommended cancer surgery were underrepresented minority race and poor patient-physician relationships. Interventions are needed to improve these barriers to care and racial disparities.

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.

Chronic Aroclor 1260 exposure alters the mouse liver proteome, selenoproteins, and metals in steatotic liver disease.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to increase due in part to the obesity epidemic and to environmental exposures to metabolism disrupting chemicals. A single gavage exposure of male mice to Aroclor 1260 (Ar1260), an environmentally relevant mixture of non-dioxin-like polychlorinated biphenyls (PCBs), resulted in steatohepatitis and altered RNA modifications in selenocysteine tRNA 34 weeks post-exposure. Unbiased approaches identified the liver proteome, selenoproteins, and levels of 25 metals. Ar1260 altered the abundance of 128 proteins. Enrichment analysis of the liver Ar1260 proteome included glutathione metabolism and translation of selenoproteins. Hepatic glutathione peroxidase 4 (GPX4) and Selenoprotein O (SELENOO) were increased and Selenoprotein F (SELENOF), Selenoprotein S (SELENOS), Selenium binding protein 2 (SELENBP2) were decreased with Ar1260 exposure. Increased copper, selenium (Se), and zinc and reduced iron levels were detected. These data demonstrate that Ar1260 exposure alters the (seleno)proteome, Se, and metals in MASLD-associated pathways.

Chronic arsenic exposure induces malignant transformation of human HaCaT cells through both deterministic and stochastic changes in transcriptome expression.

Biological processes are inherently stochastic, i.e., are partially driven by hard to predict random probabilistic processes. Carcinogenesis is driven both by stochastic and deterministic (predictable non-random) changes. However, very few studies systematically examine the contribution of stochastic events leading to cancer development. In differential gene expression studies, the established data analysis paradigms incentivize expression changes that are uniformly different across the experimental versus control groups, introducing preferential inclusion of deterministic changes at the expense of stochastic processes that might also play a crucial role in the process of carcinogenesis. In this study, we applied simple computational techniques to quantify: (i) The impact of chronic arsenic (iAs) exposure as well as passaging time on stochastic gene expression and (ii) Which genes were expressed deterministically and which were expressed stochastically at each of the three stages of cancer development. Using biological coefficient of variation as an empirical measure of stochasticity we demonstrate that chronic iAs exposure consistently suppressed passaging related stochastic gene expression at multiple time points tested, selecting for a homogenous cell population that undergo transformation. Employing multiple balanced removal of outlier data, we show that chronic iAs exposure induced deterministic and stochastic changes in the expression of unique set of genes, that populate largely unique biological pathways. Together, our data unequivocally demonstrate that both deterministic and stochastic changes in transcriptome-wide expression are critical in driving biological processes, pathways and networks towards clonal selection, carcinogenesis, and tumor heterogeneity.

Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models. METHODS: The EZH2 inhibitor EPZ011989 (EPZ) was studied in AML cell lines, primary in AML cells and normal CD34+ stem cells. A pharmacodynamic assessment of H3K27me3; studies of differentiation, cell growth, and colony formation; and in vivo therapeutic studies including the influence on primary AML cell engraftment were also conducted. RESULTS: EPZ inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition reduced colony formation in multiple AML cell lines and primary AML samples, while exhibiting no effect on colony formation in normal CD34+ stem cells. In AML cells, EPZ promoted phenotypic evidence of differentiation. Finally, the pretreatment of primary AML cells with EPZ significantly delayed engraftment and prolonged the overall survival when engrafted into immunodeficient mice. CONCLUSIONS: Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival.

Type 3 secretion system induced leukotriene B4 synthesis by leukocytes is actively inhibited by Yersinia pestis to evade early immune recognition.

Subverting the host immune response to inhibit inflammation is a key virulence strategy of Yersinia pestis. The inflammatory cascade is tightly controlled via the sequential action of lipid and protein mediators of inflammation. Because delayed inflammation is essential for Y. pestis to cause lethal infection, defining the Y. pestis mechanisms to manipulate the inflammatory cascade is necessary to understand this pathogen's virulence. While previous studies have established that Y. pestis actively inhibits the expression of host proteins that mediate inflammation, there is currently a gap in our understanding of the inflammatory lipid mediator response during plague. Here we used the murine model to define the kinetics of the synthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid chemoattractant and immune cell activator, within the lungs during pneumonic plague. Furthermore, we demonstrated that exogenous administration of LTB4 prior to infection limited bacterial proliferation, suggesting that the absence of LTB4 synthesis during plague contributes to Y. pestis immune evasion. Using primary leukocytes from mice and humans further revealed that Y. pestis actively inhibits the synthesis of LTB4. Finally, using Y. pestis mutants in the Ysc type 3 secretion system (T3SS) and Yersinia outer protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the rapid synthesis of LTB4. However, several Yop effectors secreted through the T3SS effectively inhibit this host response. Together, these data demonstrate that Y. pestis actively inhibits the synthesis of the inflammatory lipid LTB4 contributing to the delay in the inflammatory cascade required for rapid recruitment of leukocytes to sites of infection.

The Green Heart Project: Objectives, Design, and Methods.

The Green Heart Project is a community-based trial to evaluate the effects of increasing greenery on urban environment and community health. The study was initiated in 2018 in a low-to-middle-income mixed-race residential area of nearly 28,000 residents in Louisville, KY. The 4 square mile area was surveyed for land use, population characteristics, and greenness, and assigned to 8 paired clusters of demographically- and environmentally matched "target" (T) and adjacent "control" (C), clusters. Ambient levels of ultrafine particles, ozone, oxides of nitrogen, and environmental noise were measured in each cluster. Individual-level data were acquired during in-person exams of 735 participants in Wave 1 (2018-2019) and 545 participants in Wave 2 (2021) to evaluate sociodemographic and psychosocial factors. Blood, urine, nail, and hair samples were collected to evaluate standard cardiovascular risk factors, inflammation, stress, and pollutant exposure. Cardiovascular function was assessed by measuring arterial stiffness and flow-mediated dilation. After completion of Wave 2, more than 8,000 mature, mostly evergreen, trees and shrubs were planted in the T clusters in 2022. Post planting environmental and individual-level data were collected during Wave 3 (2022) from 561 participants. We plan to continue following changes in area characteristics and participant health to evaluate the long-term impact of increasing urban greenery.

Estimation of foot-and-mouth disease virus sero-prevalence rates using novel computational approach for the susceptible bovine population in India during the period 2008-2021.

Foot-and-mouth disease (FMD) is a severe contagious viral disease of cloven-hoofed animals. In India, a vaccination-based official FMD control programme was started, which got expanded progressively to cover entire country in 2019. The serological tests are used to determine non-structural protein based sero-prevalence rates for properly implementing and assessing the control programme. Since 2008, reporting of the FMD sero-surveillance was limited to the serum sample-based serological test results without going for population-level estimation due to lack of proper statistical methodology. Thus, we present a computational approach for estimating the sero-prevalence rates at the state and national levels. Based on the reported approach, a web-application ( https://nifmd-bbf.icar.gov.in/FMDSeroSurv ) and an R software package ( https://github.com/sam-dfmd/FMDSeroSurv ) have been developed. The presented computational techniques are applied to the FMD sero-surveillance data during 2008-2021 to get the status of virus circulation in India under a strict vaccination policy. Furthermore, through various structural equation models, we attempt to establish a link between India's estimated sero-prevalence rate and field FMD outbreaks. Our results indicate that the current sero-prevalence rates are significantly associated with previous field outbreaks up to 2 years. Besides, we observe downward trends in sero-prevalence and outbreaks over the years, specifically after 2013, which indicate the effectiveness of various measures implemented under the FMD control programme. The findings of the study may help researchers and policymakers to track virus infection and identification of potential disease-free zones through vaccination.

Development and validation of a product acceptability questionnaire for intranasal Q-Griffithsin COVID-19 prophylaxis (SPRAY PAL).

OBJECTIVES: Patient experiences are critical when determining the acceptability of novel interventional pharmaceuticals. Here, we report the development and validation of a product acceptability questionnaire (SPRAY PAL) assessing feasibility, acceptability and tolerability of an intranasal Q-Griffithsin (Q-GRFT) drug product designed for COVID-19 prophylaxis. DESIGN: SPRAY PAL validation was undertaken as part of an ongoing phase 1 clinical trial designed to test the safety, pharmacokinetics and tolerability of intranasally administered Q-GRFT for the prevention of SARS-CoV-2 infection. SETTING: The phase 1 clinical trial took place at a University Outpatient Clinical Trials Unit from November 2021 to September 2023. PARTICIPANTS: The initial SPRAY PAL questionnaire was piloted among healthy volunteers ages 25 to 55 in phase 1a of the clinical trial (N=18) and revised for administration in phase 1b for participants ages 24-59 (N=22). RESULTS: Spearman correlations tested convergent and discriminant validity. Internal consistency was assessed using Cronbach's alpha, and test-retest reliability was assessed using intraclass correlation coefficients of responses collected from three repeated questionnaire administrations. The initial version demonstrated excellent internal consistency. The revised version demonstrated very good internal consistency after removal of one item (alpha=0.739). Excellent test-retest reliability (intraclass coefficient=0.927) and adequate convergent (r's=0.208-0.774) and discriminant (r's=0.123-0.392) validity were achieved. Subscales adequately distinguished between the constructs of acceptability, feasibility and tolerability. CONCLUSIONS: The SPRAY PAL product acceptability questionnaire is a valid and reliable patient-reported outcomes measure that can be considered a credible tool for assessing patient-reported information about product acceptability, feasibility of use, tolerability of product and side effects and cost of product for novel intranasal drug formulations. The SPRAY PAL is generalisable, and items may be readily adapted to assess other intranasal formulations. TRIAL REGISTRATION NUMBERS: NCT05122260 and NCT05437029.

Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.

Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFß1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP-degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFß1 levels were highly correlated with PDE4 expression. TGFß1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC-specific agonist decreased TGFß1-mediated cell migration in vitro. In vivo, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis-related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.

Untangling the web of glioblastoma treatment resistance using a multi-omic and multidisciplinary approach.

Glioblastoma (GBM), the most common human brain tumor, has been notoriously resistant to treatment. As a result, the dismal overall survival of GBM patients has not changed over the past three decades. GBM has been stubbornly resistant to checkpoint inhibitor immunotherapies, which have been remarkably effective in the treatment of other tumors. It is clear that GBM resistance to therapy is multifactorial. Although therapeutic transport into brain tumors is inhibited by the blood brain barrier, there is evolving evidence that overcoming this barrier is not the predominant factor. GBMs generally have a low mutation burden, exist in an immunosuppressed environment and they are inherently resistant to immune stimulation, all of which contribute to treatment resistance. In this review, we evaluate the contribution of multi-omic approaches (genomic and metabolomic) along with analyzing immune cell populations and tumor biophysical characteristics to better understand and overcome GBM multifactorial resistance to treatment.

Disruption of the mouse liver epitranscriptome by long-term aroclor 1260 exposure.

Chronic environmental exposure to polychlorinated biphenyls (PCBs) is associated with non-alcoholic fatty liver disease (NAFLD) and exacerbated by a high fat diet (HFD). Here, chronic (34 wks.) exposure of low fat diet (LFD)-fed male mice to Aroclor 1260 (Ar1260), a non-dioxin-like (NDL) mixture of PCBs, resulted in steatohepatitis and NAFLD. Twelve hepatic RNA modifications were altered with Ar1260 exposure including reduced abundance of 2'-O-methyladenosine (Am) and N(6)-methyladenosine (m6A), in contrast to increased Am in the livers of HFD-fed, Ar1260-exposed mice reported previously. Differences in 13 RNA modifications between LFD- and HFD- fed mice, suggest that diet regulates the liver epitranscriptome. Integrated network analysis of epitranscriptomic modifications identified a NRF2 (Nfe2l2) pathway in the chronic, LFD, Ar1260-exposed livers and an NFATC4 (Nfatc4) pathway for LFD- vs. HFD-fed mice. Changes in protein abundance were validated. The results demonstrate that diet and Ar1260 exposure alter the liver epitranscriptome in pathways associated with NAFLD.

Metallomics in pulmonary arterial hypertension patients.

Pulmonary arterial hypertension (PAH) prevalence is increasing worldwide, and the prognosis is poor with 5-year survival < 50% in high risk patients. The relationship between metal exposure/essential metal dyshomeostasis and PAH/right ventricular dysfunction is less investigated. The aim of this study is to investigate vegetable consumptions and metal levels between PAH patients and controls. This was a prospective, single center pilot study. Questionnaires were completed by all study subjects (20 PAH patients and 10 healthy controls) on smoking, metal exposure risks, metal supplements, and vegetable consumptions. Blood and urine samples were collected to measure 25 metal levels in blood, plasma, and urine using an X Series II quadrupole inductively coupled plasma mass spectrometry. Statistical analysis was conducted using SAS 9.5 and results with p value < 0.05 were considered significant. Vegetables consumptions (broccoli risk ratio [RR] = 0.4, CI = (0.2, 0.9)], cabbage [RR = 0.2, CI = (0.1, 0.8)], and brussel sprouts [RR = 0.2, CI = (0.1, 0.5)]) are associated with less risks of PAH. In the plasma samples, silver (p < 0.001), and copper (p = 0.002) levels were significantly higher in PAH patients. There was significant positive correlation between cardiac output and cardiac index with plasma levels of silver (r = 0.665, p = 0.001 and r = 0.678 p = 0.001), respectively. There was significant correlation between mixed venous saturation, 6-min walk distance, and last BNP with plasma levels of chromium (r = -0.520, p = 0.022; r = -0.55, p = 0.014; r = 0.463, p = 0.039), respectively. In conclusion, there are significant differences between PAH and control groups in terms of vegetable consumptions and metal concentrations. Silver and chromium levels are correlated with clinical indicators of PAH severities.

Exposure to Volatile Organic Compounds Is Associated with Hypertension in Black Adults: The Jackson Heart Study.

BACKGROUND: The prevalence of hypertension is higher among Black adults than among White and Hispanic adults. Nevertheless, reasons underlying the higher rates of hypertension in the Black population remain unclear but may relate to exposure to environmental chemicals such as volatile organic compounds (VOCs). METHODS: We evaluated the associations of blood pressure (BP) and hypertension with VOC exposure in non-smokers and smokers in a subgroup of the Jackson Heart Study (JHS), consisting of 778 never smokers and 416 age- and sex-matched current smokers. We measured urinary metabolites of 17 VOCs by mass spectrometry. RESULTS: After adjusting for covariates, we found that amoong non-smokers, metabolites of acrolein and crotonaldehyde were associated with a 1.6 mm Hg (95%CI: 0.4, 2.7; p = 0.007) and a 0.8 mm Hg (95%CI: 0.01, 1.6; p = 0.049) higher systolic BP, and the styrene metabolite was associated with a 0.4 mm Hg (95%CI: 0.09, 0.8, p = 0.02) higher diastolic BP. Current smokers had 2.8 mm Hg (95% CI 0.5, 5.1) higher systolic BP. They were at higher risk of hypertension (relative risk = 1.2; 95% CI, 1.1, 1.4), and had higher urinary levels of several VOC metabolites. Individuals who smoke had higher levels of the urinary metabolites of acrolein, 1,3-butadiene, and crotonaldehyde and were associated with higher systolic BP. The associations were stronger among participants who were <60 years of age and male. Using Bayesian kernel machine regression to assess the effects of multiple VOC exposures, we found that the relationship between VOCs and hypertension among non-smokers was driven primarily by acrolein and styrene in non-smokers, and crotonaldehyde in smokers. CONCLUSIONS: Hypertension in Black individuals may be attributed, in part, to VOC exposure from the environment or tobacco smoke.

Associations between residential volatile organic compound exposures and liver injury markers: The role of biological sex and race.

While occupational exposures to volatile organic compounds (VOCs) have been linked to steatohepatitis and liver cancer in industrial workers, recent findings have also positively correlated low-dose, residential VOC exposures with liver injury markers. VOC sources are numerous; factors including biological make up (sex), socio-cultural constructs (gender, race) and lifestyle (smoking) can influence both VOC exposure levels and disease outcomes. Therefore, the current study's objective is to investigate how sex and race influence associations between residential VOC exposures and liver injury markers particularly in smokers vs. nonsmokers. Subjects (n = 663) were recruited from residential neighborhoods; informed consent was obtained. Exposure biomarkers included 16 urinary VOC metabolites. Serological disease biomarkers included liver enzymes, direct bilirubin, and hepatocyte death markers (cytokeratin K18). Pearson correlations and generalized linear models were conducted. Models were adjusted for common liver-related confounders and interaction terms. The study population constituted approximately 60% females (n = 401) and 40% males (n = 262), and a higher percent of males were smokers and/or frequent drinkers. Both sexes had a higher percent of White (75% females, 82% males) vs. Black individuals. Positive associations were identified for metabolites of acrolein, acrylamide, acrylonitrile, butadiene, crotonaldehyde, and styrene with alkaline phosphatase (ALP), a biomarker for cholestatic injury; and for the benzene metabolite with bilirubin; only in females. These associations were retained in female smokers. Similar associations were also observed between these metabolites and ALP only in White individuals (n = 514). In Black individuals (n = 114), the styrene metabolite was positively associated with aspartate transaminase. Interaction models indicated that positive associations for acrylamide/crotonaldehyde metabolites with ALP in females were dose-dependent. Most VOC associations with K18 markers were negative in this residential population. Overall, the findings demonstrated that biological sex, race, and smoking status influence VOC effects on liver injury and underscored the role of biological-social-lifestyle factor(s) interactions when addressing air pollution-related health disparities.

Multigroup prediction in lung cancer patients and comparative controls using signature of volatile organic compounds in breath samples.

Early detection of lung cancer is a crucial factor for increasing its survival rates among the detected patients. The presence of carbonyl volatile organic compounds (VOCs) in exhaled breath can play a vital role in early detection of lung cancer. Identifying these VOC markers in breath samples through innovative statistical and machine learning techniques is an important task in lung cancer research. Therefore, we proposed an experimental approach for generation of VOC molecular concentration data using unique silicon microreactor technology and further identification and characterization of key relevant VOCs important for lung cancer detection through statistical and machine learning algorithms. We reported several informative VOCs and tested their effectiveness in multi-group classification of patients. Our analytical results indicated that seven key VOCs, including C4H8O2, C13H22O, C11H22O, C2H4O2, C7H14O, C6H12O, and C5H8O, are sufficient to detect the lung cancer patients with higher mean classification accuracy (92%) and lower standard error (0.03) compared to other combinations. In other words, the molecular concentrations of these VOCs in exhaled breath samples were able to discriminate the patients with lung cancer (n = 156) from the healthy smoker and nonsmoker controls (n = 193) and patients with benign pulmonary nodules (n = 65). The quantification of carbonyl VOC profiles from breath samples and identification of crucial VOCs through our experimental approach paves the way forward for non-invasive lung cancer detection. Further, our experimental and analytical approach of VOC quantitative analysis in breath samples may be extended to other diseases, including COVID-19 detection.

Workplace Culture and Biomarkers of Health Risk.

Workplace culture has been studied for impact on health risk; however, connections with robust biologic markers of health remain to be established. We examined associations between the work environment and urinary levels of catecholamines and their metabolites as biomarkers of sympathetic nervous system activity, indicative of stress. We recruited participants (n = 219; 2018-2019) from a cardiovascular risk cohort to investigate workplace culture, well-being, and stress. Participants completed seven questionnaires. Urine samples were used to measure catecholamines and their metabolites by LC/MS/MS. Pearson correlation and linear regression models were used after adjusting for demographics and creatinine. Participants reporting higher well-being had lower urinary levels of dopamine, serotonin, and 3-methoxytyramine. Participants reporting a more engaged and more positive workplace had lower levels of dopamine and 3-methoxytyramine. Reported workplace isolation was correlated with higher levels of dopamine and 3-methoxytyramine. Given correlations between catecholamines, we used 3-methoxytyramine for linear regression. In fully adjusted models, in environments with a more positive culture, levels of 3-methoxytyramine remained lower (ß = -0.065 ± 0.025, p = 0.01) and indicated a positive association between workplace isolation and 3-methoxytyramine (ß = 0.064 ± 0.030, p = 0.04). These findings are consistent with an important relationship between workplace environment and sympathetic nervous system activity.

Estimation of Preclinical State Onset Age and Sojourn Time for Heavy Smokers in Lung Cancer.

Estimation of the three key parameters: onset age of the preclinical state, sojourn time and screening sensitivity is critical in cancer screening, since all other terms are functions of the three. A novel link function to connect sensitivity with time in the preclinical state and the likelihood method were used in this project; since sensitivity depends on how long one has entered the preclinical state relative to the total sojourn time. Simulations using Markov Chain Monte Carlo and maximum likelihood estimate were carried out to estimate the key parameters for male and female heavy smokers separately in the low-dose computed tomography group of the National Lung Screening Trial. Sensitivity for male and female heavy smokers were 0.883 and 0.915 respectively at the onset of the preclinical state, and increased to 0.972 and 0.981 at the end. The mean age to make the transition into the preclinical state was 70.94 or 71.15 for male and female heavy smokers respectively, and 90% of heavy smokers at risk for lung cancer would enter the preclinical state in age interval (55.7, 85.8) for males and (54.2, 87.7) for females, and the transition peaked around age 69 for both genders. The mean sojourn time in the preclinical state was 1.43 and 1.49 years, and the 99% credible intervals for the sojourn time were (0.21, 2.96) and (0.37, 2.69) years for male and female heavy smokers correspondingly. Based on the result, low-dose CT should be started at age 55 and ended before 85 for heavy smokers. This provided important information to policy makers.