Variation in oral microbiome is associated with future risk of lung cancer among never-smokers.

OBJECTIVE: To prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers. DESIGN AND SETTING: A nested case-control study within two prospective cohort studies, the Shanghai Women's Health Study (n=74 941) and the Shanghai Men's Health Study (n=61 480). PARTICIPANTS: Lifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women). MAIN OUTCOMES AND MEASURES: Metagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity. RESULTS: Subjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: ptrend=0.05; Simpson: ptrend=0.04; Observed Species: ptrend=0.64). No case-control differences were apparent for beta diversity (pMiRKAT=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (ORlow 1.00 (reference), ORmedium 0.61 (95% CI 0.32 to 1.18), ORhigh 0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (ORlow 1.00 (reference), ORmedium 0.66 (95% CI 0.35 to 1.25), ORhigh 0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (ORlow 1.00 (reference), ORmedium 1.49 (95% CI 0.73 to 3.08), ORhigh 2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (ORlow 1.00 (reference), ORmedium 2.15 (95% CI 1.03 to 4.47), ORhigh 3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer. CONCLUSIONS: Our prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.

Variation in ribosomal DNA copy number is associated with lung cancer risk in a prospective cohort study.

Disruption of ribosomal DNA (rDNA) has been linked to a variety of diseases in humans, including carcinogenesis. To evaluate the associations between rDNA copy number (CN) and risk of lung cancer, we measured 5.8S and 18S rDNA CN in the peripheral blood of 229 incident lung cancer cases and 1:1 matched controls from a nested case-control study within a prospective cohort of male smokers. There was a dose-response relationship between quartiles of both 18S and 5.8S rDNA CN and risk of lung cancer (odds ratio [OR], 95% confidence interval [CI]: 18S: 1.0 [ref]; 1.2 [0.6-2.1]; 1.8 [1.0-3.4]; 2.3 [1.3-4.1; Ptrend = 0.0002; 5.8S: 1.0 [ref]; 1.6 [0.8-2.9]; 2.2 [1.1-4.2]; 2.6 [1.3-5.1]; Ptrend = 0.0001). The associations between rDNA CN and lung cancer risk were similar when excluding cases diagnosed within 5 years of follow-up, and when stratifying by heavy (>20 cigarettes per day) and light smokers (≤20 cigarettes per day). We are the first to report that rDNA CN may be associated with future risk of lung cancer. To further elucidate the relationship between rDNA and lung cancer, replication studies are needed in additional populations, particularly those that include non-smokers.

Race/ethnicity and lung cancer survival in the United States: a meta-analysis.

PURPOSE: Lung cancer mortality has been shown to vary by race and ethnicity in cancer registries; however, studies often do not account for smoking status. We sought to summarize the independent contribution of race and ethnicity to survival in US lung cancer patients, accounting for important variables including smoking status. METHODS: PubMed was used to identify 1,877 potentially eligible studies of which 27 were included. Studies were excluded if they did not account for age, race and/or ethnicity, and smoking status. Fixed- and random-effects meta-analyses were conducted using the reported adjusted hazard ratios (HR) of Hispanic ethnicity and Asian and African-American race compared to Non-Hispanic whites (NHWs) on overall survival in lung cancer. RESULTS: Hispanic ethnicity and Asian race were associated with decreased adjusted risk of death (Hispanic: Nstudies = 5, Nsubjects = 108,810, HR = 0.95, 95% CI 0.90-1.00; Asian: Nstudies = 6, Nsubjects = 128,950, HR = 0.86, 95% CI 0.81-0.90). The results were similar when excluding studies of solely never-smokers. There was no significant difference in survival between African-American and white race after adjustment (Nstudies = 10, Nsubjects = 131,378, HR = 0.98, 95% CI 0.96-1.01). Other prognostic factors were female gender (HR = 0.88, 95% CI 0.87-0.89), unmarried status (HR = 1.08, 95% CI 1.04-1.11), ever-smoking status (HR = 1.11, 95% CI 1.08-1.15), having comorbidities (HR = 1.39, 95% CI 1.24-1.56), and treatment receipt (surgery: HR = 0.33, 95% CI 0.32-0.34; radiation: HR = 0.87, 95% CI 0.85-0.88; chemotherapy: HR = 0.64, 95% CI 0.63-0.65). CONCLUSIONS: Even after adjustment for clinical factors and smoking status, Hispanics and Asians experienced improved survival compared to NHWs. Future studies are needed to elucidate the drivers of these survival disparities.

Hypothesized Explanations for the Observed Lung Cancer Survival Benefit Among Hispanics/Latinos in the United States.

Hispanic/Latino ethnicity is associated with improved survival from non-small cell lung cancer compared to that for non-Hispanic Whites even though Hispanics/Latinos are more likely to potentially have inferior access-to-care and experience greater health disparities. To this end, we conducted a literature review to identify possible explanations for this survival benefit, including the role of chronic obstructive pulmonary disease and cardiovascular diseases, genetic variation, cultural influences, and immigration factors. Overall, intermittent smoking patterns, genetic variation, co-morbidities, and cultural influences were all factors likely to partially explain this survival benefit. On the other hand, immigration factors, acculturation, and access-to-care were less likely to support the survival advantage. Future research should analyze relevant Hispanic/Latino subgroups (e.g., Mexican, Puerto Rican, Cuban, Dominican, Central American, South American) and specifically focus on the relationship between Hispanic/Latino ethnicity and different lung cancer subtypes. If the Hispanic/Latino mortality benefit observed in lung cancer truly exists, a better understanding of the underlying mechanism(s) may help extend these benefits to other ethnic and racial groups.

Narrative review: respiratory tract microbiome and never smoking lung cancer.

Background and Objective: The lung microbiome was previously thought to be a sterile environment where only gaseous exchange takes place, but recent studies have shown the presence of microbiota in the lung. This review investigates the current literature on the effects of an environmental driven dysbiosis on the healthy oral and respiratory microbiome and its relationship to lung cancer risk in never-smokers. Methods: An online electronic search was performed on PubMed of all English-language literature using combinations of the following keywords: "lung cancer", "dysbiosis", "non-smokers", "oral microbiome", and "respiratory microbiome". All population-based studies reporting results on oral and/or respiratory microbiome in adults were considered for our narrative review. Key Content and Findings: Metagenomic analyses have been performed on isolated samples from healthy participants and compared to samples from those with lung cancer. Research shows that a decrease in alpha diversity of microbes in the oral microbiome is associated with increased risk of lung cancer, along with differences in beta diversity in the sputum of lung cancer cases and healthy controls. Further, several studies have observed that significant changes in the abundance of genera such as increased abundance of Lactobacillales, Bacilli, and Firmicutes associated with an increased lung cancer risk among participants with exposure to certain household solid fuels. Conclusions: These findings suggest potential carcinogenic processes such as increased inflammation associated with changes in flora. Additionally, studies showed that increase in certain taxa such as Bacteroides and Spirochetes might have a protective effect on lung cancer risk. The review also provides insight into how understanding the microbial changes can be beneficial for lung cancer treatment and disease-free survival. Larger studies in different populations need to be performed to strengthen the current associations between microbial diversity and lung cancer risk.

Vulnerabilities in workplace features for essential workers with breast cancer: Implications for the COVID-19 pandemic.

BACKGROUND: The coronavirus pandemic has highlighted the health and financial vulnerabilities of essential workers, especially among women. OBJECTIVE: The purpose of this study is to understand the workplace environment of essential workers. METHODS: We used data from a prospective cohort study of disparities in employment outcomes among women undergoing breast cancer treatment between 2010-2018 in New York City. We characterized participants as essential or non-essential based on self-reported occupation/industry and New York State executive orders issued during the pandemic. We compared job benefits and perceptions of workplace environment between groups. RESULTS: There were 563 participants: 341 essential and 222 non-essential workers. Essential workers less frequently reported access to disability pay through work [n(%): 148 (58) versus 130 (73), p < 0.01]. Essential workers in unions had greater availability of sick leave and disability pay than non-unionized essential workers (86% versus 53%, p < 0.01, and 76% versus 46%, p < 0.01, respectively). Health insurance differed by essential worker status (p < 0.01): essential workers more frequently had public insurance (29% versus 18%). Surprisingly, in multivariable analyses controlling for age, race/ethnicity, income, education, chemotherapy receipt, and comfort with English, essential workers were less likely to say their employer had treated them unfairly (p < 0.01). However, minorities were less likely to say their employer was accommodating (p = 0.03) and more likely to say their employer had treated them unfairly (p < 0.01) than Non-Latina Whites. CONCLUSIONS: We identified vulnerabilities in workplace protections, particularly among essential workers not in unions. Minority women more often had negative perceptions of their work environment, possibly reflecting employer bias.

Hispanics/Latinos in the Bronx Have Improved Survival in Non-Small Cell Lung Cancer Compared with Non-Hispanic Whites.

BACKGROUND: Hispanics/Latinos are a growing yet understudied population in the United States (US). Despite lower socioeconomic status, Hispanics/Latinos tend to have similar or better health outcomes than Non-Hispanic Whites (NHWs). This phenomenon has not been conclusively studied for lung cancer. METHODS: Using a cohort of patients at Montefiore Medical Center (MMC) in the Bronx, NY, we examined factors related to lung cancer survival by race/ethnicity with an emphasis on Hispanics/Latinos. Subjects were diagnosed with non-small cell lung cancer (NSCLC) between 2004 and 2017. Demographic and clinical data were obtained from MMC's clinical systems and tumor-related information from MMC/Einstein's Cancer Registry. Survival was assessed using Cox proportional hazards modeling adjusted for clinical and sociodemographic factors including smoking. Factors related to survival within each major racial/ethnic group were examined. RESULTS: Hispanics/Latinos experienced decreased risk of death relative to NHWs [hazard ratio (HR) = 0.70, 95% confidence interval (95%CI) 0.57-0.86] overall and by sex (males: HR = 0.78, 95%CI 0.59-1.03, females: HR = 0.61, 95%CI 0.44-0.86). Decreased risk among Hispanics/Latinos relative to NHWs was evident in never-smokers (HR = 0.55, 95%CI 0.29-1.01), ever-smokers (HR = 0.72, 95%CI 0.57-0.90), younger subjects (HR = 0.73, 95%CI 0.54-0.99), and older subjects (HR = 0.72, 95%CI 0.53-0.97). Surgery was associated with improved survival in Hispanics/Latinos (HR = 0.60, 95%CI 0.43-0.85), and smoking with worse survival (HR = 1.56, 95%CI 1.02-2.39). Survival did not differ between Non-Hispanic Blacks and NHWs. CONCLUSIONS: In a poor urban community, Hispanics/Latinos experience improved survival from NSCLC compared to NHWs, which is not entirely explained by smoking. Future research should investigate the drivers of this benefit and differences in survival by Hispanic/Latino origin.

A longitudinal analysis of nondaily smokers: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

PURPOSE: Nondaily smoking is increasing in the United States and common among Hispanic/Latino smokers. We characterized factors related to longitudinal smoking transitions in Hispanic/Latino nondaily smokers. METHODS: The Hispanic Community Health Study/Study of Latinos is a population-based cohort study of Hispanics/Latinos aged 18-74 years. Multinomial logistic regression assessed the baseline factors (2008-2011) associated with follow-up smoking status (2014-2017) in nondaily smokers (n = 573), accounting for complex survey design. RESULTS: After ∼6 years, 41% of nondaily smokers became former smokers, 22% became daily smokers, and 37% remained nondaily smokers. Factors related to follow-up smoking status were number of days smoked in the previous month, household smokers, education, income, and insurance. Those smoking 16 or more of the last 30 days had increased risk of becoming a daily smoker [vs. < 4 days; relative risk ratio (RRR) = 5.65, 95% confidence interval (95% CI) = 1.96-16.33]. Greater education was inversely associated with transitioning to daily smoking [>high school vs.

Urinary Arsenic Species are Detectable in Urban Underserved Hispanic/Latino Populations: A Pilot Study from the Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS).

BACKGROUND: Hispanics/Latinos represent >15% of the United States (US) population and experience a high burden of cardiovascular disease (CVD) and diabetes. Dietary exposure, particularly to arsenic (As), may be associated with CVD and diabetes in Hispanics/Latinos. Rural populations in the US exposed to As in drinking water have increased risk of diabetes and CVD; however, little is known about the risk among urban populations with low As in water who are mostly exposed to As through food. METHODS: To explore the levels of inorganic arsenic exposure (the sum of inorganic and methylated arsenic species in urine, ∑As, corrected by a residual-based method) in persons of Hispanic/Latino origin, we conducted a pilot study quantifying urinary arsenic levels among 45 participants in the Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS). RESULTS: The median (interquartile range) of the urinary arsenic species (µg/L) were as follows: inorganic As 0.6 (0.4, 1.0), monomethylarsonic acid 1.2 (0.7, 1.9), dimethylarsinic acid 7.2 (4.3, 15.3), and ∑As 6.0 (4.3, 10.5). CONCLUSIONS: This study adds to the existing evidence that harmful forms of arsenic are present in this group of Hispanics/Latinos.

The establishment of the Household Air Pollution Consortium (HAPCO).

Household air pollution (HAP) is of public health concern with ~3 billion people worldwide (including >15 million in the US) exposed. HAP from coal use is a human lung carcinogen, yet the epidemiological evidence on carcinogenicity of HAP from biomass use, primarily wood, is not conclusive. To robustly assess biomass's carcinogenic potential, prospective studies of individuals experiencing a variety of HAP exposures are needed. We have built a global consortium of 13 prospective cohorts (HAPCO: Household Air Pollution Consortium) that have site- and disease-specific mortality and solid fuel use data, for a combined sample size of 587,257 participants and 57,483 deaths. HAPCO provides a novel opportunity to assess the association of HAP with lung cancer death while controlling for important confounders such as tobacco and outdoor air pollution exposures. HAPCO is also uniquely positioned to determine the risks associated with cancers other than lung as well as non-malignant respiratory and cardiometabolic outcomes, for which prospective epidemiologic research is limited. HAPCO will facilitate research to address public health concerns associated with HAP-attributed exposures by enabling investigators to evaluate sex-specific and smoking status-specific effects under various exposure scenarios.

Corrigendum: Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats.

[This corrects the article DOI: 10.3389/fncir.2018.00028.].

Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats.

After injury to the corticospinal tract (CST) in early development there is large-scale adaptation of descending motor pathways. Some studies suggest the uninjured hemisphere controls the impaired forelimb, while others suggest that the injured hemisphere does; these pathways have never been compared directly. We tested the contribution of each motor cortex to the recovery forelimb function after neonatal injury of the CST. We cut the left pyramid (pyramidotomy) of postnatal day 7 rats, which caused a measurable impairment of the right forelimb. We used pharmacological inactivation of each motor cortex to test its contribution to a skilled reach and supination task. Rats with neonatal pyramidotomy were further impaired by inactivation of motor cortex in both the injured and the uninjured hemispheres, while the forelimb of uninjured rats was impaired only from the contralateral motor cortex. Thus, inactivation demonstrated motor control from each motor cortex. In contrast, physiological and anatomical interrogation of these pathways support adaptations only in the uninjured hemisphere. Intracortical microstimulation of motor cortex in the uninjured hemisphere of rats with neonatal pyramidotomy produced responses from both forelimbs, while stimulation of the injured hemisphere did not elicit responses from either forelimb. Both anterograde and retrograde tracers were used to label corticofugal pathways. There was no increased plasticity from the injured hemisphere, either from cortex to the red nucleus or the red nucleus to the spinal cord. In contrast, there were very strong CST connections to both halves of the spinal cord from the uninjured motor cortex. Retrograde tracing produced maps of each forelimb within the uninjured hemisphere, and these were partly segregated. This suggests that the uninjured hemisphere may encode separate control of the unimpaired and the impaired forelimbs of rats with neonatal pyramidotomy.