Publications by authors named "David C Christiani"

691 Publications

SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues.

Int J Mol Sci 2021 Aug 26;22(17). Epub 2021 Aug 26.

Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22 or ANXA1 DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.
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http://dx.doi.org/10.3390/ijms22179228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431536PMC
August 2021

Electronic cigarette smoke reduces ribosomal protein gene expression to impair protein synthesis in primary human airway epithelial cells.

Sci Rep 2021 Sep 1;11(1):17517. Epub 2021 Sep 1.

Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA, 02215, USA.

The widespread use of electronic cigarettes (e-cig) is a serious public health concern; however, mechanisms by which e-cig impair the function of airway epithelial cells-the direct target of e-cig smoke-are not fully understood. Here we report transcriptomic changes, including decreased expression of many ribosomal genes, in airway epithelial cells in response to e-cig exposure. Using RNA-seq we identify over 200 differentially expressed genes in air-liquid interface cultured primary normal human bronchial epithelial (NHBE) exposed to e-cig smoke solution from commercial e-cig cartridges. In particular, exposure to e-cig smoke solution inhibits biological pathways involving ribosomes and protein biogenesis in NHBE cells. Consistent with this effect, expression of corresponding ribosomal proteins and subsequent protein biogenesis are reduced in the cells exposed to e-cig. Gas chromatography/mass spectrometry (GC/MS) analysis identified the presence of five flavoring chemicals designated as 'high priority' in regard to respiratory health, and methylglyoxal in e-cig smoke solution. Together, our findings reveal the potential detrimental effect of e-cig smoke on ribosomes and the associated protein biogenesis in airway epithelium. Our study calls for further investigation into how these changes in the airway epithelium contribute to the current epidemic of lung injuries in e-cig users.
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http://dx.doi.org/10.1038/s41598-021-97013-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410828PMC
September 2021

Prognostic implications of differences in forced vital capacity in black and white US adults: Findings from NHANES III with long-term mortality follow-up.

EClinicalMedicine 2021 Sep 20;39:101073. Epub 2021 Aug 20.

City University of New York at Hunter College, New York, USA.

Background: Because Forced Vital Capacity (FVC) is reduced in Black relative to White Americans of the same age, sex, and height, standard lung function prediction equations assign a lower "normal" range for Black patients. The prognostic implications of this race correction are uncertain.

Methods: We analyzed 5,294 White and 3,743 Black participants age 20-80 in NHANES III, a nationally-representative US survey conducted 1988-94, which we linked to the National Death Index to assess mortality through December 31, 2015. We calculated the FVC-percent predicted among Black and White participants, first applying NHANES III White prediction equations to all persons, and then using standard race-specific prediction equations. We used Cox proportional hazard models to calculate the association between race and all-cause mortality without and with adjustment for FVC (using each FVC metric), smoking, socioeconomic factors, and comorbidities.

Findings: Black participants' age- and sex-adjusted mortality was greater than White participants (HR 1.46; 95%CI:1.29, 1.65). With adjustment for FVC in liters (mean 3.7 L for Black participants, 4.3 L for White participants) or FVC percent-predicted using White equations for everyone, Black race was no longer independently predictive of higher mortality (HR∼1.0). When FVC-percent predicted was "corrected" for race, Black individuals again showed increased mortality hazard. Deaths attributed to chronic respiratory disease were infrequent for both Black and White individuals.

Interpretation: Lower FVC in Black people is associated with elevated risk of all-cause mortality, challenging the standard assumption about race-based normal limits. Black-White disparities in FVC may reflect deleterious social/environmental exposures, not innate differences.

Funding: No funding.
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http://dx.doi.org/10.1016/j.eclinm.2021.101073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379634PMC
September 2021

Response to Hopkins, Kichenadasse, Logan, et al.

J Natl Cancer Inst 2021 Aug 27. Epub 2021 Aug 27.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 677 Huntington Ave, Boston, MA, USA.

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http://dx.doi.org/10.1093/jnci/djab161DOI Listing
August 2021

Release of particulate matter from nano-enabled building materials (NEBMs) across their lifecycle: Potential occupational health and safety implications.

J Hazard Mater 2021 Jul 29;422:126771. Epub 2021 Jul 29.

Center for Nanotechnology and Nanotoxicology, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Ave., Boston, MA 02115, USA. Electronic address:

The present study investigates potential nanomaterial releases and occupational health risks across the lifecycle of nano-enabled building materials (NEBMs), namely, insulations and coatings. We utilized real-world degradation scenarios of a) sanding (mechanical), b) incineration (thermal), and c) accelerated UV-aging (environmental) followed by incineration. Extensive physicochemical characterization of the released lifecycle particulate matter (LCPM) was performed. The LCPM aerosol size fraction was used to assess the acute biological, cytotoxic and inflammatory effects on Calu-3 human lung epithelial cells. RNA-Seq analysis of exposed cells was performed to assess potential for systemic disease. Findings indicated that release dynamics and characteristics of LCPM depended on both the NEBM composition and the degradation scenario(s). Incineration emitted a much higher nanoparticle number concentration than sanding (nearly 4 orders of magnitude), which did not change with prior UV-aging. Released nanofillers during sanding were largely part of the matrix fragments, whereas those during incineration were likely physicochemically transformed. The LCPM from incineration showed higher bioactivity and inflammogenicity compared to sanding or sequential UV-aging and incineration, and more so when metallic nanofillers were present (such as FeO). Overall, the study highlights the need for considering real-world exposure and toxicological data across the NEBM lifecycle to perform adequate risk assessments and to ensure workplace health and safety.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126771DOI Listing
July 2021

Ambient Air Pollution and Lung Cancer: Nature and Nurture.

Am J Respir Crit Care Med 2021 Aug 9. Epub 2021 Aug 9.

Harvard University T H Chan School of Public Health, 1857, Environmental Health, Boston, Massachusetts, United States.

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http://dx.doi.org/10.1164/rccm.202107-1576EDDOI Listing
August 2021

Parental metal exposures as potential risk factors for spina bifida in Bangladesh.

Environ Int 2021 Aug 3;157:106800. Epub 2021 Aug 3.

Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, United States; Department of Neurology, Harvard Medical School, 25 Shattuck St, Boston, MA, United States; Department of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, United States. Electronic address:

Background: Neural tube defects are a pressing public health concern despite advances in prevention from folic acid-based strategies. Numerous chemicals, in particular arsenic, have been associated with neural tube defects in animal models and could influence risk in humans.

Objectives: We investigated the relationship between parental exposure to arsenic and 17 metals and risk of neural tube defects (myelomeningocele and meningocele) in a case control study in Bangladesh.

Methods: Exposure assessment included analysis of maternal and paternal toenail samples using inductively coupled plasma mass spectrometry (ICP-MS). A total of 278 participants (155 cases and 123 controls) with data collected from 2016 to 2020 were included in the analysis.

Results: In the paternal models, a one-unit increase in the natural logarithm of paternal toenail arsenic was associated with a 74% (odds ratio: 1.74, 95% confidence interval: 1.26-2.42) greater odds of having a child with spina bifida, after adjusting for relevant covariates. Additionally, paternal exposure to aluminum, cobalt, chromium, iron, selenium, and vanadium was associated with increased odds of having a child with spina bifida in the adjusted models. In the maternal models, a one-unit increase in the natural logarithm of maternal toenail selenium and zinc levels was related to a 382% greater (odds ratio: 4.82, 95% confidence interval: 1.32-17.60) and 89% lower (odds ratio: 0.11, 95% confidence interval: 0.03-0.42) odds of having a child with spina bifida in the adjusted models, respectively. Results did not suggest an interaction between parental toenail metals and maternal serum folate.

Discussion: Parental toenail levels of numerous metals were associated with increased risk of spina bifida in Bangladeshi infants. Paternal arsenic exposure was positively associated with neural tube defects in children and is of particular concern given the widespread arsenic poisoning of groundwater resources in Bangladesh and the lack of nutritional interventions aimed to mitigate paternal arsenic exposure. The findings add to the growing body of literature of the impact of metals, especially paternal environmental factors, on child health.
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http://dx.doi.org/10.1016/j.envint.2021.106800DOI Listing
August 2021

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Carcinogenesis 2021 Jul 23. Epub 2021 Jul 23.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies (GWAS) of NSCLC, which included 13,327 cases and 13,328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5×10 -8 for identifying significant gene-smoking interactions and 1×10 -6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold (OR = 0.63, 95%CI: 0.54-0.74, P = 3.31×10 -8), and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95%CI: 0.63-0.82, P = 8.10×10 -7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95%CI: 0.51-0.73, P = 7.55×10 -8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.
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http://dx.doi.org/10.1093/carcin/bgab064DOI Listing
July 2021

Performance of a Machine Learning Algorithm Using Electronic Health Record Data to Identify and Estimate Survival in a Longitudinal Cohort of Patients With Lung Cancer.

JAMA Netw Open 2021 Jul 1;4(7):e2114723. Epub 2021 Jul 1.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Importance: Electronic health records (EHRs) provide a low-cost means of accessing detailed longitudinal clinical data for large populations. A lung cancer cohort assembled from EHR data would be a powerful platform for clinical outcome studies.

Objective: To investigate whether a clinical cohort assembled from EHRs could be used in a lung cancer prognosis study.

Design, Setting, And Participants: In this cohort study, patients with lung cancer were identified among 76 643 patients with at least 1 lung cancer diagnostic code deposited in an EHR in Mass General Brigham health care system from July 1988 to October 2018. Patients were identified via a semisupervised machine learning algorithm, for which clinical information was extracted from structured and unstructured data via natural language processing tools. Data completeness and accuracy were assessed by comparing with the Boston Lung Cancer Study and against criterion standard EHR review results. A prognostic model for non-small cell lung cancer (NSCLC) overall survival was further developed for clinical application. Data were analyzed from March 2019 through July 2020.

Exposures: Clinical data deposited in EHRs for cohort construction and variables of interest for the prognostic model were collected.

Main Outcomes And Measures: The primary outcomes were the performance of the lung cancer classification model and the quality of the extracted variables; the secondary outcome was the performance of the prognostic model.

Results: Among 76 643 patients with at least 1 lung cancer diagnostic code, 42 069 patients were identified as having lung cancer, with a positive predictive value of 94.4%. The study cohort consisted of 35 375 patients (16 613 men [47.0%] and 18 756 women [53.0%]; 30 140 White individuals [85.2%], 1040 Black individuals [2.9%], and 857 Asian individuals [2.4%]) after excluding patients with lung cancer history and less than 14 days of follow-up after initial diagnosis. The median (interquartile range) age at diagnosis was 66.7 (58.4-74.1) years. The area under the receiver operating characteristic curves of the prognostic model for overall survival with NSCLC were 0.828 (95% CI, 0.815-0.842) for 1-year prediction, 0.825 (95% CI, 0.812-0.836) for 2-year prediction, 0.814 (95% CI, 0.800-0.826) for 3-year prediction, 0.814 (95% CI, 0.799-0.828) for 4-year prediction, and 0.812 (95% CI, 0.798-0.825) for 5-year prediction.

Conclusions And Relevance: These findings suggest the feasibility of assembling a large-scale EHR-based lung cancer cohort with detailed longitudinal clinical measurements and that EHR data may be applied in cancer progression with a set of generalizable approaches.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.14723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264641PMC
July 2021

Validation of in vivo toenail measurements of manganese and mercury using a portable X-ray fluorescence device.

J Expo Sci Environ Epidemiol 2021 Jul 1. Epub 2021 Jul 1.

Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background And Objective: Toenail metal concentrations can be used as an effective biomarker for exposure to environmental toxicants. Typically toenail clippings are measured ex vivo using inductively coupled plasma mass spectrometry (ICP-MS). X-ray fluorescence (XRF) toenail metal measurements done on intact toenails in vivo could be used as an alternative to alleviate some of the disadvantages of ICP-MS. In this study, we assessed the ability to use XRF to measure toenail metal concentrations in real-time without having to clip the toenails (i.e., in vivo) in two occupational settings for exposure assessment of manganese and mercury.

Materials And Methods: The portable XRF method used a 3-min in vivo measurement of toenails prior to clipping and was assessed against ICP-MS measurement of toenail clippings taken immediately after the XRF measurement and work history for a group of welders (n = 16) assessed for manganese exposure and nail salon workers (n = 10) assessed for mercury exposure.

Results And Conclusions: We identified that in vivo XRF metal measurements were able to discern exposure to manganese in welders and mercury in nail salon workers. We identified significant positive correlations between ICP-MS of clippings and in vivo XRF measures of both toenail manganese (R = 0.59, p = 0.02) and mercury (R = 0.74, p < 0.001), as well as between in vivo XRF toenail manganese and work history among the welders (R = 0.55, p = 0.03). We identified in vivo XRF detection limits to be 0.5 µg/g for mercury and 2.6 µg/g for manganese. Further work should elucidate differences in the timing of exposure using the in vivo XRF method over toenail clippings and modification of measurement time and x-ray setting to further decrease the detection limit. In vivo portable, XRF measurements can be used to effectively measure toenail Mn and Hg in occupational participants in real-time during study visits and at a fraction of the cost.
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http://dx.doi.org/10.1038/s41370-021-00358-wDOI Listing
July 2021

Cord serum elementomics profiling of 56 elements depicts risk of preterm birth: Evidence from a prospective birth cohort in rural Bangladesh.

Environ Int 2021 11 28;156:106731. Epub 2021 Jun 28.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; China International Cooperation Center for Environment and Human Health, Center of Global Health, Nanjing Medical University, Nanjing 211166, China.

Maternal exposure to some individual rare earth elements and trace elements is associated with preterm birth, but few elements have been studied and little is known about the potential effect of simultaneous exposure to multiple elements. We examined individual and mixture effects of elements on preterm birth among 745 pregnant women in a prospective birth cohort in Bangladesh (2008-2011). We measured 56 elements in umbilical cord blood collected during delivery using inductively coupled plasma-mass spectrometry. Using elastic net (ENET) regularization and multivariate logistic regression, we examined independent associations between element concentrations and preterm birth. Bayesian kernel machine regression identified mixture effects of elements most critical to preterm birth, accounting for correlated exposure and interaction. ENET identified titanium (Ti), arsenic (As), and barium (Ba) as the most important predictors of shortened gestational age and preterm birth. In adjusted models, cord blood Ti (OR = 2.52; 95% CI: 1.08-5.93; P = 0.033), As (odds ratio (OR) = 1.34; 95% CI: 1.04-1.73; P = 0.023), and Ba (OR = 1.18; 95% CI: 1.02-1.38; P = 0.029) were significantly associated with preterm birth. Bayesian kernel machine regression suggested an interaction effect between As and Ba. Further, we constructed an element risk score (ERS) using estimated weights from a multivariate regression model for Ti, As, and Ba and regressed preterm birth by this score (OR = 2.72, 95% CI: 1.57-4.69; P = 3.35 × 10). Additionally, we observed a significant modification effect of child marriage on ERS, which means marriage before the age of 18 (P = 0.0438). This study identified element exposures profiles in cord blood and constructed metal risk score that are jointly associated with the risk of preterm birth. Ti, As, and Ba exposure may adversely affect birth outcomes as well as child marriage may be a modifiable factor potentially affecting environmental element exposure and preterm birth.
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http://dx.doi.org/10.1016/j.envint.2021.106731DOI Listing
November 2021

Smoking History as a Potential Predictor of Immune Checkpoint Inhibitor Efficacy in Metastatic Non-Small Cell Lung Cancer.

J Natl Cancer Inst 2021 Jun 11. Epub 2021 Jun 11.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 677 Huntington Ave, Boston, MA, USA.

Background: Despite the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients, consistent and easily obtainable predictors of efficacy remain elusive.

Methods: This study was conducted on 644 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patient smoking history, clinicopathological characteristics, tumor mutation burden (TMB) by clinical targeted next generation sequencing, and PD-L1 tumor proportion score (TPS) by immunohistochemistry were prospectively collected. The association of smoking history with clinical outcomes of ICI monotherapy in metastatic NSCLC patients was evaluated after adjusting for other potential predictors. All statistical tests were 2-sided.

Results: Of 644 advanced NSCLC patients 105 (16.3%) were never smokers, 375 (58.2%) were former smokers (median pack-years = 28), and 164 (25.4%) were current smokers (median pack-years = 40). Multivariable logistic and Cox proportional hazards regression analyses suggested that doubling of smoking pack-years is statistically significantly associated with improved clinical outcomes of patients treated with ICI monotherapy (objective response rate odds ratio = 1.21, 95% confidence interval [CI] = 1.09-1.36, P < .001; progression-free survival hazard ratio = 0.92, 95% CI = 0.88-0.95, P < .001; overall survival hazard ratio = 0.94, 95% CI = 0.90-0.99, P = .01). Predictive models incorporating pack-years and PD-L1 TPS yielded additional information and achieved similar model performance compared to using TMB and PD-L1 TPS.

Conclusions: Increased smoking exposure had a statistically significant association with improved clinical outcomes in metastatic NSCLC treated with ICI monotherapy independent of PD-L1 TPS. Pack-years may serve as a consistent and readily obtainable surrogate of ICI efficacy when TMB is not available to inform prompt clinical decisions and allow more patients to benefit from ICIs.
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http://dx.doi.org/10.1093/jnci/djab116DOI Listing
June 2021

Genetic variants of , and in the natural killer cell-related pathway are associated with non-small cell lung cancer survival.

Am J Cancer Res 2021 15;11(5):2264-2277. Epub 2021 May 15.

Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.

Although natural killer (NK) cells are a known major player in anti-tumor immunity, the effect of genetic variation in NK-associated genes on survival in patients with non-small cell lung cancer (NSCLC) remains unknown. Here, in 1,185 with NSCLC cases of a discovery dataset, we evaluated associations of 28,219 single nucleotide polymorphisms (SNPs) in 276 NK-associated genes with their survival. These patients were from the reported genome-wide association study (GWAS) from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We further validated the findings in an additional 984 cases from the Harvard Lung Cancer Susceptibility (HLCS) Study. We identified three SNPs (i.e., rs261083 G>C, rs2519996 C>T and rs36215 A>G) to be independently associated with overall survival (OS) in NSCLC cases with adjusted hazards ratios (HRs) of 1.16 (95% confidence interval [CI] = 1.07-1.26, = 3.34×10), 1.28 (1.12-1.47, = 4.57×10) and 0.75 (0.67-0.83, = 1.50×10), respectively. Additional joint assessment of the unfavorable genotypes of the three SNPs showed significant associations with OS and disease-specific survival of NSCLC cases in the PLCO dataset ( <0.0001 and <0.0001, respectively). Moreover, the survival-associated rs261083 C allele had a significant correlation with reduced transcript levels in lung adenocarcinoma (LUAD), while the rs36215 G allele was significantly correlated with reduced transcript levels in lymphoblastoid cell lines in the 1000 Genomes Project. These results revealed that and genetic variants may be prognostic biomarkers of NSCLC survival, likely via transcription regulation of respective genes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167686PMC
May 2021

Genetic variants of CHEK1, PRIM2 and CDK6 in the mitotic phase-related pathway are associated with nonsmall cell lung cancer survival.

Int J Cancer 2021 09 10;149(6):1302-1312. Epub 2021 Jun 10.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.

The mitotic phase is a vital step in cell division and may be involved in cancer progression, but it remains unclear whether genetic variants in mitotic phase-related pathways genes impact the survival of these patients. Here, we investigated associations between 31 032 single nucleotide polymorphisms (SNPs) in 368 mitotic phase-related pathway genes and overall survival (OS) of patients with nonsmall cell lung cancer (NSCLC). We assessed the associations in a discovery data set of 1185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another data set of 984 patients from the Harvard Lung Cancer Susceptibility Study. As a result, we identified three independent SNPs (ie, CHEK1 rs76744140 T>C, PRIM2 rs6939623 G>T and CDK6 rs113181986 G>C) to be significantly associated with NSCLC OS with an adjusted hazard ratio of 1.29 (95% confidence interval = 1.11-1.49, P = 8.26 × 10 ), 1.26 (1.12-1.42, 1.10 × 10 ) and 0.73 (0.63-0.86, 1.63 × 10 ), respectively. Moreover, the number of combined unfavorable genotypes of these three SNPs was significantly associated with NSCLC OS and disease-specific survival in the PLCO data set (P  < .0001 and .0003, respectively). Further expression quantitative trait loci analysis showed that the rs76744140C allele predicted CHEK1 mRNA expression levels in normal lung tissues and that rs113181986C allele predicted CDK6 mRNA expression levels in whole blood tissues. Additional analyses indicated CHEK1, PRIM2 and CDK6 may impact NSCLC survival. Taken together, these findings suggested that these genetic variants may be prognostic biomarkers of patients with NSCLC.
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http://dx.doi.org/10.1002/ijc.33702DOI Listing
September 2021

Socioeconomic Inequality in Respiratory Health in the US From 1959 to 2018.

JAMA Intern Med 2021 07;181(7):968-976

Cambridge Health Alliance, Cambridge, Massachusetts.

Importance: Air quality has improved and smoking rates have declined over the past half-century in the US. It is unknown whether such secular improvements, and other policies, have helped close socioeconomic gaps in respiratory health.

Objective: To describe long-term trends in socioeconomic disparities in respiratory disease prevalence, pulmonary symptoms, and pulmonary function.

Design, Setting, And Participants: This repeated cross-sectional analysis of the nationally representative National Health and Nutrition Examination Surveys (NHANES) and predecessor surveys, conducted from 1959 to 2018. included 160 495 participants aged 6 to 74 years.

Exposures: Family income quintile defined using year-specific thresholds; educational attainment.

Main Outcomes And Measures: Trends in socioeconomic disparities in prevalence of current/former smoking among adults aged 25 to 74 years; 3 respiratory symptoms (dyspnea on exertion, cough, and wheezing) among adults aged 40 to 74 years; asthma stratified by age (6-11, 12-17, and 18-74 years); chronic obstructive pulmonary disease ([COPD] adults aged 40-74 years); and 3 measures of pulmonary function (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC<0.70) among adults aged 24 to 74 years.

Results: Our sample included 160 495 individuals surveyed between 1959 and 2018: 27 948 children aged 6 to 11 years; 26 956 children aged 12 to 17 years; and 105 591 adults aged 18 to 74 years. Income- and education-based disparities in smoking prevalence widened from 1971 to 2018. Socioeconomic disparities in respiratory symptoms persisted or worsened from 1959 to 2018. For instance, from 1971 to 1975, 44.5% of those in the lowest income quintile reported dyspnea on exertion vs 26.4% of those in the highest quintile, whereas from 2017 to 2018 the corresponding proportions were 48.3% and 27.9%. Disparities in cough and wheezing rose over time. Asthma prevalence rose for all children after 1980, but more sharply among poorer children. Income-based disparities in diagnosed COPD also widened over time, from 4.5 percentage points (age- and sex-adjusted) in 1971 to 11.3 percentage points from 2013 to 2018. Socioeconomic disparities in FEV1 and FVC also increased. For instance, from 1971 to 1975, the age- and height-adjusted FEV1 of men in the lowest income quintile was 203.6 mL lower than men in the highest quintile, a difference that widened to 248.5 mL from 2007 to 2012 (95% CI, -328.0 to -169.0). However, disparities in rates of FEV1/FVC lower than 0.70 changed little.

Conclusions And Relevance: Socioeconomic disparities in pulmonary health persisted and potentially worsened over the past 6 decades, suggesting that the benefits of improved air quality and smoking reductions have not been equally distributed. Socioeconomic position may function as an independent determinant of pulmonary health.
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http://dx.doi.org/10.1001/jamainternmed.2021.2441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261605PMC
July 2021

Integrative omics provide biological and clinical insights into acute respiratory distress syndrome.

Intensive Care Med 2021 07 25;47(7):761-771. Epub 2021 May 25.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA.

Purpose: Acute respiratory distress syndrome (ARDS) is accompanied by a dysfunctional immune-inflammatory response following lung injury, including during coronavirus disease 2019 (COVID-19). Limited causal biomarkers exist for ARDS development. We sought to identify novel genetic susceptibility targets for ARDS to focus further investigation on their biological mechanism and therapeutic potential.

Methods: Meta-analyses of ARDS genome-wide association studies were performed with 1250 cases and 1583 controls in Europeans, and 387 cases and 387 controls in African Americans. The functionality of novel loci was determined in silico using multiple omics approaches. The causality of 114 factors potentially involved in ARDS development was assessed using Mendelian Randomization analysis.

Results: There was distinct genetic heterogeneity in ARDS between Europeans and African Americans. rs7967111 at 12p13.2 was functionally associated with ARDS susceptibility in Europeans (odds ratio = 1.38; P = 2.15 × 10). Expression of two genes annotated at this locus, BORCS5 and DUSP16, was dynamic but ultimately decreased during ARDS development, as well as downregulated in immune cells alongside COVID-19 severity. Causal inference implied that comorbidity of inflammatory bowel disease and elevated levels of C-reactive protein and interleukin-10 causally increased ARDS risk, while vitamin D supplementation and vasodilator use ameliorated risk.

Conclusion: Our findings suggest a novel susceptibility locus in ARDS pathophysiology that implicates BORCS5 and DUSP16 as potentially acting in immune-inflammatory processes. This locus warrants further investigation to inform the development of therapeutic targets and clinical care strategies for ARDS, including those induced by COVID-19.
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http://dx.doi.org/10.1007/s00134-021-06410-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144871PMC
July 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Umbilical Cord Blood Metal Mixtures and Birth Size in Bangladeshi Children.

Environ Health Perspect 2021 May 14;129(5):57006. Epub 2021 May 14.

Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Studies have evaluated environmental exposure to toxic metals such as arsenic (As), cadmium (Cd), manganese (Mn), or lead (Pb) on birth size; however, information on potential effects of exposures to metal mixtures is limited.

Objectives: We assessed the association between metal mixtures (As, Cd, Mn, Pb) in umbilical cord blood and neonate size in Bangladeshi children.

Methods: In this birth cohort study, pregnant women who were of age with an ultrasound-confirmed singleton pregnancy of gestation were recruited from two Bangladesh clinics between 2008 and 2011. Neonate size metrics were measured at the time of delivery. Metals in cord blood were measured using inductively coupled plasma mass spectrometry. We employed multivariable linear regression and Bayesian kernel machine regression (BKMR) to estimate associations of individual metals and metal mixtures with birth size parameters.

Results: Data from 1,088 participants was assessed. We found a significant negative association between metal mixture and birth length and head circumference when all metal concentrations were above the 60th and 55th percentiles, respectively, compared with the median. An interquartile range (IQR) increase in log Cd concentration {log[Cd (in micrograms per deciliter)] } was associated with a 0.13-standard deviation (SD) decrease in mean birth length (95% CI: , ) and a 0.17-SD decrease in mean head circumference (95% CI: , ), based on linear regression models adjusted for covariates and the other metals. An IQR increase in log Mn concentration {log[Mn (in micrograms per deciliter)] } was associated with a 0.07-SD decrease in mean birth weight (95% CI: , 0.002).

Discussion: Metal mixtures in cord blood were associated with reduced birth size in Bangladeshi children. Results from linear regression models adjusted and the BKMR mixtures analyses suggest adverse effects of Cd and Mn, as individual metal exposures, on birth size outcomes. https://doi.org/10.1289/EHP7502.
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http://dx.doi.org/10.1289/EHP7502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121379PMC
May 2021

Mendelian Randomization With Refined Instrumental Variables From Genetic Score Improves Accuracy and Reduces Bias.

Front Genet 2021 17;12:618829. Epub 2021 Mar 17.

Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Mendelian randomization (MR) can estimate the causal effect for a risk factor on a complex disease using genetic variants as instrument variables (IVs). A variety of generalized MR methods have been proposed to integrate results arising from multiple IVs in order to increase power. One of the methods constructs the genetic score (GS) by a linear combination of the multiple IVs using the multiple regression model, which was applied in medical researches broadly. However, GS-based MR requires individual-level data, which greatly limit its application in clinical research. We propose an alternative method called Mendelian Randomization with Refined Instrumental Variable from Genetic Score (MR-RIVER) to construct a genetic IV by integrating multiple genetic variants based on summarized results, rather than individual data. Compared with inverse-variance weighted (IVW) and generalized summary-data-based Mendelian randomization (GSMR), MR-RIVER maintained the type I error, while possessing more statistical power than the competing methods. MR-RIVER also presented smaller biases and mean squared errors, compared to the IVW and GSMR. We further applied the proposed method to estimate the effects of blood metabolites on educational attainment, by integrating results from several publicly available resources. MR-RIVER provided robust results under different LD prune criteria and identified three metabolites associated with years of schooling and additional 15 metabolites with indirect mediation effects through butyrylcarnitine. MR-RIVER, which extends score-based MR to summarized results in lieu of individual data and incorporates multiple correlated IVs, provided a more accurate and powerful means for the discovery of novel risk factors.
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http://dx.doi.org/10.3389/fgene.2021.618829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044958PMC
March 2021

Child marriage, maternal serum metal exposure, and risk of preterm birth in rural Bangladesh: evidence from mediation analysis.

J Expo Sci Environ Epidemiol 2021 05 6;31(3):571-580. Epub 2021 Apr 6.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Background: The prevalence of preterm birth in Bangladesh is estimated to be 19.1%, the highest in the world. Although prenatal exposure to several metals has been linked with preterm birth, fewer prospective studies have investigated the socioeconomic factors that affect metal exposure, leading to preterm birth risk.

Objective: We aim to identify novel metal biomarkers and their critical exposure windows, as well as the upstream socioeconomic risk factors for preterm birth in rural Bangladeshi, to shed light for future interventional strategies.

Methods: This study included data from 780 mother-offspring pairs, who were recruited to participate in a prospective birth cohort in Bangladesh (2008-2011). Serum concentrations of 19 metals were measured in the first and second trimesters using inductively coupled plasma mass spectrometry. Mediation analysis was performed to explore the upstream socioeconomic factors that affect the risk of preterm birth mediated via metal exposure concentrations.

Results: Early pregnancy exposure to serum zinc, arsenic, and strontium and mid-pregnancy exposure to barium were significantly associated with risk of preterm birth. Furthermore, younger marriage age was associated with an exponential increase in the risk of preterm birth, and women who married after 18 years old had a considerably lower risk of preterm birth. Mediation analysis indicated that these four elements mediated 30.2% of the effect of marriage age on preterm birth.

Conclusion: This study indicated that maternal serum metal exposure mediates the impact of child marriage on the increased risk of preterm birth via metal exposures. The findings shed light on the mechanisms underlying such association and provide insights into future interventional strategies.
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http://dx.doi.org/10.1038/s41370-021-00319-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134042PMC
May 2021

Progression of traction bronchiectasis/bronchiolectasis in interstitial lung abnormalities is associated with increased all-cause mortality: Age Gene/Environment Susceptibility-Reykjavik Study.

Eur J Radiol Open 2021 10;8:100334. Epub 2021 Mar 10.

Center for Pulmonary Functional Imaging, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Purpose: The aim of this study is to assess the role of traction bronchiectasis/bronchiolectasis and its progression as a predictor for early fibrosis in interstitial lung abnormalities (ILA).

Methods: Three hundred twenty-seven ILA participants out of 5764 in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who had undergone chest CT twice with an interval of approximately five-years were enrolled in this study. Traction bronchiectasis/bronchiolectasis index (TBI) was classified on a four-point scale: 0, ILA without traction bronchiectasis/bronchiolectasis; 1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion; 2, ILA with mild to moderate traction bronchiectasis; 3, ILA and severe traction bronchiectasis and/or honeycombing. Traction bronchiectasis (TB) progression was classified on a five-point scale: 1, Improved; 2, Probably improved; 3, No change; 4, Probably progressed; 5, Progressed. Overall survival (OS) among participants with different TB Progression Score and between the TB progression group and No TB progression group was also investigated. Hazard radio (HR) was estimated with Cox proportional hazards model.

Results: The higher the TBI at baseline, the higher TB Progression Score (P < 0.001). All five participants with TBI = 3 at baseline progressed; 46 (90 %) of 51 participants with TBI = 2 progressed. TB progression was also associated with shorter OS with statistically significant difference (adjusted HR = 1.68, P < 0.001).

Conclusion: TB progression was visualized on chest CT frequently and clearly. It has the potential to be the predictor for poorer prognosis of ILA.
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http://dx.doi.org/10.1016/j.ejro.2021.100334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960545PMC
March 2021

Metabolomic profiling for second primary lung cancer: A pilot case-control study.

Lung Cancer 2021 05 11;155:61-67. Epub 2021 Mar 11.

Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Objectives: Lung cancer survivors have a high risk of developing a second primary lung cancer (SPLC). While national screening guidelines have been established for initial primary lung cancer (IPLC), no consensus guidelines exist for SPLC. Furthermore, the factors that contribute to SPLC risk have not been established. This study examines the potential for using serum metabolomics to identify metabolite biomarkers that differ between SPLC cases and IPLC controls.

Material And Methods: In this pilot case-control study, we applied an untargeted metabolomics approach based on ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) to serum samples of 82 SPLC cases and 82 frequency matched IPLC controls enrolled in the Boston Lung Cancer Study. Random forest and unconditional logistic regression models identified metabolites associated with SPLC. Candidate metabolites were integrated into a SPLC risk prediction model and the model performance was evaluated through a risk stratification approach.

Results: The untargeted analysis detected 1008 named and 316 unnamed metabolites among all study participants. Metabolites that were significantly associated with SPLC (False Discovery Rate q-value < 0.2) included 5-methylthioadenosine (odds ratio [OR] = 2.04, 95 % confidence interval [CI] 1.39-3.01; P = 2.8 × 10) and phenylacetylglutamine (OR = 2.65, 95 % CI 1.56-4.51; P = 3.2 × 10), each exhibiting approximately 1.5-fold increased levels among SPLC cases versus IPLC controls. In stratifying the study participants across quartiles of estimated SPLC risk, the risk prediction model identified a significantly higher proportion of SPLC cases in the fourth compared to the first quartile (68.3 % versus 39.0 %; P = 0.044).

Conclusion: SPLC cases may have distinct metabolomic profiles compared to those in IPLC patients without SPLC. A risk stratification approach integrating metabolomics may be useful for distinguishing patients based on SPLC risk. Prospective validation studies are needed to further evaluate the potential for leveraging metabolomics in SPLC surveillance and screening.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085101PMC
May 2021

Deep learning classification of lung cancer histology using CT images.

Sci Rep 2021 Mar 9;11(1):5471. Epub 2021 Mar 9.

Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, MA, USA.

Tumor histology is an important predictor of therapeutic response and outcomes in lung cancer. Tissue sampling for pathologist review is the most reliable method for histology classification, however, recent advances in deep learning for medical image analysis allude to the utility of radiologic data in further describing disease characteristics and for risk stratification. In this study, we propose a radiomics approach to predicting non-small cell lung cancer (NSCLC) tumor histology from non-invasive standard-of-care computed tomography (CT) data. We trained and validated convolutional neural networks (CNNs) on a dataset comprising 311 early-stage NSCLC patients receiving surgical treatment at Massachusetts General Hospital (MGH), with a focus on the two most common histological types: adenocarcinoma (ADC) and Squamous Cell Carcinoma (SCC). The CNNs were able to predict tumor histology with an AUC of 0.71(p = 0.018). We also found that using machine learning classifiers such as k-nearest neighbors (kNN) and support vector machine (SVM) on CNN-derived quantitative radiomics features yielded comparable discriminative performance, with AUC of up to 0.71 (p = 0.017). Our best performing CNN functioned as a robust probabilistic classifier in heterogeneous test sets, with qualitatively interpretable visual explanations to its predictions. Deep learning based radiomics can identify histological phenotypes in lung cancer. It has the potential to augment existing approaches and serve as a corrective aid for diagnosticians.
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http://dx.doi.org/10.1038/s41598-021-84630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943565PMC
March 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Outcomes of Patients With Interstitial Lung Disease Receiving Programmed Cell Death 1 Inhibitors: A Retrospective Case Series.

Clin Lung Cancer 2021 Feb 4. Epub 2021 Feb 4.

Division of Pulmonary & Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, are used to treat multiple cancers. Limited data exist as to the use of ICIs in patients with coexistent interstitial lung disease (ILD). We conducted a retrospective case series to assess clinical and radiologic outcomes of patients with ILD treated with PD-1 inhibitors.

Methods: Eligible patients were 18 years of age or older, treated with pembrolizumab or nivolumab for oncologic indications, and had evidence of ILD on chest computed tomography scan not attributable to radiotherapy before initiation of ICI therapy. Outcomes of interest included mortality, hospitalizations for respiratory-related causes, development of pneumonitis, and radiologic change in ILD over a 1-year follow-up period.

Results: We included 41 patients in the analysis. At 1 year, 17 patients (41.5%) were alive, 23 had died (56.1%), and 1 (2.4%) was lost to follow-up. Of 23 deaths, 16 (69.6%) were due to cancer, 4 (17.4%) to causes excluding cancer and ILD, and 3 (13.0%) to hypoxemic respiratory failure from ILD- or ICI-induced pneumonitis. Three patients (7.3%) required hospitalization owing to ILD, including drug-induced pneumonitis, and 3 (7.3%) developed pneumonitis attributable to anti-PD-1 therapy. On follow-up computed tomography scans, 32 patients (78.0%) had stable or improved ILD and 9 (22.0%) had progression.

Conclusion: Patients with ILD receiving PD-1 inhibitors more frequently died of cancer-related causes than from ILD. Further research is needed to determine the safety of ICIs in patients with ILD and if ILD subtype may help to refine ICI-associated risks.
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http://dx.doi.org/10.1016/j.cllc.2021.01.014DOI Listing
February 2021

Association between Smoking History and Tumor Mutation Burden in Advanced Non-Small Cell Lung Cancer.

Cancer Res 2021 05 2;81(9):2566-2573. Epub 2021 Mar 2.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced-stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased and less frequent and mutations, whereas doubling smoking-free months was associated with more frequent . In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma. SIGNIFICANCE: This study clarifies the relationship between smoking history and clinically relevant mutations in non-small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137661PMC
May 2021

Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival.

Cancer Immunol Immunother 2021 Oct 2;70(10):2819-2833. Epub 2021 Mar 2.

Duke University Medical Center and Department of Population Health Sciences, Duke Cancer Institute, Duke University School of Medicine, 905 S LaSalle Street, Durham, NC, 27710, USA.

Background: Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients.

Methods: We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis.

Results: Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10], 0.86 (0.80-0.93, P = 9.4 × 10) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (P < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes.

Conclusion: These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.
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http://dx.doi.org/10.1007/s00262-021-02877-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410895PMC
October 2021

Early occupational exposure to lead on neutrophil-to-lymphocyte ratio and genotoxicity.

Environ Int 2021 06 19;151:106448. Epub 2021 Feb 19.

Department of Occupational Health & Toxicology, School of Public Health, Shanghai Medical College of Fudan University, 130 Dongan Road, Shanghai 200032, China. Electronic address:

Background: Lead (Pb) is known to induce detrimental health effects in exposed populations, including hematotoxicity and genotoxicity. Complete blood count (CBC) is a cost-effective and easy way to determine toxicity, and variations in proportion of different types of leukocytes: neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are further evidence of hematotoxicity. However, few studies have been conducted to systematically evaluate effects of occupational Pb exposure on NLR and LMR, and their associations with genotoxicity.

Objectives: Our study was aimed to systematically assess the effects of current occupational Pb exposure on NLR and LMR, and their associations with genotoxicity.

Methods: Our investigation was performed on 1176 workers from a newly built battery factory in North China. The workers had just entered their current job position in recent years and most of them had no previous history of occupational exposure to Pb. Blood lead levels (BLLs) and leukocytes indices were detected for all participants. Cytokinesis-blocked micronucleus assay (MN; n = 675) and alkaline comet assay (% tail DNA; n = 869) were used to assess genotoxicity. Multivariate linear and Poisson regression analyses were conducted to examine associations between leukocytes indices, genotoxic biomarkers and BLLs with adjustment for covariates. Spearman correlation and mediation analyses were used to investigate relationships between NLR and genotoxicity.

Results: Among all the exposed workers, NLR increased with increasing BLLs. However, WBC and LMR did not change significantly. Significant and dose-dependent increases in both MN frequencies and % tail DNA were observed among groups with different exposure doses. Compared with the normal NLR group (1.48 ≤ NLR < 4.58), the high NLR group (NLR ≥ 4.58) had higher % tail DNA. In addition, there was a significant and positive association between NLR and % tail DNA among all the workers, and % tail DNA mediated 15% of the effect of Pb on increasing NLR.

Conclusion: Our large-scale population study shows that Pb exposure increased NLR and induced genotoxicity. There was an association between elevated NLR and DNA damage. In addition, the mediation effect of % tail DNA on the relationship between BLLs and NLR provided mechanistic evidence that certain mechanisms, e.g. inflammation, may be involved in elevation of NLR from Pb exposure. Therefore, NLR may be a convenient and sensitive biomarker for indication of Pb toxicity. Further studies are needed to validate the proposed mechanism and NLR as a biomarker.
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http://dx.doi.org/10.1016/j.envint.2021.106448DOI Listing
June 2021
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