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Background: Lung cancer screening (LCS) can reduce lung cancer mortality but has potential harms for patients. A shared decision-making (SDM) conversation about LCS is required by the Centers for Medicare & Medicaid Services (CMS) for LCS reimbursement. To overcome barriers to SDM in primary care, this protocol describes a telehealth decision coaching and navigation intervention for LCS in primary care clinics delivered by patient navigators. The objective of the study is to evaluate the effectiveness of the intervention and its implementation potential, compared with an enhanced usual care (EUC) arm., Methods: Patients (n = 420) of primary care clinicians (n = 120) are being recruited to a cluster randomized controlled trial. Clinicians are randomly assigned to 1) TELESCOPE intervention: prior to an upcoming non-acute clinic visit, patients participate in a telehealth decision coaching and navigation session about LCS delivered by trained patient navigators and nurse navigators place a low-dose CT scan (LDCT) order for each TELESCOPE patient wanting LCS, or 2) EUC: patients receive enhanced usual care from a clinician. Usual care is enhanced by providing clinicians in both arms with access to a Continuing Medical Education (CME) webinar about LCS and an LCS discussion guide. Patients complete surveys at baseline and 1-week after the scheduled clinic visit to assess quality of the SDM process. Re-navigation is attempted with TELESCOPE patients who have not completed the LDCT within 3 months. One month before being due for an annual screening, TELESCOPE patients whose initial LCS showed low-risk findings are randomly assigned to receive a telehealth decision coaching booster session with a navigator or no booster. Electronic health records are abstracted at 6, 12 and 18 months after the initial decision coaching session (TELESCOPE) or clinic visit (EUC) to assess initial and annual LCS uptake, imaging results, follow-up testing for abnormal findings, cancer diagnoses, treatment, and tobacco treatment referrals. This study will evaluate factors that facilitate or interfere with program implementation using mixed methods., Discussion: We will assess whether a decision coaching and patient navigation intervention can feasibly and effectively support high-quality SDM for LCS and guideline-concordant LCS uptake for patients in busy primary care practices serving diverse patient populations., Trial Registration: This study was registered at ClinicalTrials.gov (NCT05491213) on August 4, 2022., Protocol Version: Version 1, April 10, 2024., (© 2024. The Author(s).)

A new synthetic route to access the natural product phytocannabinoid cannabitwinol ( 1 ) starting from commercially available raw materials is disclosed. We have also demonstrated the synthesis of other related dimers, including their enantiomers, using the present sequence. This route avoids the legal constraints concerning the acquisition of cannabis plant material or CBD.

Background: We evaluated sociodemographic and clinical predictors of financial toxicity (FT) among patients with breast cancer with higher risk clinical factors warranting regional nodal irradiation (RNI)., Methods: Among 183 participants in a clinical trial of conventional vs. hypofractionated treatment with RNI, 125 (68 %) completed a pilot survey of FT measured using the validated Economic Strain and Resilience in Cancer (ENRICh) instrument, scored from 0 (minimal) to 10 (severe) FT. Associations with predictors were evaluated using Pearson correlation coefficients and Kruskal Wallis, Mann-Whitney U, and Jonckheere-Terpstra tests. Predictors of severe FT (ENRICh≥5) were tested using multivariable logistic regression with odds ratios converted to relative risks (RR)., Results: Of the sample, all received RNI, 92 % chemotherapy, 67 % axillary dissection, 26 % mastectomy without reconstruction, and 32 % mastectomy with reconstruction. At a median follow up of 1.48 years, median FT score was 2.13 (IQR 0.93-4.6), with 20.8 % of patients experiencing severe FT. Unadjusted worse FT score was associated with younger age (P = 0.003), Hispanic ethnicity (P = 0.006), lower income (P = 0.02), shorter interval from diagnosis to FT assessment (P = 0.02), and chemotherapy receipt (P = 0.05), but not with breast surgery type (P = 0.42), axillary surgery type (P = 0.33), or pathologic T (P = 0.68) or N stage (P = 0.47). In multivariable analysis, triple negative subtype was the sole clinical factor predicting severe FT (RR = 3.38; 95 % CI 1.48-4.99; P = 0.01)., Conclusion: Among patients with breast cancer receiving RNI, triple negative subtype was associated with severe FT, suggesting that tumor receptor subtype may help identify a key breast cancer subpopulation for early FT intervention., (Copyright © 2024. Published by Elsevier Ltd.)

We present two cases of cardiac metastases adjacent to the right ventricle in a 55-year-old male and a 61-year-old female, both treated with magnetic resonance (MR)-guided adaptive stereotactic radiation therapy (SBRT). The prescribed regimen was 30Gy delivered in 3 fractions using a 1.5 Tesla magnetic resonance linear accelerator (MR-linac). Patients exhibited favorable tolerance to the treatment, with no observed acute toxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Weng, Sobremonte, Lee, Hughes, Mohammedsaid, Zhao, Wang, Zhang, Niedzielski, Shete, Court, Liao, Lee and Yang.)

Background: Secondhand smoke exposure (SHSe) among youth is a serious public health concern, leading to an increased risk of conditions such as asthma and respiratory infections. However, there is little research on SHSe among vulnerable populations, such as racial and sexual minorities. Understanding the factors associated with youth SHSe in homes and vehicles is crucial to developing better protective policies., Methods: This study utilized 2020 data from the National Youth Tobacco Survey, a representative sample of middle- and high-school students in the US. The primary outcomes were youth SHSe at home and while riding in a vehicle. Multinomial regression models were used to assess factors associated with SHSe., Results: The data included 9,912 students enrolled in grades 6 through 12 in the United States who reported never using any form of tobacco. Non-Hispanic Black students living with someone who does not use any form of tobacco products were significantly more likely to experience moderate [OR = 2.1 (1.1-3.9), p  = 0.03] and severe [OR = 5.1 (2.2-11.7), p  < 0.001] secondhand smoke exposure (SHSe) in homes compared to their non-Hispanic White counterparts. Heterosexual female students had lower odds of reporting moderate SHSe in the home compared to heterosexual males [OR = 0.7 (0.6-0.99), p  = 0.02], whereas bisexual females had two-fold increased odds of severe SHSe in homes [OR = 2.0 (1.2-3.4), p  = 0.01]., Conclusion: Significant efforts are needed to develop targeted interventions to reduce SHSe in homes and vehicles, particularly in these vulnerable populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Talluri, Shete, Shastri and Shete.)

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis., Significance: The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention., (©2023 American Association for Cancer Research.)

Background: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored., Methods: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold., Results: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10 -15 ) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10 -46 ). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74)., Conclusions: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS., (© 2024. The Author(s).)

Purpose: Accurate and comprehensive segmentation of cardiac substructures is crucial for minimizing the risk of radiation-induced heart disease in lung cancer radiotherapy. We sought to develop and validate deep learning-based auto-segmentation models for cardiac substructures., Materials and Methods: Nineteen cardiac substructures (whole heart, 4 heart chambers, 6 great vessels, 4 valves, and 4 coronary arteries) in 100 patients treated for non-small cell lung cancer were manually delineated by two radiation oncologists. The valves and coronary arteries were delineated as planning risk volumes. An nnU-Net auto-segmentation model was trained, validated, and tested on this dataset with a split ratio of 75:5:20. The auto-segmented contours were evaluated by comparing them with manually drawn contours in terms of Dice similarity coefficient (DSC) and dose metrics extracted from clinical plans. An independent dataset of 42 patients was used for subjective evaluation of the auto-segmentation model by 4 physicians., Results: The average DSCs were 0.95 (+/- 0.01) for the whole heart, 0.91 (+/- 0.02) for 4 chambers, 0.86 (+/- 0.09) for 6 great vessels, 0.81 (+/- 0.09) for 4 valves, and 0.60 (+/- 0.14) for 4 coronary arteries. The average absolute errors in mean/max doses to all substructures were 1.04 (+/- 1.99) Gy and 2.20 (+/- 4.37) Gy. The subjective evaluation revealed that 94% of the auto-segmented contours were clinically acceptable., Conclusion: We demonstrated the effectiveness of our nnU-Net model for delineating cardiac substructures, including coronary arteries. Our results indicate that this model has promise for studies regarding radiation dose to cardiac substructures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Actinic keratoses (AK) are common premalignant skin lesions with a small risk of progressing to cutaneous squamous cell carcinoma (SCC). There is some evidence that patients with AKs also have increased risks of other skin cancers beyond SCC. However, the absolute risks of skin cancer in patients with AKs are unknown., Objective: To calculate the absolute and relative risks of future skin cancer in Medicare beneficiaries with AKs., Design, Setting, and Participants: This retrospective cohort study was performed using a deidentified, random sample of 4 999 999 fee-for-service Medicare beneficiaries from 2009 through 2018. Patients with treated AKs were included, and patients with seborrheic keratoses (SKs) were included as a comparator group. All patients were required to have at least 1 year between data set entry and first AK or SK. Patients with a history of skin cancer were excluded. Data were analyzed from September 2022 to March 2023., Main Outcomes and Measures: Outcomes were first surgically treated skin cancer, including keratinocyte carcinoma (including SCC and basal cell carcinoma [BCC]) and melanoma. The absolute risks of skin cancer in patients with AKs were evaluated. Skin cancer risks in patients with AKs were compared with patients with SKs using adjusted competing risks regression., Results: A total of 555 945 patients with AKs (mean [SD] age, 74.0 [7.4] years; 55.4% female) and 481 024 patients with SKs (mean [SD] age, 73.3 [7.3] years; 72.4% female) were included. The absolute risk of skin cancer after a first AK was 6.3% (95% CI, 6.3%-6.4%) at 1 year, 18.4% (95% CI, 18.3%-18.5%) at 3 years, and 28.5% (95% CI, 28.4%-28.7%) at 5 years. Patients with AKs had increased risk of skin cancer compared with patients with SKs (any skin cancer: adjusted hazard ratio [aHR], 2.17; 95% CI, 2.15-2.19; keratinocyte carcinoma: aHR, 2.20; 95% CI, 2.18-2.22; SCC: aHR, 2.63; 95% CI, 2.59-2.66; BCC: aHR, 1.85; 95% CI, 1.82-1.87; and melanoma: aHR, 1.67; 95% CI, 1.60-1.73)., Conclusions and Relevance: In this cohort study, older patients with AKs had substantial absolute risks, as well as elevated relative risks, of skin cancer. AKs may be clinical markers of UV exposure and increased skin cancer risk, including SCC, BCC, and melanoma. However, guidelines are lacking for follow-up skin cancer surveillance in patients with AKs. Efforts to develop evidence-based recommendations for skin cancer surveillance in patients with AKs are paramount.

Synthesis and biological evaluation of silicon-incorporated phytocannabinoids with improved pharmacological properties toward inflammatory diseases are described. The synthesized sila-analogues 15a , 15b , and 15c displayed potent inhibition of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6 at 10 μM. Further, the release of heme during the lysis of red blood cells in hemolytic diseases is one of the major reasons for inflammation associated with the pathophysiology of these diseases. Due to scanty literature related to inhibitors of heme-mediated induction of the NLRP3 inflammasome, we decided to test these compounds against it. Compounds 15a and 15c significantly inhibited the heme-mediated induction of the NLRP3 inflammasome at a concentration of 0.1 μM. Interestingly, the sila-CBD derivatives also showed higher metabolic stability in contrast to their carbon analogues. Anti-NLRP3 inflammasome activity of compounds 15a and 15c were further validated in vivo against heme-mediated peritoneal inflammation. The anti-inflammatory activity of these compounds could be useful in treating diseases such as sickle cell anemia and thalassemia involving the hemolysis-mediated activation of the NLRP3 inflammasome., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival., Methods: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival., Findings: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions., Interpretation: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time., Funding: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer., Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls., Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events., Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer., (Copyright © 2023. Published by Elsevier Inc.)

Background: Financial toxicity (FT) reflects multi-dimensional personal economic hardships borne by cancer patients. It is unknown whether measures of FT-to date derived largely from English-speakers-adequately capture economic experiences and financial hardships of medically underserved low English proficiency US Hispanic cancer patients. We piloted a Spanish language FT instrument in this population., Methods: We piloted a Spanish version of the Economic Strain and Resilience in Cancer (ENRICh) FT measure using qualitative cognitive interviews and surveys in un-/under-insured or medically underserved, low English proficiency, Spanish-speaking Hispanics (UN-Spanish, n  = 23) receiving ambulatory oncology care at a public healthcare safety net hospital in the Houston metropolitan area. Exploratory analyses compared ENRICh FT scores amongst the UN-Spanish group to: (1) un-/under-insured English-speaking Hispanics (UN-English, n  = 23) from the same public facility and (2) insured English-speaking Hispanics (INS-English, n  = 31) from an academic comprehensive cancer center. Multivariable logistic models compared the outcome of severe FT (score > 6)., Results: UN-Spanish Hispanic participants reported high acceptability of the instrument (only 0% responded that the instrument was "very difficult to answer" and 4% that it was "very difficult to understand the questions"; 8% responded that it was "very difficult to remember resources used" and 8% that it was "very difficult to remember the burdens experienced"; and 4% responded that it was "very uncomfortable to respond"). Internal consistency of the FT measure was high (Cronbach's α  = 0.906). In qualitative responses, UN-Spanish Hispanics frequently identified a total lack of credit, savings, or income and food insecurity as aspects contributing to FT. UN-Spanish and UN-English Hispanic patients were younger, had lower education and income, resided in socioeconomically deprived neighborhoods and had more advanced cancer vs. INS-English Hispanics. There was a higher likelihood of severe FT in UN-Spanish (OR = 2.73, 95% CI 0.77-9.70; p  = 0.12) and UN-English (OR = 4.13, 95% CI 1.13-15.12; p  = 0.03) vs. INS-English Hispanics. A higher likelihood of severely depleted FT coping resources occurred in UN-Spanish (OR = 4.00, 95% CI 1.07-14.92; p  = 0.04) and UN-English (OR = 5.73, 95% CI 1.49-22.1; p  = 0.01) vs. INS-English. The likelihood of FT did not differ between UN-Spanish and UN-English in both models ( p  = 0.59 and p  = 0.62 respectively)., Conclusion: In medically underserved, uninsured Hispanic patients with cancer, comprehensive Spanish-language FT assessment in low English proficiency participants was feasible, acceptable, and internally consistent. Future studies employing tailored FT assessment and intervention should encompass the key privations and hardships in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shi, McGinnis, Peterson, Taku, Chen, Yu, Wu, Mendoza, Shete, Ma, Volk, Giordano, Shih, Nguyen, Kaiser and Smith.)

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Patients eligible for lung cancer screening (LCS) are those at high risk of lung cancer due to their smoking histories and age. While screening for LCS is effective in lowering lung cancer mortality, primary care providers are challenged to meet beneficiary eligibility for LCS from the Centers for Medicare & Medicaid Services, including a patient counseling and shared decision-making (SDM) visit with the use of patient decision aid(s) prior to screening., Methods: We will use an effectiveness-implementation type I hybrid design to: 1) identify effective, scalable smoking cessation counseling and SDM interventions that are consistent with recommendations, can be delivered on the same platform, and are implemented in real-world clinical settings; 2) examine barriers and facilitators of implementing the two approaches to delivering smoking cessation and SDM for LCS; and 3) determine the economic implications of implementation by assessing the healthcare resources required to increase smoking cessation for the two approaches by delivering smoking cessation within the context of LCS. Providers from different healthcare organizations will be randomized to usual care (providers delivering smoking cessation and SDM on site) vs. centralized care (smoking cessation and SDM delivered remotely by trained counselors). The primary trial outcomes will include smoking abstinence at 12-weeks and knowledge about LCS measured at 1-week after baseline., Conclusion: This study will provide important new evidence about the effectiveness and feasibility of a novel care delivery model for addressing the leading cause of lung cancer deaths and supporting high-quality decisions about LCS., Gov Protocol Registration: NCT04200534 TRIAL REGISTRATION: ClinicalTrials.govNCT04200534., Competing Interests: Declaration of Competing Interest Dr. Cinciripini served on the scientific advisory board of Pfizer Pharmaceuticals, conducted educational talks sponsored by Pfizer on smoking cessation (2006–2008), and has received grant support from Pfizer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: We explored the association of respiratory and cardiometabolic comorbidities with NSCLC overall survival (OS) and lung cancer-specific survival (LCSS), by stage, in a large, multicontinent NSCLC pooled data set., Methods: On the basis of patients pooled from 11 International Lung Cancer Consortium studies with available respiratory and cardiometabolic comorbidity data, adjusted hazard ratios (aHRs) were estimated using Cox models for OS. LCSS was evaluated using competing risk Grey and Fine models and cumulative incidence functions. Logistic regression (adjusted OR [aOR]) was applied to assess factors associated with surgical resection., Results: OS analyses used patients with NSCLC with respiratory health or cardiometabolic health data (N = 16,354); a subset (n = 11,614) contributed to LCSS analyses. In stages I to IIIA NSCLC, patients with respiratory comorbidities had worse LCCS (stage IA aHR = 1.51, confidence interval [CI]: 1.17-1.95; stages IB-IIIA aHR = 1.20, CI: 1.06-1.036). In contrast, patients with stages I to IIIA NSCLC with cardiometabolic comorbidities had a higher risk of death from competing (non-NSCLC) causes (stage IA aHR = 1.34, CI: 1.12-1.69). The presence of respiratory comorbidities was inversely associated with having surgical resection (stage IA aOR = 0.54, CI: 0.35-0.83; stages IB-IIIA aOR = 0.57, CI: 0.46-0.70)., Conclusions: The presence of either cardiometabolic or respiratory comorbidities is associated with worse OS in stages I to III NSCLC. Patients with respiratory comorbidities were less likely to undergo surgery and had worse LCSS, whereas patients with cardiometabolic comorbidities had a higher risk of death from competing causes. As more treatment options for stages I to III NSCLC are introduced into the practice, accounting for cardiometabolic and respiratory comorbidities becomes essential in trial interpretation and clinical management., (Copyright © 2022. Published by Elsevier Inc.)

Amid subpar uptake of HPV vaccination in the United States, gender-generated disparities in HPV vaccination uptake have the potential to perpetuate existing disparities in HPV-associated cancers. Yet few studies have investigated the influence of parent-child gender on intentions to refuse HPV vaccination due to safety concerns/side effects. This study used nationally representative data, spanning 2010-2019, from the National Immunization Survey-Teen (NIS-Teen). NIS-Teen respondents are parents/guardians or primary caregivers of adolescents 13-17 years old living in the United States. Over the study period, intentions to refuse HPV vaccination due to safety concerns rose among all parent-child gender pairings but were highest among respondent mothers regarding their unvaccinated daughters. The results revealed a statistically significant increased likelihood of having intentions to refuse HPV vaccination due to safety concerns among all parent-child combinations compared with father-son pairs. These odds were consistently highest among mother-daughter pairs. In 2019, compared with father-son pairs, fathers were 1.94 (95% CI: 1.21-3.12) times more likely to report the intention to not vaccinate against HPV for their daughters, while mothers were 2.23 (95% CI: 1.57-3.17) and 2.87 (95% CI: 2.02-4.09) times more likely to report intentions to refuse HPV vaccination for their sons and daughters, respectively. These findings were persistent and constantly increased over the 10-year study period. Interventions aimed at correcting gender-based misperceptions and countering misinformation about the safety of the HPV vaccine are warranted.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC)., Methods: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers., Results: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828 C6orf10 and rs204999 PRRT1 , OR interaction  = 1.17, p = 6.57 × 10 -13 ; rs3135369 BTNL2 and rs2858859 HLA-DQA1 , OR interaction  = 1.17, p = 2.43 × 10 -13 ; rs2858859 HLA-DQA1 and rs9275572 HLA-DQA2 , OR interaction  = 1.15, p = 2.84 × 10 -13 ; rs2853668 TERT and rs62329694 CLPTM1L , OR interaction  = 0.73, p = 2.70 × 10 -13 ). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828 C6orf10 and rs204999 PRRT1 , OR interaction  = 1.13, p = 0.008; rs3135369 BTNL2 and rs2858859 HLA-DQA1 , OR interaction  = 1.11, p = 5.23 × 10 -4 ; rs3135369 BTNL2 and rs9271300 HLA-DQA1 , OR interaction  = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification., Conclusions: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility., Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent., Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups., Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR  = 1.20; 95% CI 1.13-1.27; p  = 5.6 × 10 -10 ) and never smokers (e.g., maker rs1133683 Axin2; OR  = 1.27; 95% CI 1.19-1.35; p  = 1.0 × 10 -12 ). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants., Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers., (© 2022. The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs., Methods: We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10 -3 ), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster., Results: A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10 -4 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases., Conclusion: Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 -4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR MVMR = 1.28, 95% CI = 1.06-1.55, P MVMR = .011), and an inverse effect on lung adenocarcinoma (OR MVMR = 0.86, 95% CI = 0.77-0.96, P MVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR UVMR = 1.19, 95% CI = 1.01-1.40, P UVMR = .036), but this effect disappeared after adjustment of smoking (OR MVMR = 1.02, 95% CI = 0.90-1.16, P MVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer., (© 2020 UICC.)

Background: Approximately one third of needle biopsies that are performed to rule out malignancy of indeterminate pulmonary nodules detected radiologically during lung cancer screening are negative, thus exposing cancer-free patients to risks of pneumothorax, bleeding, and infection. A noninvasive confirmatory tool (eg, liquid biopsy) is urgently needed in the lung cancer diagnosis setting to stratify patients who should receive biopsy versus those who should be monitored., Methods: A novel antigen-independent, 4-color fluorescence in situ hybridization (FISH)-based method was developed to detect circulating tumor cells (CTCs) with abnormalities in gene copy numbers in mononuclear cell-enriched peripheral blood samples from patients with (n = 107) and without (n = 100) lung cancer., Results: Identification of CTCs using FISH probes at 10q22.3/CEP10 and 3p22.1/3q29 detected lung cancer cases with 94.2% accuracy, 89% sensitivity, and 100% specificity compared with biopsy., Conclusion: The high accuracy of this liquid biopsy method suggests that it may be used as a noninvasive decision tool to reduce the frequency of unnecessary needle biopsy in patients with benign pulmonary lesions., (© 2020 American Cancer Society.)

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV 1 : r g  = 0.098, p = 2.3 × 10 -8 ) and the ratio of FEV 1 to forced vital capacity (FEV 1 /FVC: r g  = 0.137, p = 2.0 × 10 -12 ). Mendelian randomization analyses demonstrate that reduced FEV 1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV 1 /FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

Cigarette smoking is the leading preventable cause of death in the United States; smoking in Mexican American adolescents, a rapidly growing population, remains a major concern. Factors associated with escalation or progression along the smoking trajectory have not been studied in adolescent Mexican Americans. A better understanding of escalation is needed for cancer prevention and overall health. N=1,328 Mexican American adolescents joined a cohort in 2005-06. At baseline participants provided demographic, acculturation and psychosocial data, and reported their smoking status using the Minnesota Smoking Index. Those that never tried a cigarette or only had a few puffs in their life were included in this study. The primary outcome of interest, escalation in smoking status, was defined as moving up the Minnesota Smoking Index by 2010-2011. The current analysis is based on 973 participants of whom 48.2% were male, mean age=11.8 (SD=0.8), and 26.0% were born in Mexico. By 2010-2011, 283 (29%) escalated their smoking status and 690 (71%) remained the same. Being older (OR=1.30; CI=1.07-1.57), male (OR=1.88, CI=1.40-2.53), having higher levels of anxiety (OR=1.03, CI=1.02-1.05), intending to smoke (OR=1.70, CI=1.18-2.46), having friends who smoke (OR=1.73, CI=1.12-2.70) and having parents' friends who smoke (OR=1.38, CI=1.02-1.88) increased risk for smoking escalation. Higher levels of subjective social status (OR=0.91, CI=0.83-0.99) were protective against smoking escalation. Contrasting previous work in smoking experimentation, parents' friends influence was a stronger predictor than the family household influence. Preventative interventions for Mexican American youth could address this risk factor to reduce smoking escalation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Treatments for head and neck squamous cell carcinoma (HNSCC) are associated with toxicities that lead to emergency department presentation., Methods: We utilized data from an ongoing prospective cohort of newly diagnosed, previously untreated patients (N = 298) with HNSCC to evaluate the association between clinical and epidemiologic factors and risk for and frequency of emergency department presentation. Time to event was calculated from the date of treatment initiation to emergency department presentation, date of death, or current date. Frequency of emergency department presentation was the sum of emergency department visits during the follow-up time., Results: History of hypertension, normal/underweight body mass index (BMI), and probable depression predicted increased risk for emergency department presentation. BMI and severe pain were associated with higher frequency of emergency department presentations., Conclusion: Clinical and epidemiologic factors can help predict patients with HNSCC who will present to the emergency department. Such knowledge may improve treatment-related patient outcomes and quality of life. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1195-1204, 2017., (© 2017 Wiley Periodicals, Inc.)

Background: This study investigated the prevalence of and risk factors for oral human papillomavirus (HPV) infection with multiple genotypes in the United States., Methods: Data were from the nationally representative 2009-2012 National Health and Nutrition Examination Survey. This analysis comprised 9257 participants for whom data on oral HPV (37 genotypes) and associated risk factors were available., Results: The weighted prevalence of multitype (2-6 types) oral HPV infection was 1.5% (2.5% for men, 0.4% for women) in the whole sample and 19.7% (22.0% for men, 12.1% for women) in those who had any type of oral HPV positivity. Most multitype oral HPV cases (83.8%) harbored one or more oncogenic types. In the adjusted multinominal logistic regression model, being male (relative risk ratio [RRR] = 3.69; 95% confidence interval [CI], 1.57-8.65), being a current cigarette smoker (RRR = 2.57; 95% CI, 1.23-5.36), and having a new sex partner in the past year (RRR = 2.10; 95% CI, 1.03-4.28) were associated with an increased risk of multitype oral HPV infection over single-type HPV infection., Conclusions: Men, smokers, and those who had new sexual partners were at a significantly higher risk for multitype oral HPV infection.

The very few studies that have examined the association between vaginal douching and genital human papillomavirus (HPV) infection have found contrary results. We investigated the associations between douching and numbers of HPV genotypes infecting 1271 participants aged 20-49 years in the 2003-2004 US National Health and Nutrition Examination Survey. After controlling for relevant covariates, douching in the past 6 months was significantly associated with infection by higher numbers of all genital HPV types (relative risk ratio, 1.26; 95% confidence interval, 1.03-1.54) and HPV high-risk types (1.40; 1.09-1.80)., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Introduction: Sunburns during childhood increase melanoma risk. Children of melanoma survivors are at higher risk, but little is known about their sunburn and sun protection. One study showed that almost half of melanoma survivors' children experienced sunburn in the past year. This study evaluated sunburn and sun protection in melanoma survivors' children, and relevant survivor characteristics from Social Cognitive Theory and the Health Belief Model., Methods: Melanoma survivors (N=340) were recruited from a comprehensive cancer center. Survivors completed a baseline questionnaire administered by telephone to report on the behavior of their children (N=340) as part of an RCT of a sun protection intervention. Data were collected in 2008 and analyzed in 2015., Results: In the prior 6 months, 28% of children experienced sunburn. "Always" or "frequent" sun protection varied by behavior: sunscreen, 69%; lip balm, 15%; wide-brimmed hats, 9%; sleeved shirts, 28%; pants, 48%; sunglasses, 10%; shade, 33%; and limiting time outdoors, 45%. Survivors' sunburn and sun protection were positively associated with these outcomes in children. Correlates of sunburn also included older child age and higher risk perceptions. Correlates of sun protection behaviors included younger child age; stronger intentions, higher self-efficacy, and more positive outcome expectations about sun protection; and greater number of melanomas in survivors., Conclusions: Melanoma survivors may have a heightened awareness of the importance of their children's sun protection, but their children are not routinely protected. Correlates of children's sunburn and sun protection suggest subgroups of survivors to target with interventions to improve sun protection., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects., (© 2015 Wiley Periodicals, Inc.)

Unlabelled: Survival outcomes in patients with squamous cell carcinoma of the head and neck (HNSCC) vary by extent of disease, behavioral factors, and socioeconomic factors. We assessed the extent to which pretreatment pain influences survival in 2,340 newly diagnosed patients with HNSCC, adjusting for disease stage, symptoms, pain medications, comorbidities, smoking, alcohol consumption, age, sex, and race/ethnicity. Patients rated their pain at presentation to the cancer center (0 = "no pain" and 10 = "pain as bad as you can imagine"). Survival time was calculated from the date of diagnosis to the date of death of any cause or last follow-up. Five-year overall survival was calculated for all the variables assessed in the study. Severe pain (≥7) was most prevalent among those with oral cancer (20.4%; pharynx = 18.8%; larynx = 16.1%) and significantly varied by tumor stage, fatigue severity, smoking status, comorbid lung disease, and race (all P < .05) across cancer diagnoses. Overall 5-year survival varied by pain for oral (severe pain = 31% vs nonsevere pain = 52%; P < .001) and pharyngeal cancer (severe pain = 33% vs nonsevere pain = 53%; P < .001). Multivariable analyses showed that pain persisted as an independent prognostic factor for survival. Pain reported prior to treatment should be considered in understanding survival outcomes in HNSCC patients., Perspective: Pretreatment pain was an independent predictor of survival in a large sample of HNSCC patients even after accounting for tumor node metastasis stage, fatigue, age, race/ethnicity, smoking, and alcohol intake. Therefore, symptoms at presentation and before cancer treatment are important factors to be considered in understanding survival outcomes in HNSCC patients., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: We studied whether a melanoma survivor-centered intervention was more effective than materials available to the general public in increasing children's sun protection., Methods: In a randomized controlled trial, melanoma survivors (n = 340) who had a child ≤ 12 years received a targeted sun protection intervention (DVD and booklets) or standard education. Primary outcomes were children's sunburns, children's sun protection, and survivors' psychosocial factors at baseline and postintervention (1 and 4 months)., Results: The intervention increased children's sunscreen reapplication at 1 month (P = 0.002) and use of wide-brimmed hats at 4 months (P = 0.045). There were no effects on other behaviors or sunburns. The intervention improved survivors' hats/clothing self-efficacy at both follow-up assessments (P = 0.026, 0.009). At 4 months, the intervention improved survivors' clothing intentions (P = 0.029), knowledge (P = 0.010), and outcome expectations for hats (P = 0.002) and clothing (P = 0.037). Children's sun protection increased with survivors' intervention use. The intervention was less effective in survivors who were female or who had a family history, older children, or children with higher baseline sun protection scores., Conclusions: A melanoma survivor-centered sun protection intervention can improve some child and survivor outcomes. The intervention may be more effective in survivors who have younger children or less experience with sun protection. Intervention delivery must be enhanced to maximize use., Impact: This is the first study to examine a sun protection intervention for children of melanoma survivors. Findings will guide interventions for this important population at increased melanoma risk.

A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS-) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS- group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS- group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments., (© 2012 Wiley Periodicals, Inc.)

Background: Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease., Methods and Results: A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene., Conclusions: Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.

A variety of changes in placental villi are known to occur in Pregnancy Induced Hypertension. In this study an attempt is made to study 49 placentae from PIH and its correlation to perinatal outcome. Quantification of villous lesions was carried out. The striking villious changes were cytotrophoblastic proliferation, paucity of vasculosyncytial membrane, trophoblastic basement membrane thickening and fibrinoid necrosis of villi. The changes were directly proportional to the severity of disease and perinatal outcome was worse with advancing grades of PIH.

Kasabach-Meritt syndrome is a combination of thromobocytopenia, hemolytic anemia, and acute or chronic consumptive coagulopathy in association with rapidly enlarging hemangioma. A male infant of 5 days was admitted in paediatric ward with this syndrome. The baby had ecchymotic patches over face and extremities and bleeding through umbilical stump. The child expired due to severe thrombocytopenia with consumptive coagulopathy leading to precipituous hemorrhage superimposed by septicemia. An autopsy was performed which confirmed retroperitoneal lesion as kaposiform hemangioendothelioma.

Background: Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome., Methods and Results: Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus., Conclusions: A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.

Reconstructing a physical map of a chromosome from a genomic library presents a central computational problem in genetics. Physical map reconstruction in the presence of errors is a problem of high computational complexity that provides the motivation for parallel computing. Parallelization strategies for a maximum-likelihood estimation-based approach to physical map reconstruction are presented. The estimation procedure entails a gradient descent search for determining the optimal spacings between probes for a given probe ordering. The optimal probe ordering is determined using a stochastic optimization algorithm such as simulated annealing or microcanonical annealing. A two-level parallelization strategy is proposed wherein the gradient descent search is parallelized at the lower level and the stochastic optimization algorithm is simultaneously parallelized at the higher level. Implementation and experimental results on a distributed-memory multiprocessor cluster running the parallel virtual machine (PVM) environment are presented using simulated and real hybridization data.

The variance component method has become popular for linkage analysis due to its computational simplicity and generally high power. In this paper we model phenotypic variability of an individual as a mixed effects model in which both the major gene as well as the polygene effects interact with age. We applied the proposed model to the simulated data of Genetic Analysis Workshop 12. We considered the quantitative trait, Q4, in the outbred population. Two major genes influence this trait, each interacting with age independently. Consequently, trait variability is a function of age and also there is interaction of major gene effects with age. By using our model we were able to detect interaction between the major gene effects and age for this trait.