Female Lung Research Articles

Non-Genotoxic and Environmentally Relevant Lower Molecular Weight Polycyclic Aromatic Hydrocarbons Significantly Increase Tumorigenicity of Benzo[a]pyrene in a Lung Two-Stage Mouse Model

The World Health Organization has classified air pollution as a carcinogen, and polycyclic aromatic hydrocarbons (PAHs) are major components of air particulates of carcinogenic concern. Thus far, most studies focused on genotoxic high molecular weight PAHs; however, recent studies indicate potential carcinogenicity of the non-genotoxic lower molecular weight PAHs (LMW PAHs) that are found in indoor and outdoor air pollution as well as secondhand cigarette smoke. We hypothesize that LMW PAHs contribute to the promotion stage of cancer when combined with benzo[a]pyrene (B[a]P), a legacy PAH. We specifically determined the effects of an LMW PAH mixture containing 1-methylanthracene (1MeA), fluoranthene (Flthn), and phenanthrene (Phe) combined with B[a]P on lung tumor promotion. To test this hypothesis, we used a two-stage, initiation/promotion BALB/ByJ female lung tumor mouse model. The mice were initiated with 3-methylcholanthrene followed by exposures to B[a]P, the LMW PAH mixture, and the combination of the LMW PAH mixture plus B[a]P, all at 10 mg/kg. The LMW PAHs combined with B[a]P significantly increased the promotion and incidence of lung tumors over that of B[a]P alone. The LMW PAHs in the absence of B[a]P did not significantly promote tumors, indicating strong co-promotional activities. We further assessed the effects of these PAHs on other hallmarks of cancer, namely, bronchoalveolar lavage fluid inflammatory infiltrates, pro-inflammatory transcripts, KC protein content, and mRNA expression of the gap junction (Gja1) and epiregulin (Ereg) genes. The LMW PAHs increased the biomarkers of inflammation, decreased Gja1 expression, and increased Ereg expression, all consistent with tumor promotion. This study indicates that non-genotoxic LMW PAHs can contribute to the cancer process and warrants further studies to assess the carcinogenic risks of other LMW PAHs.

Non-Invasive Detection of Lung Cancer: Integrating Genomic Data with Ensemble Learning for Improved Early Diagnosis

The early and accurate diagnosis of lung cancer, a significant contributor to global cancer-related mortality, remains a paramount challenge in healthcare. Conventional diagnostic methods often lack the sensitivity required for early-stage detection, prompting the exploration of non-invasive alternatives. Leveraging advancements in genomics and bioinformatics, this study investigates the potential of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) analysis for early-stage lung cancer diagnosis. Two distinct datasets are utilized: GSE4115, comprising gene expression data from bronchial airway epithelial cells of smokers, and GSE33356, focusing on genomic alterations in Taiwanese female non-smoking lung cancer patients. The research employs comprehensive data pre-processing and feature reduction techniques, including normalization and Kernel Principal Component Analysis (KPCA). Subsequently, an ensemble of diverse learners, including Random Forests, AdaBoost, Bagging, Support Vector Machines (SVMs), and Neural Networks, is trained on the original datasets. A novel ensemble stacking approach is proposed, wherein initial predictions from the base learners are combined through logistic regression - the meta-learner to enhance predictive performance. The study aims to contribute to advancements in lung cancer detection by providing a more precise and non-invasive diagnostic method. By integrating DNA and RNA analysis with ensemble learning techniques, the research endeavours to enhance medical outcomes and potentially save lives through early-stage lung cancer detection.

Sex-specific NLRP3 activation in neutrophils promotes neutrophil recruitment and NETosis in the murine model of diffuse alveolar hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus and small vessel vasculitis. We previously showed that neutrophil extracellular traps (NETs) were associated with the pathogenesis of pristane-induced DAH and demonstrated that neutrophil NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly participated in NET generation under sterile stimulation. We investigated whether NLRP3 inflammasome assembly in neutrophils may drive pulmonary NETosis in a mouse model of pristane-induced DAH. C57BL/6J mice received a single intraperitoneal injection of 0.5mL of pristane. Neutrophil NLRP3 inflammasome assembly and NETs were characterized by immunofluorescence staining of apoptosis-associated speck-like protein a CARD (ASC), co-staining of DNA, and citrullinated histones, respectively. Clinical status of mice was assessed 11 days after pristane injection by measurement of arterial oxygen saturation and of weight loss; severity of lung injury was determined using a quantification score from hematoxylin-eosin-stained slides. Pristane induced ASC speck formation in neutrophils and we confirmed that NLRP3 inflammasome was involved in NET generation after pristane stimulation in vitro. NLRP3 deficiency reduced the severity of pristane-induced DAH in female, but not male mice. Interestingly, NLRP3 deficiency reduced the number of neutrophils and NETs in the lungs of females compared to males. Our results suggest a link between female sex-specific NLRP3 inflammasome activation and subsequent pulmonary NETosis in the development of pristane-induced DAH. Therefore, we identified NLRP3 inflammasome as a potential new therapeutic target in this severe complication of pro-female autoimmune disease for which specific inhibitors of NLRP3 are currently developed.

Abstract 4144559: Sex Differences in Vascular Remodeling in Pulmonary Hypertension are mediated by Endothelin-2

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial vascular remodelingleading to increased pulmonary artery pressure causing right ventricular hypertrophy, failure anddeath. The incidence of PAH is much higher in female patients, indicating that males may have aprotective factor that could help elucidate the pathogenesis of PAH. We have recently demonstratedthat the Y chromosome gene UTY protects against PH development in mice, however the fulldownstream mechanisms remains unknown. By integrating RNA-Seq on whole lung tissues fromUty-KO and WT male mice with a publically available male and female PAH lung microarraydataset, we found increased expression of Endothelin 2 (ET-2) in the lungs of Uty-KO compared toWT mice with PH as well as in the lungs of female patients compared to males with PAH. The roleof ET-1 is known in PAH, and Endothelin receptor antagonists are a common PAH therapy to whichfemale patients are more responsive. However, ET-2 has yet to be investigated in this context. Wevalidated that ET-2 expression is significantly increased in lung tissue from PAH female patientscompared to males. Plasma ET-2 concentration is also significantly higher in PAH patients versuscontrols. Interestingly, plasma ET-2 negatively correlates with pulmonary vascular resistance (PVR)and mean pulmonary arterial pressure (mPAP) in male PAH patients, whereas plasma ET-2significantly positively correlates with PVR and mPAP in female PAH patients. Functionally, wefound that recombinant ET-2 significantly inhibits proliferation of male pulmonary artery endothelialcells (PAECs), but significantly promotes proliferation in female PAECs. Similarly, ET-2 significantlyincreased proliferation of female pulmonary artery smooth muscle cells (PASMC), but not malePASMC. Together, we show that increased ET-2 expression may contribute to worsening PH bypromoting vascular remodeling in the lung and that elevated ET2 in females may at least partiallyexplain the higher incidence of female PAH patients

Disparities in overall and site-specific cancer mortality among immigrant generations in Sweden: A nationwide follow-up study over three decades.

We examined the overall and site-specific cancer mortality disparities among first-generation - separately in adults (G1) and children (G1.5) at immigration - and second-generation (G2) immigrants and their countries of origin using population-based registries in Sweden, encompassing over 8.5 million individuals aged 20 and above residing in Sweden since 1990, with follow-up until December 31, 2023. Cox proportional hazard models were fitted, stratified by gender, to estimate hazard ratios and 95% confidence intervals compared to natives. Mortality rates for most cancers transitioned from lower in G1 towards the rate of natives in G2. However, elevated mortality rates were sustained across generations for liver cancer in males and stomach cancer in females. Among G2, mortality from lymphohematopoietic cancers in males, and lung and cervix uteri cancers in females were elevated - by 10%, 9%, and 17% respectively compared to natives. Country of origin analyses revealed substantial disparities. For instance, G2 females with Nordic parental origin had a 13% higher risk of death from lung cancer, while those with non-Western parental origin had a 54% lower risk as compared to natives. These findings suggest a generational and arrival-age dynamics of cancer mortality and highlight target groups for cancer prevention and control among immigrants.

Biological Sex Is an Effect Modifier of Allergen-Mediated Alteration of the Lung Proteome.

Asthma exhibits a distinct sex bias in the disease prevalence, severity, and response to therapy. However, sex-related differences in alterations of the lung proteome mediated by aeroallergens critical in asthma, such as house dust mites (HDM), remain unknown. In this study, we define sex-related differences in the lung proteome using an HDM-challenged mouse model by 1D LC-MS/MS. Sex-disaggregated data analysis showed that 406 proteins were uniquely altered in females, 273 proteins were uniquely altered in males, and 414 proteins were altered in both females and males in response to HDM. In a linear mixed model analysis, sex modified the HDM exposure effect for 163 proteins, i.e., a significant sex:exposure interaction was identified in 84 proteins in females and 35 proteins in males. Of these, 12 proteins showed a significant sex effect in both female and male lungs. We further selected 3 proteins Tjp1, Lamtor1, and G3BP2 for independent confirmation studies. Our findings detail the sex-specific lung proteome in response to an aeroallergen critical in asthma and demonstrate that sex is a significant effect modifier of HDM response. These results will serve as a valuable resource for delineating sex-specific mechanisms in aeroallergen-driven responses in asthma research.

Estimation of Radiation Equivalent Dose and Lifetime Attributable Risk from Pediatric CAP CT Examination

Aim: This study aims to estimate equivalent doses (EqDs) and life attributable risks (LARs) for pediatric patients who underwent chest–abdominal–pelvic (CAP) CT examinations in Madinah, Saudi Arabia. Methodology: This retrospective study collected data from 120 pediatric patients who underwent CAP CT examinations. The data were categorized by the age and gender of the pediatric patients. Then, the EqDs were computed using the NCICT (National Cancer Institute dosimetry system for computed tomography) program, and LARs were estimated from the equivalent dose (EqD) results using age- and gender-specific cancer risk models found in the Committee on the Biological Effects of Ionizing Radiation (BEIR) VII Phase 2 (2006). Results: The EqD range was 0.9 to 7.55 mSv for the prostate and colon (males and females), respectively. LARs for female breast and lung cancers were considered to have the highest values among the age groups. Nevertheless, LARs of the colon, liver, and leukemia cancers were higher for males than females. The LAR range of cancer incidence was 0.6 to 63.1 per 100,000 cases for prostate (aged 10–≤15 years) and breast (females aged 1≤–<5 years), respectively. The LAR range of cancer mortality was 0.1 to 41.9 per 100,000 cases for prostate (aged 10–≤15 years) and lung (females aged 1≤–<5 years). Conclusions: LARs of all cancer incidence and mortality from CAP CT examination were higher for pediatric females than males (with an average of 54%). This highlights the importance of considering pediatric patient gender and implementing optimization and protective measures in CAP CT examinations. LARs of breast and lung (for females) and colon (for males) cancers were found to have the highest values among the age groups. However, LARs of cancer incidence and mortality for colon, liver, and leukemia for males were higher than those for females.

Changes in cancer diagnoses and stage distribution during the second year of the COVID-19 pandemic in the US.

130 Background: During 2020, the first year of the COVID-19 pandemic, cancer diagnoses decreased, especially early-stage disease, with largest decreases in medically underserved populations. It is unknown whether this pattern continued during 2021, the second year of the COVID-19 pandemic. With newly released cancer surveillance data, this study examined nationwide changes in adult cancer diagnoses and stage distribution from 2019 to 2021 in the US. Methods: Adults aged ≥18 years who were newly diagnosed with first primary malignant cancers between 2019 and 2021 from 50 US states and the District of Colombia were identified from the National Cancer Database. We calculated monthly cases, stage distribution, and adjusted odds ratios (aOR) of stage I vs. stage II–IV cancer and stage IV vs. stage I–III cancer diagnoses in 2021 compared with 2019, controlling for sociodemographic and clinical factors and stratified by cancer type. Results: We identified 864,430 individuals diagnosed in 2019, 780,478 diagnosed in 2020, and 819,791 diagnosed in 2021. The proportion of diagnoses at stage I decreased from 39.6% in 2019 to 31.1% in April 2020, and were 39.2% overall in 2021. The decrease in stage I diagnoses was mirrored by an increase in stage IV diagnoses. The pattern was most prominent for female breast, lung, colorectal, and prostate cancers, and melanoma. Overall, compared to 2019, we found a 5.98% decrease in stage I diagnoses and a 4.55% decrease in stage IV diagnoses in 2021 (Table). Lower odds of diagnosis at stage I were most prominent among individuals who were male, aged 18-44, Hispanic, from Mid-Atlantic region, and for the cancers of melanoma, non-Hodgkin lymphoma, prostate, esophagus, and cervical cancer. Higher odds of diagnosis at stage IV in 2021 vs. 2019 were most prominent among individuals who were Hispanic, diagnosed with cancers of prostate, thyroid, liver, esophagus and cervix. Conclusions: Decreases in cancer diagnoses and proportion of early-stage diagnoses continued in 2021 in the US. The proportion of late-stage diagnoses were lower in 2021 than 2020 but have not returned to pre-pandemic levels. Changes in stage I distribution among major cancer sites 2021 vs. 2019. 2019 2021 2021 vs. 2019 Cases Cases Percent Change AdjustedOR* (95%CI) All Cancers 341971 321514 -5.98% 0.978 (0.972-0.985) Female breast 116828 116780 -0.04% 1.023 (1.007-1.038) Prostate 26323 21012 -20.18% 0.826 (0.809-0.843) Lung cancer and bronchus 28258 25966 -8.11% 1.033 (1.012-1.053) Colon and rectum 14258 12992 -8.88% 0.942 (0.918-0.968) Melanoma 21005 19542 -6.97% 0.936 (0.907-0.966) Data source: National Cancer Database 2019-2021. *Stage I vs. II-IV, models adjusted for age group, sex, race/ethnicity, zip-code level social deprivation index, comorbidity score, state-level COVID-19 age adjusted mortality rate, MSA, state, insurance status.

Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway.

This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients. Through various techniques, such as Argonaute immunoprecipitation, luciferase assays, and ChIP, this study confirmed the positive effects of androgen receptor (AR) on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models. The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level, which in turn required changes in miRNA-23a-3p. Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR. This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.

The Innate Immune System and the TRAIL-Bcl-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females.

There is a significant sex bias in lung cancer, with males showing increased mortality compared with females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex bias in humanized mice, with male patient-derived xenograft lung tumors being more progressive and deadlier than female patient-derived xenograft lung tumors, we identified mouse tumor models of lung cancer with the same sex bias. This sex bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex bias in growth and lethality required intact ovaries, functional innate NK cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anticancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-Bcl-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the Bcl-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer. Significance: Lung cancers in females are more susceptible to killing through a TRAIL-Bcl-XL axis, indicating that targeting this axis therapeutically could represent a personalized approach to treat female patients with lung cancer.

Abstract A038: Uncovering the role of social determinants of health in racial disparities in cancer incidence in Alabama

Abstract Purpose Black-White racial disparities have long been recognized in cancer incidence. National estimates may not reflect racial disparities in individual states. In Alabama (AL), a primarily rural underserved state, Black Americans are more often diagnosed with breast, prostate and colorectal cancer (CRC), with Black men more often diagnosed with lung cancer. Although rurality and area-level deprivation, as social determinants of health (SDoH), have been associated with cancer, their role in explaining racial disparities in cancer incidence remains unknown. We assessed racial disparities in breast, prostate, CRC and lung cancer incidence in AL. Methods We used the Alabama Statewide Cancer Registry (ASCR) to collect data on incident cases of breast, prostate, CRC and lung cancers diagnosed between January 1, 2010 and December 31, 2019. We categorized cases according to age group (0-14, 15-19, 20-24, 25-34, 35-44, 45-64, 65-84, ≥85 years), racial/ethnic group (non-Hispanic Black/White), rural-urban status (defined by AL Rural Health Association), and national area deprivation index (ADI) quartile (Q1-Q4) of census tract at diagnosis. For each combination of these variables, we calculated age-adjusted incidence per 100,000. We conducted bivariate descriptive analysis of incidence rates by race, and rural-urban status and ADI quartile stratified by race. Results Incidence of breast, prostate and CRC cancer was higher in Black versus White individuals (breast 143 vs 127; prostate 206 vs100; CRC males 57.2 vs 45.4, CRC females 42.7 vs 32.6). Lung cancer incidence was higher in Black males and White females (Black vs White: males 82.7 vs 77.6; females 36.9 vs 49.9). In all cancers, racial differences in incidence existed by rural versus urban status (breast Black 142 vs 144, breast White 131 vs 124; prostate Black 204 vs 207, prostate White 101 vs 99.4; male CRC Black 60 vs 55.3, male CRC White 47.7 vs 43, female CRC Black 43.5 vs 42.3, female CRC White 35.2 vs 30.2; male lung Black 84.5 vs 81.7, male lung White 85.1 vs 70.2, female lung Black 31.4 vs 40.1, female lung White 54.4 vs 45.6). In all cancers, racial differences in incidence also existed by ADI status (reporting Q1 vs Q4) [breast Black 190 vs 130, breast White 144 vs 118; prostate Black 269 vs 189, prostate White 109 vs 101; CRC male Black 64.2 vs 56.7, CRC male White 41.2 vs 49.7, CRC female Black 43.4 vs 43.5, CRC female White 29.5 vs 36.6; lung male Black 73.7 vs 91, lung male White 57.9 vs 97.6, lung female Black 41 vs 37.7, lung female White 40.8 vs 60.7]. Conclusions In AL, racial differences in incidence rates for each of the most common cancers exist overall and by key SDoH. Generally, Black individuals have higher rates of cancer, particularly those in rural and low ADI areas. Next, we will perform a decomposition analysis to decompose the Black/White differences in incidence into a portion explained and unexplained by rural-urban status and ADI. Ultimately, these results may inform interventions in a rural underserved state with a large Black population at higher risk of cancer. Citation Format: Mackenzie E. Fowler, Hayden Reeves, Melissa J. Smith, Geetanjali Saini, Mahak Bhargava, Ritu Aneja. Uncovering the role of social determinants of health in racial disparities in cancer incidence in Alabama [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A038.

The COVID-19 pandemic and associated declines in cancer incidence by race/ethnicity and census-tract level SES, rurality, and persistent poverty status.

The COVID-19 pandemic had a significant impact on cancer screening and treatment, particularly in 2020. However, no single study has comprehensively analyzed its effects on cancer incidence and disparities among groups such as race/ethnicity, socioeconomic status (SES), persistent poverty (PP), and rurality. Utilizing the recent data from the United States National Cancer Institute's Surveillance, Epidemiology, and End Results Program, we calculated delay- and age-adjusted incidence rates for 13 cancer sites in 2020 and 2015-2019. Percent changes (PCs) of rates in 2020 compared to 2015-2019 were measured and compared across race/ethnic, census tract-level SES, PP, and rurality groups. Overall, incidence rates decreased from 2015-2019 to 2020, with varying PCs by cancer sites and population groups. Notably, NH Blacks showed significantly larger PCs than NH Whites in female lung, prostate, and colon cancers (e.g., prostate cancer: NH Blacks -7.3, 95% CI: [-9.0, -5.5]; NH Whites: -3.1, 95% CI: [-3.9, -2.2]). Significantly larger PCs were observed for the lowest versus highest SES groups (prostate cancer), PP versus non-PP groups (prostate and female breast cancer), and all urban versus rural areas (prostate, female breast, female and male lung, colon, cervix, melanoma, liver, bladder, and kidney cancer). The COVID-19 pandemic coincided with reduction in incidence rates in the U.S. in 2020 and was associated with worsening disparities among groups, including race/ethnicity, SES, rurality, and PP groups, across most cancer sites. Further investigation is needed to understand the specific effects of COVID-19 on different population groups of interest.

Identification of novel pQTL-SNPs associated with lung adenocarcinoma risk: A multi-stage study.

To explore the association between protein quantitative trait loci (pQTL-SNPs) and the risk of LUAD. "Blood +" high depth blood proteomics analysis was performed on plasma from female LUAD patients and female healthy controls, and combined with proteomics data from tumors and adjacent non-tumor tissues of female LUAD patients to screen proteins uniformly expressed in plasma and tissues. pQTL-SNPs were then screened through multiple databases and subjected to multilevel screening. The associations between selected pQTL-SNPs and LUAD risk were evaluated by Female Lung Cancer Consortium in Asia GWAS (FLCCA GWAS). Enzyme linked immunosorbent assay (ELISA) is used to determine the levels of candidate protein. A total of 7 pQTL-SNPs were significantly associated with altered LUAD risk (p < 0.05). Meanwhile, the expression of their corresponding target proteins were all decreased in both plasma and tumor tissues of LUAD cases, which may play a role of tumor suppressor proteins. After mutation of 3 pQTL-SNPs (rs7683000, rs73224660, and rs2776937), the expression of corresponding target proteins BST1 and NRP1 decreased, and as potential tumor suppressor proteins, which may promote tumorigenesis and further increasing the risk of developing LUAD (OR >1, p < 0.05); while after mutation the other pQTL-SNP rs62069916, the corresponding target protein APOH expression was increased, while as a potential tumor suppressor protein, which may inhibit tumorigenesis and further reduced the risk of developing LUAD (OR <1, p < 0.05). In addition, the expression of NRP1 and APOH were significant decreased in LUAD cell lines and validated in plasma of LUAD patients. A total of 4 pQTL-SNPs (rs7683000, rs73224660, rs2776937, and rs62069916) may associate with altered LUAD risk by regulating the expression of target proteins (BST1, NRP1, and APOH) after mutation.

Metastatic Renal-Cell Carcinoma of the Oro-Facial Tissues: A Comprehensive Review of the Literature with a Focus on Clinico–Pathological Findings

Background: Metastatic tumors of the oro-facial tissuesare rare, with an incidence ranging between 1% and 8% of all oral malignant tumors. Generally reported with a peak of incidence in the 5–7th decades but possibly occurring at any age, metastases may represent the first sign of an occult cancer or manifest in patients with an already known history of a primary carcinoma, mostly from the lungs, kidney, prostate, and colon/rectum in males, and the uterus, breast, lung, and ovary in females. In the oro-facial tissues, the most involved sites are the oral mucosa, gingiva/jawbones, tongue, and salivary glands. Methods: A broad and deep literature review with a comprehensive analysis of the existing research on oro-facial metastases from renal-cell carcinoma (RCC) was conducted by searching the most used databases, with attention also paid to the clear-cell histological variant, which is the most frequent one. Results: Among the 156 analyzed studies, 206 cases of oro-facial metastases of renal cancer were found in patients with an average age of 60.9 years (145 males, 70.3%; 61 females, 29.6%). In almost 40% of the cases, metastasis represented the first clinical manifestation of the primary tumor, and 122 were histologically diagnosed as clear-cell renal-cell carcinoma (ccRCC) (59.2%). The tongue was involved in most of the cases (55 cases, 26.7%), followed by the gingiva (39 cases, 18.9%), mandible (35 cases, 16.9%), maxilla (23 cases, 11.1%), parotid gland (22 cases, 10.6%), buccal mucosa (11 cases, 5.3%), lips (7 cases, 3.3%), hard palate (6 cases, 2.8%), soft palate, masticatory space, and submandibular gland (2 cases, 0.9%), and lymph nodes, tonsils, and floor of the mouth (1 case, 0.4%). Among the 122 ccRCCs (84 males, 68.8%; 38 females, 31.1%), with an average age of 60.8 years and representing in 33.6% the first clinical manifestation, the tongue remained the most frequent site (31 cases, 25.4%), followed by the gingiva (21 cases, 17.2%), parotid gland (16 cases, 13.1%), mandibular bone (15 cases, 12.2%), maxillary bone (14 cases, 11.4%), buccal mucosa and lips (6 cases, 4.9%), hard palate (5 cases, 4%), submandibular gland and soft palate (2 cases, 1.6%), and lymph nodes, tonsils, oral floor, and masticatory space (1 case, 0.8%). The clinical presentation in soft tissues was mainly represented by a fast-growing exophytic mass, sometimes accompanied by pain, while in bone, it generally presented as radiolucent lesions with ill-defined borders and cortical erosion. Conclusions: The current comprehensive review collected data from the literature about the incidence, site of occurrence, age, sex, and survival of patients affected by oro-facial metastases from renal-cell carcinoma, with particular attention paid to the cases diagnosed as metastases from clear-cell renal-cell carcinoma, which is the most frequent histological variant. Clinical differential diagnosis is widely discussed to provide clinicians with all the useful information for an early diagnosis despite the effective difficulties in recognizing such rare and easily misdiagnosed lesionsTheir early identification represents a diagnostic challenge, especially when the clinical work-up is limited to the cervico–facial region. Nevertheless, early diagnosis and recently introduced adjuvant therapies may represent the key to better outcomes in such patients. Therefore, general guidelines about the clinical and radiological identification of oro-facial potentially malignant lesions should be part of the cultural background of any dentist.

Disparities in Cancer Stage of Diagnosis by Rurality in California, 2015 to 2019.

Cancer rates in rural areas vary by insurance status, socioeconomic status, region, race, and ethnicity. California Cancer Registry data (2015-2019) were used to investigate the stage of diagnosis by levels of rurality for the five most common cancers. The percentage of residents in rural blocks within census tract aggregation zones was categorized into deciles up to 50%. Multivariable logistic regression was used to estimate associations with rurality, with separate models by cancer site, sex, race, and ethnicity (non-Hispanic White and Hispanic). Covariates included individual-level and zone-level factors. The percentage of late-stage cancer diagnosis was 28% for female breast, 27% for male prostate, 77% for male lung, 71% for female lung, 60% for male colorectal, 59% for female colorectal, 7.8% for male melanoma, and 5.9% for female melanoma. Increasing rurality was significantly associated with increased odds of late-stage cancer diagnosis for female breast cancer (Ptrend < 0.001), male lung cancer (Ptrend < 0.001), female lung cancer (Ptrend < 0.001), and male melanoma (Ptrend = 0.01), after adjusting for individual-level and zone-level factors. The strength of associations varied by sex and ethnicity. For males with lung cancer, odds of late-stage diagnosis in areas with >50% rural population was 1.24 (95% confidence interval, 1.06-1.45) for non-Hispanic White patients and 2.14 (95% confidence interval, 0.86-5.31) for Hispanic patients, compared with areas with 0% rural residents. Increasing rurality was associated with increased odds for late-stage diagnosis for breast cancer, lung cancer, and melanoma, with the strength of associations varying across sex and ethnicity. Our findings will inform cancer outreach to these rural subpopulations.

Association of marital status with cardiovascular death risk in patients with lung cancer: A population-based study

BackgroundTo investigate the association of marital status on cardiovascular death risk in lung cancer patients. MethodsUsing data from the Surveillance, Epidemiology, and End Results (SEER) database in the United States from 2011 to 2015 (N = 118,293), the association between marital status and cardiovascular death (CVD) risk in patients with lung cancer was assessed by competing-risks regression models. ResultsUnmarried status was associated with increased risk of cardiovascular death in lung cancer patients [hazard ratio (HR) = 1.398, 95 % confidence interval (CI): 1.268–1.542], which remained significant even after adjusting for potential covariates (HR = 1.407, 95 % CI: 1.276–1.551). Further unmarried subgroups analysis showed that the different unmarried status were associated with increased cardiovascular death risk as follows: single (HR = 1.397, 95 % CI: 1.236–1.1.580), separated (HR = 1.630, 95 % CI: 1.153–2.305), divorced (HR = 1.318, 95 % CI: 1.158–1.500), and widowed (HR = 1.561, 95 % CI: 1.393–1.749). Further subgroup analysis by sex revealed that compared to male lung cancer patients with married, CVD risk was significant increased in their counterparts with widowed (adjusted HR = 1.509, 95 % CI: 1.291–1.764, P<0.001), single (adjusted HR = 1.361, 95 % CI: 1.168–1.585, P<0.001) and divorced (adjusted HR = 1.353, 95 % CI: 1.177–1.555, P<0.001) rather than those with separated. However, similar phenomena was only observed in female lung cancer patients with widowed (adjusted HR = 1.414, 95 % CI: 1.220–1.640, P<0.001) and single (adjusted HR = 1.438, 95 % CI: 1.195–1.730, P<0.001). ConclusionUnmarried status was associated with increased cardiovascular death risk in patients with lung cancer, which highlighted that more attention and humanistic/supportive care should be offered to unmarried lung cancer patients for improving the prognosis.

Role of sex as a biological variable in neonatal alveolar macrophages

The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. The primary mechanisms responsible for sexually dimorphic outcomes in bronchopulmonary dysplasia (BPD) remain unidentified. We tested the hypothesis that biological sex plays a crucial role in the transcriptional state of alveolar macrophages, using neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. The effects of neonatal hyperoxia exposure (95 % FiO2, PND1-5: saccular stage) on the lung myeloid cells acutely after injury and during normoxic recovery were measured. Alveolar macrophages (AM) from room air- and hyperoxia exposed from male and female neonatal murine lungs were subjected to bulk-RNA Sequencing. AMs are significantly depleted in the hyperoxia-exposed lung acutely after injury, with subsequent recovery in both sexes. The transcriptome of the alveolar macrophages is impacted by neonatal hyperoxia exposure and by sex as a biological variable. Pathways related to DNA damage and interferon-signaling were positively enriched in female AMs. Metabolic pathways related to glucose and carbohydrate metabolism were positively enriched in the male AMs, while oxidative phosphorylation was negatively enriched. These pathways were shared with monocytes and airway macrophages from intubated male and female human premature neonates.

Crosstalk among Alternative Polyadenylation, Genetic Variants and Ubiquitin Modification Contribute to Lung Adenocarcinoma Risk.

Ubiquitin modification and alternative polyadenylation play crucial roles in the onset and progression of cancer. Hence, this study aims to comprehensively and deeply understand gene regulation and associated biological processes in lung adenocarcinoma (LUAD) by integrating both mechanisms. Alternative polyadenylation (APA)-related E3 ubiquitin ligases in LUAD were identified through multiple databases, and the association between selected genetic loci influencing gene expression (apaQTL-SNPs) and LUAD risk were evaluated through the GWAS database of the Female Lung Cancer Consortium in Asia (FLCCA). Subsequently, the interaction between RNF213 and ZBTB20, as well as their functional mechanisms in LUAD, were investigated using bioinformatics analysis, Western blot, co-immunoprecipitation, and colony formation experiments. A total of five apaQTL-SNPs (rs41301932, rs4494603, rs9890400, rs56066320, and rs41301932), located on RNF213, were significantly associated with LUAD risk (p < 0.05), and they inhibit tumor growth through ubiquitin-mediated degradation of ZBTB20.

COVID-19 impact on incidence and stage at diagnosis of five prominent cancers: A French cancer registry-based study

The French healthcare system has been affected by the COVID-19 pandemic in 2020, including cancer care. In order to evaluate the impact of this pandemic on cancer incidence, the Isere Departmental Cancer Registry compared the actual 2020 incidence of melanoma, breast, colorectal, prostate and lung cancers with the expected 2020 incidence based on data collected by the Registry between 2015 and 2019, taking into account periods of lockdown and reopening. When available, cancer stages and/or prognostic scores were recorded. During the period of initial confinement, a 54%, 50% and 36,8% drop in incidence was observed for breast, prostate and colorectal cancer respectively. Although their annual incidence remained stable, a worsening trend emerged as a decline in the number of low stages/scores at diagnosis in favour of higher stages/scores towards the end of 2020. In contrast, a significant 17,8% drop was observed in annual incidence of melanoma, particularly for Breslow scores < 1 (-27,4%). However, this trend was noticeable before the lockdown, as well as the 14% reduction in the incidence of lung cancer in women, but not in men. The incidence of certain cancers was caught up over the year but the COVID-19 pandemic seems to be associated with a change in their severity at diagnosis throughout 2020. The downward trends in female lung cancer and melanoma incidence point to complex underlying phenomena. Further analysis is still needed to assess the global impact of the COVID-19 pandemic on cancer incidence.

Sex-based differences in the lung immune microenvironment are associated with an increased risk of lung cancer in women

ObjectiveLung cancer remains a major cause of mortality worldwide, necessitating further understanding of carcinogenesis and its driving factors, including those influenced by sex-dependent variables. We hypothesized that sex-specific lung immune composition may contribute to a greater risk of lung cancer in women. MethodsData from 1056 lung cancer screenings were examined for an association between sex and lung cancer risk using time-to-event analyses. Immune profiling by flow cytometry was performed on male and female lungs of 3 independent mouse models: nontumor bearing, KRAS mutated, and urethane-exposed carcinogenic. A comparable analysis was performed on human bronchoalveolar lavage samples (n = 81) from patients with lung cancer. ResultsOf the high-risk screening cohort examined, 60 patients (5.7%) developed lung cancer during median follow-up of 43.4 months. Multivariable stepwise modeling retained female sex (hazard ratio, 1.56; P < .01) and age (P < .01) as prognostic indicators for lung cancer development. Female lung immune profiles in patients included T-cell phenotypes consistent with exhaustion (eg, higher proportions of PD-1+ Ki67–; P = .02), an expanded pool of regulatory T-cells (P = .03), reduced effector T-cell frequencies (P = .008), and enhancements in suppressive myeloid populations (P = .02) versus male patients, and this is recapitulated in mouse studies. ConclusionsFemale smokers display higher risk for lung cancer. In murine models and humans, female sex is associated with robust immunosuppression within the lung. Further examination of this link will be important in developing immune-based approaches to lung cancer interception and their optimal application across the sexes.