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With significant advancements in the study of DNA Damage Response (DDR) and Fanconi Anemia (FA) signaling, we previously introduced the term “FA signaling” to encompass “all signaling transductions involving one or more FA proteins.” This network has now evolved into the largest cellular defense network, integrating over 30 key players, including ATM, ATR, BLM, HRR6, RAD18, FANCA, FANCB, FANCC, BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C, SLX4, ERCC4, RAD51, BRCA1, UBE2T, XRCC2, MAD2L2, RFWD3, FAAP20, FAAP24, FAAP100, and CENPX. This system responds to both endogenous and exogenous cellular insults. However, the mutational signatures associated with this defense mechanism in non-FA human cancers have not been extensively explored. In this study, we report that different types of human cancers are characterized by distinct somatically mutated genes related to DDR/FA signaling, each accompanied by a unique spectrum of potential driver mutations. For example, in pan-cancer samples, ATM emerges as the most frequently mutated gene (5%) among the 31 genes analyzed, with the highest number of potential driver mutations (1714), followed by BRCA2 (4% with 970 putative driver mutations). However, this pattern is not universal across specific cancer types. For example, FANCT is the most frequently mutated gene in breast (14%) and liver (4%) cancers. In addition, the alteration frequency of DDR/FA signaling due to these mutations exceeds 70% in a subtype of prostate cancer, with each subtype of brain, breast, lung, and prostate cancers displaying distinct patterns of gene alteration frequency. Furthermore, these gene alteration patterns significantly impact patient survival and disease-free periods. Collectively, our findings not only enhance our understanding of cancer development and progression but also have significant implications for cancer patient care and prognosis, particularly in the development of effective therapeutic strategies.

Summary: Obesity and fatty liver diseases—metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)—affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2−/− and Aldh2−/−Sptbn1+/− mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2−/− and Aldh2−/−Sptbn1+/− mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Abstract Host immunity involves various immune cells working in concert to achieve balanced immune response. Host immunity interacts with tumorigenic process impacting disease outcome. Clusters of different immune cells may reveal unique host immunity in relation to breast cancer progression. CIBERSORT algorithm was used to estimate relative abundances of 22 immune cell types in 3 datasets, METABRIC, TCGA, and our study. The cell type data in METABRIC were analyzed for cluster using unsupervised hierarchical clustering (UHC). The UHC results were employed to train machine learning models. Kaplan–Meier and Cox regression survival analyses were performed to assess cell clusters in association with relapse-free and overall survival. Differentially expressed genes by clusters were interrogated with IPA for molecular signatures. UHC analysis identified two distinct immune cell clusters, clusters A (83.2%) and B (16.8%). Memory B cells, plasma cells, CD8 positive T cells, resting memory CD4 T cells, activated NK cells, monocytes, M1 macrophages, and resting mast cells were more abundant in clusters A than B, whereas regulatory T cells and M0 and M2 macrophages were more in clusters B than A. Patients in cluster A had favorable survival. Similar survival associations were also observed in other independent studies. IPA analysis showed that pathogen-induced cytokine storm signaling pathway, phagosome formation, and T cell receptor signaling were related to the cell type clusters. Our finding suggests that different immune cell clusters may indicate distinct immune responses to tumor growth, suggesting their potential for disease management.

Abstract Background Previously studies shown a potential risk of antihypertensive medicines in relation to cancer susceptibility, which creating significant debate in the scientific community and public concern. We sought to investigate the relationship between antihypertensive medicines and cancer risk, by drug type and class. Methods We conducted a population-based cohort study and enrolled patients diagnosed with hypertension from community healthcare centers in Changning District, Shanghai, China. Antihypertensive drug administration were classified as five common antihypertensive drugs. The main outcomes were incidence of total cancer and by major cancer type. Results Between January 2013 and December 2017, a total of 101,370 hypertensive patients were enrolled in this cohort. During a mean follow-up of 5.1 (SD 1.3) years, 4970 cancer cases were newly diagnosed in the cohort. CCBs were the most frequently used antihypertensives which were associated with a moderately increased risk of total cancer (hazard ratio, HR = 1.11, 95% CI: 1.05–1.18). The second commonly used drug ARBs were also associated with increased risk of total cancer (HR = 1.10, 95%CI: 1.03–1.17) as well as lung and thyroid cancers (HR = 1.21, 95%CI: 1.05–1.39; HR = 1.62 95%CI: 1.18–2.21, respectively). No significant association was found between cancer and other antihypertensives. Hypertensive patients who use more than one class of antihypertensives drugs had a higher risk of total cancer (HR: 1.22, 95%CI: 1.10–1.35 for two classes; HR: 1.22, 95%CI: 1.03–1.45 for three or more classes), and a possible dose–response relationship was suggested (P for trend

Abstract Background Papillary thyroid microcarcinoma (PTMC) incidence has significantly increased, and some cases still exhibit invasive traits. The entire molecular landscape of PTMC, which can offer hints for the etiology of cancer, is currently absent. Methods We compared our findings with those for PTMC in the TCGA by analyzing the largest study at the current stage of whole exome sequencing and RNA-sequencing data from 64 patients with PTMC. Then, we systematically demonstrated the differences between the two PTMC subtypes based on multi-omics analyses. Additionally, we created a molecular prediction model for the PTMC subtypes and validated them among TCGA patients for individualized integrative assessment. Results In addition to the presence of BRAF mutations and RET fusions in the TCGA cohort, we also discovered a new molecular signature named PTMC-inflammatory that implies a potential response to immune intervention, which is enriched with AFP mutations, IGH@-ext fusions, elevated immune-related genes, positive peroxidase antibody, and positive thyroglobulin antibody. Additionally, a molecular prediction model for the PTMC-inflammatory patients was created and validated among TCGA patients, while the prognosis for these patients is poor. Conclusions Our findings comprehensively define the clinical and molecular features of PTMC and may inspire new therapeutic hypotheses.

BackgroundPhysical activity improves health and psychosocial functioning for people who have been diagnosed with cancer. Native Hawaiians face disparities for some cancers, including breast cancer. Delivering culturally grounded interventions has the potential to improve enjoyment and adherence to the intervention. We sought to test the adherence and impact of a 6 month randomized wait-list controlled trial of hula.MethodsIn this randomized wait-list controlled design people who had been diagnosed with breast or gynecologic cancers were invited to participate with other cancer survivors in a group based setting. Participants were randomized to begin hula immediately or after six months. Attendance was collected and heart-rate measured three times per session. In addition, demographic data, self-report psychosocial data, and biological data (findings will be reported elsewhere) were collected at three time points: baseline, 6 months, and 12 months. The study included six months of hula, twice per week, 60 min each session. In addition, participants committed to practice 60 min per week at home.ResultsParticipants in the study (n = 42) attended, on average, 72% of the sessions. Significant increase in moderate physical activity (d = 0.50, p = 0.03) was observed in the intervention versus control group. For the measures of intra-individual changes pre-and post-intervention, an increase in total physical activity were seen in the intervention group (d = 0.69, p = 0.003), daily caloric intake decreased (d = −0.62, p = 0.007), and a reduction in waist circumference (d = −0.89, p = 0.0002) that was sustained six months after completion of the intervention. Psychosocially, cognitive functioning significantly declined from baseline to 12 months (d = −0.50, p = 0.03), with role functioning improving (d = 0.55, p = 0.02), social constraints increasing (d = 0.49, p = 0.03), and financial difficulties improving (d = −0.55, p = 0.02).ConclusionSustainable physical activity is crucial to improve both the survival and quality of life of cancer survivors. Culturally grounded interventions, such as hula have the potential to increase the maintenance of physical activity. In addition, they create a support group where the benefits of people who have all experienced cancer can gather and garner those benefits of social support, too. This study was registered as a clinical trial through the National Cancer Institute (NCT02351479).Clinical trial registrationClinicaltrails.gov, NCT02351479.

Abstract Background PM2.5 exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM2.5 exposure, and aimed to find a potential intervention for people living in PM2.5 polluted regions. Methods Electron microscopy and oil-red staining were conducted to examine the lipid droplet accumulation. Masson’s trichrome staining, colony forming, scratch assay and transwell experiment were conducted to evaluate the effect of PM2.5 exposure and d-limonene intervention on the occurrence and progression of LUAD. Potential intervention targets were found by RNA-Seq and verified by luciferase reporter assay. MiR-195 KO mice constructed with CRISPR/Cas9 technology were used to investigate the pivotal role of d-limonene-miR-195-SREBP1/FASN axis. Cohort analysis of lung cancer patients, human LUAD tissues staining and human intervention trial were also conducted to validate the results of cell and animal experiments. Results Our results showed that PM2.5 exposure induced accumulation of lipid droplets in LUAD cells which accompanied by increased malignant cellular behaviors. PM2.5 exposure led to cleaved N-SREBP1 translocation into nucleus, which activated the de novo lipogenesis pathway. Same changes were also observed in normal lung epithelial cells and normal lung tissue, and mice developed pulmonary fibrosis after long-term exposure to PM2.5. Furthermore, in a cohort of 11,712 lung cancer patients, significant lipid metabolism disorders were observed in higher PM2.5 polluted areas. In view of that, d-limonene was found to inhibit the changes in lipid metabolism through upregulating the expression of miR-195, which inhibited the expression of lipogenic genes (SREBF1/FASN/ACACA) specifically. And a small human intervention trial showed that serum miR-195 was upregulated after oral intake of d-limonene. Conclusion Our findings reveal a new mechanism of pulmonary fibrosis and LUAD that is related to PM2.5 exposure-induced lipid droplet accumulation. We also demonstrate that d-limonene-miR-195-SREBP1/FASN axis is a potential preventive intervention for mediating the progression and development of LUAD induced by PM2.5 exposure. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030200. Registered 25 February 2020, http://www.chictr.org.cn/showproj.aspx?proj=48013 Graphical Abstract

Abstract Background and Aim Chronic hepatitis C virus (HCV) infection, long‐term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene–environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome‐wide association study (GWAS). Methods Two case‐control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results In this GWAS, we found that two SNPs were associated with HCC at P

Abstract Long non-coding RNAs (lncRNAs) have important biological functions, but their involvement in ovarian cancer remains elusive. We analyzed high-throughput data to identify lncRNAs associated with ovarian cancer outcomes. Our search led to the discovery of lncRNA TOPORS Antisense RNA 1 (TOPORS-AS1). Patients with high TOPORS-AS1 expression had favorable overall survival compared to low expression. This association was replicated in our study and confirmed by meta-analysis. In vitro experiments demonstrated that overexpressing TOPORS-AS1 in ovarian cancer cells suppressed cell proliferation and inhibited aggressive cell behaviors, including migration, invasion, and colony formation. Analysis of tumor cell transcriptomes indicated TOPORS-AS1′s influence on the Wnt/β-catenin signaling. Additional experiments revealed that TOPORS-AS1 increased the phosphorylation of β-catenin and suppressed the expression of CTNNB1, disrupting the Wnt/β-catenin pathway. Our experiments further discovered that vitamin D receptor (VDR) upregulated TOPORS-AS1 expression and that inhibition of β-catenin by TOPORS-AS1 required a RNA binding protein, hnRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1). Taken together, these findings suggest that TOPORS-AS1 may behave like a tumor suppressor in ovarian cancer through interrupting the Wnt/β-catenin signaling and that VDR upregulates the expression of TOPORS-AS1. Assessing TOPORS-AS1 expression in ovarian cancer may help predict disease prognosis and develop treatment strategy

Abstract Background The mechanism of rapidly increased non‐small cell lung cancer (NSCLC) among never‐smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone‐binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never‐smoking female NSCLC. Methods Candidate genes were selected by a genome‐wide association (GWAS) meta‐analysis and gene expression profiles of never‐smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two‐stage case‐control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never‐smoking Chinese women. Chi‐square test and multivariate logistic regression were applied. Results Beginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never‐smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two‐stage case‐control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15–2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02–2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients’ tumor tissues and was associated with a poor prognosis in NSCLC. Conclusion Our findings indicated that a sex hormones regulation‐related SNP rs12233719 was associated with never‐smoking female lung cancer risk, which might partially explain NSCLC‐susceptibility in Chinese women.

Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. Methods: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Results: Sequencing analyses identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Conclusion: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

Abstract Molecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. In this study, we explored the role of pro-inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) in those pathways at the genome-wide level. With single-nucleotide polymorphisms (SNPs) in the biomarkers and lifestyles together, we further constructed risk profiles to improve predictability for breast cancer. Our earlier genome-wide association gene-environment interaction study used large cohort data from the Women’s Health Initiative Database for Genotypes and Phenotypes Study and identified 88 SNPs associated with CRP and IL-6. For this study, we added an additional 68 SNPs from previous GWA studies, and together with 48 selected lifestyles, evaluated for the association with breast cancer risk via a 2-stage multimodal random survival forest and generalized multifactor dimensionality reduction methods. Overall and in obesity strata (by body mass index, waist, waist-to-hip ratio, exercise, and dietary fat intake), we identified the most predictive genetic and lifestyle variables. Two SNPs (SALL1 rs10521222 and HLA-DQA1 rs9271608) and lifestyles, including alcohol intake, lifetime cumulative exposure to estrogen, and overall and visceral obesity, are the most common and strongest predictive markers for breast cancer across the analyses. The risk profile that combined those variables presented their synergistic effect on the increased breast cancer risk in a gene–lifestyle dose-dependent manner. Our study may contribute to improved predictability for breast cancer and suggest potential interventions for the women with the risk genotypes and lifestyles to reduce their breast cancer risk.

Abstract Background Many cancer-associated single nucleotide polymorphisms (SNPs) are located in the genomic regions of long non-coding RNAs (lncRNAs). Mechanisms of these SNPs in connection to cancer risk are not fully understood. Methods Association of SNP (rs140618127) in lncRNA LOC146880 with non-small cell lung cancer (NSCLC) was evaluated in a case-control study of 2707 individuals. The mechanism of the SNP’s biologic influence was explored with in vitro and in vivo experiments, including plasmid transfection, siRNA knockdown, flow cytometry assessment, and assays of cell proliferation, migration, invasion, and colony formation. Results Association analysis showed that A allele of SNP rs140618127 was associated with low risk of NSCLC in the Chinese population. Lab experiments indicated that SNP rs140618127 contained a binding site for miR-539-5p and the binding between miR-539-5p and LOC146880 resulted in declined phosphorylation of an oncogene, ENO1. The reduced phosphorylation of ENO1 led to decreased phosphorylation of PI3K and Akt, which is further linked to the decline in cell proliferation and tumor progression. Conclusion The study demonstrates that SNP rs140618127 in lncRNA loc146880 provides an alternate binding site for microRNA miR-539-5p which affects the phosphorylation of ENO1 and activation of the PI3K and Akt pathway.

Previous genome-wide association studies have identified risk loci for pancreatic cancer but were centered on individuals of European ancestry. Here the authors identify GP2 gene variants associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Abstract Background Many previous studies reported secular trend of lung cancer incidence and mortality, but little is known about the possible reasons for these trends. Methods Data were obtained from Shanghai Cancer Registry. Age‐standardized rates were calculated and average annual percent changes (AAPCs) were evaluated by Joinpoint regression. Age, period, and birth cohort effects were assessed by age‐period‐cohort models. Results From 1973 to 2010, compared with long‐time slowly increasing trend in women, male lung cancer incidence had significantly decreased between 2001 and 2009. After that lung cancer incidence rising sharply in women (AAPC = 14.13%, 95%CI: 2.68%‐26.86%, P = .016) and similar rising trends without statistical significance in men (AAPC = 2.96, 95%CI: −2.47%‐8.69%, P = .281) between 2010 and 2014. Age‐period cohort model showed the different patterns of period effects for lung cancer incidence between men and women. The period effects for lung cancer incidence showed rising effect for women, whereas there was decline effect for lung cancer incidence for men. On the other hand, the model showed a significant period effect in both genders with a similar fashion in mortality, yielding steady falling trends during the entire study period. Conclusions The distinctive patterns of lung cancer incidence between men and women may be attributable to significant period effects, which reflected the changes in public health policies or diagnostic practices and highlighted the urgent of continued monitoring of gender‐specific risk factors for lung cancer incidence.

BackgroundDisparities in cancer genomic science exist among racial/ethnic minorities. Particularly, African American (AA) and Hispanic/Latino American (HA) women, the 2 largest minorities, are underrepresented in genetic/genome-wide studies for cancers and their risk factors. We conducted on AA and HA postmenopausal women a genomic study for insulin resistance (IR), the main biologic mechanism underlying colorectal cancer (CRC) carcinogenesis owing to obesity.MethodsWith 780 genome-wide IR-specific single-nucleotide polymorphisms (SNPs) among 4,692 AA and 1,986 HA women, we constructed a CRC-risk prediction model. Along with these SNPs, we incorporated CRC-associated lifestyles in the model of each group and detected the topmost influential genetic and lifestyle factors. Further, we estimated the attributable risk of the topmost risk factors shared by the groups to explore potential factors that differentiate CRC risk between these groups.ResultsIn both groups, we detected IR-SNPs in PCSK1 (in AA) and IFT172, GCKR, and NRBP1 (in HA) and risk lifestyles, including long lifetime exposures to cigarette smoking and endogenous female hormones and daily intake of polyunsaturated fatty acids (PFA), as the topmost predictive variables for CRC risk. Combinations of those top genetic- and lifestyle-markers synergistically increased CRC risk. Of those risk factors, dietary PFA intake and long lifetime exposure to female hormones may play a key role in mediating racial disparity of CRC incidence between AA and HA women.ConclusionsOur results may improve CRC risk prediction performance in those medically/scientifically underrepresented groups and lead to the development of genetically informed interventions for cancer prevention and therapeutic effort, thus contributing to reduced cancer disparities in those minority subpopulations.

The WW and C2 domain containing 1 (WWC1) gene encodes a protein named WWC1 (or KIBRA), which is involved in the Hippo signaling pathway. WWC1 is often lost in triple‐negative breast cancer and has been shown to suppress tumor metastasis. In this study, 470 breast cancer patients were recruited and WWC1 expression in the tumor samples was measured with quantitative reverse transcriptase PCR. Associations of WWC1 expression with breast cancer survival were analyzed using the Cox proportional hazards regression model and Kaplan–Meier survival analysis. The relationship between WWC1 expression and methylation was evaluated in a dataset from The Cancer Genome Atlas. Using our microarray data on gene expression and the Ingenuity Pathway Analysis, we predicted the WWC1‐associated signaling pathways in breast cancer. Our results showed that low expression of WWC1 was significantly associated with advanced‐stage diseases, high‐grade tumors, and estrogen receptor‐ or progesterone receptor‐negative status. Compared to those with high expression, patients with low WWC1 had higher risk of breast cancer relapse [hazard ratio (HR) = 2.06, 95% confidence interval (CI): 1.26–3.37] and higher risk of death (HR = 2.76, 95% CI: 1.51–5.03). The association with relapse‐free survival remained significant after adjustment for disease stage, tumor grade, and hormone receptor status and was replicated in a public dataset. Analysis of high‐throughput gene expression data indicated that WWC1 was involved in the Hippo signaling pathway. Online data also suggested that DNA methylation was inversely associated with WWC1 expression. The study confirmed that low WWC1 expression was associated with aggressive breast cancer and poor survival outcomes.

Abstract Background This study aimed to assess the relationship between specific nighttime-daytime sleep patterns and prevalence of different chronic diseases in an elderly population. Methods We conducted a community-based cross-sectional study in 4150 elderly Chinese, with an average age of 74 years. Sleep-related variables (nighttime sleep duration, daytime napping and duration) and chronic disease status, including diabetes, cardiovascular diseases (CVD), dyslipidemia cancer and arthritis were collected for the study. Multivariable logistic regression models were used to analyze the relationship between nighttime-daytime sleep patterns and prevalence of chronic diseases. Results Overall prevalence of any of chronic diseases was 83.8%. Nighttime-daytime sleep patterns were defined according to nighttime sleep duration and habitual nappers/non-nappers. Taking the nighttime-daytime sleep pattern “short nighttime sleep with daytime napping” as reference, those with “long nighttime sleep without daytime napping” had higher prevalence of diabetes [OR and 95% CI, 1.35 (1.01–1.80)] and lower prevalence of arthritis [OR and 95% CI, 0.46 (0.33–0.63)]. And those with “long nighttime sleep with daytime napping” had higher prevalence of diabetes [OR and 95% CI, 1.36 (1.05–1.78)] while lower prevalence of cancer [OR and 95% CI, 0.48 (0.26–0.85)] and arthritis [OR and 95% CI, 0.67 (0.51–0.86)]. Further, in habitual nappers, subjects were classified according to duration of nighttime sleep and daytime naps. Compared to “short nighttime sleep with long daytime napping”, individuals with “long nighttime sleep with short daytime napping” had significantly positive association with diabetes prevalence [OR and 95% CI, 1.73 (1.15–2.68)] while border-significantly and significantly negative association with cancer [OR and 95% CI, 0.49 (0.23–1.07)] and arthritis [OR and 95% CI, 0.64 (0.44–0.94)], respectively. Conclusions Elderly individuals with chronic diseases had different nighttime-daytime sleep patterns, and understanding these relationships may help to guide the management of chronic diseases.

Background: Hepatic encephalopathy (HE), a severe neuropsychiatric complication, is associated with increased blood levels of ammonia and bile acids (BAs). We sought to determine (1) whether abnormally increased blood BAs in liver cirrhotic patients with HE is caused by elevation of apical sodium-dependent BA transporter (ASBT)-mediated BA reabsorption; and (2) whether increased BA reabsorption would exacerbate ammonia-induced brain injuries. Methods: We quantitatively measured blood BA and ammonia levels in liver cirrhosis patients with or without HE and healthy controls. We characterized ASBT expression, BA profiles, and ammonia concentrations in a chronic liver disease (CLD) mouse model induced by streptozotocin-high fat diet (STZ-HFD) and an azoxymethane (AOM) - induced acute liver failure (ALF) mouse model. These two mouse models were treated with SC-435 (ASBT inhibitor) and budesonide (ASBT activator), respectively. Findings: Blood concentrations of ammonia and conjugated BAs were substantially increased in cirrhotic patients with HE (n = 75) compared to cirrhotic patients without HE (n = 126). Pharmacological inhibition of the enterohepatic BA circulation using a luminal- restricted ASBT inhibitor, SC-435, in mice with AOM-induced ALF and STZ-HFD -induced CLD effectively reduced BA and ammonia concentrations in the blood and brain, and alleviated liver and brain damages. Budesonide treatment induced liver and brain damages in normal mice, and exacerbated these damages in AOM-treated mice. Interpretation: ASBT mediated BA reabsorption increases intestinal luminal pH and facilitates conversion of intestinal ammonium to ammonia, leading to abnormally high levels of neurotoxic ammonia and cytotoxic BAs in the blood and brain. Inhibition of intestinal ASBT with SC-435 can effectively remove neurotoxic BAs and ammonia from the bloodstream and thus, mitigate liver and brain injuries resulting from liver failure. Keywords: Bile acids, Ammonia, Hepatic encephalopathy, Apical sodium-dependent bile acid transporter

Abstract Background Brain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC). The present study aimed to identify novel biomarkers and potential therapeutic targets for brain metastases of NSCLC. Methods We performed high-throughput Luminex assays to profile the transcriptional levels of 36 genes in 70 operable NSCLC patients, among whom 37 developed brain metastases as the first relapse within 3 years after surgery. The Cox proportional hazards regression model was used to evaluate the association between genes and brain metastases. Wound healing assay and transwell assay was carried out to estimate the function of target gene in vitro. And left ventricular injection on nude mice was used to evaluate the effect of target gene in vivo. Results Growth-associated protein 43 (GAP43) was found to be related to brain metastasis. Multivariate Cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.29-fold increase in the risk for brain metastasis compared with those with low levels (95% confidence interval: 1.55–7.00; P = 0.002). Kaplan–Meier survival curves revealed that GAP43 was also associated with overall survival. Analysis of a cohort of 1926 NSCLC patients showed similar results: patients with high levels of GAP43 had worse progression-free and overall survival rates. Furthermore, in vitro experiments showed that GAP43 facilitated cell migration. Animal studies demonstrated that GAP43-silenced NSCLC cells were less likely to metastasize to the brain and bone than control cells. Immunofluorescence and F-actin/G-actin in vivo assays indicated that GAP43 knockdown triggered depolymerization of the F-actin cytoskeleton. Rho GTPase activation assays showed that Rac1 was deactivated after GAP43 was silenced. Conclusions Our findings suggest that GAP43 is an independent predictor of NSCLC brain metastasis and that it may facilitate metastasis by regulating the Rac1/F-actin pathway.

BackgroundImmune-related etiologic pathways that influence breast cancer risk are incompletely understood and may be confounded by lifestyles or reverse causality. Using a Mendelian randomization (MR) approach, we investigated the potential causal relationship between genetically elevated C-reactive protein (CRP) concentrations and primary invasive breast cancer risk in postmenopausal women.MethodsWe used individual-level data obtained from 10,179 women, including 537 who developed breast cancer, from the Women’s Health Initiative Database for Genotypes and Phenotypes Study, which consists of five genome-wide association (GWA) studies. We examined 61 GWA single-nucleotide polymorphisms (SNPs) previously associated with CRP. We employed weighted/penalized weighted–medians and MR gene–environment interactions that allow instruments’ invalidity to some extent and attenuate the heterogeneous estimates of outlying SNPs.ResultsIn lifestyle-stratification analyses, genetically elevated CRP decreased risk for breast cancer in exogenous estrogen-only, estrogen + progestin, and past oral contraceptive (OC) users, but only among relatively short-term users (

Background. Lung cancer is one of the leading diagnosed cancers worldwide, and microRNAs could be used as biomarkers to diagnose lung cancer. hsa-miR-195 has been demonstrated to affect the prognosis of NSCLC (non-small-cell lung cancer) in a previous study. However, the diagnostic value of hsa-miR-195-5p in lung cancer has not been investigated. Methods. To evaluate the ability of hsa-miR-195-5p to diagnose lung cancer, we compared the expression of hsa-miR-195-5p in lung cancer patients, COPD patients, and normal controls. Receiver operating characteristic (ROC) curve analysis was performed to investigate the sensitivity and specificity of hsa-miR-195-5p. Coexpression network and pathway analysis were carried out to explore the mechanism. Results. We found that hsa-miR-195-5p had lower expression in lung cancer and COPD patients than in normal controls, and the AUC was 0.92 for diagnosing lung cancer. hsa-miR-143 correlated with hsa-miR-195-5p, and by combining these two microRNAs, the AUC was 0.97 for diagnosing lung cancer. Conclusions. hsa-miR-195-5p may act as a biomarker that contributes to the diagnosis of lung cancer and the detection of its high-risk population.

Objective: Long non-coding RNAs (lncRNAs) are involved in numerous biological processes in lung cancer cells. In our previous studies, we identified a lncRNA, ENST00000439577, which is highly expressed in lung carcinomas, and termed it lung cancer progression-associated transcript 1 (LCPAT1). To characterize the role of LCPAT1 in lung cancer, we conducted the current study.Methods: Expression of LCPAT1 and autophagy-associated markers in tumor tissues and lung cancer cell lines was determined by real-time quantitative polymerase chain reaction (qPCR). Hematoxylin and eosin (HE) staining, qPCR, Western blot, and immunohistochemistry were performed to evaluate xenografted tumor tissues. Autophagy induced by rapamycin was detected by Western blot and immunofluorescence in lung cancer cell lines.Results: Expression of LCPAT1 and microtubule-associated protein 1 light chain 3 beta (LC3B) was positively correlated in lung cancer. Knockdown of LCPAT1 inhibited tumor growth and suppressed cell autophagy in vivo. Moreover, LCPAT1 knockdown in lung cancer cell lines resulted in decreased autophagy-associated gene expression and alleviated the cell autophagy induced by rapamycin.Conclusions: We speculate that LCPAT1 plays a crucial role in regulating autophagy in lung cancer.

Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.

Background/Aims: Ecological studies have shown that air pollution and prevalence of cigarette smoking are positively correlated. Evidence also suggests a synergistic effect of cigarette smoking and PM2.5 exposure (Environmental Particulate Matter ≤ 2.5 µm in diameter) on lung cancer risk. We aimed to evaluate the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality and determine its underlying mechanisms in vitro. Methods: “MOVER” method was used to analyze the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality. Cell autophagy and malignant behaviors induced by cigarette smoke extract (CSE) and PM2.5 exposure were examined in vitro. Gene expression was examined by qRT-PCR and western blot. RNA and protein interaction was determined using a RNA binding protein immunoprecipitation assay. Results: An increased risk for lung cancer death (RERI (the relative excess risk) =0.28) was observed with a synergistic interaction between cigarette smoking and PM2.5 pollution. Cell migration, invasion, EMT (epithelial-mesenchymal transition) and autophagy were elevated when lung cancer cells were treated with CSE and PM2.5 in combination. A lncRNA, named lung cancer progression-association transcript 1 (LCPAT1), was up-regulated after the treatment of CSE and PM2.5, and knocking down the lncRNA impaired the effect of CSE and PM2.5 on lung cancer cells. In addition, LCPAT1 was shown to bind to RCC2, and RCC2 mediated the effect of LCPAT1 on cell autophagy, migration, invasion and EMT in lung cancer. Conclusions: Our results suggest that combined exposure to CSE and PM2.5 induces LCPAT1 expression, which up-regulates autophagy, and promotes lung cancer progression via RCC2.

Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

Childhood acute lymphoblastic leukemia is common in Latino Americans. Here, the authors conduct a genome-wide association study in a Californian cohort containing children of Latino heritage, and identify loci on 17q12 and 8q24 which may affect hematopoietic and growth-regulation pathways.

Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.

As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene–gene interaction networks enriched by those topmost pathways, we identified KDs—both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)—in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.

Objective: Recent research has indicated that altered promoter methylation of oncogenes and tumor suppressor genes is an important mechanism in lung cancer development and progression. In this study, we investigated the association between promoter methylation of TMEM88, a possible inhibitor of the Wnt/β-Catenin signaling, and the survival of patients with non-small cell lung cancer (NSCLC). Methods: Twelve pairs of tumor and adjacent non-tumor samples were used for microarray analyses of DNA methylation and gene expression. For validation, more than two hundred additional samples were analyzed for methylation using bisulfite pyrosequencing and for gene expression using qRT-PCR. Then the cell function were tested by wound healing, transwell, CCK8 and cell cycle assay. Results: Our analysis of patient specimens showed that TMEM88 methylation was higher in NSCLC tumors (82.2% ± 10.3, P < 0.01) compared with the adjacent normal tissues (65.9% ± 7.2). The survival analysis revealed that patients with high TMEM88 methylation had a shorter overall survival (46 months) compared with patients with low TMEM88 methylation (>56 months; P=0.021). In addition, we found that demethylation treatment could inhibit tumor cell proliferation, migration, and invasion, which was supportive of an association between methylation and survival. Conclusions: Based on these consistent observations, we concluded that TMEM88 may play an important role in NSCLC progression and that promoter methylation of TMEM88 may serve as a biomarker for NSCLC prognosis and treatment.

Long intergenic noncoding RNAs (lincRNAs) are a relatively new class of non-coding RNAs that have the potential as cancer biomarkers. To seek a panel of lincRNAs as pan-cancer biomarkers, we have analyzed transcriptomes from over 3300 cancer samples with clinical information. Compared to mRNA, lincRNAs exhibit significantly higher tissue specificities that are then diminished in cancer tissues. Moreover, lincRNA clustering results accurately classify tumor subtypes. Using RNA-Seq data from thousands of paired tumor and adjacent normal samples in The Cancer Genome Atlas (TCGA), we identify six lincRNAs as potential pan-cancer diagnostic biomarkers (PCAN-1 to PCAN-6). These lincRNAs are robustly validated using cancer samples from four independent RNA-Seq data sets, and are verified by qPCR in both primary breast cancers and MCF-7 cell line. Interestingly, the expression levels of these six lincRNAs are also associated with prognosis in various cancers. We further experimentally explored the growth and migration dependence of breast and colon cancer cell lines on two of the identified lncRNAs. In summary, our study highlights the emerging role of lincRNAs as potentially powerful and biologically functional pan-cancer biomarkers and represents a significant leap forward in understanding the biological and clinical functions of lincRNAs in cancers.

Background: Obesity is not a homogeneous condition across individuals since about 25–40% of obese individuals can maintain healthy status with no apparent signs of metabolic complications. The simple anthropometric measure of body mass index does not always reflect the biological effects of excessive body fat on health, thus additional molecular characterizations of obese phenotypes are needed to assess the risk of developing subsequent metabolic conditions at an individual level. Methods: To better understand the associations of free fatty acids (FFAs) with metabolic phenotypes of obesity, we applied a targeted metabolomics approach to measure 40 serum FFAs from 452 individuals who participated in four independent studies, using an ultra-performance liquid chromatograph coupled to a Xevo G2 quadruple time-of-flight mass spectrometer. Findings: FFA levels were significantly elevated in overweight/obese subjects with diabetes compared to their healthy counterparts. We identified a group of unsaturated fatty acids (UFAs) that are closely correlated with metabolic status in two groups of obese individuals who underwent weight loss intervention and can predict the recurrence of diabetes at two years after metabolic surgery. Two UFAs, dihomo-gamma-linolenic acid and palmitoleic acid, were also able to predict the future development of metabolic syndrome (MS) in a group of obese subjects. Interpretation: These findings underscore the potential role of UFAs in the MS pathogenesis and also as important markers in predicting the risk of developing diabetes in obese individuals or diabetes remission after a metabolic surgery.

Background: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are suspected to be related to the survival of lung cancer patients due to their possible influence on DNA repair capacity (DRC). However, the study results are inconsistent. Methods: A follow-up study of 610 non-small cell lung cancer (NSCLC) patients was conducted to investigate genetic polymorphisms associated with the DNA repair genes in relation to NSCLC survival; 6 SNPs were genotyped, including XRCC1 (rs25487 G>A), hOGG1 (rs1052133 C>G), MUTYH (rs3219489 G>C), XPA (rs1800975 G>A), ERCC2 (rs1799793 G>A) and XRCC3 (rs861539 C>T). Kaplan-Meier survival curve and Cox proportional hazards regression analyses were performed. SNP-SNP interaction was also examined using the survival tree analysis. Results: Advanced disease stage and older age at diagnosis were associated with poor prognosis of NSCLC. Patients with the variant ‘G' allele of hOGG1 rs1052133 had poor overall survival compared with those with the homozygous wild ‘CC' genotype, especially in female patients, adenocarcinoma histology, early stage, light smokers and without family history of cancer. For never smoking female lung cancer patients, individuals carrying homozygous variant ‘AA' genotype of XPA had shorter survival time compared to those with wild ‘G' alleles. Furthermore, females carrying homozygous variant XPA and hOGG1 genotypes simultaneously had 2.78-fold increased risk for death. Among all 6 polymorphisms, the homozygous variant ‘AA' of XPA carriers had poor prognosis compared to the carriers of wild ‘G' alleles of XPA together with other base excision repair (BER) polymorphisms. Conclusions: Besides disease stage and age, the study found DNA repair gene polymorphisms were associated with lung cancer survival.

Pancreatic cancer has been increasing in importance in Shanghai over the last four decades. The etiology of the disease is still unclear. Evidence suggests that the COX-2 pathway, an important component of inflammation, may be involved in the disease. We aimed to evaluate the association between urinary prostaglandin E2 metabolite (PGE-M) level and risk of pancreatic cancer. From a recent population-based case-control study in Shanghai, 200 pancreatic ductal adenocarcinoma cases and 200 gender- and age- frequency matched controls were selected for the present analysis. Urinary PGE-M was measured with a liquid chromatography/mass spectrometric assay. Adjusted unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A positive association was observed between PGE-M leve and pancreatic cancer risk: OR = 1.63 (95% CI 1.01-2.63) for the third tertile compared to the first. Though the interactions were not statistically significant, the associations tended to be stronger among subjects with diabetes history (OR = 3.32; 95% CI 1.20-9.19) and higher meat intake (OR = 2.12; 95% CI 1.10-4.06). The result suggests that higher urinary PGE-M level may be associated with increased risk of pancreatic ductal adenocarcinoma.

Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10-5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk.

Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p

To investigate the biologic relevance and clinical implication of genes involved in multiple gene expression signatures for breast cancer prognosis, we identified 16 published gene expression signatures, and selected two genes, MAD2L1 and BUB1. These genes appeared in 5 signatures and were involved in cell-cycle regulation. We analyzed the expression of these genes in relation to tumor features and disease outcomes. In vitro experiments were also performed in two breast cancer cell lines, MDA-MB-231 and MDA-MB-468, to assess cell proliferation, migration and invasion after knocking down the expression of these genes. High expression of these genes was found to be associated with aggressive tumors and poor disease-free survival of 203 breast cancer patients in our study, and the association with survival was confirmed in an online database consisting of 914 patients. In vitro experiments demonstrated that lowering the expression of these genes by siRNAs reduced tumor cell growth and inhibited cell migration and invasion. Our investigation suggests that MAD2L1 and BUB1 may play important roles in breast cancer progression, and measuring the expression of these genes may assist the prediction of breast cancer prognosis.