Non-hormonal contraceptives that do not require use immediately before or after intercourse would likely meet the reproductive health needs of millions of women. We previously reported the engineering of MM008, a highly multivalent monoclonal antibody with 10 Fabs against a unique human sperm antigen, which agglutinates and prevents sperm from swimming through cervicovaginal mucus to reach eggs. Here, we report the development of a versatile capsule-intravaginal ring (IVR) platform that affords precise tuning of mAb release kinetics, enabling both rapid-on and sustained release of MM008 over 30 days into vaginal fluid simulants in vitro, while fully preserving activity and stability. In vivo, MM008-released from the capsule-IVR agglutinated all human sperm introduced into the sheep vagina within 1 min over a span of at least 21 days, a duration that covers the fertility window for women with menstrual cycles up to ∼39 days. MM008-IVR was safe and well tolerated in sheep. These results support further development of MM008-IVR as a long-acting non-hormonal contraceptive, and highlight the broader potential for the capsule-IVR platform to deliver diverse biologics to reinforce female reproductive health.

Abstract An inverse association between asthma and several cancer types has been consistently observed across epidemiologic studies, yet the molecular mechanisms underlying this relationship remain unclear. To address this gap, we conducted a comprehensive genetic and functional analysis to identify variants, genes, and immune signaling pathways that may contribute to this protective association. From literature-validated genome-wide association studies, we compiled 246 asthma-associated SNPs and identified 14 variants that were also significantly associated with cancer risk. Notably, 11 of these SNPs demonstrated reversal directionality, where the asthma risk allele was associated with reduced cancer risk, particularly in glioma and colorectal cancer. Haplotype analysis further revealed 19 genes exhibiting diametric effects on asthma and cancer susceptibility. Among these, IL-9, TLR1, SMAD7, LPP, IL-7R, and HLA-DQB1 also showed inverse gene expression patterns between asthma tissues and multiple cancer types, indicating functional opposition at the transcriptional level. Pathway enrichment using Ingenuity Pathway Analysis identified Th1/Th2 immune axis regulation and glucocorticoid receptor signaling as central networks driving this biological divergence. Specifically, genes upregulated in asthma that elevate Th2-dominant IgE-mediated immune responses were linked to enhanced immunosurveillance and T-cell cytotoxic activation in cancer contexts, suggesting a mechanistic basis for reduced tumor initiation and progression. Meanwhile, glucocorticoid receptor isoform regulation emerged as a potential modulator linking asthma treatment to cancer vulnerability. Together, these results provide the first integrated genetic, transcriptomic, and pathway-level evidence supporting a causal immunologic framework for the inverse asthma-cancer association. This work highlights new molecular targets at the interface of allergic inflammation and tumor immunity and suggests opportunities for therapeutic repurposing of immune-modulating strategies used in asthma to inform cancer prevention and treatment. Citation Format: Kinsey Garofalo, Yinqiao Wang, Peyton Cook, Yujuan Guo, Yong Zhu. Genetic and immune signaling divergence underlies the inverse associationbetween asthma and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3590.

High enrichment of N-nitrosamines (NAs) and microcystins (MCs) in drinking water are major risk factors in high-risk areas of esophageal squamous cell carcinoma (ESCC) in China, however, their combined effects and underlying carcinogenic mechanisms remain unknown. The scRNA_seq sequencing and CTD database were used to identify the “chemical-epithelial cell” associated carcinogenic targets. An ESCC rat model was established to confirm the combined effect of NAs and MCs; RNA-Seq was performed to screen potential circRNAs in ESCC and matched adjacent normal tissues. Malignant transformation of esophageal epithelial cells (Het-1A-T) was induced by exposure to N-nitrosomethylbenzylamine (NMBzA) and Microcystin-LR (MC-LR). The biological function of hsa_circ_0063865 was investigated using gain- and loss-of-function experiments in vitro and in vivo. RNA pull-down, ChIRP, RIP, Co-IP and luciferase reporter assays were used to elucidate the underlying mechanisms of hsa_circ_0063865 in chemically related ESCC. The rat ESCC model and median-effect principle showed a synergistic effect of NAs and MC-LR in chemical carcinogenesis. Further, integration of single-cell and network toxicology revealed 292 “chemical-epithelial cell” associated carcinogenic targets, which were primarily involved in microRNA in cancer and cytoskeleton rearrangements. At the molecular level, the chemical carcinogenesis-related hsa_circ_0063865 was identified and found to be up-regulated in ESCC tissues. Functionally, hsa_circ_0063865 promoted malignant transformation of Het-1A cells induced by NMBzA and MC-LR by promoting cytoskeletal rearrangements and inhibiting ER stress of MYH9+ epithelial cell. Mechanistically, hsa_circ_0063865 acted as a modular scaffold to tether eEF1A2(126-177nt of hsa_circ_0063865) and NMIIA (601-658nt of hsa_circ_0063865), thereby promoting NMIIA translation by enhancing the interaction between eEF1A2 and NMIIA, which further promoted cytoskeletal reorganization; Additionally, hsa_circ_0063865 competitively upregulated RCN1 expression by sponging miR-450b-3p, resulting in ER stress inhibition and depolarization of mitochondrial membrane potential via activation of the PERK-eIF2α-ATF4-CHOP axis in MYH9+ epithelial cell. These findings identify a novel chemical carcinogenic target and elucidate the dual-regulatory mechanism of hsa_circ_0063865 in NAs and MC-LR-induced esophageal carcinogenesis.

Colorectal cancer remains a major public health concern in Arkansas and across the United States, disproportionately affecting rural and vulnerable populations. Beyond established lifestyle and genetic factors, environmental exposures, particularly agricultural chemicals, are increasingly recognized as potential contributors. In this ecological study, we screened 133 county-level estimated air pollutants to identify candidates associated with colorectal cancer incidence rates, focusing on Arkansas due to its agricultural economy and widespread herbicide use. Using publicly available environmental and cancer registry data, we applied spatial mapping, correlation tests, linear regression, and spatial regression models. Among screened pollutants, 2,4-Dichlorophenoxyacetic acid (2,4-D), a widely used herbicide, emerged as the top candidate. In Arkansas, 2,4-D emissions showed a strong positive association with colorectal cancer incidence rates (Spearman ρ = 0.338, p = 0.003; linear regression β1 = 6.28, p = 0.001), with high-emission counties aligning spatially with elevated incidence. This relationship was further confirmed in analyses of more than 2,500 U.S. counties, where 2,4-D emissions remained significantly associated with colorectal cancer (linear regression β1 = 5.94, p < 0.001; spatial regression β1 = 2.55, p = 0.001). Spatial regression improved model fit and accounted for geographic autocorrelation in both datasets. These findings suggest a potential association between 2,4-D emissions and colorectal cancer incidence rates, particularly in agricultural regions such as Arkansas. While causal inference is limited by the ecological design, the consistency of results warrants follow-up with individual-level, longitudinal, and mechanistic studies.

Nearly half of pregnancies globally are unintended, reflecting the current unmet need in safe, effective non‐hormonal contraception. While anti‐sperm IgM is responsible for infertility in many women, stability and bioprocessing challenges with IgM make them ill‐suited for non‐hormonal contraception. Similarly, IgG lacks sufficient sperm agglutination potencies. To overcome these shortcomings, a novel, multivalent mAb platform is developed, based on fusing the Laminin 511 heterotrimerization domains to Fabs and IgG1‐Fc, allowing for tuning of Fab valency (from 2–12) with molecular specificity. ‘LamH10’, the most potent mAb among the panel of polyvalent antibodies against CD52g on human sperm, comprises 10 Fabs per molecule, and achieves nanomolar potencies at physiological temperatures and retains stability in the acidic environment of human cervicovaginal mucus. In sheep, LamH10 reduced progressively motile sperm in the vagina by >99% within 2 min at just 33 µg per sheep. LamH10 utilizes the same conventional bioprocessing as IgGs, and can be formulated into rapidly dissolving tablets for on‐demand contraception, achieving 100% sperm agglutination within minutes of vaginal dosing. The laminin‐IgG hybrid platform not only forms the basis of the most potent biologic for nonhormonal contraception to date, but also represents a promising platform for multivalent mAbs for other applications.

Light at night (LAN) is a widespread environmental exposure and circadian disruptor that may influence cancer risk by interfering with biological and physiological processes. While experimental and epidemiologic evidence links LAN and circadian disruption to hormone-related cancers, large-scale ecological evidence across multiple cancer sites remains limited. We examined the association between ambient LAN and incidence of several cancers, with a focus on hormone-related sites, in the Northeastern United States. This ecological study used county-level data from all seven Northeastern states. LAN exposure was quantified using satellite-derived nighttime illumination, and age-adjusted incidence rates for breast, prostate, thyroid, non-Hodgkin lymphoma (NHL), and colon cancers were obtained from national registries. Linear regression and spatial analyses were conducted, adjusting for population density, poverty, race/ethnicity, insurance, disability, and education. We found significant positive associations between LAN and hormone-related cancers, including breast (p = 0.007), prostate (p = 0.022), non-Hodgkin Lymphoma (p = 0.049), and thyroid cancer (p < 0.001), with the thyroid association being most the robust. In contrast, a consistent inverse association was observed between LAN and colon cancer incidence (p < 0.05). These findings suggest that ambient LAN may contribute to higher risks of several hormone-related cancers, potentially modified by socioeconomic and racial/ethnic disparities. Future research using individual-level data and mechanistic studies is needed to clarify pathways linking LAN, circadian disruption, and cancer risk.

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related death globally and is the fastest-growing cause of cancer-related deaths in the United States. Current therapies, such as chemotherapy and radiotherapy, are largely ineffective in advanced HCC due to tumor-specific characteristics, resistance to drugs and radiation, and substantial adverse effects. Despite breakthroughs in immunotherapy, approximately 80-85% of American patients with advanced HCC fail to respond to treatments. These challenges underscore the urgent need for more effective therapeutic strategies to treat HCC. One emerging therapeutic strategy involves the use of small non-coding RNAs (ncRNAs), which have shown promising efficacy in both preclinical and clinical studies for various cancer types. Piwi-interacting RNAs (piRNAs) are an abundant of small non-coding RNAs (ncRNAs) involved in maintaining genomic stability and represent a promising but largely unexplored avenue for cancer treatment. The current study identified a piRNA candidate and examined its therapeutic implication for the treatment of HCC. First, we performed piRNA arrays for small RNAs isolated from 12 pairs of HCC tissues and normal liver tissues and detected significantly downregulated piRNAs in HCC tissues compared to normal liver tissues. Downregulation of piR-37213 was confirmed using the TCGA small RNA-seq data of HCC tissues (N=331) and normal liver tissues (N=48). Lipid nanoparticles (LNP) were used as a delivery vehicle to capsulate piR-37213 in functional tests. Significant tumor-suppressing effects of piR-37213 were observed in a series of in vitro assays (P<0.01), including cell proliferation assays, colony formation assays, 3D formation and invasion assays. Systemic delivery of LNP-piR-37213 was administered in animal experiments. Mice (N=44) were treated twice a week for four consecutive weeks via tail vein injection. Tumor signals were significantly reduced by 90% P<0.001) after 2 weeks of treatment. Survival was significantly improved (P<0.05). Both in vitro and in vivo experiments suggest that the identified piRNA candidates, which are downregulated in HCC tissues, play a tumor-suppressing role. A genome-wide expression profiling analysis was further performed and found that genes involved in cell cycle proliferation, replication, and DNA repair were significantly downregulated, which further provided molecular mechanisms accounting for the anti-tumor effect of under-expressed piR-37213. This preclinical study represents the crucial initial step in developing a novel, piRNA-based therapeutic strategy for liver cancer and provides proof of principle for the use of piRNAs in future clinical treatment. Future studies are needed to explore the transformative potential of this early-stage, highly innovative, piRNA-based technology in cancer treatment. Rui Han, Qin Qin, Ran Liu, Tianshu Wu, Yaya Guo, Peyton Cook, Kinsey Garofalo, Yujuan Guo, Bolni Nagalo, Yong Zhu. PiRNA as a novel therapeutic in hepatocellular carcinoma: insights from population screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2792.

Efficacy of on-demand nonhormonal contraception that targets and disables progressively motile sperm (PMS) can be studied through surrogate postcoital testing (PCT) in sheep models, due to similarities to human reproductive tract size and anatomy. We utilized PCT to assess the contraceptive potential of anti-sperm antibody in tablet form in vivo in sheep. Pooled semen from five prescreened human male donors was collected and evaluated for adequate motility prior to use. Ewes (n=6) were given a quick-dissolving tablet delivering active anti-sperm antibody, a placebo tablet, or phosphate-buffered saline (PBS) as a control measure. Coital simulation included mixing tablet/PBS in the sheep vagina for 5 minutes with 15 strokes with a test tube, instilling 1 mL of semen for 2 minutes, mixing with five test tube strokes, and retrieving the semen/drug/vaginal secretion mixture for microscopic examination. Progressively motile sperm were counted via video analysis for pooled and sheep samples, reported as #PMS/high powered field (hpf), and analyzed with ANOVA (P<.05 significant). Pooled semen had 13.4±3.1 PMS/hpf. Control sheep (PBS) had 3.7±2.6 PMS/hpf. Sheep given the antibody tablet had 0.04±0.05 PMS/hpf, whereas the placebo had 2.7±2.0 PMS/hpf (P<.001). The antibody tablet reduced the fraction of PMS by ∼99%. In clinical studies, less than 1.0 PMS/hpf has been a threshold for effective contraception; therefore, the results from this study indicate that suitably formulated tablets delivering anti-sperm antibody could serve as an effective nonhormonal contraceptive.

INTRODUCTION: An alternative to hormonal contraception utilizes vaginal methods, such as anti-sperm antibodies that bind and reduce progressively motile sperm (PMS). Sheep models, due to similar reproductive anatomy and size as humans, have been used for surrogate postcoital testing during development of vaginal products to evaluate potential for contraceptive efficacy before advancing to testing in humans. METHODS: Pooled semen from five prescreened human male donors was collected and evaluated for adequate motility prior to use. Ewes (n=12) were given a 1-mL dose of 3.3, 33, or 333 micrograms of proprietary antibody or phosphate-buffered saline (PBS) control solution, then mixed with 15 strokes with a test tube. After 5 minutes, 1 mL of semen was instilled for 2 minutes, mixed with five test tube strokes, and the semen/drug/vaginal secretion mixture was retrieved for microscopic examination. Progressively motile sperm were counted via video analysis for pooled and sheep samples, reported as #PMS/high powered field (hpf), and analyzed with ANOVA ( P <.05 significant). RESULTS: Pooled semen had 35±6 PMS/hpf. Control sheep (PBS) had 10±3 PMS/hpf. Sheep given the 3.3-, 33-, and 333-microgram doses had 3.3±2, 0.2±0.5, and 0.07±0.2 PMS/hpf, respectively. The two highest concentration solutions reduced the fraction of PMS by 98–99%. CONCLUSIONS/IMPLICATIONS: With a threshold of less than 1.0 PMS/hpf considered effective contraception in clinical studies, the 33- and 333-microgram antibody solutions showed potential for contraceptive use in this sheep PCT study. However, the solutions would require formulation into a usable product prior to advancement into human studies.

IntroductionWhile genome-wide association studies (GWAS) have identified numerous susceptibility loci in Colorectal cancer (CRC), most findings are based on European populations. Additionally, CRC shares genetic architecture with other traits, and multi-trait analysis can improve the discovery of pleiotropic loci.Materials and methodsWe conducted a multi-trait GWAS using the Multi-Trait Analysis of GWAS (MTAG) framework, leveraging large-scale genomic and phenotypic data from BioBank Japan (BBJ). We also examined genetic correlations between CRC and 70 complex traits, followed by local genetic correlation analysis and enrichment of heritability partitioned by chromatin states and tissue types.ResultsWe identified 25 genome-wide significant loci for CRC and colon polyps, including three novel loci in East Asian populations: BET1L (rs12226698, 11p15.5), OAS1 (rs2525858, 12q24.13), and BMP2 (rs4813802, 20p12.3). While BMP2 had been previously reported in European CRC studies, BET1L and OAS1 represent novel associations in East Asians. Colocalization analysis confirmed strong shared association signals between BET1L and OAS1 in CRC and colon polyps, supporting their pleiotropic effects in colorectal neoplasia. BET1L was further identified in the multi-trait analysis of CRC and myocardial infarction. Similarly, OAS1 was significantly associated with CRC and angina pectoris. Functional annotation revealed that these loci serve as expression quantitative trait loci (eQTLs) in colorectal tissues and immune-related pathways.ConclusionOur study identifies novel pleiotropic loci associated with CRC in East Asians, emphasizing the importance of population-specific genetic studies. The findings provide new insights into the genetic architecture of CRC and its shared pathways with other complex diseases.

Chemoresistance remains a major challenge in addressing T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL), underscoring the necessity for novel strategies to unravel the molecular factors driving resistance. Through transcriptomic profiling, circBPTF was found to be markedly overexpressed in chemoresistant samples. Further functional experiments demonstrated that BPTF-665aa, the protein product of circBPTF, plays a pivotal role in mediating resistance. Notably, BPTF-665aa prevents the ubiquitination degradation of full-length BPTF, and promotes chromatin accessibility at key promoter sites, such as that of c-Myc promter 2 (P2), facilitating transcriptional activation crucial for cellular survival and proliferation under therapeutic stress. Structural studies confirmed the motifs of BPTF-665aa, including the Plant Homeodomain (PHD) finger and Bromodomain, essential for its chromatin remodeling function. HY-B0509 was identified as a small-molecule inhibitor of BPTF-665aa, with molecular docking and dynamics simulations showing stable binding to critical residues within the protein's active site. Overall, this study introduces a new mechanism where circBPTF affects chromatin accessibility, causing chemoresistance, making BPTF-665aa as a potential therapeutic target for treating T-LBL/ALLs.

There are limited options available for safe and effective non-hormonal contraceptives or methods that block sexually transmitted diseases such as herpes simplex virus (HSV). Direct vaginal delivery of monoclonal antibodies (mAb) represents a promising approach toward both goals, but clinical translation has been limited by the lack of convenient dosage forms that can quickly and stably deliver mAbs without mess. Here, we report the development of fast-dissolving antibody tablets (FDAT) that allow for the complete release of fully functional mAbs within seconds in vaginal fluid simulants, and within two minutes in fresh human cervicovaginal mucus ex vivo. As proof-of-concept, we developed two FDAT formulations: one for HSV8, a potent neutralizing mAb against both HSV Type 1 and 2, and a second for MM008, a unique 10-Fab anti-sperm mAb that induces sperm agglutination and inhibits progressive sperm motility with picomolar potency. In sheep studies, vaginally inserted HSV8-FDAT achieved uniform distribution in different parts of the vagina within minutes, while fully maintaining HSV8 neutralization activity. Similarly, MM008-FDAT completely eliminated all progressively motile sperm within 2 min of human semen instillation. Finally, the FDATs were stable for at least 3 months of storage at room temperature within desiccated water-impermeant foil pouches, and repeated daily application of FDATs for 7 days was safe and well tolerated in sheep. These results underscore the potentials of the FDAT platform for delivery of biologic interventions to reinforce female reproductive health.

Objective The incidence of neuroendocrine tumors (NET) has been increasing globally for several decades. The objective of the study was to examine the most recent trend in the incidence of NET as well as disparities by sex and race/ethnicity in adults in the USA. Methods Patients with NET aged ≥20 years were identified from the SEER 22 Registries from 2000 to 2020. The age-adjusted incidence rate was calculated for overall NET and by primary site. The incidence trend was assessed by annual percent change. Disparities by sex and race/ethnicity were examined using the incidence rate ratio. Results Age-adjusted incidence rate of overall NET in adults was 9.39 per 100 000 in 2000–2020. The incidence rate increased from 2000 but reached a plateau with no significant change since 2015. The lung and bronchus, small intestine, and rectum were the most common primary sites. Sex and racial/ethnic disparities in NET incidence varied by primary sites. For example, there was a female excess in NET of the lung and bronchus, stomach, and appendix; and there was a male excess in the small intestine, pancreas, colon, rectum and other/unknown NET. Compared to non-Hispanic white, non-Hispanic black had higher incidences of stomach, small intestine, liver, pancreas, colon, rectum, and other/unknown NET; they had lower incidences of lung and bronchus, and appendix NET than non-Hispanic white. Conclusion Age-adjusted incidence rate of overall NET has reached a plateau since 2015. However, there were sex and racial/ethnic disparities in such incidence, which varied depending on the primary site of NET.

The widespread and pervasive use of artificial light at night (ALAN) in our modern 24-hour society has emerged as a substantial disruptor of natural circadian rhythms, potentially leading to a rise in unhealthy lifestyle-related behaviors (e.g., poor sleep; shift work). This phenomenon has been associated with an increased risk of type 2 diabetes mellitus (T2DM), which is a pressing global public health concern. However, to date, reviews summarizing associations between ALAN and T2DM have primarily focused on the limited characteristics of exposure (e.g., intensity) to ALAN. This literature review extends beyond prior reviews by consolidating recent studies from 2000 to 2024 regarding associations between both indoor and outdoor ALAN exposure and the incidence or prevalence of T2DM. We also described potential biological mechanisms through which ALAN modulates glucose metabolism. Furthermore, we outlined knowledge gaps and investigated how various ALAN characteristics beyond only light intensity (including light type, timing, duration, wavelength, and individual sensitivity) influence T2DM risk. Recognizing the detrimental impact of ALAN on sleep health and the behavioral correlates of physical activity and dietary patterns, we additionally summarized studies investigating the potential mediating role of each component in the relationship between ALAN and glucose metabolism. Lastly, we proposed implications of chronotherapies and chrononutrition for diabetes management in the context of ALAN exposure.

Alternative polyadenylation (APA) is a crucial mechanism for regulating gene expression during pre-mRNA 3 ' processing. Pre-mRNA 3 ' end processing factors is the main factor involved in this process. However, pre-mRNA 3 ' end processing factors in different cancer expression profiles and the relationship between pre-mRNA 3 ' end processing factors and tumor microenvironment and the prognosis of the same patient is still unclear. In this study, we conducted a comprehensive exploration of the core pre-mRNA 3 ' end processing factors across various cancer types by utilizing common cancer database, and revealing a robust correlation between the expression of these core factors and tumor characteristics. Leveraging advanced bioinformatics databases, we evaluated the expression levels and prognostic relevance of pre-mRNA 3 ' end processing factors across pan-cancer tissues. Our extensive pan-cancer analysis revealed unique expression patterns of pre-mRNA 3 ' end processing factors in both tumor and adjacent non-tumorous tissues. Notably, we found a significant correlation between the expression levels of pre-mRNA 3 ' end processing factors and patient prognosis. Furthermore, we identified strong associations between pre-mRNA 3 ' end processing factors expression and various factors, such as stromal, immune, RNA stemness, and DNA stemness scores across pan-cancer tissues. Our data also highlighted a link between the expression of pre-mRNA 3 ' end processing factors and sensitivity to specific drugs, including pyrazoloacndine, amonaflide, and chelerythrinede, among others. We found four key pre-mRNA 3 ' end processing factors that play a crucial role in mRNA preprocessing. Our study illuminates the potential promotion and inhibition role of pre-mRNA 3 ' end processing regulators in the progression of cancer, CPSF2, CPSF3, CSTF2, SYMPK offering valuable insights for future research investigations on these regulators as diagnostic markers and therapeutic targets across pan-cancer.

Oxidative stress is intimately involved in the pathogenesis of fatty liver disease (FLD). A major factor contributing to oxidative stress is the depletion of the ubiquitous antioxidant glutathione (GSH). Unexpectedly, chronic GSH deficiency renders glutamate-cysteine ligase modifier subunit (Gclm)-null mice protected from fatty liver injuries. Epigenetic regulation serves as an important cellular mechanism in modulating gene expression and disease outcome in FLD, although it is not well understood how systemic redox imbalance modifies the liver epigenome. In the current study, utilizing the Gclm-null mouse model, we aimed to elucidate redox-associated epigenomic changes and their implications in liver stress response. We performed high-throughput array-based DNA methylation profiling (MeDIP array) in 22,327 gene promoter regions (from -1300 bp to +500 bp of the Transcription Start Sites) in the liver and peripheral blood cells. Results from the MeDIP array demonstrate that, although global methylation enrichment in gene promoters did not change, low GSH resulted in prevalent demethylation at the individual promoter level. Such an effect likely attributed to a declined availability of the methyl donor S-adenosyl methionine (SAM) in Gclm-null liver. Functional enrichment analysis of liver target genes is suggestive of a potential role of epigenetic mechanisms in promoting cellular survival and lipid homeostasis in Gclm-null liver. In comparison with the liver tissue, MeDIP array in peripheral blood cells revealed a panel of 19 gene promoters that are candidate circulating biomarkers for hepatic epigenomic changes associated with chronic GSH deficiency. Collectively, our results provided new insights into the in vivo interplay between liver redox state and DNA methylation status. The current study laid the groundwork for future epigenetic/epigenomic investigations in experimental settings or human populations under conditions of liver oxidative stress induced by environmental or dietary challenges.

Concerns are raised over the risk to digestive system's tumors from the N-nitrosamines (NAs) exposure in drinking water. Albeit considerable studies are conducted to explore the underlying mechanism responsible for NAs-induced esophageal squamous cell carcinoma (ESCC), the exact molecular mechanisms remain largely unknown, especially at the epigenetic regulation level. In this study, it is revealed that the urinary concentration of N-Nitrosodiethylamine is higher in high incidence area of ESCC, and the lncRNA-UCA1(UCA1) is significantly decreased in ESCC tissues. In vitro and in vivo experiments further show that UCA1 is involved in the malignant transformation of Het-1A cells and precancerous lesions of the rat esophagus induced by N-nitrosomethylbenzylamine (NMBzA). Functional gain and loss experiments verify UCA1 can affect the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Mechanically, through binding to heterogeneous nuclear ribonucleoprotein F (hnRNP F) protein, UCA1 regulates alternative splicing of fibroblast growth factor receptor 2 (FGFR2), which promotes the FGFR2IIIb isoform switching to FGFR2 IIIc isoform, and the latter activates epithelial-mesenchymal transition via PI3K-AKT signaling pathways impacting tumorigenesis. Therefore, NAs-mediated downregulation of UCA1 promotes ESCC progression through targeting hnRNP F/FGFR2/PI3k-AKT axis, which provides a new chemical carcinogenic target and establishes a previously unknown mechanism for NAs-induced ESCC.

Supplementary Tables 1-3 from Clock-Cancer Connection in Non–Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2