[This corrects the article on p. 2537 in vol. 11, PMID: 34249415.].

Diet rich in antioxidant may protect against chronic respiratory disease (CRD), but few studies have evaluated the association between composite dietary antioxidant index (CDAI) and CRD. The study aimed to examine the association of CDAI with the risk of CRD and all-cause mortality in CRD patients from the US. Data were obtained from the National Health and Nutrition Examination Survey, 2003–2018. Logistic and Cox regression analyses were used to estimate association of CDAI with CRD and all-cause mortality. Dose-response relationship was examined by restricted cubic spline analyses. Total 44,094 participants were eligible for CRD (aged 1–85 years; mean age: 45.71 years old), and 7,685 CRD patients for all-cause mortality (median follow-up: 7.58 years; 1,136 deaths before 12/31/2019). The risk for CRD, asthma, and chronic obstructive pulmonary disease was significantly decreased by 13–32

[This corrects the article on p. 4141 in vol. 11, PMID: 34659881.].

Hepatocellular carcinoma (HCC) is resistant to multiple conventional drugs including sorafenib, leading to poor prognosis. Inducing cell death has been inextricably pursued in therapeutics, although targeted therapy and immunotherapy have made very limited progress. ASPH (Aspartate β-hydroxylase) can be breakthrough in meeting this unmet clinical need. In HCC, high expression of ASPH enhanced proliferation, migration and invasion. High levels of ASPH predicted worse clinical outcomes of sorafenib-treated HCC patients. Mechanistically, ASPH upregulated SQSTM1/P62 and SLC7A11-GPX4 axis, thereby promoting tumor cell autophagy but blocking ferroptosis. Sorafenib-induced enhancement of autophagy was attenuated by knockout (KO) of ASPH, resulting in sensitization of tumor cells to sorafenib. By silencing ASPH combined with sorafenib, senescence, apoptosis and ferroptosis were mediated, whereas proliferation, migration, invasion, tube formation and stemness were inhibited. As validated by in vivo murine models of HCC, ASPH promoted tumor growth, distant metastasis, and resistance to sorafenib. By contrast, KO ASPH combined with sorafenib effectively inhibited tumor development and progression, including intrahepatic, pulmonary, and splenic metastases. Targeting ASPH generated antitumor efficacy will pave the way for HCC therapy.

Visceral adiposity index (VAI) vividly reflects body fat distribution through comprehensively integrating body mass index, sex, waist circumference, triglycerides, and high-density lipoprotein cholesterol. While VAI is an established predictor of various clinical outcomes, its relationship with premature mortality and life expectancy remains unclear. To explore the association between VAI and premature mortality or life expectancy in a nationally representative cohort of US adults. This study included adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018, linked to the National Death Index through December 31, 2019. Data were analyzed from August to October, 2024. VAI was categorized into quartiles from the lowest Q1 to the highest Q4. Primary endpoints were premature mortality (death before 80 years of age) and life expectancy. A total of 43,672 participants (women: 22,164; men: 21,508) aged > 20 years were included. Over a median follow-up of 9.2 years (IQR: 4.9–13.8), 3,187 premature deaths were documented. Higher VAI quartiles were significantly associated with increased multi-adjusted premature mortality risk compared to Q1 (Q3 vs. Q1: hazard ratio [HR], 95

The prognosis of lung adenocarcinoma (LUAD) is strongly influenced by its histologic growth patterns, with the micropapillary component (MPC) being a poor prognostic indicator. However, the molecular mechanisms driving the poor prognosis of the MP subtype remain unclear, particularly regarding spatial transcriptomic (ST) insights. Spatial transcriptomics (10X Genomics) was performed on 4 LUAD cases to map gene expression. Targeted next-generation sequencing (NGS) on 72 LUAD samples evaluated genetic alterations. The roles of TCF12 and its regulation via the TGF-β pathway were explored through in vitro and in vivo studies, including CCK-8 assays for cell proliferation, Transwell migration and invasion assays, and sphere formation assays to assess tumorigenic potential. Western blotting and PCR were used to analyze protein and gene expression levels, respectively. Immunohistochemistry of 160 LUAD samples validated TCF12 and PD-L1 expression correlations. Furthermore, mouse xenograft tumor models were employed to verify the effects of TCF12 on tumor growth and its interaction with the TGF-β pathway and PD-L1 expression in vivo. The first spatial transcriptomic map of LUAD revealed significant spatial heterogeneity, with the MP pattern strongly linked to TGF-β signaling and immune responses. TCF12 was highly expressed in MP regions, activating TGF-β signaling and upregulating PD-L1 expression. Functional assays demonstrated that TCF12 overexpression promoted proliferation, invasion, and angiogenesis in LUAD, which were suppressed by TGF-βRI kinase inhibition. In animal models, dual inhibition of TGF-β and PD-L1 significantly reduced tumor growth in TCF12-overexpressing tumors compared to single-drug and control groups. Immunohistochemistry showed that increased TCF12 expression correlated with poor survival, lymph node metastasis, and MP pattern presence. TCF12 drives PD-L1 expression via TGF-β signaling, fostering an immunosuppressive microenvironment in LUAD. Dual inhibition of TGF-β and PD-L1 restores immune function, offering a promising strategy for MP-LUAD precision therapy. TCF12, Spatial transcriptomics, TGF-β signaling, PD-L1, Lung adenocarcinoma, Micropapillary component Yifei Liu, Ting Wang, Tingting Bian, Jia Feng, Qiushi Lin, Xiaoqun Dong. TCF12 regulates PD-L1 expression through TGF-beta signaling and modulates the immune microenvironment in micropapillary lung cancer [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 203.

Importance Obesity, especially visceral obesity, is an established risk factor associated with all-cause mortality. However, the inadequacy of conventional anthropometric measures in assessing fat distribution necessitates a more comprehensive indicator, body roundness index (BRI), to decipher its population-based characteristics and potential association with mortality risk. Objective To evaluate the temporal trends of BRI among US noninstitutionalized civilian residents and explore its association with all-cause mortality. Design, Setting, and ParticipantsFor this cohort study, information on a nationally representative cohort of 32 995 US adults (age >= 20 years) was extracted from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and NHANES Linked Mortality File, with mortality ascertained through December 31, 2019. Data were analyzed between April 1 and September 30, 2023. Exposures Biennial weighted percentage changes in BRI were calculated. Restricted cubic spline curve was used to determine optimal cutoff points for BRI. Main Outcome and MeasuresThe survival outcome was all-cause mortality. Mortality data were obtained from the Centers for Disease Control and Prevention website and linked to the NHANES database using the unique subject identifier. Weibull regression model was adopted to quantify the association between BRI and all-cause mortality. Results Among 32 995 US adults, the mean (SD) age was 46.74 (16.92) years, and 16 529 (50.10%) were women. Mean BRI increased gradually from 4.80 (95% CI, 4.62-4.97) to 5.62 (95% CI, 5.37-5.86) from 1999 through 2018, with a biennial change of 0.95% (95% CI, 0.80%-1.09%; P < .001), and this increasing trend was more obvious among women, elderly individuals, and individuals who identified as Mexican American. After a median (IQR) follow-up of 9.98 (5.33-14.33) years, 3452 deaths (10.46% of participants) from all causes occurred. There was a U-shaped association between BRI and all-cause mortality, with the risk increased by 25% (hazard ratio, 1.25; 95% CI, 1.05-1.47) for adults with BRI less than 3.4 and by 49% (hazard ratio, 1.49; 95% CI, 1.31-1.70) for those with BRI of 6.9 or greater compared with the middle quintile of BRI of 4.5 to 5.5 after full adjustment. Conclusions and Relevance This national cohort study found an increasing trend of BRI during nearly 20-year period among US adults, and importantly, a U-shaped association between BRI and all-cause mortality. These findings provide evidence for proposing BRI as a noninvasive screening tool for mortality risk estimation, an innovative concept that could be incorporated into public health practice pending consistent validation in other independent cohorts.

ObjectivesThis study aimed to describe the trends of urine lead among US adults aged ≥45 years and to explore its association with all-cause and disease-specific mortality.MethodsThis study enrolled 9,669 participants from the National Health and Nutrition Examination Survey, 1999–2018. Trends in urine lead were described by logistic regression analysis using the survey cycle as a continuous variable. Cox proportional hazard regression analyses were used to quantify the association between urine lead and mortality.ResultsThere was an obvious decline in urine lead concentrations from 1.203 μg/L (95% confidence interval [CI]: 1.083–1.322) in 1999–2000 to 0.478 μg/L (95% CI: 0.433–0.523) in 2017–2018, and this decline was statistically significant (P < 0.001). Referring to the first tertile of urine lead concentrations, risk magnitude for all-cause mortality was significantly and linearly increased after adjustment (P = 0.026 and 0.020 for partially and fully adjusted models, respectively), and significance was attained for the comparison of the third vs. first tertile after full adjustment (hazard ratio [HR]: 1.17, 95% CI: 1.01 to 1.35). Treating urine lead continuously, the risk for all-cause mortality was statistically significant (HR: 1.18 and 1.19, 95% CI: 1.01 to 1.39 and 1.00 to 1.40 for partially and fully adjusted models). For cardiovascular disease-specific and cancer-specific mortality, there was no hint of statistical significance.ConclusionsOur findings indicated that urine lead exhibited a declining trend from 1999–2000 to 2017–2018 in US adults aged ≥45 years, and high urine lead was a significant and independent risk factor for all-cause mortality.

Background Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate β-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1 + cancer cells and PD-1 + T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4 + T helper type 1 (Th1)/CD8 + cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4 + /CD25 + /FOXP3 + Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH + cancer cells recruited CXCR5 + /CD8 + T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5 + immune cells and to lyse CXCR5 + cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. Conclusions Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death attributed to high frequency of metastasis and multiple drug resistance. We aim to examine the underlying molecular mechanism and to seek potential strategies to reverse primary/acquired resistance to regorafenib. Topoisomerase IIα (TOP2A) is critical for tumorigenesis and carcinogenesis. Clinically, high-TOP2A expression was correlated to shorter overall survival (OS) of patients, but its role in drug resistance of HCC remains unknown. Here, we screened the expression profiling of TOP2A in HCC and identified TOP2A as an upregulated gene involved in the resistance to regorafenib. Sustained exposure of HCC cells to regorafenib could upregulate the expression of TOP2A. Silencing TOP2A enhanced HCC cells' sensitivity to regorafenib. TOP2A inhibition by doxorubicin or epirubicin synergized with regorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant features both in vitro and in vivo. Thus, targeting TOP2A may be a promising therapeutic strategy to alleviate resistance to regorafenib and thus improving the efficacy of HCC treatment.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate β-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against β-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of β-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

The role of microRNA-21-5p (miR-21-5p) in sepsis-induced acute kidney injury (AKI) has been seldom discussed. Therefore, the objective of this present study was to investigate the mechanism of endothelial progenitor cells-derived exosomes (EPCs-exos) in sepsis-induced AKI via miR-21-5p/runt-related transcription factor 1 (RUNX1) axis. miR-21-5p was downregulated and RUNX1 was upregulated in the kidney of cecal ligation and puncture (CLP) rats, and miR-21-5p targeted RUNX1. Elevation of miR-21-5p improved renal function and renal tissue pathological damage, attenuated serum inflammatory response, as well as reduced apoptosis and oxidative stress response in renal tissues, and regulated endothelial glycocalyx damage marker proteins syndecan-1 and heparanase-1 in CLP rats. Overexpression of RUNX1 abolished the impacts of elevated miR-21-5p in CLP rats. Also, EPCs-exos upregulated miR-21-5p expression, and functioned similar to elevation of miR-21-5p for CLP rats. Downregulating miR-21-5p partially reversed the effects of EPCs-exos on sepsis-induced AKI. Collectively, our study suggests that EPCs release miR-21-5p-containing exosomes to alleviate sepsis-induced AKI through RUNX1 silencing.

Triple negative breast cancer (TNBC) is more aggressive and has a poorer prognosis than other sub-types of breast tumors. This study elucidates how aspartate beta-hydroxylase (ASPH) network promotes drug resistance, and immunotherapy targeting ASPH may improve the efficacy of Doxorubicin (DOX) therapy. An orthotopic model of breast cancer generated by 4T1 cells in immunocompetent mice was used to explore efficacy of immunotherapy in combination with DOX chemotherapy. We evaluated mRNA and protein expression in cultured tumor cells and tissue, as well as assessed cell proliferation, apoptosis, soluble factors/cytokine production, immune cell population diversity and function. We observed that ASPH expression enables TNBC cells to exhibit primary resistance to DOX induced single-/double-strand breaks (SSB/DSB) and enhanced proliferation and survival. Specific bio-nanoparticle based therapeutic vaccine (BNP-TV) promoted ASPH uptake by and maturation of DCs. This BNP-TV combined with DOX induces immunogenic cell death (ICD) in orthotopic xenograft tumors and significantly suppressed primary mammary tumor growth and distant multi-organ metastases. Immunogenic cell death induced by BNP-TV targeting ASPH combined with DOX provides opportunities to treat a highly resistant and metastatic form of breast cancer.

To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.