Hormel (United States)

Early and accurate diagnosis of Sjögren’s syndrome (SjD) remains a significant challenge due to the disease’s heterogeneous clinical presentation and the high dimensionality of transcriptomic data. Meta-heuristic optimizers are attractive for navigating such landscapes, yet existing algorithms tend either to over-explore or to converge prematurely. To address this, we propose DSMAL, a Differential-Evolution & Slime-Mould Algorithm with adaptive Refresh Local Search, as the first hybrid optimization framework tailored to SjD diagnostics. DSMAL partitions the population into two co-evolving sub-swarms: a Differential-Evolution (DE) cohort that drives broad exploration through differential mutation, and a Slime-Mould (SMA) cohort that intensifies exploitation via adaptive position updates. A novel Refresh Local Search (RLS) operator periodically re-diversifies both cohorts, mitigating stagnation without sacrificing convergence speed. For SjD diagnostics, DSMAL is integrated with an XGBoost classifier, forming the DSMAL-XGBoost model, which is trained and validated using gene expression profiles derived from three GEO datasets (GSE23117, GSE40611, and GSE84844). DSMAL optimizes XGBoost hyperparameters in a cross-validation loop to identify the most predictive feature set and classifier configuration. The final model is evaluated using an independent external test set (GSE7451) and demonstrates superior diagnostic performance, achieving 96.6% F1-score, 96.4% recall, 95.0% precision, and 97.6% AUC. Benchmark testing on the IEEE CEC 2021 suite further validates DSMAL’s theoretical strengths, outperforming ten state-of-the-art optimizers in both accuracy and computational efficiency. These findings underscore the potential of DSMAL-XGBoost as a robust tool for transcriptomic-based SjD diagnosis, with broader implications for complex autoimmune disease modeling.

Abstract Chronic ultraviolet (UV) exposure is a key driver of cutaneous squamous cell carcinoma (cSCC), yet the molecular mechanisms connecting genotoxic stress to tumor–stromal signaling remain unclear. Here, we identify CD70, a TNF superfamily member, as a UV- and DNA damage–inducible regulator that coordinates communication between cSCC cells and fibroblasts. At the expression level, integrative transcriptomic, proteomic, and histological analyses revealed strong CD70 induction in sun-exposed skin, actinic keratoses, and cSCC tissues. At the functional level, silencing CD70 suppressed cSCC proliferation and xenograft tumor growth, whereas solar UV or DMBA exposure markedly elevated its expression. Mechanistically, E2F1 directly bound and activated the CD70 promoter, establishing a transcriptional link between the DNA damage response and CD70 induction. Loss of CD70 attenuated MAPK/NF-κB signaling and reduced inflammatory gene expression in UV-irradiated keratinocytes. In dermal fibroblasts, CD70 expression enhanced NF-κB activation and secretion of IL-6 and MCP3, amplifying paracrine inflammatory loops that promoted cSCC spheroid expansion and tumor progression. Together, these findings define CD70 as a stress-responsive signaling hub that integrates DNA damage, cell proliferation, and epithelial–stromal communication to drive skin carcinogenesis. Targeting CD70 may disrupt this pro-inflammatory circuit and offer a novel therapeutic strategy for inflammation-associated skin cancer. Citation Format: Qiushi Wang, Asad U. Khan, Chengcheng Hu, Emanuel F. Petricoin, Rebecca Morris, Sally Dickinson, Georg T. Wondrak, Ann M. Bode, Clara Curiel-Lewandrowski, Tianshun Zhang. CD70 Links DNA Damage, Proliferation, and Tumor–Stromal Communication [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B028.

Abstract INTRODUCTION: Increased physical activity (PA) in breast cancer patients has been associated with multiple benefits including lower fatigue, depression and anxiety levels, better tolerance of treatment related side effects, and lower cancer recurrence rates (1). The American Cancer Society recommends that cancer survivors undergo at least 150-300 minutes of moderate intensity activity or 75-150 minutes of vigorous activity per week and encourages meeting or exceeding these upper limits (2). Given limited data on PA in Chinese American breast cancer survivors, this study aimed to evaluate and better quantify PA in this population. METHODS: As a part of a broader prospective cohort study investigating survivorship in Chinese American breast cancer patients compared to Non-Hispanic white (NHW) patients over a 12-month period, participants underwent a baseline phone survey administered by trained staff. All participants were women aged over 18, diagnosed with stage 0-III breast cancer within 10 years, and had completed primary surgical or medical treatment. The survey included the Global Physical Activity Questionnaire developed by World Health Organization (WHO), which was used to evaluate time spent on moderate and vigorous activity during work, travel and leisure and to calculate weekly metabolic equivalent (MET) minutes per week for each group. Group differences were evaluated using T-tests for significance. RESULTS: A total of 133 NHW and 110 Chinese American patients completed the baseline survey. The average age was 56 for Chinese Americans and 59 for NHWs, and the difference was not statistically significant. The average BMI of Chinese Americans (23.6) was statistically significantly lower than that of NHWs (25.7). Chinese Americans spent an average of 71 minutes per week on vigorous activity and 424 minutes per week on moderate activity compared to NHWs who spent an average of 179 minutes per week and 627 minutes per week, respectively. Combined, Chinese Americans averaged 2266 MET-minutes per week, while NHWs averaged 3952 MET-minutes per week, this difference was statistically significant (p = 0.0053). Additionally, for patients reporting use of a step counter, the average daily step count for Chinese Americans was 6592 compared to 8432 for NHWs. The reported average daily sedentary time for Chinese Americans (337 minutes) was not statistically different from that for NHWs (348 minutes). CONCLUSION: While both groups exceeded recommended PA minimums, Chinese American women with breast cancer self-reported significantly lower levels of PA than their NHW counterparts. Further studies should focus on the impact of this discrepancy on survivorship and possible interventions to bridge the gap between the two groups to mitigate health disparity after breast cancer treatment. KEYWORDS: breast cancer; survivorship; exercise; disparity SOURCES: (1) Le Y, Gao Z, Gomez SL, Pope Z, Dong R, Allen L, Chang MW, Wang JH. Acculturation and Adherence to Physical Activity Recommendations Among Chinese American and Non-Hispanic White Breast Cancer Survivors. J Immigr Minor Health. 2019 Feb;21(1):80-88. doi: 10.1007/s10903-018-0721-x. PMID: 29569102; PMCID: PMC6151158. (2) Rock CL, Thomson C, Gansler T, Gapstur SM, McCullough ML, Patel AV, Andrews KS, Bandera EV, Spees CK, Robien K, Hartman S, Sullivan K, Grant BL, Hamilton KK, Kushi LH, Caan BJ, Kibbe D, Black JD, Wiedt TL, McMahon C, Sloan K, Doyle C. American Cancer Society guideline for diet and physical activity for cancer prevention. CA Cancer J Clin. 2020 Jul;70(4):245-271. doi: 10.3322/caac.21591. Epub 2020 Jun 9. PMID: 32515498. Citation Format: C. Cao, T. Shao, A. Tsang, M. Kwa, R. Brown, L. Chen, M. Schwartz, D. Roblin, M. H. Antoni, L. Hilakivi-Clarke, G. Kowk, A. Lin, K. Joseph, J. X. Osorio, J. H. Wang, S. Cai. Physical activity level differences among Non-Hispanic White and Chinese American breast cancer survivors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-02-24.

Cancer-associated fibroblasts (CAFs) transdifferentiated from hepatic stellate cells (HSCs) are a critical determinant of liver metastasis of colorectal cancer (CRC). However, the mechanisms behind transforming growth factor β (TGF-β)-stimulated activation of HSCs into CAFs remain poorly understood. Immunoprecipitation coupled with mass spectrometry identified tuftelin 1 (TUFT1) as a novel TGF-β receptor II (TβRII) binding protein in primary human HSCs and immortalized LX2 cells. TUFT1 interacts with TβRII via its fragments (amino acids 1-86, 87-157), protecting TβRII from lysosomal degradation to facilitate TGF-β signaling and myofibroblastic activation of HSCs. Mechanistically, TUFT1 competes with caveolin-1 for TβRII binding, retrieving TβRII from the lipid rafts/caveolae-mediated degradation pathway and sorting it into the endosome-mediated trafficking and signaling pathway. Clinically, TUFT1 expression was confirmed in the CAFs of patient-derived colorectal cancer liver metastasis (CRCLM) tissues. Both protein and transcript analyses revealed higher TUFT1 expression in the CAFs of CRCLM than in HSCs. Furthermore, bulk RNA sequencing indicated that knocking down TUFT1 altered the TGF-β transcriptome of HSCs and suppressed HSC expression of tumor-promoting factors. In HSC/CRC co-implantation and portal vein tumor injection mouse models, targeting TUFT1 of HSCs inhibited HSC activation and restricted CRC growth in both subcutaneous and hepatic sites. Taken together, our findings uncover the novel function of TUFT1 in the hepatic tumor microenvironment, highlighting its role as a critical regulator of HSC activation and the pro-metastatic hepatic niche via promoting TβRII protein stability. Targeting TUFT1 in HSCs presents a promising therapeutic approach for combating CRCLM.

Reliable load frequency control (LFC) in multi-source (thermal-hydro-gas) grids remains challenging due to large step load disturbances. This paper benchmarks metaheuristic tuning of a single Fractional-Order PID (FOPID) controller using four optimizers: Genetic Algorithm (GA), Particle Swarm Optimization (PSO), Differential Evolution (DE), and Enhanced PSO (EPSO). Controllers are tuned against four standard time domain indices (IAE, ITAE, ITSE, ISE) and stress tested under <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\pm 5 \%$</tex> and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\pm 20 \%$</tex> load changes. Across all indices, EPSO consistently achieves the best speed robustness trade-off: with IAE it attains a minimum settling time of 23.10 s, while with ITSE it limits transients to overshoot 0.006 p.u. and undershoot 0.013 p.u.. The alternative optimizers exhibit longer settling and larger peak deviations under identical conditions. The study provides a unified, reproducible comparison for FOPID tuning in LFC and indicates EPSO as a strong default choice when both rapid recovery and low transient excursions are required in multi-source power systems.

Abstract The unfolded or misfolded proteins lead to endoplasmic reticulum stress (ER-stress), which activates the unfolded protein response (UPR) through IRE1, PERK, and ATF6 downstream pathways to enhance the survival, proliferation, and development of therapy resistance in glioblastoma cells. We previously demonstrated that the RBBP4/p300 complex regulates transcription of genes critical for glioblastoma (GBM) aggressiveness and response to therapy. However, the role of this complex in regulating UPR genes remains unclear. Therefore, we used RNA- and ChIP-sequencing to identify whether UPR genes are regulated by the RBBP4/p300 complex in patient-derived GBM43 cells. Our data show that silencing RBBP4 or p300 by shRNA suppresses the expression of key UPR genes, including XBP1, PPP1R15A, ERN1, ATF4, DDIT3, and ATF6. ChIP-sequencing confirmed the co-occupancy of RBBP4 and p300 proteins within promoters or enhancers of the UPR genes regulated by the RBBP4/p300 complex. Moreover, silencing either RBBP4 or p300 diminished the decoration of the promoters/enhancers of RBBP4/p300 target UPR genes by the acetylated lysine 27 of histone H3 (H3K27ac). Interestingly, tunicamycin induced ER-stress and activated UPR signaling in GBM43 cells expressing the control shRNA (shNT) but not in the shRBBP4 expressing cells, as evidenced by the increased spliced XBP1 variant, CHOP, and phosphorylation of serine 51 of ELF2α (ELF2αS51). In addition, tunicamycin increased the expression of cleaved-PARP in the control shNT cells but not in the shRBBP4 expressing cells, suggesting that disrupting RBBP4/p300 complex enhances vulnerability to ER-stress in GBM cells. Finally, the expression of UPR genes directly correlated with RBBP4 and p300 expression in GBM patient specimens. In conclusion, these findings suggest that the RBBP4/p300 complex plays a role in regulating ER-stress-induced UPR signaling by controlling the UPR genes. Further studies are required to establish the impact of disrupting this complex on sensitivity to ER-stress-inducing drugs, including inhibitors of protein deubiquitylation.

Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, or KIF3A, followed by exposure to the genotoxic agents cisplatin, methyl methanesulfonate (MMS), or irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, and DNA damage was assessed using comet assays and phosphorylated H2AX (γH2AX) quantification. An in vivo liver-specific IFT88 knockout model, generated using Albumin-Cre/Lox recombination, was used to study the loss of primary cilia in the liver. Results showed that RAD51 localized predominantly at the base of the cilium, whereas Ataxia Telangiectasia and Rad3-related protein (ATR), PARP1, CHK1, and CHK2 were also detected within the ciliary shaft. Deciliated cells displayed dysregulation in critical DNA repair pathways. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges as compared with ciliated cells. Enhanced DNA damage was observed via increased γH2AX signals and comet assay results. An increase in γH2AX expression was also observed in our in vivo model, indicating elevated DNA damage. In addition, key DDR proteins such as Ataxia Telangiectasia Mutated protein (ATM), p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair and suggests that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA.NEW & NOTEWORTHY Our study reveals a novel link between primary cilia and DNA repair in cholangiocytes. We show that DNA damage response (DDR) and repair proteins localize to cilia, and deciliation impairs survival and induces S-phase arrest under genotoxic stress. Deciliated cells exhibit increased DNA damage after cisplatin, irradiation, or methyl methanesulfonate (MMS) challenge. Following irradiation, Ataxia Telangiectasia Mutated protein (ATM), p53, and p21 are downregulated in deciliated cells. Similarly, IFT88 knockout mice show heightened DNA damage, highlighting the role of primary cilia in genome stability.