Citations

With rapid industrial expansion, air pollution’s adverse neurological effects have gained increasing attention. Children face a greater risk of neurological damage because of their higher breathing rates, developing brains, and limited ability to detoxify harmful substances. Fine particulate matter has been identified as a primary neurotoxic contributor affecting developing brains. Strong evidence connects environmental pollutant exposure to the prevalence of Autism Spectrum Disorder (ASD), a neurodevelopmental condition marked by lasting difficulties with social communication and interaction. This study explores the association between long-term PM2.5 exposure and ASD symptom exacerbation, investigating underlying mechanisms. We hypothesize that long-term PM2.5 exposure exacerbates ASD symptoms through neuroinflammatory activation, leading to neuronal damage and impaired synaptic plasticity. Our investigation employs three complementary approaches: First, integrated analysis combining Global Burden of Disease data with Mendelian randomization demonstrates a significant association between PM2.5 exposure and increased ASD severity risk. Second, utilizing the China High-Resolution Air Pollution Database in conjunction with cohort studies, we provide evidence that ambient air pollution substantially influences autism severity, with PM2.5 identified as the predominant environmental determinant. Third, through network toxicology, single-cell transcriptomics, and animal experimentation, we demonstrate that chronic PM2.5 exposure exacerbates valproic acid-induced autism-like behaviors in murine models, identifying CTNNB1, PTEN, CCR2, AKT1, and mTOR as potential core mediating genes. Importantly, these findings represent preliminary results. Several potential confounding factors such as co-exposure to other pollutants and socioeconomic variables have not been fully addressed. While our multi-modal approach provides converging lines of evidence, further validation in larger, more diverse populations with refined control of confounders will be essential to establish causality and elucidate mechanisms. Nonetheless, these early insights advance our understanding of PM2.5-induced neurotoxicity in the context of ASD and offer timely, albeit preliminary, evidence to inform public health policy.

Background Immune checkpoint therapies targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have been met with limited clinical responses in the treatment of patients of varying cancer types. Current US Food and Drug Administration (FDA)-approved therapies function to prevent PD-1 binding to PD-L1, thereby preventing T-cell suppression. However, these therapies fail to prevent PD-L1 intrinsic signaling and recycling, which can render these treatments ineffective. Moreover, most research primarily focuses on how these antibodies affect tumor cells and their interactions with T cells. Myeloid cells, which also express PD-L1 and influence T-cell responses, are integral to the efficacy of these therapies. However, strategies that can target these cells to boost antitumor responses have not been effective. Methods Our group has developed a new anti-PD-L1 antibody (H1A), which disrupts PD-L1 recycling and redirects it towards degradation. Due to the loss of available PD-L1 protein, H1A effectively prevents PD-L1 intrinsic signaling. Using in vivo humanized PD-1/PD-L1 mouse tumor models, we evaluated the therapeutic efficacy of H1A against current FDA-approved PD-L1 blocking antibodies. Using human-derived immune cell in vitro assays, we pinpoint the biological consequences of H1A-induced PD-L1 degradation in myeloid cells. Results H1A demonstrated improved tumor control and established immunological memory responses in vivo in the treatment of tumors with moderate immunogenicity that are less responsive to current immunotherapies. This was supported by enhanced activation of myeloid cells (major histocompatibility complex (MHC)-II and CD80) and frequencies of effector T-cell populations found intratumorally. Human myeloid cells treated with H1A were also observed to have increased activation (MHC-II and CD80) and cytokine secretion. Similar to our in vivo findings, human peripheral blood lymphocyte cultures demonstrated increased frequencies of effector T-cell populations and greater tumor cell killing. Conclusions This work highlights the importance of targeting PD-L1 recycling and intrinsic signaling, specifically in myeloid cells, to boost antitumor responses. Our studies suggest that H1A can provide a solution to the lack of responses seen with current therapeutics, while also revealing previously unknown intrinsic functions of PD-L1 in myeloid cells.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, with particularly high burdens among people living with HIV (PLWH) in low‐resource settings like Nigeria. Effective early detection remains a major challenge due to limited access to imaging‐based surveillance and the low sensitivity of current biomarkers such as alpha‐fetoprotein (AFP). We conducted an epigenome‐wide association study (EWAS) of circulating cell‐free DNA (ccfDNA) methylation in a Nigerian cohort of HIV‐positive individuals ( n = 245), spanning HCC, cirrhosis (FibroScan ≥12.3 kPa), fibrosis (FibroScan ≥7.6 and <12.3 kPa), and HCC‐free without fibrosis (FibroScan <7.6 kPa) groups. Using random forest modeling, we developed and evaluated a ccfDNA methylation classifier (ccfDNAmRF) for HCC risk prediction. We identified 73 CpG sites significantly associated with HCC (false discovery rate <0.01). The ccfDNAmRF model demonstrated strong discriminatory power, achieving 100% sensitivity and 80%–91% specificity for distinguishing HCC from cirrhosis, fibrosis, and HCC‐free groups (area under the curve [AUC]: 92%–97%). Combining ccfDNA methylation risk scores with AFP further improved classification accuracy (AUC up to 98.5%). Notably, ccfDNA methylation patterns displayed clear dose–response relationships across the disease spectrum, supporting their utility for early‐stage detection and risk stratification. Our findings highlight the promise of ccfDNA methylation biomarkers as a non‐invasive, blood‐based screening tool for improving early identification of HCC cases among PLWH.

Abstract Context Thyroid nodules are common in clinical practice, and inappropriate selection of patients for thyroid biopsy can contribute to thyroid cancer overdiagnosis or delayed diagnosis. Objective This work aimed to evaluate the frequency of inappropriate thyroid biopsies in practice, following a framework that integrates thyroid nodule ultrasound (US) features and patient-specific clinical factors. Methods This cross-sectional study was conducted at a single academic center in the United States. Participants included adult patients who underwent their first thyroid fine-needle aspiration (FNA) biopsy between January 1, 2016, and December 31, 2023, at the University of Florida. Data collection included thyroid US characteristics, clinical factors (eg, comorbidities, patient preferences), and context for biopsy decision-making. Main outcome measures included the appropriateness of thyroid biopsy assessed using a tiered framework incorporating US features and additional clinical factors. Results A total of 899 patients were evaluated, with 441 meeting the inclusion criteria and undergoing 481 thyroid biopsies. Of these, 388 of 481 (80.7%) were classified as likely appropriate (L-APP) based on the American College of Radiology Thyroid Imaging Reporting and Data System criteria. In 34 of 481 (7%) of cases, clinical factors such as thyroid cancer risk features, comorbidities, symptoms, or patient preferences led to reclassification from likely inappropriate (L-INAP) to L-APP. In 50 of 481 (10%) of cases, limited life expectancy (eg, chemotherapy, end-stage disease) led to reclassification from L-APP to possibly or extremely inappropriate (EXT-INAP). EXT-INAP biopsies occurred in only 0.8% (4/481) of cases. Conclusion This study underscores the value of integrating US findings with clinical context to guide thyroid biopsy decisions and enhance patient-centered care.

Abstract Disclosure: A. Zhang: None. J. Kapoor: None. C. Deveney: None. A.G. Cope: None. M.M. Walther-Antonio: None. N. Chia: None. C.W. Pattanayak: None. M.J. Tetel: None. The vaginal microbiome (VM) consists of the microorganisms and their metabolites residing in the vaginal tract and is critical for maintaining female reproductive health. The Lactobacillus species predominate most VMs and produce lactic acid, which has been cited as a key protector of vaginal health. Alterations in the finely balanced vaginal microbiome can cause infections, such as bacterial vaginosis, and may contribute to the development of endometrial and ovarian cancer. While it is well-established that stress and the gut microbiome impact each other via the gut-brain axis, the influence of stress, hormones, and lifestyle factors on the VM composition remains poorly understood. We investigated the relationship between stress, hormones (menstruation, hormonal contraception), lifestyle factors (diet, exercise, sleep), and the VM composition. In this 10-week study, healthy, young female volunteers (n=62) provided daily vaginal and fecal swabs, weekly stress ratings, daily data on sleep and activity (via FitBit) and diet information. High-throughput 16S rRNA sequencing was used to identify the vaginal microbial composition of each sample. Types of hormonal birth control were none (n=30), local progestin (n=9), systemic progestin-only (n=7), or systemic estrogens and progestin combined (n=16). Consistent with our previous study, vaginal microbial diversity, as measured by the Shannon index, varied by type of hormonal birth control, with participants not on hormonal birth control having the highest average diversity. There was a positive relationship between average stress and vaginal microbial diversity, with preliminary results suggesting that this relationship depends on hormonal birth control status. Participants who menstruated during the 10-week study had a higher vaginal microbial diversity than those who did not. We are currently analyzing which microbes contribute to these differences in vaginal microbial diversity. Microbiota and fungal data from the daily vaginal and fecal swab samples will be analyzed to determine how stress, hormones and/or lifestyle factors relate to crosstalk between the vaginal and gut microbiomes. These findings may provide long-term, time-longitudinal insights into how these two important microbiomes are involved in important aspects of women’s health. Presentation: Sunday, July 13, 2025

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor characterized by invasive growth, genetic heterogeneity and resistance to therapy. Alterations in the epithelial growth factor receptor (EGFR) are frequently detected in GBM, including gene amplifications, mutations and exon deletions, exemplified by the expression of EGFR variant III (EGFRvIII). To target both wild-type and EGFRvIII, we generated the humanized antibody A10, which reacts with the 287-302 loop that is fully exposed on the extracellular domain of EGFRvIII and conditionally exposed on cells expressing gene-amplified EGFR. However, A10 showed little or no reactivity for cells expressing normal levels of wild type EGFR. We engrafted antibody fragments derived from A10 on to ARTEMIS® Cell Receptor Platform, which introduces two separate receptors into engineered T cells to provide activation and co-stimulatory signals. Specifically, the A10 antigen-binding fragment (Fab) was fused to the N-terminus of a γδTCR-signaling domains (A10-AbTCR) while the A10 single chain variable fragment (scFv) was fused to a costimulatory signaling receptor (A10-CSR). The resulting A10 ARTEMIS® T cells were cytotoxic for tumor cell lines displaying amplified or overexpressed EGFR and EGFRvIII. Further, glioblastoma PDXs were sensitive to A10 ARTEMIS® T cell killing. This prompted an in vivo evaluation in EGFR-driven cancers. GBM39 PDX tumors (expressing amplified EGFRvIII) were implanted into the brains of NSG mice. Mice received one or two infusions. Treatment with one infusion of A10 ARTEMIS® cells resulted in prolonged survival of tumor bearing mice with 40 % of mice were long-term survivors (74 days) compared to a median survival of 32 days (control) or 52 days (mock T-cells). For mice receiving two A10 ARTEMIS® T cell infusions, there was 100% survival of mice beyond 60 days, while all control and mock treated mice were dead by 28 days. Further, treatments of EGFR-amplified MDA-MB-468 tumors resulted in complete tumor regression with one treatment of A10 ARTEMIS® cells. Thus, this new format of A10 engineered T-cells appears to be a particularly promising for treating cancers with high levels of EGFR or EGFRvIII including GBM. Citation Format: Antonella Antignani, Danielle Burgenske, Guangyan Xiong, Hongbing Zhang, Cheng Liu, Jann Sarkaria, David FitzGerald. Engineered T-cells, targeting overexpressed EGFR and EGFRvIII, produce complete remissions in a PDX model of human glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B056.

Abstract Failure to repair radiation (RT)-induced DNA damage results in cell lethality, and combined treatment with DNA repair inhibitors can markedly enhance tumor control achieved with radiation. These inhibitors also can potentiate acute RT toxicities by suppressing DNA repair. Capitalizing on this normal tissue radiosensitizing effect, we determined effective radiosensitizing dosing regimens in mice for the ATM inhibitor WSD0628 and the DNAPK inhibitor WNC0901 in mice. Drugs were administered via oral gavage prior to each RT dose, and RT was delivered using an anterior/posterior 225 kVp beam. In an initial iteration of this model, various combinations of WSD0628 and RT were administered to cohorts of mice (n=5/group) and body weight was followed for 2 weeks. The resulting data were modeled to define the total dose of radiation estimated to cause 50% of mice to lose &gt;20% body weight (D50). There was an inverse relationship between the WSD0628 and D50 doses: 0 mg/kg WSD0628/24.0 Gy (95% confidence interval (CI) 24.5–24.7); 0.25 mg/kg/19.2 Gy (95% CI 16.7–21.8); 1 mg/kg/13.7 Gy (95% CI 13.2–14.2); 2.5 mg/kg/11.0 Gy (95% CI 10.5–11.5); 5 mg/kg/11.3 Gy (95% CI 6.7–15.9) and 7.5 mg/kg/7.8 Gy (95% CI 7.8–7.9). Histological review of tongues from animals treated with 15 Gy RT (5Gy x 3) + 7.5 mg/kg WSD0628 demonstrated epithelial denudation and acute inflammation consistent with oral mucositis, while these features were not seen with the same dose as RT alone. Similar WSD0628 doses were evaluated in combination with 8 Gy supratentorial RT (via lateral beams) in orthotopic GBM43 PDX tumors. By treatment arm, the median time to a moribund state was: sham (29 days (d)), RT (39d), 1 mg/kg (42d), 2.5 mg/kg (49d), 5 mg/kg (65d), and 10 mg/kg (123d, overall p&lt;0.0001). A second mucositis model was used for evaluation of WNC0901. Cohorts of 5 mice/group were treated with a set dose of RT (4Gy x 3) to the oral cavity alone and in combination with various doses of WNC0901, and the fraction of mice with &gt;20% weight loss within 2 weeks was determined. The results of this study are as follows: placebo (0 of 5 mice with &gt;20% weight loss); 15 mg/kg (3 of 5 mice); 25, 50, or 100 mg/kg (5 of 5 mice). Based on these data, we defined 25 mg/kg WNC0901 as the minimally effective dose and predicted that 50 mg/kg would provide robust radiosensitization. Consistent with this prediction, co-treatment of B16 melanoma flank tumor xenografts with RT (8Gy x 1) and WNC0901 (50 mg/kg) more than doubled the median tumor control duration (median 42 [range 24-45] days; time from implantation for tumor to exceed 1500 mm3) as compared to RT alone (24 [13-30] days) or sham treatment (17 [13-17] days; overall p&lt;0.0001). This study describes how a radiation-induced oral mucositis model can be used to identify effective radiosensitizing regimens faster and with fewer resources than relying on tumor control studies alone. Citation Format: Danielle Burgenske, Darwin Garcia, Jiayan Le, Wenjuan Zhang, Sneha Rathi, Katrina K. Bakken, Lauren L. Ott, Zeng Hu, Brett L. Carlson, Ann Mladek, Jessica L. Abraham, Paul A. Decker, Matthew L . Kosel, Jeanette E. Eckel-Passow, William F. Elmquist, Wei Zhong, Jann N. Sarkaria. Radiation-induced oral mucositis to rapidly determine effective radiosensitizing dosing regimens for ATM and DNAPK inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B090.

Abstract The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here, we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Our data reveal non-epistatic interactions between HELLS and PARP1 and suggest that HELLS functionally compensates for PARP1 deficiency in promoting cell survival in response to DNA alkylation damage. Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer.