tbuckley/cabot-search huggingface dataset:
Transcranial Pulsed Current Stimulation and Social Functioning in Children With Autism
Authors: Zhenhuan Liu, Sandra Zhong, Roger C. M. Ho, Xuguang Qian, Yan Tang, Hui Tian, Chuntao Zhang, Nuo Li, Yong Zhao, Yuqiong Zhang, Huituan Liu, Meifeng Wu, Yingjie Zhan, Min Li, Zhihai Lv, Fengyi Hao, Wilson Tam, Jeremy Lin Bingyuan, Alvaro Pascual-Leone
Journal: JAMA Network Open (2025)

Importance Transcranial pulsed current stimulation (tPCS) may improve social functioning and sleep disorders in children with autism spectrum disorder (ASD). Prior trials have been limited by small sample sizes, single-center designs, and often a lack of sham controls. Objective To examine the safety and efficacy of tPCS in improving social functioning and sleep disorders in children with ASD. Design, Setting, and Participants This multicenter, double-blind, 2-armed, sham-controlled randomized clinical trial, conducted from May 1, 2022, through November 30, 2023, assessed children aged 3 to 14 years with ASD at 8 medical centers in China. Interventions Participants underwent daily 20-minute sessions of active tPCS (0.7 mA) or sham tPCS (brief 0.7 mA ramp-up and ramp-down) for 20 sessions over 4 weeks with anode over the right cerebellar hemisphere and cathode over the left dorsolateral prefrontal cortex (12.56-cm 2 -circular, 4-cm-diameter circular electrodes). Each day after tPCS, all participants received 1 hour of standard therapy. Main Outcomes and Measures Social functioning was assessed using the Autism Treatment Evaluation Checklist as the primary outcome. Secondary outcomes included the Autism Behavior Checklist and the Childhood Sleep Habits Questionnaire. Results A total of 312 participants (155 in the active group and 157 in the sham group; 248 [79.5%] boys; mean [SD] age, 5.1 [1.6] years; 276 [88.5%] aged 3-6 years and 36 [11.5%] aged 7-14 years) completed the trial. After 20 sessions, the mean Autism Treatment Evaluation Checklist total score improved by 4.13 points (5.8%) in the sham tPCS group and 7.17 points (10.7%) in the active tPCS group. Analysis of covariance showed significantly greater improvement in the active tPCS group (difference, −3.50; 95% CI, −5.56 to −1.43; P &amp;amp;lt; .001). Both treatments were well tolerated. Conclusions and Relevance In this randomized clinical trial of prefrontal-cerebellar tPCS in children aged 3 to 14 years with ASD, 20 sessions over 4 weeks improved social functioning and sleep. These findings suggest that tPCS may serve as a viable nonpharmacologic alternative for ASD. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2200059118
Abstract 5037: Accelerated somatic mutation calling for whole-exome sequencing of tumor samples
Authors: Jessica Castrillon Lal, Shuangxi Ji, Ruonan Li, Scott Kopetz, Wenyi Wang
Journal: Cancer Research (2025)

Abstract Background: Integrating next-generation sequencing (NGS) data into clinical practice faces several challenges. High-throughput sequencing generates massive amounts of data that need to be processed quickly to deliver timely clinical insights. Additionally, formalin-fixed paraffin embedded (FFPE) tissue is the primary resource for tumor molecular profiling in clinical settings. However, nucleic acids extracted from FFPE are prone to chemical alterations and technical artifacts during sequencing. Therefore, distinguishing tumor-specific variants from artifacts and germline variation with a low false discovery rate rapidly with high accuracy remains challenging. Methods: We recently developed MuSE2, an advanced somatic mutation caller for cancer genomics that integrates a nucleotide-specific Markov substitution model for molecular evolution, a tumor-specific error model to determine tier-based cutoffs for selecting SNVs, and an optimized multi-threaded processing pipeline. It was demonstrated significantly enhanced accuracy and up to 8-80 folds faster performance compared to other common variant callers. Next, we evaluated the performance of our variant calling pipeline on FFPE derived whole exome sequencing data as part of a liquid biopsy test from patients with colorectal cancer at MD Anderson (n=808). We benchmarked our consensus calls from two out of three of the following callers, MuSE2, Strelka2, and MuTecT2, using a patient matched Medical Diagnostic Lab genetic panel sequencing as the ground truth. Our consensus calls performed well in both panel 1 (n=126 genes, F1=0.726) and panel 2 (n=146 genes, F1=0.773). Results: MuSE2 achieves high sensitivity when combined with existing callers for both whole exome sequencing (WES, F1=0.88 0.04) and whole genome sequencing (WGS, F1=0.93 0.02). Furthermore, the calls had optimal performance when benchmarking the top driver genes in colorectal cancer (TP53, F1=0.95, KRAS, F1=0.99, PIK3CA, F1=0.74, and BRAF, F1=0.88). However, for less frequent genes the performance drops indicating additional measures are required to remove potential technical artifacts. Conclusion: Our results suggest that a consensus mutation calling strategy including MuSE2 achieves high efficiency without compromising accuracy for clinical tumor sequencing. This is an urgent matter as genetic screening is considered a fundamental aspect of translational cancer research and is entering cancer care standard practice. 2, 134 characters (max allowed = 2, 600) Citation Format: Jessica Castrillon Lal, Shuangxi Ji, Ruonan Li, Scott Kopetz, Wenyi Wang. Accelerated somatic mutation calling for whole-exome sequencing of tumor samples [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 5037.
Abstract 2472: HER2 protein localization in super-resolution and anti-HER2 therapy response in breast cancer
Authors: Vicente Peg, Yuko Saruta, Yun Li, Santiago Ramon y Cajal
Journal: Cancer Research (2025)

Abstract Introduction: Human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is an important biomarker for a better decision making of anti-HER2 therapy. Trastuzumab has been the standard of care treatment for HER2 positive patients, but recently new antibody-drug conjugates (ADCs) have given an alternative option in clinical practice. Since ADCs efficacy is due to HER2 antibody localization and internalization in the cell, we hypothesize that cellular sensitivity to the drug may be linked to cellular vesicle trafficking systems and membrane protrusions which indicate the resistance of HER2 internalization. Super resolution fluorescence microscope named HM-1000 achieves a resolution less than 20 nm. With this new tool, we aim to study the intracellular distribution pattern of HER2 including vesicle-like structures and membrane protrusions to better identify responders of anti-HER2 therapies, especially ADCs. Method: A retrospective unicentric study is designed to recruit BC patients who have received ADCs treatment that have formalin fixed paraffin-embedded tissue samples stored for routine diagnosis. 5 baseline tumor samples were stained by commercialized HER2 in situ immunofluorescence, and O2 scavenging buffer was applied and sealed to capture the fluorescent blinking every 30 milliseconds by HM-1000. The 50, 000 image frames per microscopic field were processed using ImageJ software and created super-resolution images. Results: We observed that HER2 signals from ADCs responding patients exhibit predominant membrane localization, especially in those with 3+ immunohistochemistry staining status, compared to ADCs non-responding HER2 3+ cases which show low membrane localization of HER2 and more intracellular distribution. Additionally, this finding is highlighted by intense membrane protrusions in HER2 3+ tumor which present very good response of ADCs. Conclusion: We found different HER2 localization in ADC responding and non-responding patients. The presence of membrane protrusions may facilitate HER2 targeted antibody binding and induce both cellular cytotoxicity from immune effector cells and endocytosis of cytotoxic drug, which explains ADCs response. Further studies are needed to support this finding and better predict the effectiveness of ADCs therapies in HER2 positive tumors. Citation Format: Vicente Peg, Yuko Saruta, Yun Li, Santiago Ramon y Cajal. HER2 protein localization in super-resolution and anti-HER2 therapy response in breast 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 2472.
Abstract 1506: Protein acyl-protein thioesterases affect redox homeostasis and ROS signaling through peroxiredoxin
Authors: Tian Qiu, Saara-Anne Azizi, Shubhashree Pani, Bryan C. Dickinson
Journal: Cancer Research (2025)

Peroxiredoxins (PRDXs) are among the most abundant antioxidants and are widely distributed in cancers. They are associated with tumor cell resistance to cell death, such as apoptosis and ferroptosis. Post-translational modifications of PRDX play a critical role in modulating its activity and tuning the balance between reactive oxygen species (ROS) signaling and stress. We previously discovered that mitochondrial localized PRDX3 and PRDX5 are S-acylated, with dynamic PRDX5 active site cysteine acylation regulating mitochondrial redox homeostasis. In this investigation, we found that all the PRDX family proteins are subject to S-acylation at the nucleophilic cysteine residue in their active site, and that PRDX S-acylation responds dynamically to ROS levels in the cell. The PRDX S-acylation level decreases under acute ROS stress, and increases under physiological, signaling levels of H2O2. Using activity-based fluorescent imaging with DPP-Red, a red-shifted fluorescent indicator for acyl-protein thioesterase (APT) activity, we also discovered that ROS-stress via exogenous H2O2 activates both the cytosolic and mitochondrial APTs, whereas EGF-stimulated endogenous H2O2 deactivates the cytosolic APTs. These results indicate that APTs help tune H2O2 signal transduction and ROS protection through PRDX S-deacylation. Citation Format: Tian Qiu, Saara-Anne Azizi, Shubhashree Pani, Bryan C. Dickinson. Protein acyl-protein thioesterases affect redox homeostasis and ROS signaling through peroxiredoxin [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 1506.
Abstract 3485: T cell receptor (TCR)-Based cellular therapy for Fibrolamellar HCC
Authors: Kayla J. Bendinelli, Allison M. Kirk, Paul G. Thomas, Mark Yarchoan
Journal: Cancer Research (2025)

Abstract Background: Fibrolamellar carcinoma (FLC) is a rare and often lethal liver cancer that primarily affects children and young adults without cirrhosis. There is no standard systemic treatment for FLC and the median survival for patients with advanced, unresectable FLC is approximately 12 months. The FLC transcriptome is characterized by an in-frame fusion of exon 1 of DNAJB1 with exons 2-10 of PRKACA, the catalytic subunit of protein kinase A (PKA), leading to expression of a chimeric protein, DNAJ-PKAc that has thus far been “undruggable” due to unacceptable on-target toxicity. Our overall goal is to target this “undruggable” oncogenic driver using T Cell Receptor (TCR)-Based cellular therapy. Methods: We are performing a clinical trial of a peptide-based therapeutic vaccine targeting DNAJ-PKAc, in combination with the immune checkpoint inhibitors nivolumab and ipilimumab. We analyzed PBMCs from a subset of patients who demonstrated a clinical response to this immune-based combination therapy to identify TCRs with specificity for DNAJ-PKAc. Results: To identify fusion specific T cell receptors (TCRs) generated in response to the vaccine patient peripheral lymphocytes were expanded and 10x single cell transcriptomic with paired TCR sequencing was performed. Candidate TCRs were reconstructed and expressed in T cells prior to co-culturing with HLA matched antigen presenting cells that were pulsed with DNAJ-PKAc peptides to verify fusion specificity via flow cytometry for T cell activation. We reconstructed and verified fusion specificity for multiple TCRs from several patients, and characterized them functionally by HLA specificity, affinity, and killing capacity in vitro. We identified TCRs recognizing DNAJ-PKAc-derived peptides in the context of class II HLAs, including HLA-DRB1*13:01 and HLA-DRB3*01. The TCRs that were identified recognize distinct DNAJ-PKAc-derived epitopes, with variable HLA specificity, TCR affinity, and cytokine response profiles after DNAJ-PKAc antigen stimulation. In general, TCRs with specificity for DNAJ-PKAc presented in the context of HLA-DRB1*13:01 were higher affinity than those recognizing HLA-DRB3*01, even when obtained from the same original patient. Conclusion: This work identifies and characterizes multiple TCRs with specificity for DNAJ-PKAc. Our data provides evidence that the therapeutic efficacy of a peptide-based therapeutic vaccine may be mediated by a CD4 T cell response, and provides potential candidates for off-the-shelf TCR therapy for FLC. Citation Format: Kayla J. Bendinelli, Allison M. Kirk, Paul G. Thomas, Mark Yarchoan T cell receptor (TCR)-Based cellular therapy for Fibrolamellar HCC [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 3485.
Abstract 3487: Mechanistic role of CD70 in UV exposed keratinocytes and cutaneous squamous cell carcinoma (cSCC)
Authors: Asad Khan, Qiushi Wang, Chengcheng Hu, Emannuel Petricoin, Rebecca Morris, Georg T. Wondrak, Ann M. Bode, Clara Curiel-Lewandrowski, Tianshun Zhang
Journal: Cancer Research (2025)

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising due to limited prevention strategies. Significant gaps persist in understanding the mechanisms of UV-induced DNA damage and immune modulation in skin cancer development. By analyzing expression data from sun-exposed and sun-protected skin in the Genotype-Tissue Expression (GTEx) database and the Gene Expression Omnibus (GEO), we identified CD70 as a key gene linking solar UV exposure, immune responses, and photocarcinogenesis. Reverse Phase Protein Microarray Analysis (RPPA) revealed a significant upregulation of CD70 in sun-damaged skin compared to sun-protected skin. CD70 expression was also markedly higher in actinic keratosis (AK) and cSCC compared to normal tissue. In this study, we investigated the mechanistic role of CD70 in solar simulated light (SSL,149 kJ/m2 UVA &amp; 7.2 kJ/m2 UVB)-exposed keratinocytes and cSCC. CD70 expression was found to increase in keratinocytes following SSL irradiation in a dose- and time-dependent manner. Deletion of CD70 effectively suppressed cSCC cell growth in both 2D and 3D culture models. RNA sequencing (RNA-seq) analysis (shCon vs. shCD70) revealed that CD70 regulates gene expression changes induced by solar UV exposure through multiple oncogenic pathways. CD70-associated genes are strongly linked to AK and cSCC and involve critical signaling pathways, including MAPK, Rap1, and others. Additionally, CD70 deletion inhibits NFkappa B nuclear translocation, as demonstrated by luciferase assays and immunofluorescence analysis. In summary, these findings underscore the pivotal role of CD70 in SSL-induced skin damage and photocarcinogenesis. The CD70 inhibition may offer a novel targeted strategy for preventing and treating cSCC. Citation Format: Asad Khan, Qiushi Wang, Chengcheng Hu, Emannuel Petricoin, Rebecca Morris, Georg T. Wondrak, Ann M. Bode, Clara Curiel-Lewandrowski, Tianshun Zhang. Mechanistic role of CD70 in UV exposed keratinocytes and cutaneous squamous cell carcinoma (cSCC) [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 3487.
Abstract 5526: Inhibition of MEK and AKT synergistically induces melanoma stem cell apoptosis and blocks NRAS-mutant xenograft growth
Authors: Nusrat Islam, Ryyan Alobaidi, Toni M. Olkey, Yogameenakshi Haribabu, Mathew Shamo, Peter Sykora, Cynthia M. Simbulan-Rosenthal, Dean S. Rosenthal
Journal: Cancer Research (2025)

Abstract Melanoma-initiating cells (MIC) are involved in tumorigenesis, drug resistance and metastasis, and are characterized by upregulated stem cell markers, including CD133. Our previous studies showed that CD133 siRNA increases apoptosis in response to the MEK inhibitor trametinib. The current study employs CRISPR-Cas9 CD133-KO or Dox-induced expression of CD133 to investigate the anti-apoptotic mechanism of CD133 in patient-derived BAKP melanoma cells, harboring an NRASQ61K driver mutation. CD133-KO cells downregulated pro-survival markers p-AKT and p-BAD, and upregulated pro-apoptotic BAX. On the flip side, Dox-induced CD133 increased expression of p-AKT and p-BAD, and decreased activation of BAX and caspase-3. Hence, an alternate survival pathway may be activated in MICs, wherein CD133 induces AKT phosphorylation and activation, which phosphorylates and inactivates BAD, decreasing BAX activation, and reducing caspases-3 activity and caspase-mediated PARP cleavage, ultimately resulting in apoptosis inhibition and chemoresistance in melanoma. However, trametinib in combination with the pan-AKT inhibitor, capivasertib, can synergistically reduce cell survival even in trametinib-resistant CD133-expressing MICs in vitro, as determined by XTT, annexin-FITC, and colony forming assays. Similarly, in vivo mouse xenograft studies using Dox-inducible BAKP cells revealed increased rates of tumor growth after induction of CD133 expression in trametinib-treated +Dox mice, an effect that was most effectively suppressed by the combination treatment. Therefore, targeting nodes of the AKT and MAPK survival pathways with trametinib and capivasertib underscores the potential for combination therapies for difficult-to-treat NRAS-mutant melanoma stem cells, paving the path towards improved treatment strategies for patients with high-risk melanoma. Citation Format: Nusrat Islam, Ryyan Alobaidi, Toni M. Olkey, Yogameenakshi Haribabu, Mathew Shamo, Peter Sykora, Cynthia M. Simbulan-Rosenthal, Dean S. Rosenthal. Inhibition of MEK and AKT synergistically induces melanoma stem cell apoptosis and blocks NRAS-mutant xenograft growth [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 5526.
Abstract 5546: Sorting to enrich for chemotherapeutic-resistant glioma cells based on unique membrane properties
Authors: Vi P. Dang, Alan Y. Jiang, Jaclyn N. Hanamoto, Nicole S. Lav, Christopher R. Douglas, Daniela A. Bota, Lisa A. Flanagan
Journal: Cancer Research (2025)

The purpose of this study was to leverage dielectrophoresis (DEP) as a novel method for sorting glioma cells based on their innate cell electrophysiological properties. Glioblastoma, astrocytoma, and oligodendroglioma comprise a class of aggressive and deadly brain tumors, termed as diffuse gliomas, with 20,000 cases diagnosed annually in the US. The current standard chemotherapy treatment, temozolomide (TMZ), is insufficient as the 5-year survival rate of glioblastoma patients has remained at roughly 8%. One major contributing factor to treatment inefficacy is the presence of TMZ-resistant cells within tumors that lead to chemoresistance and tumor recurrence. Thus, there is an unmet need to further understand the molecular properties of TMZ-resistant cells which could enable more effective means of targeting them and improve patient outcomes. Here we utilized microfluidic sorting devices and applied DEP, a phenomenon by which non-uniform electric fields induce differential movement of cells, as a novel label-free technique to sort glioma cells based on their membrane electrophysiological properties. With this technique, we successfully sorted cells from glioblastoma and oligodendroglioma established cell lines, which yielded fractions that differed in membrane capacitance, the membrane’s ability to store charge. Interestingly, the DEP-sorted cell fractions also exhibited significant differences in TMZ resistance, indicating that DEP can be used robustly to enrich for TMZ-resistant cells across different gliomas. Further, differences in TMZ resistance were coupled with membrane capacitance differences. Since we previously identified links between membrane capacitance and cell-surface glycosylation, we utilized lectin analysis to assess the glycan expression of DEP-sorted oligodendroglioma cells and found inverse correlation between TMZ resistance and mannose glycan expression. Collectively, our study concluded the novel finding that (a) TMZ-resistant glioma cells can be enriched by DEP, and (b) TMZ resistance is correlated with membrane capacitance and cell surface glycosylation. These results could enable downstream molecular characterization of TMZ-resistant cells to uncover less explored mechanisms of TMZ resistance and the development of more effective treatment strategies for gliomas that specifically target membrane properties such as glycosylation. Citation Format: Vi P. Dang, Alan Y. Jiang, Jaclyn N. Hanamoto, Nicole S. Lav, Christopher R. Douglas, Daniela A. Bota, Lisa A. Flanagan. Sorting to enrich for chemotherapeutic-resistant glioma cells based on unique membrane properties [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 5546.