bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB198: The PAX5 oncogene encodes circular RNA products involved in B cell cancer processes
Authors: Martin Danick , Hannay Brandon , McGraw Farrah , Martin Alexis , Veilleux Vanessa , Finn Nicholas , Robichaud Gilles A.
Published: April 2024

Introduction: B-cell cancers represent some of the most prevalent hematological lesions in adult and children. B-cell cancers are also notable for their malignancy and resistance to drug therapies. Our group studies B-cell oncogenes and recently discovered that the prominent PAX5 oncogene, which usually encodes transcription factors, also generates non-coding circular RNA transcripts. Circular RNAs (circRNAs) represent a new class of gene products involved in many biological processes and cancer disease. Due to their innate ability to bind and modulate co-interacting proteins and microRNAs (miRs), circRNAs represent new signaling avenues in cancer biology.

Hypothesis: Given that products from the PAX5 oncogene are important regulators of B-cell cancers, we hypothesized that PAX5 circRNAs (circPAX5) are also involved in B-cell oncogenesis.

Objective: We therefore set out to study circPAX5 products, and their co-interacting miRs, in B-cell cancers.

Results: Using a series of B-cell cancer models and clinical samples, we first profiled the expression of circPAX5 products and found that B-cell leukemias overexpress circPAX5 where its predominant circRNA isoform consisted of exons 2 to 5 sequences of the PAX5 locus. To establish a functional role of circPAX5 on cancer processes, we evaluated B-cell proliferation and chemosensitivity in cancer models expressing conditioned levels of circPAX5. Interestingly, we found that the suppression of circPAX5 levels resulted in the alteration of cancer growth rates, which were dependent upon B-cell differentiation state and population subtype. Mechanistically, we also found that circPAX5 interacts with specific miRs, which were profiled by circRNA precipitation and deep sequencing. Selected sponged miRs were then studied by bio-informatic analyses and mapped to downstream mRNA targets and B-cell cancer pathways.

Conclusions: Altogether, our findings uncover PAX5 circular products, which are involved in B-cell cancer processes and could potentially represent a new cancer pathway targeted for therapeutic and/or diagnostic strategies in B-cell cancer lesions.

Citation Format: Danick Martin, Brandon Hannay, Farrah McGraw, Alexis Martin, Vanessa Veilleux, Nicholas Finn, Gilles A. Robichaud. The PAX5 oncogene encodes circular RNA products involved in B cell cancer processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB198.
Abstract LB262: Reprogramming the tumor microenvironment by targeting IGF2-IGF1R signaling, enhancing viro-immunotherapy
Authors: Noh Min Hye , Miller Alexandra , Nguyen Grace , Nakashima Hiroshi , Chiocca E. Antonio , Kaur Balveen , Zhao Zhongming , Lee Tae Jin , Yoo Ji Young
Published: April 2024

While an FDA-approved oncolytic herpes simplex-1 virus (oHSV) has shown therapeutic promise with superior safety, accumulating clinical data revealed that its therapeutic efficacy is observed in a small subset of patients. Here, we show that NFκB-mediated Insulin-like Growth Factor 2 (IGF2)/Insulin-like Growth Factor-1 Receptor (IGF1R) signaling pathway as a key modulator for oHSV therapy-mediated tumor resistance. RNA sequencing on the oHSV-infected primary glioblastoma (GBM) and breast cancer (BC) cells identified IGF2 as one of the top 10 upregulated secretomes. Transcriptomic analysis also revealed significant upregulation/enrichment of genes related to IGF2-IGF1R-MAPK pathway in oHSV-treated tumor cells. Infection with oHSV in GBM and BC cells up-regulated IGF2 transcription via direct binding of NFκB in the IGF2 promoter 3. Compromising the IGF2-IGF1R signaling pathway using IGF2 neutralizing antibody significantlDB7 BC tumors in vivo. To circumvent this and promptly translate our findings in clinical settings, we have developed a novel oHSV, oHSV-D11mt, by incorporating modified IGF2R domain 11 into the parental oHSV genome to function as IGF2 decoy receptor as a single-agent modality. oHSV-D11mt specifically bind to IGF2 not IGF1, blocks oHSV-induced IGF2-IGF1R signaling, increases tumor cell killing, decreases oHSV-induced neutrophils/PMN-MDSCs infiltration, immune suppressive/proangiogenic cytokine secretion, and increases CD8+ cytotoxic T lymphocytes (CTLs) activation, resulting in increased virus propagation and mice survival. These findings suggest that IGF2-IGF1R signaling is a novel target to overcome oHSV therapy resistance and oHSV-D11mt could be used for improved viro-immunotherapy.

Citation Format: Min Hye Noh, Alexandra Miller, Grace Nguyen, Hiroshi Nakashima, E. Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo. Reprogramming the tumor microenvironment by targeting IGF2-IGF1R signaling, enhancing viro-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB262.
Abstract LB268: Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797
Authors: Gao Yeqing , Lu Yuqian , Chen Bo , Jiang Benke , Wang Feng , Zhang Genyan , Ma Xifeng , Zhou Dapeng , Shi Chunmin , Wang Yunling , Liu Zhipeng , Sun Jun , Zhou Huimin , Xu Mei , Li Jiakui , Liu Bin
Published: April 2024

First-generation PARP1/2 inhibitors are approved for the treatment of cancers, such as ovarian, prostate, pancreas, and breast cancers, with maximal activity against tumors harboring BRCA1/2 mutation or homologous recombination deficiency (HRD). However, PARP1/2 inhibitors in clinical use have severe hematological toxicities due to the inhibition of PARP2, which has been shown to play an important role in the survival of hematopoietic progenitor cells. Furthermore, the current data indicate that synthetic lethality with BRCA mutations is primarily caused by PARP1 inhibition and trapping, whereas PARP2 inhibition and trapping are not critical for anticancer activity. Therefore, the development of selective PARP1 inhibitors is expected to reduce the hematological adverse effects associated with PARP2 inhibition while maintaining the required efficacy. XZP-7797 is a potent, selective, and brain-penetrating PARP1 inhibitor with trapping ability. In biochemical assays, XZP-7797 is more than 1000-fold selective for PARP1 over PARP2 and other members of the PARP family, including PARP3, PARP5a, PARP5b, and PARP6. XZP-7797 can significantly inhibit MDA-MB-436 cell proliferation in vitro (IC50=2.4nM). In MDA-MB-436 tumor cells, XZP-7797 inhibits PARylation and increases γH2AX level in a concentration-dependent manner. XZP-7797 demonstrates rapid tumor regression in a dose-dependent manner in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. In a pancreatic cancer xenograft model, XZP-7797 can also significantly inhibit tumor growth. To evaluate the ability of XZP-7797 to cross the blood-brain barrier, an intracranial xenograft model of breast cancer is used. The results show that XZP-7797 can significantly inhibit the growth of intracranial tumors in mice at a dose of 10 mg/kg, demonstrating the brain-penetrating ability of XZP-7797. Additionally, XZP-7797 has great PK profiles in preclinical species after oral dosing and good ADME properties. In a 14-day toxicology study of XZP-7797 in SD Rats, XZP-7797 has no hematological adverse effects at the exposure that is 10 times higher than the exposure required to achieve superior efficacy.

Citation Format: Yeqing Gao, Yuqian Lu, Bo Chen, Benke Jiang, Feng Wang, Genyan Zhang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yunling Wang, Zhipeng Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu. Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB268.
Abstract LB286: Extrachromosomal DNA in lung cancer from never smokers
Authors: Khandekar Azhar , Zhang Tongwu , Diaz-Gay Marcos , Luebeck Jens , Alexandrov Ludmil , Landi Maria
Published: April 2024

Extrachromosomal DNA (ecDNA), circular DNA that resides outside of the linear chromosome, is a potent form of oncogene amplification in cancer. The structure and properties of ecDNA are markedly different from those of linear DNA, characterized by features like non-Mendelian inheritance and an altered epigenetic landscape. A prior pan-cancer analysis ​​indicated patients with cancers harboring ecDNA have statistically worse overall survival when compared to cancer patients with other types of focal amplification. Moreover, its unique characteristics also make it a promising target for therapy. Recently, efforts have intensified to profile ecDNA across many cancer types, yet comprehensive studies of ecDNA in lung cancer in never smokers (LCINS) is lacking. Given that LCINS is partially driven by somatic copy number alterations, we hypothesized that ecDNA-driven focal amplifications significantly influence LCINS tumor evolution. As part of the Sherlock-Lung project (current data freeze, 1217 samples), we comprehensively profiled 871 treatment-naive samples using a robust computational pipeline that refined copy number segmentation by accounting for tumor purity and ploidy. ecDNA was present in 151 (17.3%) of tumor samples, with a third of ecDNA-positive samples harboring more than one distinct ecDNA amplicon. Consistent with prior reports, no ecDNA was found in bulk sequenced blood or matched normal lung tissues. These ecDNA often included genes (84%), frequently overlapping with known oncogenes like MDM2, TERT, and MYC, which showed higher expression levels compared to non-amplified or other amplified genes. Notably, most MDM2 amplifications (36/45) were on ecDNA. ecDNA was significantly associated with whole genome doubling, tumor stage, and several endogenous mutational signatures, including APOBEC (SBS2 and SBS13), and clock-like signature (SBS1). Intriguingly, ecDNA-positive tumors were associated with significantly worse survival compared to tumors without any focal amplifications, though tumors with other amplification types (e.g. breakage-fusion-bridge, linear amplification, or complex events) had similar survival impacts. The unprecedented size of our cohort and the integration of clinical, epidemiologic, and multi-omics data allowed us to perform the first in-depth characterization of ecDNA in LCINS. We reconstructed the genomic regions involved in ecDNA and revealed the full spectrum of simple and complex ecDNAs across cancer histologies as well as the clinical and functional impact of ecDNA on LCINS.

Citation Format: Azhar Khandekar, Tongwu Zhang, Marcos Diaz-Gay, Jens Luebeck, Ludmil Alexandrov, Maria Landi. Extrachromosomal DNA in lung cancer from never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB286.
Abstract LB292: Glutathione supports lipid abundance in vivo
Authors: Asantewaa Gloria , Tuttle Emily T. , Ward Nathan P. , Kang Yun P. , Kim Yumi , Kavanagh Madeline , Huber Aaron R. , Munger Joshua , Cravatt Benjamin , Cole Calvin L. , DeNicola Gina M. , Harris Isaac S.
Published: April 2024

Glutathione (GSH), the most abundant antioxidant, scavenges free radicals and prevents the detrimental effects of oxidative stress. As a result, GSH levels are associated with protection from stress-related conditions, such as aging and cancer. Given this rationale, antioxidants are routinely consumed by the public, mainly because they are viewed as “cure-alls” and almost uniformly beneficial to a range of diseases. This is an oversimplification, as the relationship between antioxidants and diseases is much more complex. Recent evidence has implicated GSH in protecting cancer cells from oxidative stress and promoting their survival. Therefore, understanding GSH metabolism in vivo and its intricate crosstalk with other cellular pathways is vital to improving the efficacy of therapies for diseases, including cancer. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance via the LXR/SREBP signaling pathway, as well as by repressing NRF2, a transcription factor induced by oxidative stress. Overall, these findings suggest an essential function for GSH in maintaining circulating lipids levels and lipid depots, possibly as a mechanism to prevent lipid peroxidation and redox imbalances. Notably, the accumulation of oxidized lipids propagates oxidative stress and associated cell death phenotypes (i.e., ferroptosis). This also highlights a potentially novel mechanism by which GSH regulates lipid production and suggests a possible link between oxidative stress (caused by GSH deficiency) and cachexia (commonly characterized by loss of fat and lean mass), a disorder linked to cancer but poorly understood. Consequently, by elucidating the contributions of GSH to lipid homeostasis, we can better understand the basic biology surrounding GSH and obtain critical insight into potentially improving the treatment of cancer-related cachexia.

Citation Format: Gloria Asantewaa, Emily T. Tuttle, Nathan P. Ward, Yun P. Kang, Yumi Kim, Madeline Kavanagh, Aaron R. Huber, Joshua Munger, Benjamin Cravatt, Calvin L. Cole, Gina M. DeNicola, Isaac S. Harris. Glutathione supports lipid abundance in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB292.
Abstract LB318: Exploring early precursor lesions of ovarian cancer: Insights from an in vitro model
Authors: Wang Yan E. , Levina Vera , Galson Deborah L. , Lokshin Anna E.
Published: April 2024

Ovarian cancer ranks as the fifth leading cause of cancer-related deaths in women, surpassing other cancers of the female reproductive system. Recent epidemiological and molecular studies highlight the significance of high-grade serous carcinoma (HGSC), the most aggressive subtype of ovarian cancer, constituting nearly 96% of cases with mutations in p53. HGSC originates from fallopian tube secretory epithelial (FTSEC) cells through a progression of precursor lesions, ranging from p53 signatures to serous tubal intraepithelial carcinoma (STIC). The p53 signature involves a linear expansion of over 12 TP53 mutant FTSECs, morphologically normal and displaying no increase in proliferative activity. In this study, we established a model system for P53 signature by either overexpressing p53 mutations (R175H and R273H) or knocking down P53 expression in normal FTSECs maintained as 2D, 3D, or organoid cultures. We have characterized the cells using RNA seq, mass spectroscopy and functional assays. Functional assays revealed increased migration and proliferation, along with decreased apoptosis in response to the cytotoxic stimulus (cisplatin). Despite the inability of p53 signature cells to proliferate or migrate in vivo, our hypothesis posited that clonal expansion of progenitor cell with a p53 mutation maintains plasticity by preserving the stemness of one or more cells capable of responding to cues from the microenvironment. Our experiments revealed heterogeneity in the model system, reflecting the composition of p53 signature in vivo. We also observed that stem-like cells tend to organize into clusters. Notably, stem-like cluster cells bearing a p53 signature exhibit migratory behavior, whereas clusters lacking p53 do not demonstrate such mobility. Given that most high-grade serous carcinoma (HGSC) cases occur in postmenopausal women, we demonstrated induction of proliferation and migration of p53 mutant stem cells in response to stimuli from aging stromal cells (fibroblasts and autologous immune cells) and to changes in hormonal background in our model. Conclusion: This study illuminates a novel aspect of ovarian cancer development, underscoring the role of a distinct population of fallopian tube epithelial cells with stem-like properties within p53 signatures. Further investigations into the tumorigenicity of these cells hold promise for providing valuable insights into future therapeutic strategies.

Citation Format: Yan E. Wang, Vera Levina, Deborah L. Galson, Anna E. Lokshin. Exploring early precursor lesions of ovarian cancer: Insights from an in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB318.
Abstract LB320: Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis
Authors: Lee Keun-Woo , Sohn Insuk , Kim Seok-Hyung , Yeo So-Young
Published: April 2024

Cancer associated fibroblasts (CAFs) express a variety of cytokines and factors that activate and contribute to pathways that favor tumorigenesis. CAFs disrupt normal cellular functions, such as cell cycle regulation and cell death including apoptosis, or signal certain types of cells to abnormally activate pro-tumor activities. In addition, when it is abnormally activated, it is characterized by increased collagen deposition and more contractility. Likewise, This pattern of abnormal activation is often observed in keloid disease. Keloid constitutes an abnormal fibroproliferative wound healing response with excessive collagen deposition causing abnormal wound healing. To better understand the CAF subtypes with abnormal activation and cancer-promoting properties and the subtypes of keloid fibroblasts with similar activation properties, it is essential to find the master transcription factors (TFs) that determine their identity. To identify functionally important TFs in abnormal CAFs and keloid fibroblasts, we analyzed H3K27ac ChIP-seq of CAFs and keloid fibroblasts and observed that Runx2 significantly enriched the two types of abnormal fibroblasts.To investigate the biological function of Runx2 , we established CAFs from colon cancer patients and performed ShRNA-mediated knockdown of the RUNX2 gene. We confirmed that knockdown of RUNX2 in CAFs suppressed the migration or invasion of cancer cells. Additionally, using a gel contraction assay, we confirmed that fibroblast contractility was significantly reduced by RUNX2 knockdown. Similarly, in keloid fibroblasts, it was confirmed that the migration and gel contraception abilities of fibroblasts were significantly reduced following knockdown of RUNX2 [A1] gene. Last but not least, expression of ECM elements, such as collagens and fibronectin, were significantly as a result of the knockdown of the RUNX2 gene in both abnormally activated fibroblasts. To conclude, we believe that Runx2 acts as a key TF that maintains the contractility and ECM remodeling ability of abnormally activated fibroblasts. Our findings indicate that Runx2 is a attractive therapeutic target not only for pro-tumorigenesis in the cancer microenvironment, but also for keloid fibroblasts.

Citation Format: Keun-Woo Lee, Insuk Sohn, Seok-Hyung Kim, So-Young Yeo. Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB320.
Abstract LB342: Potent Anti-Tumor Activity Demonstrated by Anti-AXL CAR T Cell Therapy and AXL-ADC in Lung Cancer and Breast Cancer Models
Authors: Wu Zhongen , Gao Yang , Pei Jingpeng , Zhao Enfeng , Mei Shenglin , Feng Yuxiong , Zhu Di
Published: April 2024

AXL is over-expressed in various cancers. Its signaling pathway is related to tumor progress. We created a novel a novel AXL-ADC (Hu002-MMAE) based on humanized AXL-targeted antibody (Hu002). We also developed anti-AXL CAR T cells and AXL-CAR iNKT to evaluate anti-tumor effect. Methods: 1) Evaluate the cytotoxicity of Hu002-MMAE in 5 AXL-high-expressing cells. 2) in vivo efficacy validation of Hu002-MMAE into LCLC-103H-bearing Nude mice and U87MG-bearing nude mice. 3) Evaluate the cytotoxicity of anti-AXL CAR-T and AXL CAR-iNKT cells in cell lines with different AXL expression levels to validate the selectivity. 4) in vivo efficacy validation of anti-AXL CAR T cells into MDA-MB-231-bearing mice.Results: Hu002 demonstrates potent binding affinity significantly inhibited the migration of AXL-high tumor cells. The Hu002-MMAE showed potent cytotoxicity against AXL-high tumor cells (IC50 < 0.1 nmol/L) and had a longer-term therapeutic effect in a variety of NSCLC and glioma tumors in vivo (MED < 0.5 mg/kg). Anti-AXL CAR-T cells and AXL CAR-iNKT exhibited strong killing activity to AXL-high-expressed cell lines LCLC-103H and MDA-MB-231 in vitro, while shows minimum effect of anti-tumor effect in AXL-low-expressed cell lines H460 and MDA-MB-453. In in vivo models of MDA-MB-231, we observed increased infiltration of T cells in primary tumor and reduced lung metastasis after AXL CAR-T treamtment.Conclusion: Anti-AXL CAR T and AXL-ADC cells showed strong and selective killing activity, improved TME in primary tumor and mitigate lung metastasis, which makes it a potential strategy for cancers.

Citation Format: Zhongen Wu, Yang Gao, Jingpeng Pei, Enfeng Zhao, Shenglin Mei, Yuxiong Feng, Di Zhu. Potent Anti-Tumor Activity Demonstrated by Anti-AXL CAR T Cell Therapy and AXL-ADC in Lung Cancer and Breast Cancer Models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB342.
Abstract LB349: Cysteine restriction enhances antitumor immunity in colorectal cancer
Authors: Li Jichang , Xia Kang , Yang Zeruo , Pan Xiaoxue , Yang Xiaojing , Wang Pengyuan , Chen Shanwen
Published: April 2024

Background: Colon cancer is the second leading cause of cancer mortality worldwide, however, there are still issues with multidrug resistance and severe adverse reactions. Previous studies have shown that sulfur-containing amino acids are involved in cancer development, drug resistance, and immune evasion. Here, Our experimental findings suggested that restricting the intake of sulfur-containing amino acids may present a novel strategy for treating colorectal cancer.

Methods: We assessed the impact of sulfur-containing amino acid restriction (SAR) on distinct cellular subpopulations within the tumor microenvironment through single-cell sequencing on colon carcinogenesis induced by azoxymethane/dextran sodium sulfate (AOM/DSS). Employing our custom-produced neutralizing antibodies against SLC7A11 to restrict cysteine intake, we examined the therapeutic implications and underlying molecular mechanisms by RNA-seq, Multiplexed immunofluorescence staining and Western blotting.

Results: In the AOM/DSS model, SAR led to a slight reduction in mouse body weight compared to the normal diet. However, this dietary restriction significantly enhanced the survival rate of mice and effectively suppressed tumor growth. The single-cell sequencing results indicated a significant increase in the proportion of T cells within the tumor microenvironment in response to SAR. This suggested that restricting the intake of sulfur-containing amino acids may be a promising anti-tumor strategy. Previous studies have indicated high expression of the SLC7A11, a cysteine transporter protein, in various cancers, including colorectal cancer. To further investigate the role of cysteine in colorectal cancer, we developed the neutralizing antibody 1A4 against SLC7A11. Our results indicated that 1A4 markedly inhibited colorectal cancer development in mice. As known, 85% of colorectal cancers are microsatellite stable, which hardly benefit from treatment with immune checkpoint inhibitors (ICIs). Compared to anti-PD-1 and anti-CTLA4, 1A4 significantly inhibited the growth of CT26 in vivo. Multiplexed immunofluorescence staining results demonstrated that 1A4 significantly increased the proportion of CD8+ T cells in colorectal cancer tissues.

Conclusion: Limiting cysteine intake significantly inhibits the growth of colorectal cancer, increases the proportion of CD8+ T cells, and enhances anti-tumor immunity.

Citation Format: Jichang Li, Kang Xia, Zeruo Yang, Xiaoxue Pan, Xiaojing Yang, Pengyuan Wang, Shanwen Chen. Cysteine restriction enhances antitumor immunity in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB349.
Abstract LB405: CTP synthase 1 is a synthetic vulnerability in prostate cancer treated with supraphysiological androgen
Authors: Jonnatan Sheila , Kumar Rajendra , Vakkala Varsha , Vasan Karthik , Chalmers Zachary R. , Schmidt Daniel R. , Beer Philip A. , Heiden Matthew G. Vander , Denmeade Samuel R. , Chandel Navdeep S. , Sena Laura A.
Published: April 2024

Bipolar androgen therapy (BAT) is the cyclical administration of supraphysiological androgen (SPA), which can be an effective treatment for 30-40% of patients with castration-resistant prostate cancer. We sought to improve the efficacy of BAT by better understanding its molecular consequences in prostate cancer. Given that the androgen receptor (AR) regulates cellular metabolism, we hypothesized that SPA induces dependencies on specific metabolic pathways that might be exploited therapeutically. A negative selection metabolism-focused CRISPR-KO screen in LNCaP cells treated with SPA suggested that the deletion of several enzymes involved in de novo nucleotide synthesis enhances growth suppression by SPA. A top hit was cytidine triphosphate synthase 1 (CTPS1). CTPS1 converts UTP to CTP in the final step of de novo pyrimidine synthesis. Exposure of SPA-treated prostate cancer cell lines to STP-B, a potent and highly selective inhibitor of CTPS1 (PMID 37008165), increased cell death in vitro and in vivo, indicating that CTPS1 constitutes a metabolic vulnerability in this context. Inhibition of CTPS1 with STP-B induced S phase cell cycle arrest and replication stress, as indicated by phosphorylation of RPA and CHEK proteins, which was augmented by treatment with SPA. CTPS1 likely becomes a vulnerability in SPA-treated prostate cancer due to the downregulation of MYC by SPA, which we found leads to a reduced abundance of enzymes required for nucleotide synthesis and nucleotides, particularly CTP. This rewires nucleotide synthesis and salvage pathway such that de novo synthesis of CTP is required to avoid replication stress and cell death. Altogether, this work suggests that inhibition of CTPS1 may enhance the efficacy of BAT through the induction of replication stress. Selective inhibitors of CTPS1 have entered clinical development (NCT05463263), increasing the feasibility of a combination therapy clinical trial design for patients with prostate cancer.

Citation Format: Sheila Jonnatan, Rajendra Kumar, Varsha Vakkala, Karthik Vasan, Zachary R. Chalmers, Daniel R. Schmidt, Philip A. Beer, Matthew G. Vander Heiden, Samuel R. Denmeade, Navdeep S. Chandel, Laura A. Sena. CTP synthase 1 is a synthetic vulnerability in prostate cancer treated with supraphysiological androgen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB405.
Abstract SY41-01: Selection of targeted neoantigens for personalized cancer vaccines
Authors: Keskin Derin
Published: April 2024

Neoantigen targeting personalized cancer vaccines (PCV) have the potential to revolutionize cancer treatment. These personalized vaccines rely on accurate epitope prediction and selection. We previously reported phase I trials of neoantigen targeting PCV in melanoma and glioblastoma multiforme (GBM). Recently we concluded a trial in renal cell carcinoma (RCC) where the neoantigen targeting PCV was immunogenic in all patients, targeted cancer drivers, and demonstrated in vitro reactivity to primary patient tumors. The neoantigen selection pipeline at DFCI supporting clinical trials utilizes immunopeptidome-trained epitope prediction algorithms to design synthetic long peptides as vaccine antigens containing predicted HLA Class I neoantigens. We also prioritize highly expressed neoantigens and neoantigens originating from cancer drivers as vaccine epitopes. For future iterations of this pipeline, we aspire to include novel classes of neoantigens originating from endogenous human retroviruses (ERV), fusion epitopes, novel or unannotated open reading frames (nuORFs), and immunopeptidome-identified neoantigens. The neoantigen selection pipeline is currently supporting multiple cancer vaccine trials at DFCI targeting melanoma, GBM, RCC, ovarian cancer, and chronic lymphocytic leukemia (CLL).

Citation Format: Derin Keskin. Selection of targeted neoantigens for personalized cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY41-01.
Long-Term Growth and Neurodevelopmental Outcomes of Neonates Infected with SARS-CoV-2 during the COVID-19 Pandemic at 18–24 Months Corrected Age: A Prospective Observational Study
Authors: Goyal Medha , Mascarenhas Dwayne , RR Prashanth , Nanavati Ruchi
Published: April 2024

Introduction: During the early coronavirus disease (COVID-19) pandemic in 2020, researchers cautioned about the potential neuroinvasive capability of the virus and long-term neurological consequences. Although a few preliminary studies have found delayed communication, fine motor, and problem-solving skills in infants after COVID-19 infection, there continues to be a paucity of data on long-term development of neonates diagnosed with COVID-19. Methods: We conducted a prospective study of 20 neonates who acquired severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the first wave of the pandemic (April–July 2020). At 18–24 months corrected age, we assessed neurodevelopment by Bayley Scales of Infant and Toddler Development, the third edition (BSID-III), along with growth, hearing, and vision evaluation. Results: The mean corrected age at assessment was 21 months 11 days ± 1 month 28 days. We found developmental delay in nearly half of the children with scores below one standard deviation in either of the BSID-III domains. Mild delay in either motor, cognitive, or language domains was found in 9 (45%) children and moderate delay in 2 (10%). Expressive language, fine motor, and receptive language were predominantly affected. None of the children had hearing impairment, blindness, or significant growth faltering including clinically severe microcephaly. The mean composite cognitive, language, and motor scores were significantly lower in those with neurodevelopmental delay (p value – 0.02, 0.000, and 0.03, respectively) without any differences in their disease characteristics. Conclusion: Neonates infected with SARS-CoV-2 have an increased risk of developmental delays in expressive language, fine motor, and receptive language skills at 18–24 months of age. The severity of delays is predominantly mild.
Clinicopathological Correlates of Ocular Surface Squamous Neoplasia
Authors: Kalas Timothy , Vagenas Dimitrios , Maccheron Luke , Toalster Nicholas
Published: April 2024

Introduction: This study examined the distribution of histopathological disease severity amongst a cohort of patients treated for clinically suspected ocular surface squamous neoplasia and evaluated the relationship between various patient and clinical factors and the severity of pathological grade as well as treatment outcomes. Methods: A retrospective cohort study of demographic and clinicopathological factors of 150 patients clinically diagnosed with suspected ocular surface squamous neoplasia who underwent excision of lesion with histopathological diagnosis. Results: The study included 125 cases; the mean age at diagnosis was 64 years (SD = 11.26). 74% of cases were histologically confirmed as ocular surface squamous neoplasia. Pathological distribution was conjunctival intraepithelial neoplasia I (13.6%), conjunctival intraepithelial neoplasia II (16.8%), conjunctival intraepithelial neoplasia III (21.6%), carcinoma in situ (21.6%), and squamous cell carcinoma (2.4%). Lesion appearance was leukoplakic (18%), gelatinous (15%), dysplastic (11%), vascular (6%), papilliform (2%), nodular (2%). Lesion location was nasal (43%), temporal (42%), and superior or inferior (14%). Recurrence occurred in 7 cases (5.6%). A significant association was found between presence of leukoplakia and pathological grade (p = 0.05). Conclusions: Ocular surface squamous neoplasia is most frequently diagnosed in conjunctival intraepithelial neoplasia III and carcinoma in situ stages, and treatment outcomes are usually favourable.
Strategies for improving the quality of community detection based on modularity optimization
Authors: Setiadi Tedy , Yaakub Mohd Ridzwan , Abu Bakar Azuraliza
Published: April 2024

Community detection is a field of interest in social networks. Many new methods have emerged for community detection solution, however the modularity optimization method is the most prominent. Community detection based on modularity optimization (CDMO) has fundamental problems in the form of solution degeneration and resolution limits. From the two problems, the resolution limit is more concerned because it affects the resulting community's quality. During the last decade, many studies have attempted to address the problems, but so far they have been carried out partially, no one has thoroughly discussed efforts to improve the quality of CDMO. In this paper, we aim to investigate works in handling resolution limit and improving the quality of CDMO, along with their strengths and limitations. We derive six categories of strategies to improve the quality of CDMO, namely developing multi-resolution modularity, creating local modularity, creating modularity density, creating new metrics as an alternative to modularity, creating new quality metrics as a substitute for modularity, involving node attributes in determining community detection, and extending the single objective function into a multi-objective function. These strategies can be used as a guide in developing community detection methods. By considering network size, network type, and community distribution, we can choose the appropriate strategy in improving the quality of community detection.
Design of drought early warning system based on standardized precipitation index prediction using hybrid ARIMA-MLP in Banten province
Authors: Soekirno Santoso , Ananda Naufal , Wicaksana Haryas Subyantara , Yulizar David , Prabowo Muhammad Agung , Adi Suko Prayitno , Santoso Bayu
Published: April 2024

Drought Early Warning System (DEWS) is an effort to disseminate early warning information based on climate and hydrology aspects. The DEWS design uses ARIMA, MLP, and hybrid ARIMA-MLP models to predict drought based on SPI for 1, 3, and 6 months. Predictions were made using ERA5 monthly rainfall data from 1981-2022 corrected based on observation data on 9 grids of observation rain gauges in Banten Province. The design of the ARIMA model is determined by selecting the combination of p and q parameters with the lowest AIC value, while the MLP architecture is determined by referring to the study literature and by trial and error testing. ARIMA models and hybrid models are not able to follow actual data fluctuations and have high error values in both SPI1, SPI3, and SPI6, so they are not recommended in this study. The MLP model has the best prediction ability, namely in SPI6 prediction with NSE value reaching >0.5 and RMSE value.
Tuning the k value in k-nearest neighbors for malware detection
Authors: Abualhaj Mosleh M. , Abu-Shareha Ahmad Adel , Shambour Qusai Y. , Al-Khatib Sumaya N. , Hiari Mohammad O.
Published: April 2024

Malicious software, also referred to as malware, poses a serious threat to computer networks, user privacy, and user systems. Effective cybersecurity depends on the correct detection and classification of malware. In order to improve its effectiveness, the K-Nearest Neighbors (KNN) method is applied systematically in this study to the task of malware detection. The study investigates the effect of the number of neighbors (K) parameter on the KNN's performance. MalMem-2022 malware datasets and relevant evaluation criteria like accuracy, precision, recall, and F1-score will be used to assess the efficacy of the suggested technique. The experiments evaluate how parameter tuning affects the accuracy of malware detection by comparing the performance of various parameter setups. The study findings show that careful parameter adjustment considerably boosts the KNN method's malware detection capability. The research also highlights the potential of KNN with parameter adjustment as a useful tool for malware detection in real-world circumstances, allowing for prompt and precise identification of malware.
Ventromedial frontoinsular connectivity is associated with long-term smoking behavior change in aging
Authors: Thovinakere Nagashree , Ai Meishan , Colina Adrián Noriega de la , Walker Caitlin , Baracchini Giulia , Tremblay-Mercier Jennifer , Villeneuve Sylvia , Spreng Nathan , Geddes Maiya R.
Published: April 2024

A central question in the field of cognitive aging and behavioral neuroscience is what enables some individuals to successfully change their behavior more than others? Smoking is a significant risk factor for cognitive decline, particularly in vulnerable populations, including those who are at an elevated risk for Alzheimer’s disease (AD). Developing effective smoking reduction strategies is therefore a public health priority. The goal of the current study is to better understand the brain mechanisms underlying long-term smoking behavior change in cognitively normal, but at-risk, older adults. Neuroimaging and human lesion studies have implicated the insula and its functional network in subjective interoceptive awareness of cigarette craving and smoking-cue reactivity. We sought to characterize the extent to which anterior insular resting-state functional connectivity (RSFC) MRI predicted long-term smoking reduction (mean: 2.7 years, range 8 months–4 years) using a seed-to-voxel approach. Twenty-three (18 women; 26% APOE4 carriers; 61.5 years, SD = 3.7) cognitively unimpaired older individuals who smoked cigarettes at their baseline visit and have a first-degree family history of AD (at least one parent or multiple siblings affected) were included from a prospective longitudinal cohort, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) in the current study. We found that reduced long-term smoking behavior was associated with enhanced antagonistic RSFC between bilateral anterior insula (aINS) and ventromedial prefrontal cortex (vmPFC). In a second pre-registered replication study within a larger, independent sample of 118 cognitively normal older adults who smoked cigarettes at baseline from the UK Biobank (73 women; 27.9% APOE4 carriers; 60.3 years, SD = 2.7), we found that baseline enhanced antagonistic RSFC between anterior insula and vmPFC predicted long-term smoking reduction (mean 5.2 years; ranging from 3 years to 7 years). To our knowledge, this is the largest study to examine the neural substrates of long-term smoking cessation in human aging. Our results suggest that antagonistic RSFC between aINS and vmPFC is a brain marker of future smoking reduction and disease prevention in older adults at risk for AD.
Men of Letters: Perspectives on Multisensory Environments in the Hall-McLuhan Correspondence, 1961–1977
Authors: Muench Wolfgang
Published: April 2024

This paper introduces critical elements in the substantial, albeit mostly unpublished, correspondence between cultural anthropologist Edward T. Hall and media theorist Marshall McLuhan related to artistic practice with emerging media technologies in the 1960s. It contextualizes their exchange within the broader theoretical discourses and artistic practices surrounding systems theory and media technology and highlights intersections between Hall and McLuhan’s theoretical frameworks related to concepts of indeterminism, systems theory, and cybernetics in technology-based, kinesthetic, multisensory mediated environments in the 1960s. It particularly focuses on overlapping conceptual approaches toward the interrelation between the individual, the socio-cultural environment, and the emerging media-technological ecosystem.
Genetic basis for Rapana venosa with different peristome color based on microsatellite, DNA methylation, and transcriptome analysis
Authors: Zou Shanmei , Gao Zhan , Wu Xuemin , Yu Xinke , Sun Tiantian , Wang Changhai
Published: April 2024

Rapana venosa, a well-known and economic species mainly distributed in the Asian region, has three distinct color patterns in the peristome: pure orange, pure dark stripes, and part stripes. The present study combined microsatellite, DNA methylation, and transcriptome to assess the genetic basis of three color patterns of R. venosa in the peristome. The different color patterns of R. venosa showed no significant genetic differentiation, and each color group was relatively independent with respect to gene flow. Each color pattern showed a high methylation rate of more than 60%. The full-methylation rates for the three color patterns were 34.47%, 35.67%, and 32.54%, respectively. The Gene Ontology (GO) classification and functional enrichment revealed three ontologies: molecular function, cellular components, and biological processes. The function of translation, ribosomal structure, and biogenesis accounted for the top classification, followed by general function prediction. This study also revealed some functional genes related to color and shell formation, including Scavenger receptor cysteine-rich protein (SRCR), beta-carotene ketolase, tyrosinase proteins, and Lustrin A. These findings suggest that the color polymorphism of R. venosa is possibly attributed to environmental effects. The research is also essential for selecting better germplasm for the breeding of Rapana venosa.
Zonal Wavenumber 3 Forces Extreme Precipitation in South America
Authors: Ortiz-Guzmán Valentina , Jucker Martin , Sherwood Steven C.
Published: April 2024

The Southern Hemisphere climate and weather are affected by several modes of variability and climate phenomena across different time and spatial scales. An additional key component of the atmosphere dynamics that greatly influences weather is quasi-stationary Rossby waves, which attract particular interest as they are often associated with synoptic-scale extreme events. In the Southern Hemisphere extratropical circulation, the most prominent quasi-stationary Rossby wave pattern is the zonal wavenumber 3 (ZW3), which has been shown to have impacts on meridional heat and momentum transport in mid- to high latitudes and on the Antarctic sea ice extent. However, little is known about its impacts outside of polar regions. In this work, we use ERA5 reanalysis data on monthly time scales to explore the influence of phase and amplitude of ZW3 on temperature and precipitation across the Southern Hemisphere midlatitudes. Our results show a significant impact in various regions for all seasons. One of the most substantial effects is observed in precipitation over southeastern Brazil during austral summer, where different phases of the ZW3 force opposite anomalies. When using the ZW3 phase and amplitude as prior information, the probability of occurrence of precipitation extremes in this region increases up to three times. Additionally, we find that this ZW3 weather signature is largely independent of the zonally symmetric Southern Annular Mode (SAM); neither does it seem to be linked to El Niño–Southern Oscillation (ENSO) or Indian Ocean dipole (IOD) signal.
Cross-Shelf Exchange in Prograde Antarctic Troughs Driven by Offshore-Propagating Dense Water Eddies
Authors: Gaul Alan , Zhang Weifeng (Gordon) , Cenedese Claudia
Published: April 2024

This study examines the link between near-bottom outflows of dense water formed in Antarctic coastal polynyas and onshore intrusions of Circumpolar Deep Water (CDW) through prograde troughs cutting across the continental shelf. Numerical simulations show that the dense water outflow is primarily in the form of cyclonic eddies. The trough serves as a topographic guide that organizes the offshore-moving dense water eddies into a chain pattern. The offshore migration speed of the dense water eddies is similar to the velocity of the dense water offshore flow in the trough, which scaling analysis finds to be proportional to the reduced gravity of the dense water and the slope of the trough sidewalls and to be inversely proportional to the Coriolis parameter. Our model simulations indicate that, as these cyclonic dense water eddies move across the trough mouth into the deep ocean, they entrain CDW from offshore and carry CDW clockwise along their periphery into the trough. Subsequent cyclonic dense water eddies then entrain the intruding CDW further toward the coast along the trough. This process of recurring onshore entrainment of CDW by a topographically constrained chain of offshore-flowing dense water eddies is consistent with topographic hotspots of onshore intrusion of CDW around Antarctica identified by other studies. It can bring CDW from offshore to close to the coast and thus impact the heat flux into Antarctic coastal regions, affecting interactions among ocean, sea ice, and ice shelves.

Significance Statement

Troughs cutting across the Antarctic continental shelf are a major conduit for the transport of dense shelf water from coastal formation regions to the shelf break. This study describes a process in which clockwise-spinning eddies moving offshore in prograde troughs successively entrain filaments of relatively warm Circumpolar Deep Water from offshore across the entire shelf and into the coastal region. This eddy-induced transport provides a new understanding of the shelf edge exchange process identified in previous studies and a mechanism for further onshore intrusion of the warm Circumpolar Deep Water over parts of the Antarctic shelf. The resultant onshore heat flux could potentially bring a substantial amount of heat from offshore into the coastal region and thus affect ice–ocean interactions through melting sea ice and ice shelves.