bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventing broken hearts in women with breast cancer: a concise review on chemotherapy-mediated cardiotoxicity
Authors: Bews Hilary J. , Mackic Lana , Jassal Davinder S. 
Published: December 2023

Cancer and cardiovascular disease are the leading causes of death for Canadian women. One in eight Canadian women will receive the life-changing diagnosis of breast cancer (BC) in their lifetime, with 1 in 34 dying from the disease. Although doxorubicin (DOX) and trastuzumab (TRZ) have significantly improved survival in women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive BC, approximately one in four women who receive this treatment are at risk of developing chemotherapy-induced cardiotoxicity. Cardiotoxicity is defined as a decline in left ventricular ejection fraction (LVEF) of >10% to an absolute value of <53%. Current guidelines recommend the serial monitoring of LVEF in this patient population using non-invasive cardiac imaging modalities including transthoracic echocardiography or multi-gated acquisition scan; however, this will only allow for the detection of established cardiotoxicity. Recent studies have demonstrated that a reduction in global longitudinal strain by speckle tracking echocardiography can identify pre-clinical systolic dysfunction prior to a decline in overall LVEF. Implementation of early detection techniques would allow for the prompt initiation of cardioprotective strategies. In addition to the early detection of chemotherapy-mediated cardiotoxicity, the prophylactic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, statins, exercise, and nutraceutical therapies have been studied in the setting of cardio-oncology.
3D seismic analysis of Cenozoic slope deposits and fluid-flow phenomena along the Nigerian Transform Margin
Authors: Olobayo Oluwatobi , Huuse Mads 
Published: December 2023

Abstract

3D seismic data provide new insights on
c.
2 km thick Cenozoic post-transform slope sediments and fluid-flow phenomena along the Nigerian Transform Margin. The study documents large-scale mass-transport deposits (MTDs), deep-water channels, sediment waves, and a range of fluid-flow phenomena such as pockmarks, pipes, seabed mound and gas hydrates. They are observed from Pliocene-aged sediments and distributed above structural highs, regional faults, and active and relict deep-water channels in the eastern part of the area, closest to the Niger Delta cone. The fluid-flow features are interpreted to be indicative of an active petroleum system in the deeper subsurface and from fluid migration along planes of deep-seated faults. MTDs are mapped at multiple levels and the volume of failed sediments increased through time within the western part of the study area. The repeated and increased volume of MTDs in the area is attributed to an increased rate of sedimentation through time and slope gradient during the late Cenozoic. The presence of repeated MTDs and fluid-flow phenomena on the Nigerian Transform Margin has implications for installations of offshore facilities as they constitute potential geohazards. The study also documents, for the first time, polygonal fault systems offshore Nigeria.
Abstract A004: Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating cancer
Authors: Ikeda Osamu , Kikuchi Aya , Tsuzuki Hirofumi , Matsuda Toshihiro , Weng Jane , Kawashima Tomoko , Kiso Tetsuo , Suzuki Atsushi , Nagashima Takeyuki , Suzuki Tomoyuki , Yamano Kazuya , Yoshida Taku 
Published: December 2023

Abstract
Background: Studies of diacylglycerol kinase ζ (DGKζ) in DGKζ-knockout mice have revealed its role as an intracellular immune checkpoint in T cells. Although enhancing antitumor immunity by pharmacological inhibition of DGKζ is desirable, selective DGKζ inhibitors for clinical use remain largely unexplored. Here, we report a novel, small-molecule, DGKζ inhibitor—ASP1570—which is currently under phase 1 development (NCT05083481), and describe its nonclinical properties and potential application in cancer immunotherapy.
Methods: ASP1570 was characterized by evaluating T cell receptor signaling and T cell function under immunosuppressive conditions relevant to the tumor microenvironment. Antitumor efficacy was evaluated in 2 types of syngeneic mouse models: anti-PD-1-antibody–sensitive MC38 and anti-PD-1-antibody–insensitive B16F1/F10.
Results: ASP1570 enhanced T cell activation with increased diacylglycerol downstream signaling and released anergic T cells from their hyporesponsive state. Further, ASP1570 restored T cell functions suppressed by multiple immunosuppressive signals (TGF-β, prostaglandin E2, adenosine, PD-1, CTLA-4, and TIGIT) and induced tumor-growth inhibition in MC38 and B16F1/F10 syngeneic mouse models. The antitumor efficacy of ASP1570 was cancelled by CD8+ T cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T cell activation.
Conclusions: ASP1570 potentially improves antitumor efficacy in both anti-PD-1-therapy–resistant and anti-PD-1-therapy–responsive tumors by overcoming multiple immunosuppressive signals.
Citation Format: Osamu Ikeda, Aya Kikuchi, Hirofumi Tsuzuki, Toshihiro Matsuda, Jane Weng, Tomoko Kawashima, Tetsuo Kiso, Atsushi Suzuki, Takeyuki Nagashima, Tomoyuki Suzuki, Kazuya Yamano, Taku Yoshida. Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A004.
Abstract A015: Prediction of immunotherapy response using mutations to cancer protein assemblies
Authors: Kong JungHo , Bachelder Robin , Zhao Xiaoyu , Park Sungjoon , Singhal Akshat , Carter Hannah , Ideker Trey 
Published: December 2023

Abstract
While immune checkpoint inhibitors (ICI) have substantially advanced cancer treatment, favorable responses are limited to a subset of patients and are not strongly predicted by histology or overall mutation burden. Here, we factor mutational burden across a landscape of known and putative multimeric protein assemblies, yielding Assembly Mutation Burden (AMB) scores for each patient. Predictive modeling identifies 14 assemblies in which mutation is associated with ICI response in 555 bladder cancer (BLCA) and non-small-cell lung cancer (NSCLC) patients, outperforming predictions based on genome-wide mutation burden alone. The assemblies capture immunogenic hallmarks and accurately predict treatment outcomes in a validation cohort of 68 immunotherapy-treated NSCLC patients. We explore a predictive assembly of 50 immunoregulatory complex proteins, in which we show CRISPR/Cas9 genetic disruptions influence ICI-treatment outcomes in mice. This study provides a roadmap for using knowledge of tumor cell biology to interpret the immunogenome.
Citation Format: JungHo Kong, Robin Bachelder, Xiaoyu Zhao, Sungjoon Park, Akshat Singhal, Hannah Carter, Trey Ideker. Prediction of immunotherapy response using mutations to cancer protein assemblies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A015.
Abstract A018: Optimizing cancer immunotherapy response prediction by tumor aneuploidy score and fraction of copy number alterations
Authors: Chang Tian-Gen , Cao Yingying , Shulman Eldad D , Ben-David Uri , Schäffer Alejandro A. , Ruppin Eytan 
Published: December 2023

Abstract
Identifying patients that are likely to respond to cancer immunotherapy is an important, yet highly challenging clinical need. Using 3139 patients across 17 different cancer types, we comprehensively studied the ability of two common copy-number alteration (CNA) scores—the tumor aneuploidy score (AS) and the fraction of genome single nucleotide polymorphism encompassed by copy-number alterations (FGA)—to predict survival following immunotherapy in both pan-cancer and individual cancer types. First, we show that choice of cutoff during CNA calling significantly influences the predictive power of AS and FGA for patient survival following immunotherapy. Remarkably, by using proper cutoff during CNA calling, AS and FGA can predict pan-cancer survival following immunotherapy for both high-TMB and low-TMB patients. However, at the individual cancer level, our data suggest that the use of AS and FGA for predicting immunotherapy response is currently limited to only a few cancer types. Therefore, larger sample sizes are needed to evaluate the clinical utility of these measures for patient stratification in other cancer types. Finally, we propose a simple, non-parameterized, elbow-point-based method to help determine the cutoff used for calling CNAs.
Citation Format: Tian-Gen Chang, Yingying Cao, Eldad D Shulman, Uri Ben-David, Alejandro A. Schäffer, Eytan Ruppin. Optimizing cancer immunotherapy response prediction by tumor aneuploidy score and fraction of copy number alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A018.
Abstract A022: CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction
Authors: Schomer Nathan , Chen Jinhong , Pang Wei , Zhou Tingru , Liu Xipan , Liang Wenhen , Guo Yali , Cheng Dai , Li Fang , Liang Jiaqi , Chen Yaoyu , Sheng Qing 
Published: December 2023

Abstract
Small cell lung cancer (SCLC), a malignant thoracic neoplasm genetically defined by dysregulation of the Retinoblastoma (RB1) gene and tumor suppressor protein 53 (TP53), remains one of the world’s deadliest tumors with a 5-year overall survival rate ranging from 5% to 10%. Despite numerous clinical trials and recent FDA approval of immune checkpoint inhibitors, the prognosis for SCLC has not significantly improved in decades. There remains a strong need for new therapeutic approaches. In this study, we found that the combined effect of dysregulation or deletion of RB1 and TP53, as is found in the majority of SCLC, results in sensitivity to CDK2 inhibition or ablation. This relationship is reflected in the DepMap database, with cell lines harboring deleterious mutations in RB1 demonstrating markedly higher susceptibility to CDK2 inhibition. This relationship is surprising given CDK2’s established role in suppressing the growth inhibition activity of RB and CDK2’s ability to thus facilitate G1/S transition. To validate this discovery, we evaluated the effects of CDK2 inhibition on a panel of SCLC cell lines. ARTS-021 is a potent and highly selective orally administered inhibitor of CDK2 currently in clinical development. In contrast to CCNE1 amplified cells, which undergo G1 arrest upon ARTS-021 treatment, SCLC cells treated with ARTS-021 exhibited minimal G1 accumulation. Instead, ARTS-021 treatment induced apoptosis in SCLC cell lines with loss of functional RB1 and TP53, as demonstrated by a dose-dependent increase in Caspase 3/7 activity and the accumulation of cleaved PARP. This phenotype was further demonstrated to be CDK2 dependent though generation of stable cell lines expressing a dox-inducible shRNA targeting CDK2. Combination studies further demonstrated that this apoptotic phenotype can be enhanced synergistically through inhibition of the anti-apoptotic proteins BCL-2 and BCL-xL with clinical stage inhibitor Navitoclax. In addition, combinations with currently approved standard of care chemotherapies were tested both in vitro and in vivo, and demonstrated potent combinatorial activity. These findings suggest that the clinical development of CDK2 inhibitors for SCLC may represent a novel therapeutic option for this difficult to treat malignancy.
Citation Format: Nathan Schomer, Jinhong Chen, Wei Pang, Tingru Zhou, Xipan Liu, Wenhen Liang, Yali Guo, Dai Cheng, Fang Li, Jiaqi Liang, Yaoyu Chen, Qing Sheng. CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A022.
Abstract A027: A photoactivatable microtubule-targeting rigidin prodrug
Authors: Kornienko Alexander , Bonnet Sylvestre 
Published: December 2023

Abstract
Analogues of marine alkaloid rigidins have been found to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was “caged” by coordination of its thioether group to a photosensitive ruthenium polypyridyl complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell lines monolayers, 3D lung cancer tumor spheroids (A549), and in a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also, remarkably, in hypoxic conditions (1% O2). In vivo, light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the efficacy of a ruthenium-based photocaged compounds in a tumor xenograft. In subsequent unpublished work, we fine-tuned the excited states in this complex by adding an amide functional group on the ruthenium cage. By doing so, a new caged complex was obtained that was activated by red light (instead of green light). We demonstrated the red light activation of this compound in solution and in vitro. This result demonstrates that functionalization of ruthenium cage with electron-withdrawing groups can radically enhance their photochemical properties, which is essential for this method development (red light penetrates better into tissues than green light). We will present our results of in vivo testing of this caged compound activated by tumor penetrable red light, where significant tumor reduction is seen in mice xenografted with subcutaneous human uveal melanoma liver metastatic cells.
Citation Format: Alexander Kornienko, Sylvestre Bonnet. A photoactivatable microtubule-targeting rigidin prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A027.
Abstract A030: Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model
Authors: Toivanen Kirsi , De Sutter Luna , Wozniak Agnieszka , Böhling Tom , Schöffski Patrick , Sihto Harri 
Published: December 2023

Abstract
Anagrelide is a phosphodiesterase 3A inhibitor that is used to treat essential thrombocythemia. The drug stabilizes the interaction of PDE3A and Schlafen 12 (SLFN12), resulting in complex stabilization, activation of SLFN12 RNase activity and cytotoxic effects in cancer cells. Gastrointestinal stromal tumors (GIST) exhibit high levels of PDE3A expression compared to other cancers or healthy tissue. Orally administered anagrelide has shown antitumor effects in patient-derived GIST xenograft (PDX) mouse models. In this study, we investigated the efficacy of subcutaneously administered, sustained-release anagrelide in UZLX-GIST2B, a PDX mouse model characterized by a KIT mutation in exon 9 and typical dose-dependent imatinib sensitivity. We assessed changes in tumor volume and evaluated histological drug responses including hyalinization, fibrosis, myxoid generation, and tumor necrosis. Anagrelide was administered either orally (2.5 mg/kg, twice a day) or subcutaneously (35 mg/kg and 70 mg/kg, every fourth day) for a duration of 11 days. Treatments with both 35 mg/kg and 70 mg/kg doses resulted in a significant reduction in average tumor volume compared to untreated control mice (both doses 25% vs.129%, P &lt; 0.001) or mice treated with oral anagrelide (25% vs. 61%, P =0 .08, P &lt; 0.05, respectively). The histological response in tumor tissue was positively correlated with dose level, and tumors treated with the highest dose exhibited grade 3 to 4 responses in all cases. These results suggest that sustained-release anagrelide holds promise as a therapeutic option for the treatment of GIST. Further preclinical studies are warranted to investigate the pharmacokinetics and toxicity of this treatment approach.
Citation Format: Kirsi Toivanen, Luna De Sutter, Agnieszka Wozniak, Tom Böhling, Patrick Schöffski, Harri Sihto. Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A030.
Abstract A032: Cell membrane coated- Biomimetic biodegradable nanoparticles for tumor targeted delivery of THP-doxorubicin using polylactic acid based redox responsive polymer
Authors: Kaur Harshdeep , Singh Harpal , Singh Neetu 
Published: December 2023

Abstract
Chemotherapy is a widely used systemic treatment modality for cancer treatment as it kills the rapidly dividing cells. However, the administered chemo-drugs cause systemic toxicity, have fast degradation rate at physiological conditions hence low bioavailability and poor tumor accumulation. These shortcomings can be mitigated by the use of tumor targeting drug delivery systems. The nanoparticles can further be tailor made according to physiological conditions of the tumor microenvironment. Herein, the redox responsive polymer has been synthesized by introducing the disulphide linkage in the polymer. The drug release profile indicated the release of the drug is more efficient in presence of 10mM Dithiothreitol(reducing agent for disulphide linkage) when compared to 0mM dithiothreitol. In this context, this study investigates the therapeutic efficacy of THP-doxorubicin encapsulated in polylactic acid based redox responsive nanoparticle(NP) whose surface have been modified with tumor (4T1) and macrophage (J774) cell membranes. The coated cell membrane provides advantages such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. The prepared nanoparticles have a hydrodynamic size of 210±10 nm with zeta potential of -30±3 mV. The cellular internalization studies of free drug vs the cell membrane coated NPs (CMNPs) were done and it was confirmed that CMNPs were internalized more efficiently in one hour drug incubation study. The same was confirmed when cancer cell proliferation inhibition assay was done, and half maximal inhibitory concentration of free drug, uncoated NPs and CMNPs were 0.31µM , 0.463µM and 0.137µM respectively. This study provides the synthesis and characterization of redox responsive polymer, preparation of cell membrane coated nanoparticles and in-vitro studies for the same. This study has a future scope in the field of personalized medicine at much cheaper price when compared to active targeting methods by antibodies, CART, proteins etc.
Citation Format: Harshdeep Kaur, Harpal Singh, Neetu Singh. Cell membrane coated- Biomimetic biodegradable nanoparticles for tumor targeted delivery of THP-doxorubicin using polylactic acid based redox responsive polymer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A032.
Abstract A042: Targeting vulnerabilities arising from global DNA hypomethylation in cancer
Authors: Mustafi Pallabi , Hanratty Brian , Coleman Ilsa , Patel Radhika , Mohamed Adil , Sarthy Jay , Ha Gavin , Haffner Michael 
Published: December 2023

Abstract
Background: DNA methylation alterations are a universal feature of cancer. In addition to site specific gain of DNA methylation (hypermethylation), a global loss of methylation (hypomethylation) was noted in most cancer genomes. Whereas numerous studies have focused on the role of hypermethylation in disease progression, less is known about the biology of hypomethylation in cancer. Recently, we have identified tumors across all major cancer types that are characterized by severe loss of DNA methylation. Our preliminary data suggest that these DNA hypomethylated cancers (hereafter DHMCs) show distinct alterations influencing gene expression and tumor microenvironment composition.
Objective: We hypothesize that since DNA methylation is critical for genome organization and gene expression. Severe global hypomethylation is likely to result in distinct epigenomic and genomic alterations. We therefore investigate common molecular changes associated with DNA hypomethylation to develop novel therapeutic approaches targeting unique vulnerabilities arising in DHMCs.
Study design: To delineate the biology of DHMCs, we determined methylation changes with validated orthogonal methods in large representative cohorts of patient samples (The Cancer Genome Atlas (TCGA), University of Washington rapid autopsy cohorts), patient derived xenografts and cancer cell lines. We assessed the patterns of common molecular alterations by performing genome wide epigenome mapping experiments and by defining common driver gene events in DHMCs. We further determined tumor cell intrinsic therapeutic vulnerabilities in broad pharmacologic and CRISPR-Cas9 genomic screens.
Results: We observed that DNA hypomethylation is a relatively common feature of solid tumors affecting overall 15-20% of all cancers, with highest rates observed in urothelial, melanoma, hepatocellular and lung and head and neck squamous cell carcinoma. In in vivo tumor models of DHMCs, we observe distinct shifts in epigenetic states upon DNA hypomethylation. Most notably, we found that DHMCs are characterized by unique intrinsic drug sensitivities to drug classes affecting core histone levels.
Impact: This is the first study to show druggable vulnerabilities arising from DNA hypomethylation. Collectively, these studies define a novel epigenetic subtype of cancer, determine its clinical and molecular features, and pave the way for new targeted therapies.
Citation Format: Pallabi Mustafi, Brian Hanratty, Ilsa Coleman, Radhika Patel, Adil Mohamed, Jay Sarthy, Gavin Ha, Michael Haffner. Targeting vulnerabilities arising from global DNA hypomethylation in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A042.