tbuckley/cabot-search huggingface dataset:
Abstract A027: Development of small molecule inhibitors of the Ku-DNA interaction: Impacts on NHEJ, DDR signaling, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer
Authors: John J. Turchi, Pamela L. Mendoza-Munoz, Pamela S. VanderVere-Carozza, Navnath S. Gavande, Joseph R. Dynlacht, Joy E. Garrett, Dineshsinha Chauhan, Katherine S. Pawelczak
Journal: Cancer Research (2024)

Abstract DNA-PK, the DNA-dependent protein kinase is a validated target for cancer therapeutics that drives the DNA damage response (DDR) and plays a critical role in the non-homologous end joining (NHEJ) DNA repair pathway. NHEJ is responsible for the repair of DNA double strand breaks (DSB), particularly those induced by ionizing radiation (IR). The generation of DNA DSBs drives clinical efficacy of radiation therapy and numerous DNA damaging chemotherapeutic drugs used to treat cancer. Modulating the DSB repair pathways is an effective mechanism to increase clinical efficacy of IR and certain chemotherapeutic regimens. We have taken the novel approach to inhibit target the DDR and NHEJ by developing small molecule inhibitors of the DSB sensor Ku, and its interaction with DNA. The Ku heterodimer serves as initiator of the NHEJ pathway following DSB induction and is the key DNA-binding component of the DNA-PK. We have created an extensive library of Ku DNA binding inhibitors (Ku-DBis) and demonstrate a direct interaction with the Ku heterodimer and potent inhibition of Ku-DNA binding and DNA-PK catalytic activity. In vitro analysis of a series of Ku truncation mutants defines the necessary domains for Ku-DBi activity. Ku-DBi’s show potent inhibition of in vitro and cellular NHEJ and, as a result, potentiate cellular sensitivity to DSB-inducing agents. Enhancement of sensitivity is a function of inhibiting DNA-PKcs autophosphorylation and dysregulation of signaling to the DDR. Recent chemical optimization has identified independent pharmacophores that drive off-target cytotoxicity, direct Ku inhibitory potency, and enhance cellular uptake activity. These data served as the basis for creation of a novel series of Ku-DBi’s towards interrogating NHEJ and DDR signaling in vivo, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer. Citation Format: John J. Turchi, Pamela L. Mendoza-Munoz, Pamela S. VanderVere-Carozza, Navnath S. Gavande, Joseph R. Dynlacht, Joy E. Garrett, Dineshsinha Chauhan, Katherine S. Pawelczak. Development of small molecule inhibitors of the Ku-DNA interaction: Impacts on NHEJ, DDR signaling, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A027.
Endoscopic ultrasound-directed transgastric ERCP for disconnected pancreatic duct syndrome: finding the edge to bridge the gap
Authors: Mark Henrik Bonnichsen, Prima Bianca Gaffud Chua, Clement Chun-Ho Wu, Ravishankar Asokkumar, Christopher J. Khor, Damien M.Y. Tan
Journal: Endoscopy (2024)

Altered anatomy from Roux-en-Y gastric bypass makes access to the papilla difficult. Solutions such as balloon-assisted and laparoscopy-assisted endoscopic retrograde cholangiopancreatography (ERCP) are complicated by sub-optimal technical success and adverse event rates [1]. EUS-directed transgastric ERCP (EDGE) is a promising solution with high technical and clinical success rates [2] and provides ease of access if multiple procedures are required.
Bridging endoscopic pancreatic stenting for disconnected pancreatic duct syndrome using a rendezvous technique from a walled-off necrosis cavity
Authors: Shuntaro Mukai, Takao Itoi, Atsushi Sofuni, Takasyoshi Tsuchiya, Reina Tanaka, Ryosuke Tonozuka, Hiroyuki Kojima
Journal: Endoscopy (2024)

Disconnected pancreatic duct syndrome (DPDS) is sometimes complicated by walled-off necrosis (WON) and is associated with a prolonged disease course [1] [2]. Treatment with endoscopic pancreatic stenting to bridge the disconnected pancreatic duct is useful, but it is technically challenging in many cases [3] [4] [5]. Here, we report a case of successful bridging with an endoscopic pancreatic stent for DPDS using the rendezvous technique from a WON cavity into which a lumen-apposing metal stent (LAMS) was placed.
Successful resection of a sessile serrated lesion completely involving a colonic diverticulum by endoscopic submucosal dissection with water pressure method
Authors: Takahiro Matsunaga, Seiichiro Fukuhara, Motoki Sasaki, Motohiko Kato
Journal: Endoscopy (2024)

Endoscopic submucosal dissection (ESD) for lesions involving colonic diverticula is technically challenging owing to lack of a proper muscle layer. Herein, we describe successful resection of a colonic lesion, which extended along the entire length of a diverticulum, using ESD with water pressure method ([Video 1]); this method is used in highly difficult duodenal ESD [1].
Abstract B013: A quest for deeper understanding of BRCA2 Variants of Uncertain Significance (VUS)
Authors: Cole Niedmann, Judit Jimenez Sainz
Journal: Cancer Research (2024)

Abstract Deleterious mutations in homology-directed repair pathway genes impact both future cancer risk and therapeutic intervention options for cancer diagnosis and prognosis. Homology-directed repair pathway is a high-fidelity DNA repair pathway for resolving double-strand breaks (DSBs) throughout the human genome. BRCA2, as a homology-directed repair factor, is essential to ensure genome integrity through an error-free process. Deleterious BRCA2 mutations increase the lifetime risk of breast, ovarian, melanoma, prostate, and pancreatic cancers. Deleterious BRCA2 mutations cover only 25% of the total BRCA2 mutations identified in the population by genetic testing whereas 60% are mutations with unknown connection to the disease called Variants of Uncertain Significance (VUS). The majority of BRCA2 VUS are missense mutations with one point mutation which could potentially alter BRCA2 cellular localization and/or nuclear functions. Thus, evaluating BRCA2 cellular localization and function in BRCA2 missense carriers and tumors is urgently needed to provide clinical guidance regarding cancer risk and treatment options. We have identified a paradoxical relationship between BRCA2 nuclear import and treatment. Deleterious missense mutations in the DNA binding domain of BRCA2 direct the protein to the cytosol which increase sensitivity to PARP inhibitors (PARPi) and platinum drugs. Therefore, although BRCA2 mislocalization might be a cause of cancer, keeping it out of the nucleus allows for much better treatment outcomes. Here, we present how BRCA2 cancer-driver missense mutations lead to cytosolic mislocalization and how BRCA2 localization can be used as a diagnostic tool to stratify patients. Our robust multi-step molecular approach will guide future clinical decision rules surrounding BRCA2 VUS. By providing reliable and accurate functional assays to correctly evaluate the pathogenicity of BRCA2 VUS, our goal is to improve personalized medicine by providing actionable information to patients and their physicians. Citation Format: Cole Niedmann, Judit Jimenez Sainz. A quest for deeper understanding of BRCA2 Variants of Uncertain Significance (VUS) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B013.
Abstract A009: DNA damage-induced senescence as a driver of glioblastoma recurrence
Authors: Sandeep Burma, Nozomi Tomimatsu, Luis Cristofaro, Suman Kanji, Benjamin Jordan, Bipasha Mukherjee
Journal: Cancer Research (2024)

Abstract Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR), yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. An understanding of mechanisms driving GBM recurrence is critical for improving therapy. During GBM therapy, both the tumor and the normal brain tissue surrounding the tumor are treated with up to 60 Gy of IR. IR is a potent inducer of senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting proteases, cytokines and growth factors that create a senescence-associated secretory phenotype (SASP). We have shown previously that IR-induced senescence of astrocytes in the brain leads to the secretion of SASP factors that promote the growth and invasiveness of tumor cells in mouse models of GBM (Fletcher-Sananikone, et al, Cancer Research, 2021). Following up on this study, we irradiated a panel of GBM cell lines and found that a significant fraction of these cells senesced rapidly in a p21-dependent manner. Senescent glioma cells upregulated SASP genes in a NF-kB-dependent manner, prominently, the interleukin IL6, which is an activator of the JAK-STAT pathway. Conditioned media from senescent GBM cells activated the JAK-STAT pathway in non-senescent GBM cells and promoted tumor cell proliferation and radiation resistance. Interestingly, conditioned media from senescent GBM cells could also activate the NF-kB pathway and induce SASP in non-senescent cells. These results indicate that senescent GBM cells can activate pro-tumorigenic pathways in their non-senescent counterparts and SASP can spread from senescent to non-senescent cells. Bioinformatic analyses of the transcriptomic profiles of irradiated GBM cells and the TCGA database revealed that the inhibitor of apoptosis protein cIAP2 is a critical survival factor for senescent glioma cells. We find that targeting cIAP2 using Smac mimetics triggers apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells like astrocytes. Upregulation of cIAP2 in irradiated tumor cells was also seen in multiple PDX models of GBM. Using these PDX lines, we demonstrate that adjuvant senolytic treatment can delay or even prevent recurrence in pre-clinical mouse models of GBM. In sum, our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence after radiotherapy. Citation Format: Sandeep Burma, Nozomi Tomimatsu, Luis Cristofaro, Suman Kanji, Benjamin Jordan, Bipasha Mukherjee. DNA damage-induced senescence as a driver of glioblastoma recurrence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A009.
Endoscopic membrane resection using a scissors-type knife in a pediatric patient with congenital duodenal membranous stenosis
Authors: Jun Nakamura, Takuto Hikichi, Hideaki Tanaka, Minami Hashimoto, Tsunetaka Kato, Takumi Yanagita, Hiromasa Ohira
Journal: Endoscopy (2024)

Congenital duodenal membranous stenosis (DMS) is a narrowing of the lumen caused by formation by the mucosa of membrane-like structures; it is a rare disease with a frequency of 1 in 10.000–40.000 [1]. Notably, some endoscopic treatments for congenital DMS have been reported [1] [2] [3] [4]; however, the endoscope's maneuverability in pediatric patients' duodenums is limited because of their small physique. Herein, we present a case of congenital DMS in which a scissors-type knife was successfully used to treat the membranous stenosis.
Abstract B029: Enhanced anticancer effects through synergistic targeting of DDX5 and DNA damage-related factors
Authors: Hye-Ran Seo, Hwani Ryu, Jiyeon Ahn
Journal: Cancer Research (2024)

Abstract Dead-box RNA helicase 5 (DDX5) is a member of the DDX RNA helicase family, commonly overexpressed in most carcinomas and plays an important role in tumor development and malignant progression. While DDX5 functions as a helicase in cells, it also plays various other roles in DNA damage repair, and resistance to radiotherapy or anticancer drugs. However, due to the diverse functions of DDX5, the anticancer effects solely from inhibiting helicase function of DDX5 are limited. Here, we inhibited DDX5 along with other factors to investigate their impact on the immune response and assess the cell viability of cancer cells. Our findings reveal that inhibiting DDX5 and DNA damage-related factors simultaneously in TNBC cells leads to a significantly greater decrease in cell viability than DDX5 knockdown alone. Through MTT assays using siRNA libraries related to DNA damage, we confirmed that when RAD51 and XRCC5 were knocked down along with DDX5, cell viability decreased by more than 20%. Furthermore, we noted an enhancement in innate immune activity and a more pronounced reduction in cell viability when simultaneously targeting the DNA damage-related factors alongside DDX5. In conclusion, our study identifies an augmented anticancer effect through the concurrent targeting of DDX5 and other critical factors. Citation Format: Hye-Ran Seo, Hwani Ryu, Jiyeon Ahn. Enhanced anticancer effects through synergistic targeting of DDX5 and DNA damage-related factors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B029.
Abstract PR008: Elucidating the mechanistic role of the MRE11-NDRG1 interaction in DNA repair and chemoresistance
Authors: Hanna M Doh, Nina Kozlova, Taru Muranen
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with limited treatment options. PDAC patients are commonly treated with chemotherapeutic drugs to induce DNA damage in rapidly dividing tumor cells, however tumors frequently develop resistance to chemotherapies, underscoring the need for more effective therapeutic strategies. The DNA damage response (DDR) is required for detecting and repairing chemotherapy-induced DNA damage, and DDR alterations have been shown to contribute to chemoresistance. Another key factor driving chemoresistance in PDAC is the dense stroma, which is composed of a variety of non-tumor cell types including cancer associated fibroblasts (CAFs). We have recently identified a novel CAF-induced resistance mechanism involving NDRG1 (N-myc downstream regulated gene 1), a protein that plays a role in stress responses. CAF-induced signaling cascade results in the phosphorylation of NDRG1 and NDRG1-dependent DNA repair and protection from chemotherapies in pancreatic cancer cells. Specifically, inhibition of SGK1-mediated phosphorylation of NDRG1 and NDRG1 knockout both resulted in increased chemotherapy-induced DNA damage assessed via comet assay, and decreased replication fork speed and recovery after fork stalling assessed via DNA fiber spreading assay. To gain insight into the molecular mechanism of NDRG1-mediated DNA repair and replication, we performed a BioID screen to identify binding partners of NDRG1 and we have identified meiotic recombination 11 (MRE11), a nuclease involved in critical DNA repair pathways, as a novel binding partner of NDRG1. We have found that the interaction between MRE11 and NDRG1 is enriched during late S/early G2 cell cycle phases and under hydroxyurea-induced replication stress. Furthermore, we have found that the interaction is weakened when SGK1-mediated phosphorylation is inhibited. Interestingly, using the fork protection fiber spreading assay, we have found that blocking SGK1-mediated NDRG1 phosphorylation and blocking MRE11 exonuclease activity using mirin both result in increased protection of nascent DNA at stalled forks. However, in NDRG1 knockout cells, treatment with mirin leads to decreased protection of nascent DNA, suggesting that NDRG1 and MRE11 may be acting in the same pathway and that NDRG1 is required for MRE11’s activity at stalled forks. In summary, our work has uncovered a novel protein interaction that may play a key role in pancreatic cancer chemoresistance due to its role in the processing of stalled replication forks. Citation Format: Hanna M Doh, Nina Kozlova, Taru Muranen. Elucidating the mechanistic role of the MRE11-NDRG1 interaction in DNA repair and chemoresistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR008.
Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction
Authors: Qiuyu Sun, Berna Güven, Cory S Wagg, Amanda Almeida de Oliveira, Heidi Silver, Liyan Zhang, Brandon Chen, Kaleigh Wei, Ezra B Ketema, Qutuba G Karwi, Kaya L Persad, Jennie Vu, Faqi Wang, Jason R B Dyck, Gavin Y Oudit, Gary D Lopaschuk
Journal: Cardiovascular Research (2024)

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. Methods and results Eight-week-old C57BL/6 male mice were subjected to a ‘2-Hit’ HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure–volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient’s heart samples. Conclusion In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.
Molecular Evolution of Protein Sequences and Codon Usage in Monkeypox Viruses
Authors: Ke-Jia Shan, Changcheng Wu, Xiaolu Tang, Roujian Lu, Yaling Hu, Wenjie Tan, Jian Lu
Journal: Genomics Proteomics & Bioinformatics (2023)

The monkeypox virus (mpox virus, MPXV) epidemic in 2022 has posed a significant public health risk. Yet, the evolutionary principles of MPXV remain largely unknown. Here, we examined the evolutionary patterns of protein sequences and codon usage in MPXV. We first demonstrated the signal of positive selection in OPG027, specifically in the Clade I lineage of MPXV. Subsequently, we discovered accelerated protein sequence evolution over time in the variants responsible for the 2022 outbreak. Furthermore, we showed strong epistasis between amino acid substitutions located in different genes. The codon adaptation index (CAI) analysis revealed that MPXV genes tended to use more non-preferred codons compared to human genes, and the CAI decreased over time and diverged between clades, with Clade I > IIa and IIb-A > IIb-B. While the decrease in fatality rate among the three groups aligned with the CAI pattern, it remains unclear whether this correlation was coincidental or if the deoptimization of codon usage in MPXV led to a reduction in fatality rates. This study sheds new light on the mechanisms that govern the evolution of MPXV in human populations.
Tyrosine phosphorylation-mediated YAP1-TFAP2A interactions coordinate transcription and trastuzumab resistance in HER2+ breast cancer
Authors: Hailin Zou, Juan Luo, Yibo Guo, Liang Deng, Leli Zeng, Yihang Pan, Peng Li
Journal: Drug Resistance Updates (2024)

Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including EGFR, HER2, H19 and CTGF. Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.
Abstract IA020: Micronuclei are a nexus of DNA damage signaling and genomic instability
Authors: Shane M. Harding
Journal: Cancer Research (2024)

Abstract Micronuclei have classically been considered inert biomarkers of genomic instability arising from failed DNA damage repair and chromosome segregation errors in mitosis. Work from several groups including our own have now demonstrated that micronuclei are active contributors to the cellular response to DNA damage by driving chromothripsis and through induction of anti-viral gene expression programs mediated by the cGAS-STING pathway. We now show that the specific DNA damage type leading to micronuclei formation influences the capacity for cGAS localization and activation. This arises in part due to discrete chromatin features, present prior to DNA damage induction, that are retained in micronuclei several days after their formation. Together these data demonstrate that micronuclei connect the pre-damage chromatin status and the chromatin context of micronuclei-inciting lesions to the long-term signaling outcomes important for anti-tumor immunity. This finding implies that micronuclei represent archives for the nature of DNA repair failure and downstream signaling consequences. Based on this premise we will present our efforts in micronuclear proteomics where we uncover common features of micronuclei including splicing deficiencies. Such deficiencies presage exacerbated MN-associated DNA damage that is upstream of chromothripsis. These studies have direct implications for how cells sense the aftermath of DNA damage and how micronuclei contribute to ongoing genomic instability. Citation Format: Shane M. Harding. Micronuclei are a nexus of DNA damage signaling and genomic instability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA020.