tbuckley/cabot-search huggingface dataset:
Access to the left intrahepatic bile duct using an endoscopic ultrasound-guided rendezvous technique
Authors: Nobuhiko Hayashi, Toshiki Entani, Jun Matsuno, Ichiro Yasuda
Journal: Endoscopy (2024)

Appropriate preoperative biliary drainage in patients with hilar cholangiocarcinoma and severe jaundice reduces mortality after extensive hepatic resection. In this situation, endoscopic transpapillary drainage of the future remnant liver is generally performed as the first-line approach [1]. However, it is sometimes difficult to pass the guidewire into the target biliary branch because of stenosis and steep angulation of the bile duct.
Abstract B007: Mutations in chromatin remodelers produce intra-chromosomal deletions in cancer cells
Authors: Abdulaziz B. Hamid, Lauren E. Frank, Devi D. Nelakurti, Anna Valentine, Mehak Kaur, Ali Latif, Renee A. Bouley, Ruben C. Petreaca
Journal: Cancer Research (2024)

Abstract Cancer cells are characterized by chromosomal re-arrangements which range from small deletions and insertions (InDels) to complete genome re-organization such as kataegis and chromothripsis. These genomic re-arrangements accompanied by other mutation signatures act as drivers of cellular transformation and immortalization. One form of re-arrangement is the intra-chromosomal deletion (ICD) which is larger than an InDel and can wipe out entire genomic sequences. Recurrent ICDs have been shown to inactivate key cell cycle regulators (e.g., Rb, PTEN, TP53) and contribute to cellular transformation. However, cancer cells are replete with ICDs of unknown function. ICDs arise due to failure of the DNA double strand break (DSB) repair machinery but the mechanism remains elusive. Mutations in three Mutations in key DNA damage repair genes such as the breast cancer susceptibility genes BRCA1 and BRCA2 as well as the accessory gene RAD52 accelerate ICD formation. Using the yeast model system, we identified physical and genetic interactions between RAD52 and two chromatin remodeling factors (KAT5 and HIRA). KAT5 is a histone acetyltransferase with functions in both transcription and DSB repair while HIRA is a histone chaperone required for re-deposition of nucleosomes following repair. We will present results from computational analysis of cancer genomes as well as experimental bench data that show that mutations in KAT5 and HIRA affect ICD formation. Epistatic analysis between the histone remodelers and BRCA1, BRCA2 and RAD52 reveals that co-occurring mutations contribute to destabilization of the repair machinery. In silico protein structure analysis was performed to model how mutations affect the function of these enzymes. Our data uncovers unexpected functions of chromatin remodelers in modulating the function of DNA recombinases and other accessory factors. Citation Format: Abdulaziz B. Hamid, Lauren E. Frank, Devi D. Nelakurti, Anna Valentine, Mehak Kaur, Ali Latif, Renee A. Bouley, Ruben C. Petreaca. Mutations in chromatin remodelers produce intra-chromosomal deletions in cancer cells [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 B007.
Abstract PR006: Elucidating the effect of PARP inhibitors on MMEJ-mediated DNA repair
Authors: Raquel Ortega, Nausica Arnoult, Benjamin G Bitler
Journal: Cancer Research (2024)

Abstract First-line maintenance treatment for homologous recombination (HR)-deficient (HRD, e.g., BRCA1/2 mutations) cancers includes poly ADP-ribose inhibitors (PARPi, e.g., olaparib, niraparib). PARPi are lethal through multiple mechanisms, including PARP trapping and PARP activity inhibition, which both destabilize the replication fork machinery in the absence of BRCA1/2. However, only 50% of HRD tumors respond to PARPi treatment due to intrinsic resistance and of those that respond, most tumors eventually relapse due to acquired drug resistance. Because MMEJ is essential in HRD-cancers, it has emerged as a promising target to combat PARPi resistance, with POLQ inhibitors currently in clinical trials. Thus, understanding the interplay between MMEJ and PARP inhibitors is critical. While PARP1 is proposed to promote MMEJ, PARP regulates numerous aspects of DSB repair, and therefore its overall impact on MMEJ levels remains unclear. For instance, the effect of PARP inhibition on DSB end-resection, a critical step of MMEJ, remains controversial. Utilizing a DNA repair reporter, we assessed MMEJ levels following treatment with various PARP inhibitors, including those with minimal PARP trapping activity. Remarkably, we find that PARP inhibition systematically leads to elevated MMEJ levels in a POLQ-dependent fashion. Furthermore, PARP inhibition also induces higher MMEJ levels in cells treated with NHEJ inhibitors as well as in HR-deficient cells, including an HRD ovarian cancer cell line (PEO1, BRCA2mut). Therefore, this MMEJ upregulation cannot be simply attributed to a PARPi-mediated suppression of NHEJ or HR activity. Taken together, our data suggests that the overall effect of PARP inhibitors may lead to upregulation, rather than suppression, of MMEJ activity. We are currently assessing the contribution of PARP1 and PARP2 in MMEJ regulation and are testing whether PARPi also increase MMEJ levels at sites of replication induced DSBs. We hypothesize that PARPi could upregulate MMEJ through modulating DSB end-resection. This insight bears significant implications for the development of combination therapies of MMEJ and PARP inhibitors in treating HRD cancers. Citation Format: Raquel Ortega, Nausica Arnoult, Benjamin G Bitler. Elucidating the effect of PARP inhibitors on MMEJ-mediated DNA repair [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 PR006.
Abstract IA017: Drugging the DNA damage response (DDR) in the Clinic: Going beyond the approved PARP inhibitors
Authors: Timothy A. Yap
Journal: Cancer Research (2024)

Abstract Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements, and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumor agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATR, ATM, CHK1, WEE1, PKMYT1 and PARG. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of response (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational combinations to improve patient outcomes and widen the application of DDR agents. Citation Format: Timothy A. Yap. Drugging the DNA damage response (DDR) in the Clinic: Going beyond the approved PARP inhibitors [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 IA017.
Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial
Authors: Luis Eduardo López-Cortés, Mercedes Delgado-Valverde, Elisa Moreno-Mellado, Josune Goikoetxea Aguirre, Laura Guio Carrión, María José Blanco Vidal, Leyre Mónica López Soria, María Teresa Pérez-Rodríguez, Lucía Martínez Lamas, Francisco Arnaiz de las Revillas, Carlos Armiñanzas, Carlos Ruiz de Alegría-Puig, Patricia Jiménez Aguilar, María del Carmen Martínez-Rubio, Carmen Sáez-Bejar, Carmen de las Cuevas, Andrés Martín-Aspas, Fátima Galán, José Ramón Yuste, José Leiva-León, Germán Bou, Patricia Capón González, Lucía Boix-Palop, Mariona Xercavins-Valls, Miguel Ángel Goenaga-Sánchez, Diego Vicente Anza, Juan José Castón, Manuel Recio Rufián, Esperanza Merino, Juan Carlos Rodríguez, Belén Loeches, Guillermo Cuervo, José Manuel Guerra Laso, Antonio Plata, Salvador Pérez Cortés, Pablo López Mato, José Luis Sierra Monzón, Clara Rosso-Fernández, José María Bravo-Ferrer, Pilar Retamar-Gentil, Jesús Rodríguez-Baño, Marina De Cueto, Irene Borreguero, Javier Nieto Aranda, Adrián Sousa Domínguez, Claudia González-Rico, María Carmen Fariñas, María Luisa Fernández Ávila, Alberto Romero Palacios, Francisca María Guerrero Sánchez, Marta Rúa Gómez, Idoia Bilbao del Olmo, Esther Calbo, Beatriz Dietl, Maialen Ibarguren Pinilla, Marta Gómez-Ruiz de Arbulo, Isabel Torres Beceiro, Isabel Machuca, Ángela Cano, Livia Giner Oncina, Héctor Pinargote Celorio, Emilio Cendejas, María Romero Gómez, Adrián Argüelles Curto, José María Reguero, María Dolores Díaz-López, José Ramón Paño
Journal: The Lancet Infectious Diseases (2024)
Abstract A008: Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer
Authors: Ozge Saatci, Mein Cetin, Meral Uner, Unal Metin Tokat, Ioulia Chatzistamou, Pelin Gulizar Ersan, Elodie Montaudon, Aytekin Akyol, Sercan Aksoy, Aysegul Uner, Elisabetta Marangoni, Mathew Sajish, Ozgur Sahin
Journal: Cancer Research (2024)

Abstract Estrogen receptor (ER)-positive (ER+) breast cancer has the highest incidence rate and accounts for around 75% of all cases. Endocrine therapy and CDK4/6 inhibitors are the standard of care (SOC) in ER+ breast cancer; however, resistance is common, and it greatly reduces patient survival. Therefore, elucidating the mechanisms of sensitivity and resistance to SOC therapy and identifying actionable targets are urgently needed. Here, we show that SOC therapy causes DNA damage and toxic PARP1 trapping upon generation of a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading to increased histone parylation and reduced H3K9 acetylation, resulting in transcriptional blockage and cell death. Mechanistically, SOC therapy downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene in a feedforward loop with ER, resulting in increased cAMP, PKA-dependent phosphorylation of mitochondrial COXIV-I, ROS generation and DNA damage. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun-mediated transcription. Importantly, we demonstrated that high PDE4D mRNA and protein expression is associated with dramatically worse disease-free survival and overall survival in endocrine therapy-treated ER+ breast cancer. Notably, combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status in multiple acquired SOC resistant cell line models, primary cultures and organoids of endocrine resistant ER+ PDXs in vitro and in vivo, providing actionable targets for restoring SOC efficacy. Considering the availability of potent and non-toxic PDE4D inhibitors, clinically approved EGFR and PARP1 inhibitors, our findings have great translational potential. Citation Format: Ozge Saatci, Mein Cetin, Meral Uner, Unal Metin Tokat, Ioulia Chatzistamou, Pelin Gulizar Ersan, Elodie Montaudon, Aytekin Akyol, Sercan Aksoy, Aysegul Uner, Elisabetta Marangoni, Mathew Sajish, Ozgur Sahin. Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast 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 A008.
Abstract A018: GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination
Authors: John A. Tainer, Katharina Schlacher, Bin Wang, Guang Peng, Zamal Ahmed
Journal: Cancer Research (2024)

Abstract Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adaptor for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover, in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination. Citation Format: John A. Tainer, Katharina Schlacher, Bin Wang, Guang Peng, Zamal Ahmed. GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination [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 A018.
Measuring Equity in Readmission as a Distinct Assessment of Hospital Performance
Authors: Katherine A. Nash, Himali Weerahandi, Huihui Yu, Arjun K. Venkatesh, Louisa W. Holaday, Jeph Herrin, Zhenqiu Lin, Leora I. Horwitz, Joseph S. Ross, Susannah M. Bernheim
Journal: JAMA (2024)

Importance Equity is an essential domain of health care quality. The Centers for Medicare &amp;amp;amp; Medicaid Services (CMS) developed 2 Disparity Methods that together assess equity in clinical outcomes. Objectives To define a measure of equitable readmissions; identify hospitals with equitable readmissions by insurance (dual eligible vs non–dual eligible) or patient race (Black vs White); and compare hospitals with and without equitable readmissions by hospital characteristics and performance on accountability measures (quality, cost, and value). Design, Setting, and Participants Cross-sectional study of US hospitals eligible for the CMS Hospital-Wide Readmission measure using Medicare data from July 2018 through June 2019. Main Outcomes and Measures We created a definition of equitable readmissions using CMS Disparity Methods, which evaluate hospitals on 2 methods: outcomes for populations at risk for disparities (across-hospital method); and disparities in care within hospitals’ patient populations (within-a-single-hospital method). Exposures Hospital patient demographics; hospital characteristics; and 3 measures of hospital performance—quality, cost, and value (quality relative to cost). Results Of 4638 hospitals, 74% served a sufficient number of dual-eligible patients, and 42% served a sufficient number of Black patients to apply CMS Disparity Methods by insurance and race. Of eligible hospitals, 17% had equitable readmission rates by insurance and 30% by race. Hospitals with equitable readmissions by insurance or race cared for a lower percentage of Black patients (insurance, 1.9% [IQR, 0.2%-8.8%] vs 3.3% [IQR, 0.7%-10.8%], P &amp;amp;lt; .01; race, 7.6% [IQR, 3.2%-16.6%] vs 9.3% [IQR, 4.0%-19.0%], P = .01), and differed from nonequitable hospitals in multiple domains (teaching status, geography, size; P &amp;amp;lt; .01). In examining equity by insurance, hospitals with low costs were more likely to have equitable readmissions (odds ratio, 1.57 [95% CI, 1.38-1.77), and there was no relationship between quality and value, and equity. In examining equity by race, hospitals with high overall quality were more likely to have equitable readmissions (odds ratio, 1.14 [95% CI, 1.03-1.26]), and there was no relationship between cost and value, and equity. Conclusion and Relevance A minority of hospitals achieved equitable readmissions. Notably, hospitals with equitable readmissions were characteristically different from those without. For example, hospitals with equitable readmissions served fewer Black patients, reinforcing the role of structural racism in hospital-level inequities. Implementation of an equitable readmission measure must consider unequal distribution of at-risk patients among hospitals.
Abstract PR001: 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 PR001.
Abstract A032: Identifying the binding partners of a long noncoding RNA involved in the DNA damage response
Authors: Michele Ramos Correa, Jonathan Castillo, Crystal N. Marconett
Journal: Cancer Research (2024)

Abstract Lung adenocarcinoma (LUAD) is the most common histological subtype of the deadliest cancer in the United States. This cancer can arise from a high rate of mutations exaggerated by dysregulation in DNA damage and repair signaling that cause genomic instability. LUAD has largely been studied in the context of protein-coding genes, however, recent studies have implicated long noncoding RNAs (lncRNAs) as critical regulators of gene expression in the DNA damage response, controlling the repair mechanism response's magnitude, duration, and resolution. My lab has identified the lncRNA LINC00261 as a tumor suppressor in LUAD that regulates the activation of the DNA damage repair system; however, its exact mechanisms of action remain unknown. We found that the reintroduction of LINC00261 in LUAD is associated with G2/M cell cycle arrest and phosphorylation-mediated activation of key DNA damage response pathway components. We hypothesize that LINC00261 protects DNA fidelity through direct interaction with repair components and aim to obtain insights into the essential functions that LINC00261 plays in the DNA damage response. We observe that LINC00261 is differentially highly expressed upon increased DNA damage with UV-light and ionizing radiation alongside enhanced expression of DDR components like p53. We have conducted initial RNA-FISH and ChIRP-MS studies to characterize the molecular mechanisms of this lncRNA. We demonstrate that subcellular localization of LINC00261 is found to be distributed in both the cytoplasm and nucleus, inferring an ability to function in cis and in trans to interact with partners locally and genome wide. Initial ChIRP mass spectrometry pilot data shows significant enrichment for DNA replication and p53 pathway activity. These findings contribute valuable information to understanding the role of LINC00261 in the DNA damage response and have implications for how lncRNA-mediated dysregulation of DNA repair leads to genomic instability and oncogenic activation. Citation Format: Michele Ramos Correa, Jonathan Castillo, Crystal N. Marconett. Identifying the binding partners of a long noncoding RNA involved in the DNA damage response [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 A032.