Repair Activity Research Articles

Genome-wide lone strand adenine methylation in Deinococcus radiodurans R1: Regulation of gene expression through DR0643-dependent adenine methylation.

DNA methylation is a covalent modification of adenine or cytosine in the genome of an organism and is found in diverse microbes including the radiation resistant bacterium Deinococcus radiodurans R1. Although earlier findings have confirmed repression or de-repression of certain genes in adenine methyltransferase (DR_0643/Dam1DR) deficient D. radiodurans mutant however, the overall regulatory aspects of Dam1DR-mediated adenine methylation remain mostly unexplored. In the present study, we compared the genome-wide methylome and the corresponding transcriptome of D. radiodurans WT and Δdam1 mutant to explore the correlation between methylation and gene expression. In D. radiodurans, deletion of DR_0643 ORF (Δdam1) led to hypomethylation of 512 genes resulting in differential expression of 168 genes (99 genes are upregulated and 69 genes are downregulated). The modification patterns deduced for Dam1DR (DR_0643) and Dam2DR (DR_2267) were non-palindromic and atypical. Moreover, we observed methylation at opportunistic sites that show adenine methylation only in D. radiodurans Δdam1 and not in D. radiodurans WT. Correlation between the methylome and transcriptome suggests that hypomethylation at Dam1DR specific sites had both negative as well as a positive effects on gene expression. Pathways such as amino acid metabolism, transport, oxidative phosphorylation, quorum sensing, signal transduction, two-component system, glycolysis/gluconeogenesis, TCA cycle, glyoxylate and dicarboxylate metabolism were modulated by Dam1DR-mediated adenine methylation in D. radiodurans. Processes such as DNA repair, recombination, ATPase and transmembrane transporter activity were enriched when Dam1DR mutant was subjected to radiation stress. We further evaluated the molecular interactions and mode of binding between Dam1DR protein and S-adenosyl methionine using molecular docking followed by MD simulation. To get a better insight into the methylation mechanism, the Dam1DR-SAM complex was also docked with a DNA molecule to elucidate DNA-Dam1DR structural interaction during methyl-group transfer reaction. In summary, our work presents comprehensive and integrative approaches to investigate both functional and structural aspects of DNA adenine methyltransferase (Dam1DR) in D. radiodurans biology.

Loss of Claudin-4 Reduces DNA Damage Repair and Increases Sensitivity to PARP Inhibitors.

High-grade serous ovarian cancer is the deadliest gynecologic malignancy due to progression to resistant disease. Claudin-4 is classically defined as a tight junction protein and is often associated with epithelial cancers. Claudin-4 is aberrantly expressed in nearly 70% of all ovarian cancer tumors and conveys a worse overall prognosis. Elevated claudin-4 expression correlates to increased DNA repair activity and resistance to DNA damaging agents. PARP inhibitors are emerging as an effective therapeutic option for patients with ovarian cancer and function by promoting DNA damage. The study examines the relationship between claudin-4 expression and the response to PARP inhibitors using both genetic and pharmacologic inhibition of claudin-4 in in vitro and ex vivo models of ovarian cancer to examine DNA repair markers and functional activity. Genetic inhibition of claudin-4 results in the downregulation of several DNA damage repair effectors, including 53BP1 and XRCC1. Claudin-4 knockdown did not change homology-directed repair but inhibited nonhomologous end-joining and reduced 53BP1 foci formation. In 15 primary ovarian cancer tumors, higher claudin-4 expression significantly correlated to a dampened PARP inhibitor-mediated antiproliferation response. Further, claudin-4 inhibition in high claudin-4 tumors sensitized tumor sections to PARP inhibition. These data highlight that claudin-4 expression in ovarian cancer tumors could serve as both a marker of PARP inhibitor response and a therapeutic target to improve PARP inhibitor response.

Overexpression of Ubiquilin4 is associated with poor prognosis in patients with cervical cancer.

BACKGROUNDUbiquilins (UBQLNs) are important factors for cell proteostasis maintenance. UBQLNs are involved in the modulation of the cell cycle, as well as in apoptosis, membrane receptors regulation, DNA repair, epithelial-mesenchymal transition, and miRNA activities. They also affect the selection of double-strand break repair pathways. Abnormal UBQLNs expression can lead to many diseases, including cancer. Studies have found that the expression of Ubiquilin4 (UBQLN4) is associated with the development of several tumor types. However, the association between UBQLN4 and cervical cancer has not been examined yet.AIMTo investigate the expression of UBQLN4 in cervical cancer and to evaluate its correlation with disease prognosis.METHODSImmunohistochemistry was performed to examine the expression of UBQLN4 in 117 cervical cancer tissues and 32 matching pericervical tissues. Paired t-test (two-tailed) was used to compare the differences between groups. We collected patients’ clinical characteristics, including age, histological grade, pathologic type, lymph node metastasis, and FIGO stage (2018) and compared them by chi-square test. All patients were followed for 5.5 to 6.8 years. Kaplan-Meier method and log-rank test were used to compare the differences in the overall survival (OS) and progression-free survival (PFS) among the different groups.RESULTSOverexpression of UBQLN4 was observed in 70.9% (83/117) of all cervical cancer tissues and in 15.6% (5/32) of the paired parauterine tissues. The expression of UBQLN4 was associated with lymph node metastasis, poor differentiation, and advanced stage, but the difference was not significant. Kaplan-Meier and log-rank test results suggested the high expression of UBQLN4 was associated with short OS and PFS. Regardless of UBQLN4 expression, the patient age and FIGO stage were also associated with disease prognosis. The statistically significant variables obtained from univariate the Kaplan-Meier analysis were subjected to Cox multivariate survival regression analysis, which showed that, in addition to the FIGO stage and age, UBQLN4 was also an independent prognostic marker for OS and PFS (P = 0.011 and P = 0.024, respectively).CONCLUSIONThe overexpression of UBQLN4 was associated with poor prognosis in cervical cancer. Our study proposed a novel prognostic factor and improved the existing understanding of the pathogenesis of cervical cancer.

Sustainability of mobile IT sector in industrially developing countries by supporting repairability

This article aims to provide a design intervention to support the repairability of mobile phones and, in turn, promote sustainability. Typically, mobile phones are designed with a view towards obsolescence for users in industrially developed countries, as the expected repair in these circumstances is minimal. In contrast, in developing countries, such as India, these phones are constantly repaired and are owned several times by different people before their final demise. Therefore, to support repairability, a field study based in Mumbai, India, was conducted to understand the cognitive basis of repair. The results were further analyzed using a cognitive work analysis framework that provides insight into the possibilities for informational requirements for design. The findings indicate that small-scale repair shops (3–4 repairmen) and the hole-in-the-wall shops (1 repairman) can benefit from the intervention in terms of informational support for the repair activity. If the cognitive dimension of repair is supported for these low-cost repair shops, we can expect an increase in the capability and efficacy of the repairmen, resulting in fewer phones ending up as e-waste. Thus, due to its low cost, informational diagrams that support the repair activity can be incorporated by the manufacturer without any radical changes in existing proprietary technology, resulting in the possibility for the long-term growth of the repair ecology in a country such as India.

Drugs repurposing: An approach to identify new hits against anticancer drug target TFIIH subunit p8

Drug repositioning is one of the most effective approaches towards drug discovery and development. It involves the identification of new therapeutic indications of existing drugs. The present study evaluated several drugs for their ability to modulate activity of the p8 subunit of TFIIH complex. Negative modulation of p8 subunit activity disrupts protein–protein interactions (PPIs) among the subunits of TFIIH complex, and thereby the TFIIH-associated functions. TFIIH complex has key role in the transcription and nucleotide excision repair activity in cancerous cells. TFIIH complex has emerged as a privileged drug target in anticancer research. Out of 60 drugs, amlopipine (13), diltiazem (16), gemfibrozil (19), levocitrizine dihydrochloride (20), losartan potassium (22), clorthalidone (24), and escitalopram (28) showed interactions with subunit p8 in the ligand-protein binding and chemical shift perturbation studies. The Kd values were found to be between 0.25 and 1 mM. These drugs also caused thermal destabilization of the subunit p8 by negatively shifting the melting temperature by ≥ 2 °C. Molecular docking studies indicated the interaction of these drugs with important residues of p8-p52 complex, such as Glu48, Lys51, Glu496, and Glu455 via non-covalent interactions. This study has thereby identified 7 drugs that can be investigated further as potential anticancer drugs.

Pre-activation of autophagy impacts response to olaparib in prostate cancer cells

Poly (ADP-ribose) polymerase 1 (PARP1) plays an essential role in DNA repair and is targeted by anticancer therapies using PARP inhibitors (PARPi) such as olaparib. PARPi treatment in prostate cancer (PC) is currently used as a monotherapy or in combination with standard therapies (hormonotherapy) in clinical trials for patients with DNA damage response mutation. Unfortunately, 20% of these patients did not respond to this new treatment. This resistance mechanism in PC is still not well understood. Here, we report that autophagy affects differently the response of PC cell lines to olaparib depending on its activation status. Pre-activation of autophagy before olaparib resulted in an increase of DNA repair activity by homologous recombination (HR) to repair double-strand breaks induced by olaparib and enhanced cell proliferation. When autophagy was activated after olaparib treatment, or completely inhibited, PC cells demonstrated an increased sensitivity to this PARPi. This autophagy-mediated resistance is, in part, regulated by the nuclear localization of sequestrosome 1 (SQSTM1/p62). Decrease of SQSTM1/p62 nuclear localization due to autophagy pre-activation leads to an increase of filamin A (FLNA) protein expression and BRCA1/Rad51 recruitment involved in the HR pathway. Our results reveal that autophagy basal levels may in part determine amenability to PARPi treatment.

Damage detection on a historic iron bridge using satellite DInSAR data

Structural Health Monitoring (SHM) allows tracking the structural behavior in time and support decisions regarding, for instance, the need for maintenance and repair activities. Most traditional SHM systems require sensors that are directly applied to the structure to get insights into the structural performance. Satellite technologies can provide an appealing alternative to traditional SHM. They allow to measure displacements at a large scale and to follow their evolution without the need of directly accessing the structure. Further to this, the possibility to monitor large areas opens new avenues for the development of automatic alert systems able to issue an alarm and early-flag damaged structures. However, displacements of civil structures might also be induced by sources other than damage such as thermal or periodic hydrogeological variations. These can hinder the onset and development of damage or lead to false alarms if such displacements are erroneously interpreted as damages. This paper aims to present a new method for damage detection based on DInSAR measurements, that tackles both aspects providing reliable information about the onset of damage under environmentally changing conditions in a period corresponding to about twice the revisit time of the satellite. A case study is presented to demonstrate the applicability of the proposed method, namely the Palatino bridge in Rome, Italy. The satellite data are acquired by COSMO-SkyMed of the Italian Space Agency and consist of displacements of the observed structure recorded during a period spanning between 2011 and 2019.

Ligand‐Directed Caging Enables the Control of Endogenous DNA Alkyltransferase Activity with Light inside Live Cells

AbstractThe control of endogenous protein activity with light inside live cells is helpful for the high spatiotemporal probing of their dynamic roles. Herein, we report the first small‐molecule‐ligand‐directed caging approach to control the endogenous human O6‐alkylguanine‐DNA alkyltransferase (AGT) activity with light, and the caged AGT is constructed from the native intracellular AGT. The photo‐responsive O6‐benzylguanine derivative O6‐NBG3 is developed to site‐specifically cage the AGT′s catalytic cysteine residue, and the light irradiation on‐demand restores AGT′s activity in vitro, in bacteria, and in mammalian cells. With O6‐NBG3, the alkylated AGT is dealkylated for the first time to recover the DNA repair activity in breast cancer MCF‐7 cells by the dose‐dependent light irradiation. This decaging strategy enables the localized modulation of endogenous AGT activity with high temporal precision without genetic engineering, which holds great potential for therapeutic applications.

Ligand-Directed Caging Enables the Control of Endogenous DNA Alkyltransferase Activity with Light inside Live Cells.

The control of endogenous protein activity with light inside live cells is helpful for the high spatiotemporal probing of their dynamic roles. Herein, we report the first small-molecule-ligand-directed caging approach to control the endogenous human O6 -alkylguanine-DNA alkyltransferase (AGT) activity with light, and the caged AGT is constructed from the native intracellular AGT. The photo-responsive O6 -benzylguanine derivative O6 -NBG3 is developed to site-specifically cage the AGT's catalytic cysteine residue, and the light irradiation on-demand restores AGT's activity in vitro, in bacteria, and in mammalian cells. With O6 -NBG3, the alkylated AGT is dealkylated for the first time to recover the DNA repair activity in breast cancer MCF-7 cells by the dose-dependent light irradiation. This decaging strategy enables the localized modulation of endogenous AGT activity with high temporal precision without genetic engineering, which holds great potential for therapeutic applications.

Quality management in radiotherapy treatment delivery.

Radiation Oncology continues to rely on accurate delivery of radiation, in particular where patients can benefit from more modulated and hypofractioned treatments that can deliver higher dose to the target while optimising dose to normal structures. These deliveries are more complex, and the treatment units are more computerised, leading to a re-evaluation of quality assurance (QA) to test a larger range of options with more stringent criteria without becoming too time and resource consuming. This review explores how modern approaches of risk management and automation can be used to develop and maintain an effective and efficient QA programme. It considers various tools to control and guide radiation delivery including image guidance and motion management. Links with typical maintenance and repair activities are discussed, as well as patient-specific quality control activities. It is demonstrated that a quality management programme applied to treatment delivery can have an impact on individual patients but also on the quality of treatment techniques and future planning. Developing and customising a QA programme for treatment delivery is an important part of radiotherapy. Using modern multidisciplinary approaches can make this also a useful tool for department management.

P53 reactivating small molecule PRIMA‑1MET/APR‑246 regulates genomic instability in MDA‑MB‑231 cells.

Pharmacological reactivation of tumor‑suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non‑functional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and apoptosis. By contrast, non‑functional mutp53 compromises the aforementioned genome stabilizing mechanisms through gain of function, thereby increasing genomic instability in human cancers. Restoring the functional activity of p53 using both genetic and pharmacological approaches has gained prominence in targeting p53‑mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA‑1MET/APR‑246 small molecules, in both MDA‑MB‑231 and MCF‑7 breast cancer cell lines, which carry mutp53 and wild‑type p53, respectively. Results of the present study revealed that reactivation of p53 through APR‑246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDA‑MB‑231 cells with APR‑246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR‑246 may act as a promising small molecule to control the genomic instability in p53‑mutated tumors.

DNA repair defects in cancer and therapeutic opportunities.

DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.

Targeting the Macrophage: Immune Cells May Be the Key to Phthalate-Induced Liver Toxicity.

Targeting the Macrophage: Immune Cells May Be the Key to Phthalate-Induced Liver Toxicity.

Energy Autonomous Wireless Sensor Nodes for Freight Train Braking Systems Monitoring.

Nowadays, railway freight transportation is becoming more and more crucial since it represents the best alternative to road transport in terms of sustainability, pollution, and impact on the environment and on public health. Upgrading the potentiality of this kind of transportation, it would be possible to avoid delays in goods deliveries due to road accidents, traffic jams, and other situation occurring on roads. A key factor in this framework is therefore represented by monitoring and maintenance of the train components. Implementing a real time monitoring of the main components and a predictive maintenance approach, it would be possible to avoid unexpected breakdowns and consequently unavailability of wagons for unscheduled repair activities. As highlighted in recent statistical analysis, one of the elements more critical in case of failure is represented by the brake system. In this view, a real time monitoring of pressure values in some specific points of the system would provide significant information on its health status. In addition, since the braking actions are related to the load present on the convoy, thanks to this kind of monitoring, it would be possible to appreciate the different behavior of the system in case of loaded and unloaded trains. This paper presented an innovative wireless monitoring system to perform brake system diagnostics. A low-power system architecture, in terms of energy harvesting and wireless communication, was developed due to the difficulty in applying a wired monitoring system to a freight convoy. The developed system allows acquiring brake pressure data in critical points in order to verify the correct behavior of the brake system. Experimental results collected during a five-month field test were provided to validate the approach.

A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response

Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation affects global cellular stress responses is sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver, using mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by XBP1, a key UPR effector. Importantly, this response is significantly reduced in the Aag knockout. To investigate how AAG affects alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cells expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, AAG knockdown compromised UPR induction and led to a defect in XBP1 activation. To verify the requirements for the DNA repair activity of AAG in this response, AAG knockdown cells were complemented with wild-type Aag or with an Aag variant producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective Aag does not fully protect AAG knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, besides its enzymatic activity, AAG has noncanonical functions in alkylation-induced UPR that contribute to cellular responses to alkylation.

Control of Occupational Safety and Health Risk Using the Hirarc Method (Case Study : PT Sari Warna Asli V Kudus)

PT Sari Warna Asli V is a yarn spinning manufacturing company. Based on the company's work accident record, in 2019 in the production department there were 19 work accidents and in 2020 as many as 18 work accidents. Total work accidents in 2019 were 14 cases that occurred in Spinning Mills I and 5 cases in Spinning Mills II. Meanwhile, in 2020, 12 cases occurred in Spinning Mills I and 6 cases in Spinning Mills II. The purpose of this research is to identify the potential hazards that exist, assess the risks that may occur at each work station in Spinning Mills I, so that risk control can be given so that the company can avoid any possible harm. The method used is Hazard Identification Risk Assessment Risk Control (HIRARC). Research data collection was obtained from observations at Spinning Mills I, interviews, documentation, and literature studies. The results of the study at 6 work stations on repair and maintenance activities obtained the percentage of potential hazards of 61% (49 risks) are low risk (low risk), 13% (10 risks) are moderate risk (moderate risk), 26% (21 risks) are high risk (high risk), and there are not potential work hazards with very high category (extreme risk). Risks included in the high risk category are falling from above when clearing blockages, broken hands/fingers exposed to rotating machines, fire, hearing loss, and fatigue. Risk control that can be done by the company includes adding SOPs, safety signs, and safety talk, K3 training to increase worker knowledge, providing PPE that must be used according to standards, installing automatic sensors that can detect approaching hands, providing safe distance limits/floor markings. production and routine cleaning.

Lean Approach for Waste Reduction in Production Line by Integrating DMAIC, VSM, and VALSAT Method (Study Case: Assembling Bracket Manufacturing Automotive Industry)

The automotive manufacturing industry is a manufacture that produces four-wheeled automotive accessories parts. One of the products is the audio unit and bracket. This research aims to reduce waste in production and reduce cycle time, affecting increasing production output to adapt it to customer needs. Waste identification by integrating lean six sigma, namely DMAIC, VSM, and VALSAT. Based on the analysis results, it was found that the four biggest wastes were motion, inventory, waiting, and process. After carrying out the repair activities, the cycle time decreased at station three from 704 seconds to 246 seconds, thereby increasing the capacity efficiency from 75% to 91 %.

Direct Synthesis of Photosensitizable Bacterial Cellulose as Engineered Living Material for Skin Wound Repair.

Living materials based on bacterial cellulose (BC) represent a natural and promising candidate for wound dressing. Both physical adsorption and chemical methods have been applied to BC for realizing antibacterial function. However, effective and long-lasting incorporation of bactericidal moieties to BC remains challenging. Herein, a Komagataeibacter sucrofermentans-based direct synthetic method to fabricate photosensitizer-grafted BC throughin situbacterial metabolism in the presence of TPEPy-modified glucose is explored. The results verify that the direct biosynthesis method is efficient and convenient to endow BC with outstanding fluorescence and light-triggered photodynamic bactericidal activity for skin wound repair. This work presents a new approach to fabricate eco-friendly and active wound dressing with light-controlled bactericidal activity by microbial metabolism. The successful modification of the glucose carbon source of microorganisms also offers insights for biosyntheses of other living materials through microbial metabolism.

Nucleotide Excision Repair Pathway Activity Is Inhibited by Airborne Particulate Matter (PM10) through XPA Deregulation in Lung Epithelial Cells.

Airborne particulate matter with a diameter size of ≤10 µm (PM10) is a carcinogen that contains polycyclic aromatic hydrocarbons (PAH), which form PAH–DNA adducts. However, the way in which these adducts are managed by DNA repair pathways in cells exposed to PM10 has been partially described. We evaluated the effect of PM10 on nucleotide excision repair (NER) activity and on the levels of different proteins of this pathway that eliminate bulky DNA adducts. Our results showed that human lung epithelial cells (A549) exposed to 10 µg/cm2 of PM10 exhibited PAH–DNA adducts as well as an increase in RAD23 and XPD protein levels (first responders in NER). In addition, PM10 increased the levels of H4K20me2, a recruitment signal for XPA. However, we observed a decrease in total and phosphorylated XPA (Ser196) and an increase in phosphatase WIP1, aside from the absence of XPA–RPA complex, which participates in DNA-damage removal. Additionally, an NER activity assay demonstrated inhibition of the NER functionality in cells exposed to PM10, indicating that XPA alterations led to deficiencies in DNA repair. These results demonstrate that PM10 exposure induces an accumulation of DNA damage that is associated with NER inhibition, highlighting the role of PM10 as an important contributor to lung cancer.

Abstract P1-16-07: A synthetic lethality treatment strategy for p53 mutant breast cancer

Abstract Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we report preclinical data supporting a novel combination therapy strategy for treatment of p53-mutant cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-mutant breast cancers. We designed a new methodology for testing BER in live cells. The BER studies revealed a significant dysregulation in BER-mediated repair in p53-mutant cancer cells. Taken advantage in the BER defect, we developed a novel treatment strategy that specifically targets p53-mt cancers. We found that treatment with deoxyuridine analogues induced accumulation of DNA damage selectively in p53-mutant cells. Further, inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response and increased cell death, although PARPi as a single agent was not effective. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of p53 in p53 wild-type cell lines conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients. Citation Format: Andrei Bakin, Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Renuka Iyer, Ben Park, Christos Fountzilas. A synthetic lethality treatment strategy for p53 mutant breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-07.