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BackgroundIn patients with severe renal failure, coronary artery bypass surgery (CABG) was found to have better long-term outcomes than percutaneous coronary intervention (PCI). This study aims to provide a retrospective analysis of short-term in-hospital peri-operative outcomes between PCI and CABG in patients with severe renal failure.MethodsPatients who underwent CABG and PCI in Q4 2015-2020 were identified in National Inpatient Sample (NIS) database. Patients of ageResultsIn NIS, 4,512 CABG and 13,242 PCI cases were identified. Compared to CABG, patients who underwent PCI had lower mortality (4.24% vs 5.47%, aOR 0.725, pConclusionNIS is a comprehensive database of nationwide providers, providing robust power in analysis. In patients with severe renal failure, PCI offers an advantage over CABG in terms of short-term in-hospital perioperative outcomes.

Ctx+R428 in HN30-AXL-Y821F

Figure legends to accompany supplemental data

Clinical characteristics of tumors

BackgroundDespite extensive research on coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) outcome differences, current literature lacks representation of short-term in-hospital outcomes in patients with existing medical conditions. This study aimed to compare perioperative outcomes of these two revascularization procedures in diabetes mellitus (DM) patients.MethodsThe National Inpatient Sample (NIS) was used to extract patients who received CABG or PCI surgery between the last quarter of 2015 to 2020 based on ICD10-PCS. Patients of ageResultsA total number of 90,662 CABG and 173,725 PCI cases of patients with DM were identified in NIS. Compared to CABG, patients who underwent PCI had increased mortality (2.75% vs 2.00%, aOR 1.266, pConclusionsThe NIS database collects enormous records from nationwide providers, offering great statistical power. PCI was associated with a markedly higher in-hospital mortality rate but a lower morbidity rate in patients with DM as compared to CABG. Therefore, physicians should weigh both mortality and morbidity when considering surgical treatment to DM patients.

The authors have withdrawn their manuscript because a major revision is in progress to incorporate additional data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Human papillomavirus (HPV) is a ubiquitous DNA virus that infects squamous epithelia. Though HPV only encodes 8 genes, it is capable of causing cellular transformation and ultimately cancer in host cells. In this article we review the classification of HPV viruses, their genetic structure and life cycle, viral gene biology, and provide an overview of the role of HPV in cancer. We explain how the viral life cycle can lead to integration of viral DNA into the host genome leading to increased cell cycle progression, decreased apoptosis, altered DNA repair, and chromosomal instability. We describe the multifaceted roles of the canonical oncogenes E6 and E7 in promoting tumorigenesis and the important role of other viral genes in regulating cancer development. We also review how the virus actively suppresses innate and adaptive immunity to evade immune detection and promote a pro-tumorigenic microenvironment. The biology presented here will serve as a foundation to the other chapters in this edition and we hope it will incite enthusiasm for continued research on this fascinating virus that causes significant morbidity and mortality worldwide.

Introduction: Cancer cells exhibit a high degree of plasticity to adapt the rapidly changing tumor microenvironment (TME), in part by altering cellular metabolic pathways at a faster and more efficient pace than normal cells. Cancer cell plasticity, with genetic and epigenetic alterations, promote the diversity of cancer cells contributing to heterogeneity within the tumor. Head and neck cancer (HNC) is a notable example of this diversity; HNC tumors harbor cells with a wide genetic and metabolic heterogeneity, including cancer stem cells (CSC). Despite current treatment approaches, more than 40% of HNC patients have disease recurrence. Thus, we developed a multimodal approach to effectively prevent the development of radio/drug-resistance. Experimental Procedures: Nuclear-localized mkate2 expressing HNC cell numbers detected for every 6 hours by using IncuCyte S3 instrument. Apoptotic cells detected via NucView 488 Caspase-3 substrate and ROS levels determined using CellROX green simultaneously with cell numbers in the IncuCyte S3 instrument. Synergy scores calculated according to viability in SynergyFinder 2.0 web-application. Results: Our preliminary data profiling of metabolic regulators as radiosensitizer indicate that auranofin (AUR, thioredoxin reductase inhibitor) and buthionine sulfoximine (BSO, γ-glutamylcysteine synthetase inhibitor), given in combination with radiation (RT+AUR+BSO): 1) significantly inhibit proliferation in HNC cell lines, 2) increase ROS accumulation, and 3) reduce the surviving fraction of cells in colony forming assays compared to individual/dual agent applications. Furthermore, we added an autophagy inhibitor, SAR405, in our treatment regimen because of the crosstalk between ROS levels and autophagy. Human (FaDu and UM-SCC-47) and murine (MOC1 and MOC2) HNC cell were treated with +/-AUR+/-BSO+/-SAR405 and high-throughput combinatorial screening of cell numbers obtained over time. The combination of AUR+BSO+SAR405 registered a higher synergy score than the double combinations. Furthermore, as compared to single or double drug applications, the AUR+BSO+SAR405 group had a greater apoptotic cell rate and ROS levels. Conclusion: We present here a high-throughput method to screen multi-drug synergy. Multi-modal approach is important to prevent recurrence by providing a broader effect on heterogenous cancer cells in tumor. Moreover, multi-drug combinations allow usage of lower doses of drugs effectively, hence lowers the treatment-related adverse effects. This approach indicated the possibility of HNC treatment by increasing the ROS levels beyond the containable threshold which is consistent with the recent findings about the alterations in redox metabolism, particularly upregulation in thioredoxin and glutathione pathways, in many cancer types. In vivo experiments are ongoing to evaluate the potential of this combination for clinical studies. Citation Format: Zafer Gurel, Qianyun Luo, Michael S. Luy, Randall J. Kimple. ROS metabolism and autophagy as potential targets to improve head and neck cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1403.

BackgroundHuman papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HPV+ HNSCC) is a disease that has moderate response to anti-PD-1/L1 immune checkpoint blockade, with the response rates less than 20% and median progression-free survival less than 3 months. A greater understanding of tumor intrinsic and extrinsic factors that restrict anti-tumor immunity in the tumor immune microenvironment (TIME) is needed to identify other immune checkpoints to enhance therapeutic efficacy.MethodsTwo cohorts (TCGA n=72 and a separate cohort n=84) of surgically resected, treatment-naïve HPV+ HNSCC with RNA-seq were analyzed to understand the immune features. In addition, single-cell RNA-seq and TCR-seq were performed on 18 cases to further delineate the immune molecules' interactions. An immune-competent murine HPV+ HNSCC model was used to preliminarily evaluate the therapeutic efficacy.ResultsIn two bulk-sequenced HPV+ HNSCC cohorts, TIGIT ligands PVR and NECTIN2 were found to associate with an epithelial-to-mesenchymal gene expression signature, suppression of IFNα and IFNγ signaling, a stromal-enriched or immune-excluded TIME, and poor survival. Single-cell RNA-seq of over 72,000 cells of HPV+ HNSCC revealed that the PVR/NECTIN ligand TIGIT was highly prevalent in T-cells (34%), significantly higher than PD1- (20%, pConclusionsTIGIT-PVR/NECTIN receptors/ligands are more abundant than PD-1/L1 in the TIME of HPV+ HNSCC. Co-blockade of TIGIT and PD-1 immune checkpoints enhanced anti-tumor efficacy in a CD8+ T-cell-dependent manner and conferred long-term immune protection in a murine model. Our study nominates TIGIT as a therapeutic target for HPV+ HNSCC.

Purpose: Radiation and cetuximab are therapeutics used in management of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of this disease. The purpose of this study was to investigate signaling of the receptor tyrosine kinase AXL in resistance to radiation and cetuximab treatment. Experimental Design: To study AXL signaling in the context of treatment-resistant HNSCC, we used patient-derived xenografts (PDXs) implanted into mice and evaluated the tumor response to AXL inhibition in combination with cetuximab or radiation treatment. To identify molecular mechanisms of how AXL signaling leads to resistance, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and examined for their sensitivity to cetuximab and/or radiation. Furthermore, reverse phase protein array (RPPA) was employed to analyze the proteomic architecture of signaling pathways in these genetically altered cell lines. Results: Treatment of cetuximab- and radiation-resistant PDXs with AXL inhibitor R428 was sufficient to overcome resistance. RPPA analysis revealed that such resistance emanates from signaling of tyrosine 821 of AXL via the tyrosine kinase c-ABL. In addition, inhibition of c-ABL signaling resensitized cells and tumors to cetuximab or radiotherapy even leading to complete tumor regression without recurrence in head and neck cancer models. Conclusions: Collectively, the studies presented herein suggest that tyrosine 821 of AXL mediates resistance to cetuximab by activation of c-ABL kinase in HNSCC and that targeting of both EGFR and c-ABL leads to a robust antitumor response.

Potassium channels such as Kv2.1 are targeted to specific subcellular compartments to fulfill various functions. However, the mechanisms for their localization are poorly understood. Here, we show that KVS-4/Kv2.1 somatodendritic localization in Caenorhabditis elegansDA9 neuron requires UNC-101(AP-1 μ subunit). We define a bipartite sorting signal within KVS-4 consisting of a C-terminal EQMIL and N-terminal WNIIE motifs. The bipartite signal is sufficient to target nonpolarized transmembrane protein MIG-13 into DA9 somatodendritic compartments. Furthermore, we found that AP-1 interacts with the bipartite signal through UNC-101/AP-1 μ N-terminal predicted Longin-like domain. Our results provide new insight into the mechanisms of Kv2.1 post-Golgi sorting and targeting.