bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4832: Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC
Authors: Benej Martin , Benejova Katarina , Kreamer McKenzie , Wu Jinghai , Ashraf Syed , Wheeler Caroline , Hoyd Rebecca , Spakowicz Daniel , Denko Nicholas C.
Published: June 2023

Non-small cell lung cancer (NSCLC) is a highly aggressive disease with a dismal prognosis associated with high rates of treatment resistance and disease recurrence. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for locally advanced non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1) has been introduced as first-line NSCLC treatment, yet long-term disease control occurs in less than 25% of patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the need for novel synergistic therapies to sensitize refractory NSCLC tumors to anti-cancer treatment. Tumor hypoxia has been associated with treatment resistance for decades, yet its role in the clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS) and the expression of validated hypoxia-regulated genes (Buffa hypoxia score). The oxygen-consumption expression signature was implemented in software that enables the calculation of numerous tumor microenvironment expression signatures, called tmesig. Furthermore, we have observed a direct positive correlation between the hypoxia expression signatures levels in NSCLC patient samples and the copy number amplification (CNA) of essential OXPHOS genes. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may indirectly regulate oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function, which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC.

Citation Format: Martin Benej, Katarina Benejova, McKenzie Kreamer, Jinghai Wu, Syed Ashraf, Caroline Wheeler, Rebecca Hoyd, Daniel Spakowicz, Nicholas C. Denko. Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4832.
Abstract 529: Novel inhibitors of the NRF2 pathway also arrest lung cancer cells in G2/M
Authors: Occhiuto Christopher John , Lockwood Lizbeth , Hou Zhilin , Odom Aaron , Liby Karen
Published: June 2023

Background: Non-small cell lung (NSCLC) constitutes approximately 80% of all diagnosed cases of lung cancer. Up to 30% of NSCLC acquire mutations that result in constitutive NRF2 pathway activity, which correlates with worse patient prognosis. NRF2 regulates antioxidant genes that confer cytoprotection and chemoresistance. Inhibiting NRF2 activity increases tumor susceptibility to chemotherapy in preclinical lung cancer models; however, there are no FDA-approved NRF2 inhibitors available. Because current inhibitors have low potency and specificity, we developed novel compounds that target the NRF2 pathway. Previously, a high throughput screen identified MSU-38225, which was efficacious in sensitizing chemoresistant lung cancer to chemotherapy in a mouse xenograft model. We sought to improve the poor pharmacokinetics of this compound and developed and characterized a series of novel derivatives with increased solubility.

Hypothesis: Derivatives of MSU-38225 inhibit the NRF2 pathway and decrease cancer cell viability.

Methods: The efficacy of our NRF2 pathway inhibitors was assessed in A549 and H460 human lung cancer cells with constitutive NRF2 pathway activity using western blotting, RT-PCR, and MTT or Cell Titer Glow viability assays. Cell death and cell cycle analysis were evaluated using flow cytometry. Data were evaluated with one or two-way ANOVA and the Dunnett post-hoc test.

Results: The NRF2 pathway inhibitors decreased NRF2 protein level in A549 and H460 cells by approximately 60%, as measured by western blotting. As a result, NRF2-mediated transcription of cytoprotective genes NQO1, GCLC, GCLM, and AKR1C2 were decreased by 30-60% (p<0.05) by qPCR. Further, these compounds decreased lung cancer cell viability, as measured in an MTT assay, by 50% in A549 cells and by 90% in H460 (p<0.05). We then evaluated a specific inhibitor, MSU-71, to determine the cause of decreased viability and found it did not induce annexin-V positive apoptosis. However, subsequent analysis of the cell cycle with propidium iodide univariate analysis showed MSU-71 arrests lung cancer cells. 50% of H460 and 75% of A549 cells were arrested in G2/M (p<0.05). Finally, we developed several “click” chemistry tool compounds that have equitable NRF2 pathway inhibition, which will aid in target identification of the new inhibitors.

Conclusion: Taken together, the new NRF2 pathway inhibitors are efficacious in blocking NRF2 activation. Optimization of these inhibitors could lead to a new therapy to treat lung cancer.

Citation Format: Christopher John Occhiuto, Lizbeth Lockwood, Zhilin Hou, Aaron Odom, Karen Liby. Novel inhibitors of the NRF2 pathway also arrest lung cancer cells in G2/M [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 529.
Abstract 5304: Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature
Authors: Dou Rongzhang , Irajizad Ehsan , Cai Yining , Fahrmann Johannes F. , Vykoukal Jody V. , Chen Yihui , Katayama Hiroyuki , Sater Ali H. Abdel , Pizzi Melissa , Yamashita Kohei , Da Silva Matheus Sewastjanow , Ostrin Edwin J. , Ajani Jaffer , Hanash Samir M.
Published: June 2023

Background: Gastric cancer is frequently diagnosed at an advanced stage and is associated with poor outcomes. Harnessing the immune response to tumor antigens which occurs early during tumor development has potential for the early detection of gastric cancer.

Methods: Plasma samples from gastric cancer patients were collected before and after treatment and from healthy controls for identification of immunoglobin (Ig)-bound antigens using mass spectrometry. Ingenuity pathway analysis(IPA) was utilized to investigate networks and pathways associated with Ig bound proteins identified in plasmas from cases. A combined biomarker panel was established based on a logistic-regression model and ROC analysis was used to assess panel performance.

Results: A total of 65 Ig bound proteins were identified that were upregulated in gastric cancer patients’ plasma compared with healthy control. Canonical pathways involving these immunogenic proteins included HIF-1α, VEGF, actin cytoskeleton, and immunogenic cell death signaling which play important roles in both gastric cancer development and progression. Four of the top ten performing proteins exhibited high mRNA levels in gastric cancer tissue. The association of these four Ig bound proteins in gastric cancer plasmas was further validated using as controls a cohort of MEN1 patients plasmas. A blood-biomarker panel based on these four biomarkers was established using a logistic-regression model which yielded an area under the curve (AUC) of 0.963 (95% confidential interval [CI] =0.89-1.00) for gastric cancer discrimination with a sensitivity of 0.889 at 95% specificity.

Conclusion: Our data reveal a panel of plasma Ig-bound antigens associated with the development of gastric cancer with potential application for early detection and monitoring.

Citation Format: Rongzhang Dou, Ehsan Irajizad, Yining Cai, Johannes F. Fahrmann, Jody V. Vykoukal, Yihui Chen, Hiroyuki Katayama, Ali H. Abdel Sater, Melissa Pizzi, Kohei Yamashita, Matheus Sewastjanow Da Silva, Edwin J. Ostrin, Jaffer Ajani, Samir M. Hanash. Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5304.
Abstract 5477: An investigation to study differential gene expression of lung cancer cells, tumor associated macrophages, and bone marrow derived mesenchymal stems cells in the tumor microenvironment
Authors: Banerjee Hirendra N. , Hedley Joseph , Aurelus Cheslsey , Banerjee Narendra , Rawat Kuldeep , Reaves Quentin , Brown Shennel , Gilmartin Darla , Liverman Makieyah , Cuffee Jazmine , Cagle Elizabeth , Armstrong Erik , Lake Brent , Mandal Santosh , Ghosh Somiranjan , Beebe Stephen , Asadipour Kamal , Krauss Christopher , Bhattacharya Santanu , Kulkarni Tanmay , Abedin Zahidur
Published: June 2023

Cancer is a public health crisis affecting approximately 19.3 million globally, annually. Lung cancer has the highest percentage of incidence and is responsible for 27% of cancer-related deaths. The prevalence of lung cancer worldwide led us to investigate differential gene expression in lung adenocarcinoma and small cell lung cancer cell lines in comparison to a healthy lung cell line. We also investigated the effect of lung tumor microenvironment to bone marrow derived pluripotent mesenchymal stem cells (PMSC) and tumor associated macrophages. This research involved cancer and healthy cell line culture with appropriate medium. Whole transcriptomic and small non-coding RNA sequencing and analysis by Ingenuity Pathway Analysis (Qiagen, USA), Quantitative RT-PCR and ELISA assays. We further studied morphological changes and differential gene expression in extracellular vesicles(exosomes) isolated from the TAM and TME exposed PMCs by atomic force microscopy and RNA sequencing techniques. The results of our investigation showed differential gene expression and novel core canonical pathways in the lung cancer cells, TME exposed TAM, and PMSC. We also observed morphological changes in TME derived exosomes from TAM and PMSC. RNA sequencing results showed differential gene expression of both coding and non-coding RNAs including tRNA fragments. Thus, our findings of this investigation led to identification of multiple cancer related genes and small non-coding microRNA, long non-coding RNA, and tRNA fragments which will have potential diagnostic and therapeutic target value that demands further future research. Acknowledgement: This research is supported by a grant from US NIH-NIGMS- 5T34GM100831-08 and US-NIH Grant# U 54 MD007597-31-5959.

Citation Format: Hirendra N. Banerjee, Joseph Hedley, Cheslsey Aurelus, Narendra Banerjee, Kuldeep Rawat, Quentin Reaves, Shennel Brown, Darla Gilmartin, Makieyah Liverman, Jazmine Cuffee, Elizabeth Cagle, Erik Armstrong, Brent Lake, Santosh Mandal, Somiranjan Ghosh, Stephen Beebe, Kamal Asadipour, Christopher Krauss, Santanu Bhattacharya, Tanmay Kulkarni, Zahidur Abedin. An investigation to study differential gene expression of lung cancer cells, tumor associated macrophages, and bone marrow derived mesenchymal stems cells in the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5477.
Abstract 548: The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma
Authors: Ghosh Subrata , Lazarus Douglas , Robertson Neil , Crosier Edward , Liu Peter , Medarova Zdravka
Published: June 2023

Non-coding RNAs, such as miRNAs, represent promising targets for cancer therapy, given their role as critical players in oncogenic processes, including tumor initiation and progression, metastasis and therapeutic resistance. We and others demonstrated that miRNA-10b is a critical driver of tumor cell viability, especially in the metastatic setting. Based on this discovery, it became feasible to treat established metastatic cancer by inhibiting miR-10b. This was accomplished using a therapeutic, termed TTX-MC138, composed of antagomirs against miR-10b, conjugated to dextran-coated iron oxide nanoparticles. In our previous studies in murine models of metastatic breast cancer, we demonstrated the effectiveness of TTX-MC138 at preventing and eliminating existing metastases. Here, we describe the application of TTX-MC138 for the treatment of pancreatic adenocarcinoma. TTX-MC138 was administered weekly via intravenous injection into mice bearing orthotopic xenografts derived from human pancreatic adenocarcinoma cells. Tumor burden was measured by in vivo bioluminescence imaging. Animal survival, body weight, and tumor and metastatic burden at necropsy were also analyzed. Serum and tumor miR-10b expression, as well as global gene expression using RNA-seq were assessed to provide insight into target engagement and molecular function. Animals treated with vehicle or gemcitabine served as controls. Tumor growth rate was found to be significantly lower in animals treated with TTX-MC138 vs controls (p < 0.0001 for TTX-MC138 vs. PBS and vs. gemcitabine). Importantly, 40% of the animals treated with TTX-MC138 regressed their tumors completely as measured by bioluminescence imaging. Treatment continued for 10 weeks, after which the responding mice were monitored for disease recurrence without treatment for an additional 10 weeks. The animals showed evidence of continued weight gain and durable survival. They were sacrificed 10 weeks after treatment was discontinued, despite no evidence of morbidity, to perform necropsy. No tumors or metastases were found at the time of sacrifice. Gene expression analysis confirmed target engagement and molecular mechanism of action. Against the background of our earlier work, these studies provide further evidence of the potential of TTX-MC138 for cancer therapy and expand its relevance beyond metastatic breast cancer to also include pancreatic adenocarcinoma.

Citation Format: Subrata Ghosh, Douglas Lazarus, Neil Robertson, Edward Crosier, Peter Liu, Zdravka Medarova. The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 548.
Abstract 5672: Comparative mouse pharmacokinetics of matched- and unmatched-isotype anti-PD-L1 antibodies
Authors: Demestichas Breanna , Kleeman Sam , Chvasta Matthew , Janowitz Tobias
Published: June 2023

Immune checkpoint inhibitors (ICI) are highly effective for a minority of patients with cancer. Pre-clinical research into mechanisms of ICI resistance is reliant upon anti-PD-1 or anti-PD-L1 antibody treatment in mouse models of cancer. Common approaches utilize commercially-available rat isotype anti-PD-L1 antibodies given by intraperitoneal (IP) injection at relatively high doses (5mg/kg every 2-3 days), often for extended periods. However, there has been limited investigation into the pharmacokinetics of these antibodies with single and repeat dosing, which could inform rational dose scheduling. Non-species-matched antibodies are known to induce accelerated anti-drug immune responses, compared to species-matched antibodies. As a result, we hypothesized that matched-isotype anti-PD-L1 (based on the grafting of atezolizumab variable regions onto a mouse IgG2a scaffold) and unmatched-isotype rat IgG2b anti-PD-L1 would be associated with distinct pharmacokinetics on single and repeated dosing. We first confirmed that both matched and unmatched antibodies have nanomolar-range affinity for mouse PD-L1 by surface plasmon resonance (0.85nM and 0.37nM, respectively). Using a single IP injection in 8-week-old male C57BL/6J mice followed by repeated tail-vein plasma sampling and an indirect anti-PD-L1 ELISA, we detected a trend towards prolonged median half-life for the matched (n=17 mice) versus unmatched (n=19) antibody (91.5 versus 39.0 hours). We detected a particularly wide range of half-life measurements for matched antibody experiments (19.8 to 337.7 hours), suggesting that antibody clearance can be highly heterogeneous. Using repeated IP injection (2 doses, 14 days apart), we identified markedly accelerated antibody clearance for both antibodies resulting in comparable antibody half-lives after dose 2 (11.9 versus 12.5 hours, n=13 and n=8 mice, respectively), suggestive of a time-dependent anti-drug adaptive immune response. These findings have significant implications for in vivo antibody treatment experiments, demonstrating that repeat dosing is associated with rapid antibody clearance, irrespective of the antibody species. These data should be taken into consideration when planning longer-term antagonism of PD-1/PD-L1 signaling with antibodies in mice and strengthen the basis for short term window studies that examine the intratumoral immune biology. Furthermore, the high variability in antibody half-life suggests that antibody pharmacokinetics could confound ICI treatment response studies in vivo.

Citation Format: Breanna Demestichas, Sam Kleeman, Matthew Chvasta, Tobias Janowitz. Comparative mouse pharmacokinetics of matched- and unmatched-isotype anti-PD-L1 antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5672.
Abstract 625: PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
Authors: Wong Chun Wai , Evangelou Christos , Sefton Kieran N. , Leshem Rotem , Sergiou Kleita , Carro Macarena Lucia Fernandez , Uzuner Erez , Mole Holly , Telfer Brian A. , Wilcock Daniel J. , Smith Michael P. , Kunii Kaiko , Perl Nicholas R. , Lorigan Paul , Williams Kaye J. , Rao Patricia E. , Nagaraju Raghavendar T. , Niepel Mario , Hurlstone Adam F.
Published: June 2023

Adaptive resistance limits immune checkpoint blockade therapy (ICBT) response duration and magnitude. Interferon γ (IFNγ), a critical cytokine that promotes cellular immunity, also induces adaptive resistance to ICBT. Using syngeneic mouse tumor models, we confirmed that chronic IFNγ exposure confers resistance to anti-Programmed cell death protein 1 (α-PD-1) therapy. We identified consistent upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in both chronic IFNγ-treated cancer cells and patient melanoma with elevated IFNG expression. Knockdown or pharmacological inhibition of PARP14 increased effector T cell infiltration into tumors derived from cells pre-treated with IFNγ and decreased the presence of regulatory T cells, leading to restoration of α-PD-1 sensitivity. Finally, we determined that tumors which spontaneously relapsed following α-PD-1 therapy could be re-sensitized upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.

Citation Format: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Kleita Sergiou, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Brian A. Telfer, Daniel J. Wilcock, Michael P. Smith, Kaiko Kunii, Nicholas R. Perl, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. Hurlstone. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 625.
Abstract 6288: Discovery and characterization of potent, selective CBP degraders
Authors: La Bonte Laura , Sappal Darshan
Published: June 2023

CREB binding protein (CBP) and E1A binding protein (p300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in a variety of cancers. Due to the high homology between CBP and p300, identification of selective chemical matter that specifically and directly targets CBP has proven challenging. Here, we describe a potent, highly selective CBP heterobifunctional degrader with selective biological activity in CBP dependent cancer lines.

Citation Format: Laura La Bonte, Darshan Sappal. Discovery and characterization of potent, selective CBP degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6288.
Abstract 6301: Post-translational modifications regulate sensitivity to Polatuzumab Vedotin in DLBCL
Authors: Corcoran Sean R. , Staudt Louis M. , Hodson Daniel
Published: June 2023

Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive malignancy of which one-third of diagnosed patients ultimately relapse and die. New treatment paradigms for relapsed-refractory patients are needed. Most DLBCL tumors are reliant on signaling through their cell surface B-cell receptor (BCR) mediated by ITAMs on CD79A and CD79B to drive anti-apoptotic NF-kB and PI3 kinase signaling. In order to understand how surface BCR is regulated, we performed whole genome CRISPR screens in 9 DLBCL cell lines in which we sorted for high and low surface CD79B or added the CD79B targeted antibody-drug conjugate Polatuzumab-Vedotin (POLA-V). Strikingly, independent of genetic or cell of origin subtype, sgRNAs encoding the entire N-linked glycosylation pathway and specific sugar modification by addition of galactose and sialic acid were found to be enriched in high CD79B fractions and depleted in POLA-V treated samples compared to control. Further testing showed that removing sialic acid by treating with a small molecule inhibitor of sialic acid, genetic perturbation of golgi sugar transporters SLC35A1 and SLC35A2, or the a2,6 sialyltransferase ST6GAL1 resulted in more surface CD79B antibody binding with no significant change in CD79B protein abundance. The specificity of the effect of sialic acid loss on POLA antibody binding was confirmed by removing cell surface sialic acid with exogenous sialidase and observing increased binding of POLA, but not other therapeutic antibodies like Rituximab or CD19 FMC-63. Loss of SLC35A1, SLC35A2, and ST6GAL1 synergized with POLA-V but not the drug conjugate MMAE alone, showing a BCR dependent mechanism of sialic acid loss on POLA-V sensitization. In a further cell of origin subtype analysis of the germinal center B-cell (GCB) DLBCL cell lines, loss of the E3 ligase KLHL6 was found to synergize with POLA-V. Importantly, KLHL6 is heavily mutated across all germinal center derived malignancies, is more highly expressed in germinal center B-cells than other members of the B-cell lineage, and plays an unknown role in the development of autoimmune diseases. Further work will give evidence for the target of KLHL6 mediated ubiquitination and will show how this gene can drive lymphoma and autoimmune disease development in the germinal center.

Citation Format: Sean R. Corcoran, Louis M. Staudt, Daniel Hodson. Post-translational modifications regulate sensitivity to Polatuzumab Vedotin in DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6301.
Abstract 6430: Single-cell transcriptomic and epigenomic landscapes of innate and adaptive immune cells in metastatic melanoma treated with immunotherapy
Authors: Yang Jiekun , Fu Doris , Galani Kyriakitsa , Ho Li-Lun , Robitschek Emily J. , Frederick Dennie T. , Yadav Sandeep K. , Deng Wentao , Singh Anand K. , Burke Kelly P. , Wang Cassia , Sharova Tatyana , Liu David , Rai Kunal , Boland Genevieve M. , Kellis Manolis
Published: June 2023

Immune checkpoint inhibitors (ICIs) have revolutionized the care for cancer and extended survival for advanced cancer patients. While ICIs have shown astonishing clinical benefits, less than 50% of patients experience a durable response. To find better biomarkers for ICI response and understand the diverse cellular players in the tumor microenvironment (TME), we performed single-cell RNA sequencing (scRNA; 222,351 cells; 39 samples), single-nucleus transposase-accessible chromatin sequencing (scATAC; 45,478 cells; 15 samples), and bulk RNA sequencing (39 samples) on a metastatic melanoma cohort with rich phenotypic and molecular data. In ICI resistant tumors, we revealed how cell-adhesion and ribosomal activity changes in adaptive immune cells can reflect tumor-level therapeutic failure. We characterized T cell diversity in the TME and discovered an early activated state and a terminally exhausted state. Among the innate immune cells, we detected a mature dendritic cell (DC) state as a strong prognostic predictor of progression-free survival associated with ICI treatment. We studied its differentiation trajectory, transcriptome signatures, epigenome landscape and interactome with T-cells, in comparison to conventional dendritic cell types 1 and 2. We also showed that CRISPR deactivation of the enhancers induced by the mature DC state compromised DCs’ antigen-presentation capabilities and their interactions with antigen-specific T-cells. Lastly, we identified genes and functional modules associated with ICI response (e.g. cell-adhesion) and resistance (e.g. oxidative phosphorylation). Given their functional roles in strengthening immune response to cancer, the molecular and cellular mediators discovered here can help predict ICI regimen efficacy, guide therapeutic development and drug combinations, and pave the path to targeted therapies with long-term effects and new immunotherapies.

Citation Format: Jiekun Yang, Doris Fu, Kyriakitsa Galani, Li-Lun Ho, Emily J. Robitschek, Dennie T. Frederick, Sandeep K. Yadav, Wentao Deng, Anand K. Singh, Kelly P. Burke, Cassia Wang, Tatyana Sharova, David Liu, Kunal Rai, Genevieve M. Boland, Manolis Kellis. Single-cell transcriptomic and epigenomic landscapes of innate and adaptive immune cells in metastatic melanoma treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6430.
Supplementary Data S8 from Optimizing precision medicine for breast cancer brain metastases with functional drug response assessment.
Authors: Morikawa Aki , Li Jinju , Ulintz Peter , Cheng Xu , Apfel Athena , Robinson Dan , Hopkins Alex , Kumar-Sinha Chandan , Wu Yi-Mi , Serhan Habib , Verbal Kait , Thomas Dafydd , Hayes Dan , Chinnaiyan Arul M. , Baladandayuthapani Veerabhadran , Heth Jason , Soellner Matthew B , Merajver Sofia Diana , Merrill Nathan
Published: June 2023

DSS3 values for chemotherapies commonly used in breast cancer treatment
Supplementary Data S7 from Optimizing precision medicine for breast cancer brain metastases with functional drug response assessment.
Authors: Morikawa Aki , Li Jinju , Ulintz Peter , Cheng Xu , Apfel Athena , Robinson Dan , Hopkins Alex , Kumar-Sinha Chandan , Wu Yi-Mi , Serhan Habib , Verbal Kait , Thomas Dafydd , Hayes Dan , Chinnaiyan Arul M. , Baladandayuthapani Veerabhadran , Heth Jason , Soellner Matthew B , Merajver Sofia Diana , Merrill Nathan
Published: June 2023

PDX molecular profiling
Data from Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma
Authors: Nisnboym Michal , Vincze Sarah R. , Xiong Zujian , Sneiderman Chaim T. , Raphael Rebecca A. , Li Bo , Jaswal Ambika P. , Sever ReidAnn E. , Day Kathryn E. , LaToche Joseph D. , Foley Lesley M. , Karimi Hanieh , Hitchens T. Kevin , Agnihotri Sameer , Hu Baoli , Rajasundaram Dhivyaa , Anderson Carolyn J. , Blumenthal Deborah T. , Pearce Thomas M. , Uttam Shikhar , Nedrow Jessie R. , Panigrahy Ashok , Pollack Ian F. , Lieberman Frank S. , Drappatz Jan , Raphael Itay , Edwards Wilson B. , Kohanbash Gary
Published: June 2023

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM.
Significance:
Immunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM.
Orbital Apex Syndrome With Encephalitis: A Rare and Serious Complication of Herpes Zoster Ophthalmicus
Authors: Melino Ludwig , Setiohadji Bambang , Kartika Antonia , Sari Rusti Hanindya , Ginting Dianita Veulina , Yollamanda Prettyla
Published: June 2023

Introduction: Herpes zoster reactivation is more common in the elderly population. Although ocular complications are seen in 20-70% of patients with herpes zoster ophthalmicus, orbital apex syndrome is a rare case. Encephalitis is also a rare neurologic complication of HZO. Purpose: To report a Herpes Zoster Ophthalmicus (HZO)case with rare neurologic complication that ophthalmologist should be aware of. Case Presentation: A 68-year-old man had a chief complaint of a sudden blurred vision in right eye two days before admission, followed by rash and pain on the right upper eyelid and forehead. Visual acuity was hand movement on the right eye and 0.5 on the left eye. The patient had total ophthalmoplegia and total ptosis on his right eye, reverse relative afferent pupillary defect on his left eye and right peripheral facial nerve palsy. Optic discs were found to be normal on both eyes. The patient was diagnosed as orbital apex syndrome on his right eye associated HZO and right peripheral facial nerve palsy. The patient received oral acyclovir 800 mg five times/day and intravenous methylprednisolone 250 mg four times/day for three days. After four days of admission, the patient had a seizure and loss of his consciousness. The patient was consulted to neurology department and was given anticonvulsant therapy. The spinal tap revealed pleocytosis and increased protein. The patient was diagnosed as herpes zoster encephalitis. After one week, the patient regained full consciousness and his visual acuity was improved to 0.16 on the right eye. Color vision, visual field, and contrast sensitivity were also improved, ophthalmoplegia were partially resolved and peripheral facial nerve palsy was fully resolved. Conclusion: Herpes Zoster Ophthalmicus affect the central and peripheral nervous system at the same time and can be life-threatening with delayed diagnosis and treatment. It may be necessary to collaborate with the neurology department for every HZO case to minimize the life-threatening complications of HZO.
The Role of Diabetic Retinopathy Pathogenesis in Diabetic Retinopathy Therapy
Authors: Priatna Anisha Sefina , Virgana Rova
Published: June 2023

Introduction: The estimation of diabetes mellitus (DM) patients nowadays are 486 million people. Diabetic retinopathy (DR) serves as one of the most common microvascular disease complications. About 2,6 million people with DM are suffered from visual disturbance. The pathogenesis of DR consists of several mechanisms. These mechanisms are the basics of the DR standard therapies. This review is conducted to observe the pathogenesis of diabetic retinopathy related to the treatment that existed through current literature Methods: An online literature search was conducted in PubMed for relevant publications between 2011 and 2021 by combining the following search terms: retina, diabetic retinopathy, pathogenesis, hyperglycemia, oxidative stress, and management. Results: Retinal neurodegeneration consists of several steps that cause ROS elevation. Retinal microvasculopathy causes increase microvasculature. Chronic inflammation cause progressive damage to the retina. Based on diabetic retinopathy pathogenesis, the therapy includes pharmacological and nonpharmacological treatment. Pharmacological treatment aims to reduce blood glucose and progress through anti-VEGF and anti-inflammatory drugs. Non-pharmacological treatment is the option to treat severe DR and acts as conjunctive therapy towards pharmacological therapy. Conclusions: Based on the current literature, it can be concluded that the pathogenesis of diabetic retinopathy plays an important role in the DR therapy that already existed, especially in the micovasculopathy and inflammation stage.
A CASE SERIES OF ACUTE POSTOPERATIVE ENDOPHTHALMITIS: MANAGEMENT AND OUTCOMES
Authors: Gunanegara Abdi Sastra , Pramita Ida Ayu Ary , Juliari I Gusti Ayu Made , Susila Ni Ketut Niti , Kusumadjaja I Made Agus
Published: June 2023

Background: Endophthalmitis is one of the rare and most devastating complications of intraocular surgery. Although the prevalence of post-cataract surgery endophthalmitis is very small, it has become an important eye health problem. Case Presentation: Six patients, 5 male and 1 female, were diagnosed with post-phacoemulsification endophthalmitis on the same day. Four patients had a visual acuity of 1/300, and two patients had 6/60. All patients underwent intravitreal injection of vancomycin-ceftazidime, and culture samples were taken from the vitreous tap and AC tap. Five patients were planned to undergo pars plana vitrectomy. Intravitreal injection of triamcinolone acetonite was performed on 1 patient, due to macular oedem. Brevundimonas diminuta was found from 1 patient and Stenotrophomonas maltophilia from 1 patient. Final visual acuity in 4 patients was > 6/30, and 3/60 in 1 patient. Discussion: Management must be carried out immediately, once there is a suspicion of acute postoperative endophthalmitis. All patients had intravitreous injection of vancomycin-ceftazidime. Pars plana vitrectomy was performed on 5 patients with 80% having final visual acuity > 6/30. Intravitreal injection of antibiotics followed by pars plana vitrectomy can provide a good prognosis for final visual acuity, although various factors predispose to poorer prognosis. Conclusion: Intravitreal injection of antibiotics and pars plana vitrectomy is a treatment for acute postoperative endophthalmitis, where this action will provide a good prognosis for the patient's final visual acuity if done immediately.
The Right to Exclude and the Duty to Include: Self-determination, Equal Opportunity, and Immigration
Authors: Kollar Eszter , Banai Ayelet
Published: June 2023

The immigration debate in political theory has produced a series of accounts that justify the state’s right to exclude potential immigrants, where the right of self-determination figures prominently. We challenge two prominent accounts of the self-determination-based right to exclude and defend a circumscribed right to exclude and a corollary duty to admit immigrants, based on our ‘people relationship goods’ account of self-determination. Our conception reconciles the moral claims of global opportunity migrants with the well-being and non-alienation interests of the locals. It therefore provides a principled answer to the philosophical question underlying pressing political conflicts today, namely what is the permissible scope of exclusion by self-determining political communities, in light of weighty global moral demands of inclusion.
The Quadrupole Precipitation Pattern over Eastern China and Its Associated Atmospheric Circulations and Ocean Conditions
Authors: Liu Yuting , Huang Danqing , Zhu Jian , Cheng Chad Shouquan
Published: June 2023

The diversity of summer precipitation regimes over eastern China has raised concerns. Its variations during different warming periods and the relevant mechanisms remain unclear. In this study, the decadal precipitation changes and the associated atmospheric circulations, ocean conditions, and warming over Northern Hemisphere were investigated. The results indicated a quadrupole precipitation pattern over eastern China in the boreal summer, with a significant shift around 1998. From 1985–98 to 1999–2014, two wet anomalies were over North China (NC) and South China (SC), while two dry anomalies were over the Yangtze–Huaihe River basin (YHRB) and northeastern China (NEC). This quadrupole pattern is associated with the circumglobal teleconnection (CGT), the negative phase of the interdecadal Pacific oscillation (“−IPO”), the warming over the high latitudes of North Atlantic (“+HNA”), and the warming rate over the Northern Hemisphere (NWR). The CGT would induce the weakened polar front jet (PJ), southward shift of the PJ, and northward shift of the entire subtropical jet (SJ), which decreased the meridional distance between the PJ and SJ, and therefore resulted in the NC-wet–YHRB-dry–SC-wet variation. As well, the dry NEC was attributed to the enhanced PJ, weakened Iranian Plateau subtropical jet (IPSJ), and northward movement of the PJ and Tibetan Plateau subtropical jet (TPSJ), which were accompanied by −IPO and +HNA. Moreover, the NWR led to the weakened PJ and SJ, as well as the southward shift of PJ, also contributed to the dry YHRB, and wet anomalies over NC and SC. Particularly, the +HNA plays an important role in this quadrupole precipitation variation. Our findings have highlighted the role of jet streams in complex precipitation patterns, which will contribute to understanding the diverse variations in precipitation regimes over eastern China under global warming.

Significance Statement

The purpose of this study is to understand the regime shifts of the East Asian summer monsoon precipitation in different warming periods. We revealed a new precipitation pattern over eastern China as a “+ − + −” precipitation pattern from south to north. The circumglobal teleconnection, the negative phase of the interdecadal Pacific oscillation, the warming over the high-latitude North Atlantic, and the warming over Northern Hemisphere can be used to explain the quadrupole precipitation pattern. These findings could highlight the role of jet streams linking the quadrupole pattern to the teleconnections, dominant decadal ocean variabilities and the warming over Northern Hemisphere. Future work will focus on the role of Arctic rapid warming in summer precipitation over eastern China.
Disentangling Dynamic from Thermodynamic Summer Ice Area Loss from Observations (1979–2021): A Potential Mechanism for a “First-Time” Ice-Free Arctic
Authors: Le Guern-Lepage Alice , Tremblay Bruno L.
Published: June 2023

In recent decades, the Arctic minimum sea ice extent has transitioned from a predominantly thick multiyear ice cover to a thinner seasonal ice cover. We partition the total (observed) Arctic summer area loss into thermodynamic and dynamic (convergence, ridging, and export) sea ice area loss during the satellite era from 1979 to 2021 using a Lagrangian sea ice tracking model driven by satellite-derived sea ice velocities. Results show that the thermodynamic signal dominates the total summer ice area loss and the dynamic signal remains small (∼20%) even in 2007 when dynamic loss was largest. Sea ice loss by compaction (within pack ice convergence) dominates the dynamic area loss, even in years when the export is largest. Results from a simple (Ekman) free-drift sea ice model, supported by results from the Lagrangian model, suggest that nonlinear effects between dynamic and thermodynamic area loss can be important for large negative anomalies in sea ice extent, in accord with previous modeling studies. A detailed analysis of two all-time record minimum years (2007 and 2012)—one with a semipermanent high in the southern Beaufort Sea and the other with a short-lived but extreme storm in the Pacific sector of the Arctic in late summer—shows that compaction by Ekman convergence together with large thermodynamic melt in the marginal ice zone dominated the sea ice area loss in 2007 whereas, in 2012, it was dominated by Ekman divergence amplified by sea–ice albedo feedback—together with an early melt onset. We argue that Ekman divergence from more intense summer storms when the sun is high above the horizon is a more likely mechanism for a “first-time” ice-free Arctic.
Outer Size Distribution of Landfalling Tropical Cyclones over China Changes in the Recent Decades
Authors: Shen Zheng-Qin , Nie Gao-Zhen , Qiu Xin , Gu Jian-Feng , Zhang Yi
Published: June 2023

This study examines the changes in the outer size distribution of landfalling tropical cyclones (TCs) over the Chinese mainland from 1977 to 2020. The period was divided into two epochs: 1977–98 and 1999–2020. The results show that the size distribution of landfalling TCs over South China has no apparent change, while that of landfalling TCs over East China (LTCEC) is narrower in the second epoch, and the difference in the median sizes between East China and South China become more significant. Furthermore, it is found that LTCEC formed over the western part of the western North Pacific (W-WNP) shifted to a larger size range (300–500 km) at landfall, while those formed over the eastern part of the western North Pacific (E-WNP) rarely grew to extremely large size (>500 km). Further investigation revealed that over the W-WNP, the genesis position of LTCEC migrated equatorward during the second epoch, leading to a longer TC lifetime before landfall. Also, the increase of background relative vorticity and moisture associated with the southward migration is conducive to larger initial vortices. For TCs originating from the E-WNP, the change in the active area of TC passages reduced the frequency of TCs affecting the Chinese coast. Moreover, the growth of TC size during the intensification stage was significantly suppressed, lowering the occurrence probability of extremely large TCs. Changes in the large-scale thermodynamic environments between the two epochs were explored. Increased static stability and decreased convective available potential energy are possible factors limiting TC size increase.
A Deep Learning–Based Approach for Empirical Modeling of Single-Point Wave Spectra in Open Oceans
Authors: Song Yuhao , Jiang Haoyu
Published: June 2023

Directional wave spectra are of importance for numerous practical applications such as seafaring and ocean engineering. The wave spectral densities at a certain point in the open ocean are significantly correlated to the local wind field and historical remote wind field. This feature can be used to predict the wave spectrum at that point using the wind field. In this study, a convolutional neural network (CNN) model was established to estimate wave spectra at a target point using the wind field from the ERA5 dataset. A geospatial range where the wind could impact the target point was selected, and then the historical wind field data within the range were analyzed to extract the nonlinear quantitative relationships between wind fields and wave spectra. For the spectral densities at a given direction, the wind data along the direction where waves come from were used as the input of the CNN. The model was trained to minimize the mean square error between the CNN-predicted and ERA5 reanalysis spectral density. The data structure of the wind input is reorganized into a polar grid centered on the target point to make the model applicable to different open-ocean locations worldwide. The results show that the model can predict well the wave spectrum shapes and integral wave parameters. The model allows for the prediction of single-point wave spectra in the open ocean with low computational cost and can be helpful for the study of spectral wave climate.

Significance Statement

The directional wave spectra (DWS) describe the distribution of wave energy among different frequencies and directions. They are useful for many marine practical applications. Usually, DWS are modeled using numerical wave models (NWMs) based on wave action balance differential equations. Although contemporary NWMs perform well after years of development, their computational costs are relatively high. The fast-developed artificial intelligence (AI) might provide an alternative solution to this task. In this study, convolutional neural networks are used to model the DWS at some selected points in the open ocean. By “learning” from NWM data, AI can effectively simulate single-point DWS in open oceans with low computational cost, which can serve as a faster data-driven surrogate model in related applications.