bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Lithiophilic Substrates on Lithium Metal Batteries at Low Temperature
Authors: Kim Kangwoon , Li Mingqian , Kim Taehee , Yin Yijie , Cai Guorui , Holoubek John , Chen Zheng
Published: December 2022

Lithium metal batteries (LMBs) are an emerging technology that promises to provide high energy density that could compensate for the energy loss of lithium-ion batteries (LIBs) at low temperatures. However, tip-driven growth during lithium deposition remains a problem for LMBs at low temperatures, which should be mitigated for improved cyclability and safety. Tailoring lithium metal nucleation with lithiophilic substrates has shown effectiveness in improving cycling performance at room temperature, but the investigation at low temperatures is limited. For this work, promoting homogeneous lithium nucleation by implementing a lithiophilic substrate, lithiated graphite (LiC6), the adverse effects of low temperature on Li cycling were alleviated in a model electrolyte. This lithiated graphite substrate provided 4.2% and 4.5% higher measured coulombic efficiency for Li cycling compared to copper at −20 °C and −40 °C, respectively, which demonstrated higher specific capacity and improved cyclability for 2× excess Li||Ni0.6M0.2C0.2O2 full cells.
Review–Modern Data Analysis in Gas Sensors
Authors: Sagar Md. Samiul Islam , Allison Noah Riley , Jalajamony Harikrishnan Muraleedharan , Fernandez Renny Edwin , Sekhar Praveen Kumar
Published: December 2022

Development in the field of gas sensors has witnessed exponential growth with multitude of applications. The diverse applications have led to unexpected challenges. Recent advances in data science have addressed the challenges such as selectivity, drift, aging, limit of detection, and response time. The incorporation of modern data analysis including machine learning techniques have enabled a self-sustaining gas sensing infrastructure without human intervention. This article provides a birds-eye view on data enabled technologies in the realm of gas sensors. While elaborating the prior developments in gas sensing related data analysis, this article is poised to be an entrant for enthusiast in the domain of data science and gas sensors.
Long-term cardiovascular health status and physical functioning of nonhospitalized patients with COVID-19 compared with non-COVID-19 controls
Authors: van der Sluijs Koen M. , Bakker Esmée A. , Schuijt Tim J. , Joseph Jayaraj , Kavousi Maryam , Geersing Geert-Jan , Rutten Frans H. , Hartman Yvonne A. W. , Thijssen Dick H. J. , Eijsvogels Thijs M. H.
Published: December 2022

We examined cardiovascular and physical functioning outcomes in nonhospitalized patients with COVID-19, at a median of 6 mo postinfection. When compared with matched controls, minor differences in physical functioning were found, but objective measures of cardiovascular risk and arterial stiffness did not differ between groups. However, one in three former patients with COVID-19 reported residual symptoms, notably fatigue. Follow-up studies should investigate the origins of residual symptoms and their long-term consequences in former, nonhospitalized patients with COVID-19.
Regulation of cerebrovascular compliance compared with forearm vascular compliance in humans: a pharmacological study
Authors: Moir M. Erin , Klassen Stephen A. , Zamir Mair , Hamner J. W. , Tan Can Ozan , Shoemaker J. Kevin
Published: December 2022

Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.
Dichotomous effects of in vivo and in vitro ionizing radiation exposure on lymphatic function
Authors: Singh Reetu , Heaps Cristine L. , Muthuchamy Mariappan , Deveau Michael A. , Stewart Randolph H. , Laine Glen A. , Dongaonkar Ranjeet M.
Published: December 2022

Earlier studies leading to the common belief that lymphatic vessels are radioresistant either did not characterize lymphatic pumping, deemed necessary for the resolution of edema and inflammation, or did it in vivo. By characterizing pumping in vitro, the present study, for the first time, demonstrated that lymphatic pumping was impaired in vessels irradiated in vivo and enhanced in vessels irradiated in vitro. Furthermore, the pathways implicated in ionizing radiation-induced blood vessel damage did not mediate lymphatic responses.
Assessing systolic and diastolic reserves in male and female mice
Authors: Coyle-Asbil B. , Holjak E. J. B. , Marrow J. P. , Alshamali R. , Ogilvie L. M. , Edgett B. A. , Hopkinson L. D. , Brunt K. R. , Simpson J. A.
Published: December 2022

Cardiac reserve is a globally used health indicator and prognostic tool that is used by clinicians and preclinical scientists. In physiology, we have a long-standing appreciation of how to assess systolic reserve but lack insight into sex differences and have no frame of reference for measuring diastolic reserve to certainty across cardiac techniques or the influence of sex. Here, we show that the primary means for assessing diastolic reserve is incorrect. Furthermore, we provided proof and clarity on how to correctly measure systolic and diastolic reserve capacities. We also highlight the imperative of sex differences to the measures of both systolic and diastolic reserves using several techniques (i.e., echocardiography, invasive hemodynamics, and Langendorff) in mice.
Lymphatic/blood vessel plasticity: motivation for a future research area based on present and past observations
Authors: Lampejo Arinola O. , Ghavimi Soheila Ali Akbari , Hägerling René , Agarwal Shailesh , Murfee Walter L.
Published: December 2022

The lymphatic system plays a significant role in homeostasis and drainage of excess fluid back into venous circulation. Lymphatics are also associated with a number of diseases including lymphedema, tumor metastasis, and various lymphatic malformations. Emerging evidence suggests that lymphatics might have a bigger connection to the blood vascular system than originally presumed. As these two systems are often studied in isolation, several knowledge gaps exist surrounding what constitutes lymphatic vascular plasticity, under what conditions it arises, and where structures characteristic of plasticity can form. The objective of this review is to overview current structural, cell lineage-based, and cell identity-based evidence for lymphatic plasticity. These examples of plasticity will then be considered in the context of potential clinical and surgical implications of this evolving research area. This review details our current understanding of lymphatic plasticity, highlights key unanswered questions in the field, and motivates future research aimed at clarifying the role and therapeutic potential of lymphatic plasticity in disease.
Framework for Bidirectional Knowledge-Based Maintenance of Wind Turbines
Authors: Vives Javier , Palaci Juan , Heart Janverly
Published: December 2022

Artificial intelligence (AI) techniques, such as machine learning (ML), are being developed and applied for the monitoring, tracking, and fault diagnosis of wind turbines. Current prediction systems are largely limited by their inherent disadvantages for wind turbines. For example, frequency or vibration analysis simulations at a part scale require a great deal of computational power and take considerable time, an aspect that can be essential and expensive in the case of a breakdown, especially if it is offshore. An integrated digital framework for wind turbine maintenance is proposed in this study. With this framework, predictions can be made both forward and backward, breaking down barriers between process variables and key attributes. Prediction accuracy in both directions is enhanced by process knowledge. An analysis of the complicated relationships between process parameters and process attributes is demonstrated in a case study based on a wind turbine prototype. Due to the harsh environments in which wind turbines operate, the proposed method should be very useful for supervising and diagnosing faults.
Long-Term Adherence and Persistence to Low-Dose Aspirin for the Prevention of Cardiovascular Disease: A Population-Based Cohort Study
Authors: Vora Pareen , Soriano-Gabarró Montse , Russell Beth , Morgan Stewart Henry
Published: December 2022

Background and Aim. Adherence and persistence to low-dose aspirin are key to maximising its cardiovascular benefits in patients with a history of cardiovascular disease (CVD) or those at high CVD risk; however, few studies have provided population-based estimates of its long-term (>2–3 years) use. We aimed to determine long-term (up to 10 years) adherence and persistence to low-dose aspirin for primary/secondary prevention of CVD. Methods. Using information from electronic health records in Germany and the United Kingdom (UK) in a common data model, we followed adults with ≥2 low-dose aspirin prescriptions (75–100 mg) during 2007–2018 for up to 10 years. Included individuals had no low-dose aspirin prescriptions in the year before the follow-up started (date of first low-dose aspirin prescription) and ≥12 months’ observation. Adherence was determined using the medication possession ratio (MPR), and persistence was defined as continuous treatment disregarding gaps between prescriptions of <60 days; analyses were undertaken according to indication (primary/secondary CVD prevention). Results. We identified 144,717 low-dose aspirin users from Germany and 190,907 from the UK. Among patients with 5–10 years’ follow-up, median adherence among secondary CVD prevention users was 60% in Germany and 75% in the UK. Among primary prevention users, median adherence was 50% for both countries. Persistence among secondary CVD prevention users was 58.3% at 2 years, 47.0% at 5 years, 35.2% at 10 years (Germany), and 67.5% at 2 years, 58.0% at 5 years, and 46.8% at 10 years (UK). Among primary CVD prevention users, persistence was 52.8% at 2 years, 41.6% at 5 years, 32.1% at 10 years (Germany), 56.3% at 2 years, 45.4% at 5 years, and 33.8% at 10 years (UK). Conclusions. Long-term adherence and persistence to low-dose aspirin are suboptimal; efforts for improvement could translate into a lower CVD burden in the general population.
Modeling and Optimal Control Analysis for Malaria Transmission with Role of Climate Variability
Authors: Keno Temesgen Duressa , Dano Lemessa Bedjisa , Makinde Oluwole Daniel
Published: December 2022

In this paper, we present a nonlinear deterministic mathematical model for malaria transmission dynamics incorporating climatic variability as a factor. First, we showed the limited region and nonnegativity of the solution, which demonstrate that the model is biologically relevant and mathematically well-posed. Furthermore, the fundamental reproduction number was determined using the next-generation matrix approach, and the sensitivity of model parameters was investigated to determine the most affecting parameter. The Jacobian matrix and the Lyapunov function are used to illustrate the local and global stability of the equilibrium locations. If the fundamental reproduction number is smaller than one, a disease-free equilibrium point is both locally and globally asymptotically stable, but endemic equilibrium occurs otherwise. The model exhibits forward and backward bifurcation. Moreover, we applied the optimal control theory to describe the optimal control model that incorporates three controls, namely, using treated bed net, treatment of infected with antimalaria drugs, and indoor residual spraying strategy. The Pontryagin’s maximum principle is introduced to obtain the necessary condition for the optimal control problem. Finally, the numerical simulation of optimality system and cost-effectiveness analysis reveals that the combination of treated bed net and treatment is the most optimal and least-cost strategy to minimize the malaria.
A Time and Place for Inhibiting Autophagy
Authors: Gan Boyi
Published: December 2022

Autophagy is an attractive therapeutic target in cancer. Successful autophagy-focused clinical intervention will require a detailed understanding of when and where autophagy is important during tumorigenesis. In this issue of Cancer Research, Khayati and colleagues use state-of-the-art genetically engineered mouse models to demonstrate that transient systemic inhibition of autophagy can irreversibly impair the growth of established lung tumors with a good tolerability in normal tissues, suggesting a therapeutic strategy for cancer treatment.

See related article by Khayati et al., p. 4429
Discovery of STRO-002, a Novel Homogeneous ADC Targeting Folate Receptor Alpha, for the Treatment of Ovarian and Endometrial Cancers
Authors: Li Xiaofan , Zhou Sihong , Abrahams Cristina L. , Krimm Stellanie , Smith Jennifer , Bajjuri Krishna , Stephenson Heather T. , Henningsen Robert , Hanson Jeffrey , Heibeck Tyler H. , Calarese Daniel , Tran Cuong , Yin Gang , Stafford Ryan L. , Yam Alice Y. , Kline Toni , De Almeida Venita I. , Sato Aaron K. , Lupher Mark , Bedard Kristin , Hallam Trevor J.
Published: December 2022

STRO-002 is a novel homogeneous folate receptor alpha (FolRα) targeting antibody–drug conjugate (ADC) currently being investigated in the clinic as a treatment for ovarian and endometrial cancers. Here, we describe the discovery, optimization, and antitumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the nonnatural amino acid para-azidomethyl-L-phenylalanine incorporated at specific positions within a high affinity anti-FolRα antibody using Sutro's XpressCF+, which resulted in a homogeneous ADC with a drug–antibody ratio (DAR) of 4. STRO-002 binds to FolRα with high affinity, internalizes rapidly into target positive cells, and releases the tubulin-targeting cytotoxin 3-aminophenyl hemiasterlin (SC209). SC209 has reduced potential for drug efflux via P-glycoprotein 1 drug pump compared with other tubulin-targeting payloads. While STRO-002 lacks nonspecific cytotoxicity toward FolRα-negative cell lines, bystander killing of target negative cells was observed when cocultured with target positive cells. STRO-002 is stable in circulation with no change in DAR for up to 21 days and has a half-life of 6.4 days in mice. A single dose of STRO-002 induced significant tumor growth inhibition in FolRα-expressing xenograft models and patient-derived xenograft models. In addition, combination treatment with carboplatin or Avastin further increased STRO-002 efficacy in xenograft models. The potent and specific preclinical efficacy of STRO-002 supports clinical development of STRO-002 for treating patients with FolRα-expressing cancers, including ovarian, endometrial, and non–small cell lung cancer. Phase I dose escalation for STRO-002 is in progress in ovarian cancer and endometrial cancer patients (NCT03748186 and NCT05200364).
Abstract A022: A field survey of histone PTM antibodies in epigenomic mapping approaches reveals widespread liabilities: Best practices and resources for reliable epigenetic studies
Authors: Johnstone Andrea L. , Maryanski Danielle N. , Rodriguez Keli L. , Weinzapfel Ellen N. , Venters Bryan J. , Novitzky Katherine , Marunde Matthew R. , Lin Carolina P. , Keogh Michael-Christopher
Published: December 2022

Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has long been suspected that the poorly understood capability of ‘PTM-specific’ antibodies (i.e., their specificity and efficiency) is a prime driver of the reproducibility crisis in biomedical research. Here we confirm the validity of this concern as it applies to epigenomic mapping studies. Extensive spike-in panels of PTM-defined DNA-barcoded nucleosome standards show that >70% of >500 commercial antibodies (and >80% of the most highly cited) to >50 histone lysine methyl and acyl states have failing performance in ChIP (>20% cross reactivity/<5% target recovery; www.ChromatinAntibodies.com). Variable lot behavior (of both polyclonals and monoclonals) shows the danger of focusing on catalog numbers without considering the inherent variability of biological reagents. Ultimately, these studies support the inclusion of in situ standards to control genomic mapping assays as an improved path out of this morass. Despite these advances, the application of ChIP-seq for cancer research has been hampered by its requirement for high cell inputs and low reliability. The recent development of immunotethering assays, such as Cleavage Under Targets and Release Using Nuclease (CUT&RUN), deliver high signal-to-noise mapping data using a fraction of the required cells compared to ChIP-seq. These innovations enable the application of epigenomics for cancer research, particularly for primary cells, sorted populations, and clinical samples where cell numbers are limited. By adapting our nucleosome spike-in control approach for CUT&RUN assays, we show that while the same antibody problems observed in ChIP-seq also pervade CUT&RUN, continuous use of spike-in controls improves assay rigor and reproducibility to realize the potential of CUT&RUN to advance cancer research.

Citation Format: Andrea L. Johnstone, Danielle N. Maryanski, Keli L. Rodriguez, Ellen N. Weinzapfel, Bryan J. Venters, Katherine Novitzky, Matthew R. Marunde, Carolina P. Lin, Michael-Christopher Keogh. A field survey of histone PTM antibodies in epigenomic mapping approaches reveals widespread liabilities: Best practices and resources for reliable epigenetic studies. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A022.
Abstract A024: PRC2 loss drives MPNST metastasis and matrix remodeling
Authors: Brockman Qierra R. , Scherer Amanda , McGivney Gavin R. , Gutierrez Wade R. , Voigt Andrew , Isaacson Alexandra , Laverty Emily A. , Roughton Grace , Knepper-Adrian Vickie , Darbro Benjamin , Tanas Munir R. , Stipp Christopher , Dodd Rebecca D.
Published: December 2022

Epigenetic reprogramming alters gene transcription in response to different cellular cues and can occur at both the DNA level as well as histone post-translational modifications. Polycomb repressive complex 2 (PRC2) is a common epigenetic modifier that is responsible for adding methyl groups to the twenty-seventh lysine of histone 3. This modification is associated with decreased gene transcription and recruits complexes that further compact chromatin. PRC2 mutations have been implicated in the tumorigenesis of many cancer types; however, the role that PRC2 plays in tumorigenesis is complex and not well understood. PRC2 loss-of-function mutations have been identified in malignant peripheral nerve sheath tumors (MPNST), an aggressive sarcoma. PRC2 mutations are found in the EED and SUZ12 subunits in 70-92% of tumors. There are currently no effective therapies for MPNSTs resulting in a poor prognosis for individuals with inoperable tumors. Using a CRISPR/Cas9 system to delete EED or SUZ12, we developed in vitro and in vivo models to further study the biology of PRC2 loss in MPNSTs. Our data suggests that loss of PRC2 subunits increases the expression of extra-cellular matrix (ECM) remodeling genes, promotes cell migration in vitro, and increases pulmonary metastasis in vivo. We also observed that loss of either EED or SUZ12 increases collagen handling and a clustering metastatic phenotype. Additionally, loss of H3K27me3 was correlated with increased ECM and ECM remodeling genes as well as metastasis and overall survival in patient RNA-seq and tumor microarray data, respectively. Further characterization of the underlying mechanisms of PRC2-dependent metastasis will allow us to better understand the role of PRC2 in MPNST biology and test novel therapies for these patients.

Citation Format: Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew Voigt, Alexandra Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher Stipp, Rebecca D. Dodd. PRC2 loss drives MPNST metastasis and matrix remodeling. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A024.
Abstract A027: Identification and role of mega-trans-factors in epithelial ovarian cancer
Authors: Jaiswal Sushil Kumar , Fedkenheuer Kevin , Elnitski Laura
Published: December 2022

Epithelial ovarian cancer (EOC) accounts for over 90% of ovarian cancer cases and results in 14,000 U.S. deaths annually. It is the leading cause of death attributed to gynecological cancers. Aside from recent scientific advances, the 5-year survival rate for late-stage invasive EOC has been near 30% for several decades. Our computational transcriptional regulatory analysis in low-grade serous ovarian cancers (LGSOCs) vs. high-grade serous ovarian cancers (HGSOCs) identified a master regulatory complex, Megatrans complex (MTC), the objective of this study is to identify role of MTC in ovarian cancer, never reported before. MTC is estrogen-responsive master regulatory complex containing a multitude of DNA-binding transcription factors (MTC_TFs), including ER-alpha, RAR-alpha, GATA3, AP2-gamma, STAT1, AP1, RUNX1, and FOXA1. Given that we found MTC gene targets are downregulated in HGSOC, and that some target genes are prognostic for poor patient survival, understanding the function of MTC and modulating its activity may improve prognostic outcomes for HGSOC patients. We hypothesize that different combinations of MTC_TFs produce distinct regulatory signatures in different grades of ovarian cancers. In the grade, PEO4, cell line, we have confirmed MTC formation using a gel filtration assay and identified the presence of MTC_TFs by western blot. We discovered tumor suppressor, PITX1, as a novel MTC_TF in ovarian cancer, not previously reported in a breast cancer MTC. Methylation analysis revealed PITX1 and ER-alpha binding to hypomethylated, but repressed promoters and ChIP-seq analysis revealed PITX1 co-occupying 98.8% of ER-alpha binding sites, suggesting a repressive role of PITX1 on ER-alpha regulated genes. We are performing additional ChIP-seq experiments of MTC_TFs in HGSOC and LGSOC cell lines to test whether the MTC_TF binding distinguishes their regulatory signatures. Our findings of a nuclear hormone-regulated MTC complex controlling the transcriptional landscape of ovarian cancer are expected to facilitate new breakthroughs in disease treatment.

Citation Format: Sushil Kumar Jaiswal, Kevin Fedkenheuer, Laura Elnitski. Identification and role of mega-trans-factors in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A027.
Abstract IA014: SWI/SNF complexes in development and disease
Authors: Gatchalian Jovylyn , Ahmed Nasiha , Loo Chin-San , Zheng Ye , Hargreaves Diana C.
Published: December 2022

The Hargreaves laboratory is focused on understanding the molecular mechanisms of SWI/SNF complex function in immune cell differentiation and response relating to cancer and inflammation. SWI/SNF complexes are broadly required for embryonic development and cellular differentiation. Mutations in SWI/SNF complex genes are observed in ~20% of human cancers and in a number of rare intellectual disability disorders. However, it remains unclear how SWI/SNF complexes mechanistically regulate cellular differentiation through complex targeting, engagement with transcription factors, and function in transcription. We approach these questions in immune cells by employing molecular and proteomic methods in conjunction with next-generation sequencing approaches with the ultimate goal of connecting the functions of specific SWI/SNF subunits to the regulation of specific gene networks important for inflammatory responses and immune cell differentiation. This approach has allowed us to reveal the role of the canonical BAF complex (cBAF) in the establishment and maintenance of epigenetic transitions that occur during cellular differentiation, including activation of cell type-specific enhancers and engagement of transcription factors. Further, we and others have identified a new variant, referred to as the noncanonical BAF (ncBAF) complex, which exhibits distinct modes of targeting, unique regulatory interactions, and specific function in inflammatory gene transcription (Ahmed, Gatchalian et al PNAS 2022). Following up on the identification of the ncBAF subunit Brd9 in a CRISPR genome wide screen for regulators of Foxp3 performed in collaboration with the Zheng lab at the Salk Institute, we performed sgRNA knockdown to identify the role of each of the three SWI/SNF complex variants (BAF, ncBAF, and PBAF) (Loo, Gatchalian et al Immunity 2020). We found that ncBAF positively regulates the expression of Foxp3, while PBAF complexes negatively regulate Foxp3. Using epigenomic and transcriptomic analysis in Tregs following knockdown or chemical degradation of BRD9, we found that BRD9 positively regulates Foxp3 expression and its target genes by stabilizing Foxp3 binding at BRD9/Foxp3 co-bound sites, including at the Foxp3 locus. In an MC38 colorectal cancer model, transfer of Brd9 deficient Tregs resulted in significantly slower tumor growth than control Tregs, with increased infiltration of IFN-γ producing CD8 and CD4 T cells, suggesting that Brd9 deletion in Tregs reduces Treg-mediated suppression of anti-tumor responses. Thus, these results highlight BRD9 and the ncBAF complex as novel targets that could be exploited to manipulate Treg function in cancer.

Citation Format: Jovylyn Gatchalian, Nasiha Ahmed, Chin-San Loo, Ye Zheng, Diana C. Hargreaves. SWI/SNF complexes in development and disease. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA014.
Abstract B008: UBXN2A targets Rictor-mTORC2 signaling pathway to inhibit colorectal cancer metastasis
Authors: Rezvani Khosrow S.
Published: December 2022

The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood in CRC. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic and pharmacological studies showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. UBXN2A induction in tumor organoids suppresses the mTORC2 pathway. These findings provide new insights into the functions of a ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.

Citation Format: Khosrow S. Rezvani. UBXN2A targets Rictor-mTORC2 signaling pathway to inhibit colorectal cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B008.
Abstract B031: The effects of tissue processing and microfluidic factors on single-cell RNA-sequencing data quality in colorectal tissues
Authors: Arceneaux Deronisha L. , Chen Zhengyi , Simmons Joey , Chen Bob , Heiser Cody , Xu Yanwen
Published: December 2022

Our HTAN (Human Tumor Atlas Network) study presented in Chen et al. documented single-cell RNA-sequencing (scRNA-seq) data on 128 human colonic specimens for mapping out distinct paths for polyp to cancer transformations. What we have not detailed is our optimizations on the droplet-based scRNA-seq approach that generate high quality data from challenging tissues such as the colonic epithelium. In this work, we provide a systematic dissection of tissue processing and microfluidic encapsulation factors that affect data quality generated on colonic epithelial cells using an open droplet-based scRNA-seq platform (inDrops). We optimized our process based on these factors to significantly decrease dying cell bodies and ambient RNA from being co-encapsulated with true cells, which led to the development of the current scRNA-seq protocol used for human specimens. We have also developed pre-filtering data metrics to score data quality stemming from degree of ambient contamination. We envision that these experimental optimizations reduce the amount of introduced artifacts, leading to more rigorous biological interpretations.

Citation Format: Deronisha L. Arceneaux, Zhengyi Chen, Joey Simmons, Bob Chen, Cody Heiser, Yanwen Xu. The effects of tissue processing and microfluidic factors on single-cell RNA-sequencing data quality in colorectal tissues [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B031.
Abstract IA010: Patient derived organoids in precision oncology
Authors: Valeri Nicola
Published: December 2022

Limits in the predictive power of molecular profiling and shortcomings of some pre-clinical models used in drug development represent important obstacles hampering the success of personalized medicine and drug discovery. LGR5+ stem cells can be isolated from a number of organs and propagated as epithelial organoids in vitro. Mouse and human organoids have been used to study the physiology and neoplastic transformation of the liver, pancreas, bowel and prostate among other organs. During my talk, I will highlight opportunities, limitations and potential clinical applications of patient-derived organoids in personalized oncology, emphasizing strengths and hurdles in the use of the organoid technology in forward and reverse translational cancer research. In particular, I will stress the importance of patient-derived organoids as pre-clinical tools to define mechanisms of drug resistance and to design novel drug combinations.

Citation Format: Nicola Valeri. Patient derived organoids in precision oncology [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA010.
Abstract IA014: Synthetic essentiality identifies TDO2 as a key target in APC-deficient CRC
Authors: Lee Rumi , Li Jiexi , Li Jun , Wu Chang-Jiun , Jiang Shan , Hsu Wen-Hao , Chakravarti Deepavali , Chen Peiwen , LaBella Kyle A. , Li Jing , Spring Denise J. , Zhao Di , Wang Y. Alan , DePinho Ronald A.
Published: December 2022

Loss of adenomatous polyposis coli (APC) is considered a critical initiating event in colorectal cancer (CRC), where it occurs in 90% of sporadic CRCs. APC deficiency results in activation of WNT; however, major hurdles persist to therapeutic intervention of this pathway. Here, the synthetic essentiality framework was used to discover other potential druggable vulnerabilities for APC-deficient cancers. Through this approach, tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient CRC. Upregulation of TDO2 activates the Kyn-AhR pathway, increasing glycolysis. Subsequent cancer cell growth and CXCL5 secretion leads to macrophage recruitment into the tumor microenvironment. APC-deficient CRC models were found to be susceptible to both TDO2 depletion and pharmacologic inhibition. Overall, this study identifies the TCF4-TDO2-AhR-CXCL5 axis as a critical pathway in the maintenance of APC-deficient CRC, informing potential genotype-specific therapeutic targets and the use of TDO2 inhibitors to combat this disease.

Citation Format: Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A. LaBella, Jing Li, Denise J. Spring, Di Zhao, Y. Alan Wang, Ronald A. DePinho. Synthetic essentiality identifies TDO2 as a key target in APC-deficient CRC [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA014.
Abstract IA028: Circulating tumor DNA in the management for colorectal cancer: Are we there yet?
Authors: Morris Van Karlyle
Published: December 2022

Assessment of circulating tumor DNA represents a highly specific and highly sensitive "liquid biopsy" methodology to detect the presence (or absence) of microscopic disease for patients with colorectal cancer. With performance of available circulating tumor DNA assays rapidly evolving, the clinical and scientific applications subsequently continue to expand. Data generated by circulating tumor DNA/liquid biopsies has translated into the clinical management of colorectal cancer as a prognostic biomarker forecasting disease recurrence after resection and also for quantitative and qualitative characterization of treatment response in patients with metastatic colorectal cancer. To date, evidence of utility of circulating tumor DNA as a predictive biomarker for systemic treatment remains missing and illustrates a critical gap in knowledge. To address this unmet need, currently assessment of patients' blood specimens can provide critical cancer-specific insight into the dynamics not only of the colorectal cancer genome but also of the epigenome and transcriptome. Clinical trials are evaluating circulating tumor DNA as a novel approach to identifying micrometastatic colorectal cancer as a biologically distinct pathology that differs from larger, clinically detectable disease, with the intention for development of unique, targeted approaches which may ultimately improve outcomes for patients with colorectal cancer.

Citation Format: Van Karlyle Morris. Circulating tumor DNA in the management for colorectal cancer: Are we there yet? [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA028.
Epigenetic Rewiring UnderliesSMARCA4-Dependent Maintenance of Progenitor State in PediatricH3K27MDiffuse Midline Glioma
Authors: Beytagh Mary Clare , Weiss William A.
Published: December 2022

Epigenetic reprogramming drives tumorigenesis in pediatric H3K27M diffuse midline glioma (DMG) by altering the canonical functions of chromatin remodeling complexes. These studies (i) identified BRG1 (encoded by SMARCA4), the catalytic subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex, as a novel dependency in pediatric H3K27M glioma; (ii) investigated the molecular mechanisms underlying the maintenance of the progenitor state; and (iii) demonstrated efficacy for BRG1 inhibitors.

The authors identified the BRG1 ATPase as a dependency in pediatric H3K27M-mutant DMG. SOX10 recruits BRG1 to regulatory elements to drive progression. Pharmacologically targeting BRG1 reduced tumor volume and improved survival in vivo. Inhibiting BRG1 ATPase represents a potential therapeutic strategy for pediatric H3K27M DMG.

See related article by Panditharatna et al., p. 2880 (5)

See related article by Mo et al., p. 2906 (4) .
Cancer in 2022
Authors:   The AACR Cancer Progress Report 2022 Steering Committee
Published: December 2022

Excerpts from the 12th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to U.S. Congress and the public highlight how medical research continues to extend and improve lives by accelerating advances in cancer prevention, detection, diagnosis, and treatment. Current challenges are described, and a call to action is issued.
Highlights of FDA Oncology Approvals in 2022: Tissue-Agnostic Indications, Dosage Optimization, and Diversity in Drug Development
Authors: Duke Elizabeth S. , J. Fusco Michael , DeMoss Patrick , Dilawari Asma , Pamuk Gulsum E. , Boehmer Jessica , Mixter Bronwyn , Goldberg Kirsten B. , Kluetz Paul , Pazdur Richard
Published: December 2022

In 2022, cancer drug development continued to progress rapidly despite the lingering COVID-19 pandemic. Highlights of U.S. drug approvals for oncology indications this year include ongoing development in rare diseases and molecular subgroups, improved dosage optimization, and updated data for drugs granted accelerated approval, with confirmatory studies demonstrating verification of clinical benefit in some instances, as well as indication withdrawal when clinical benefit was not verified.
Abstract A27: TRIM29-mediated immune evasion in bladder cancer invasive progression
Authors: Kelleher Alan , Wang Yin , Broses Luke , Lei Yu Leo , Palmbos Phillip
Published: December 2022

Background: Progression from noninvasive to muscle-invasive and then metastatic bladder cancer causes >17,000 deaths each year in the United States. Unfortunately, the molecular drivers of progression remain poorly understood and no strategies to prevent progression exist. We have identified an E3 ubiquitin ligase, TRIM29, which is highly expressed in 70% of muscle invasive bladder cancers (MIBC). Global overexpression of TRIM29 in a genetically engineered mouse model (GEMM) is sufficient to induce urothelial cancer initiation and invasive progression. TRIM29 has also been shown to bind and ubiquitinate STING (Stimulator of Interferon Genes), a regulator of anti-tumor cytokine production. However, the role of TRIM29-mediated suppression of STING and innate immune responses in invasive progression was not previously understood. Hypothesis: Given the importance of Trim29 in invasive progression demonstrated in our GEMM, we hypothesized TRIM29-mediated degradation of STING creates an immune-privileged niche required for muscle invasion. Methods: To determine the requirement for Trim29-mediated immune suppression and bladder cancer invasive progression, we generated a urothelial specific tamoxifen inducible Trim29 knockout (KO) GEMM. To induce bladder tumorigenesis, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), a urothelial specific chemical carcinogen with similarities to tobacco, was delivered to mice via drinking water. Results: As expected, BBN promoted development of muscle-invasive urothelial tumors in 50% of mice after 24 weeks. Tamoxifen-induced Trim29 KO completely blocked progression to muscle-invasion, although these mice did demonstrate development of low grade, non-muscle invasive tumors. BBN upregulated Trim29 expression in the urothelium, but only modestly increased Sting and infiltrating macrophage and T cells. In contrast, Trim29 KO mice, which did not develop invasive tumors, harbored substantially elevated Sting levels in the urothelium and substantially increased macrophage and T cell infiltration in the bladder and tumor. In vitro, TRIM29 promoted STING ubiquitination and TRIM29 knockdown increased STING protein levels in bladder cancer cell lines. TRIM29 KO in these cells also resulted in increased expression of innate immune cytokines. Conclusion: These results suggest that TRIM29-mediated downregulation of STING in the bladder results in decreased immune surveillance in the tumor microenvironment, contributing to the development of an immune privileged niche required for MIBC progression.

Citation Format: Alan Kelleher, Yin Wang, Luke Broses, Yu Leo Lei, Phillip Palmbos. TRIM29-mediated immune evasion in bladder cancer invasive progression [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A27.
Abstract B22: B7-H3 promotes progression of prostate cancer harboring PTEN and TP53 defects
Authors: Shi Wei , Zhao Di
Published: December 2022

Prostate cancer is the most diagnosed cancer in men worldwide and the leading cause of cancer death in men worldwide. Genetic inactivation of PTEN and TP53 are common in advanced prostate cancers. Checkpoint immunotherapy has yielded meaningful responses across many cancers but shown minimal activity in advanced prostate cancer. Prior studies showed that overexpression of immune checkpoint B7-H3 (CD276) correlates with the increased risks of clinical recurrence, disease spread, and poor outcomes in various cancer types, including prostate cancer. However, the roles of B7-H3 in prostate cancer development and its tumor microenvironment remain unclear, partially due to the lack of tissue-specific deletion mouse models. This gap in knowledge hinders the application of immunotherapy targeting B7-H3 in prostate cancers. To identify PTEN- and p53-associated immune checkpoints, we performed multi-omics analyses of expression patterns of 51 checkpoint molecules in human prostate cancer samples. Then, we generated a novel generated genetically engineered mouse model to elucidate the role of B7-H3 in tumor development and progression of PTEN/p53-deficient prostate cancer. We also performed unbiased immunoprofling using Mass Cytometry (CyTOF) and Immunofluorescence to visualize B7-H3's impact on immune components in prostate tumors. Our multi-omics analyses in human samples revealed that B7-H3 is one of the most significantly overexpressed immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Mechanistically, we found that the PTEN-AKT pathway co-operates with the p53 pathway in modulating B7-H3 expression in cancer cells. In Pten/Trp53 genetically engineered mouse (GEM) models, prostate-specific deletion of Cd276 resulted in markedly delayed tumor progression. Cd276 deletion also reversed the immunosuppression characterized by increased tumor-infiltrating lymphocytes. Our studies also provided mechanistic insights into potential combinatorial strategies for immunotherapy targeting B7-H3 in advanced prostate cancer harboring PTEN and TP53 defects.

Citation Format: Wei Shi, Di Zhao. B7-H3 promotes progression of prostate cancer harboring PTEN and TP53 defects [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B22.
Abstract B25: Novel regulation and function of Dishevelled 2 in the tumor microenvironment
Authors: Boligala Geetha P , Martinez-Marin Dalia , Melkus Michael W , Rahman Rakhshanda Layeequr , Pruitt Kevin
Published: December 2022

Background: The Wnt/β-catenin pathway contributes to tumorigenesis and recently has been shown to modulate T cell infiltration into the tumor microenvironment (TME). Dishevelled paralogs (DVL1-3) are key mediators of β-catenin dependent and independent Wnt signaling. Though DVL proteins are significant drivers of oncogenic Wnt signaling, little is known about their post-translational regulation and its impacts on tumor immunity. We aimed to study novel DVL post translational modifications (PTMs) and their influence on transcription and epigenetic regulation of immune associated genes in breast cancer (BC). Previous DVL1/3 ChIP-seq analyses revealed that other DVL paralogs bind to genes in tumor cells that modulate immune cell function. We hypothesize that tumor-intrinsic DVL2 regulates the expression of immunomodulatory genes. We further hypothesize that our recently discovered DVL PTMs will impact DVL function and immune cell infiltration into the TME. Experimental design: The cancer genome atlas (TCGA) database was mined for DVL2 expression in BC patients. To determine DVL2 localization to promoters of immune associated genes across a panel of BC cells, DVL2 ChIP-PCR was performed. To determine whether DVL2 was a positive or negative regulator of these genes, RT-qPCR was performed in BC cells in which DVL2 was stably depleted via shRNA. Finally, to identify novel DVL2 post-translational modification, immunoprecipitation and LC-MS/MS were performed.Result: TCGA analyses suggested a significant positive correlation between high DVL2 expression and poor overall and metastasis free survival in BC patients. DVL2 ChIP-PCR analyses showed that DVL2 binds to genes involved in antigen presentation and TIL recruitment. Moreover, RT-qPCR analyses revealed that DVL2 regulates mRNA expression of genes that modulate immune cell function, and Wnt target genes that impact cell proliferation, angiogenesis, and invasion. Interestingly, we have identified novel DVL2 PTMs from proteomic analyses and investigated its impact on genes involved in BC tumor immunity.Summary: Our study examines the novel biology of DVL2 and shows its aberrant expression in BC. We also show for the first time that DVL2 binds to gene promoters and regulates the expression of targets that influence TIL recruitment to the tumor microenvironment. A deeper understanding of DVL2 biology in BC tumors may lead to the development of novel therapeutic strategies.

Citation Format: Geetha P Boligala, Dalia Martinez-Marin, Michael W Melkus, Rakhshanda Layeequr Rahman, Kevin Pruitt. Novel regulation and function of Dishevelled 2 in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B25.