bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative Analysis of the Multicomponent and Spectrum–Effect Correlation of the Antispasmodic Activity of Shaoyao-Gancao Decoction
Authors: Xu Yanli , Li Chenxi , Chen Ting , Li Xiaochun , Wu Xiaoyu , Zhang Qili , Zhao Lei
Published: December 2022

Shaoyao-Gancao Decoction (SGD) is a well-known classic traditional Chinese medicine (TCM) with antispasmodic, anti-inflammatory, and analgesic effects. This preparation has been widely used to treat spasticity diseases in the clinic. To date, the material basis of SGD remains unclear, and the spectrum-effect correlation of its antispasmodic activity has not been reported yet. In this study, high-performance liquid chromatography (HPLC) was used to establish the fingerprint and determine the multiple components of SGD. The common peaks of fingerprints were evaluated by the similarity with the chromatographic fingerprints of the TCM. Meanwhile, the multiple components were quantified and analysed using the heatmap and box size analysis. Furthermore, data on the antispasmodic effect were extracted through in vitro smooth muscle contraction assay. Grey relational analysis combined with partial least square regression was used to study the spectrum–effect correlation of SGD. Finally, the potential antispasmolytic components were validated using an isolated tissue experiment. The HPLC fingerprint was established, and 20 common peaks were identified. The similarities of 15 batches of SGD were all above 0.965. The HPLC method for simultaneous determination of the multiple components was accurate and reliable. The contents of albiflorin, paeoniflorin, liquiritin, and glycyrrhizic acid were higher than the other components in SGD. The heatmap and box size also showed that X3 (albiflorin), X4 (paeoniflorin), X5 (liquiritin), X11 (liquirtigenin), and X16 (glycyrrhizic acid) could be used as quality indicators in the further establishment of quality standards. The spectrum–effect correlation results indicated that X4, X11, and X16 were highly correlated with antispasmolytic activity. Verification tests showed that paeoniflorin (11.7–29.25 μg/mL) and liquirtigenin (17.19–28.65 μg/mL) could significantly reduce the maximum contractile (

P
<
0.01

). These compounds exerted concentration-dependent spasmolytic effects with the inhibitory response for acetylcholine (Ach)-evoked contraction. Thus, SGD had a significant antispasmodic effect, which resulted from the synergistic activity of its multiple components. These findings can be used for the pharmacodynamics study of SGD and are of great significance for the determination of quality markers and quality control.
Computational Model of Recommender System Intervention
Authors: Ojeniyi Adegoke , Ajibade Samuel-Soma M. , Obafunmiso Christiana Kehinde , Adegbite-Badmus Tawakalit
Published: December 2022

A recommender system is an information selection system that offers preferences to users and enhances their decision-making. This system is commonly implemented in human-computer-interaction (HCI) intervention because of its information filtering and personalization. However, its success rate in decision-making intervention is considered low and the rationale for this is associated with users’ psychological reactance which is causing unsuccessful recommender system interventions. This paper employs a computational model to depict factors that lead to recommender system rejection by users and how these factors can be enhanced to achieve successful recommender system interventions. The study made use of design science research methodology by executing a computational analysis based on an agent-based simulation approach for the model development and implementation. A total of sixteen model concepts were identified and formalized which were implemented in a Matlab environment using three major case conditions as suggested in previous studies. The result of the study provides an explicit comprehension on interplaying of recommender system that generate psychological reactance which is of great importance to recommender system developers and designers to depict how successful recommender system interventions can be achieved without users experiencing reactance and rejection on the system.
A Study on Weight Loss Cause as per the Side Effect of Liraglutide
Authors: Yu Jin , Lee Jeongmin , Lee Seung-Hwan , Cho Jae-Hyung , Kim Hun-Sung
Published: December 2022

Purpose. Liraglutide is known to have much lower weight loss effects in real clinical fields than in randomized clinical trials because of its side effects (SE) and discomfort associated with injections. This study is aimed at determining whether the side effects of liraglutide affect weight reduction and its maintenance in real-world practice. Methods. Endocrinologists conducted a retrospective chart review of data from two tertiary university hospitals. All patients who had been prescribed liraglutide at least once between January 2014 and December 2019 were included. For an average of 3 and 6 months, weight changes due to the presence or absence of SE and discontinuation (MAIN or STOP) of liraglutide were checked. Results. Only 40.8% (64/157) of the patients remained on liraglutide for 6 months; 14.7% (23/157) maintained the drug despite SEs (MAIN_SE(+)), and 40.1% (63/157) discontinued the drug despite not having SEs (STOP_SE(-)). At 3 months, there was

−
5.9
±
0.6
%

,

−
7.9
±
0.9
%

,

−
4.5
±
0.5
%

, and

−
3.4
±
0.6
%

weight reduction in the MAIN_SE(-), MAIN_SE(+), STOP_SE(-), and STOP_SE(+) groups, respectively (all

p
<
0.001

compared to the baseline). However, there were no significant differences in the weight loss between the MAIN (

p
=
0.062

) and STOP (

p
=
0.204

) groups. At 6 months, the weight reduction was

−
2.0
±
0.5
%

(

p
<
0.001

) in MAIN_SE(-),

−
2.2
±
0.7
%

(

p
<
0.005

) in MAIN_SE(+),

−
1.7
±
0.7
%

(

p
<
0.01

) in STOP_SE(-), and

−
2.0
±
0.6
%

(

p
=
0.01

) in STOP_SE(+), compared to baseline. SEs also caused no significant differences in weight loss between the MAIN (

p
=
0.787

) and STOP (

p
=
0.694

) groups. Conclusions. Our study confirmed that the side effects of liraglutide did not affect weight reduction. Moreover, in the real world, the continuous rate of liraglutide use is not high, and the weight gradually increases after 3 months. Therefore, in addition to the side effects of liraglutide, the medical staff should consider various factors that affect drug adherence, consider ways to increase compliance, and continue to ensure management so that patients can maintain their weight.
Asymptomatic Hyperuricemia Is Associated with Achilles Tendon Rupture through Disrupting the Normal Functions of Tendon Stem/Progenitor Cells
Authors: Liang Jingjing , Chen Biao , Li Yanmei , Nie Daibang , Lei Changbin , Yang Qing , Zhou Yiqin , Li Shenglong , Chen Shuaizhi , Li Bin , Shu Lin , Chen Liaobin , Wang Wang
Published: December 2022

Hyperuricemia is a metabolic disorder that is essential to the development of inflammatory gout, with increasing prevalence over recent years. Emerging clinical findings has evidenced remarkable tendon damage in individuals with longstanding asymptomatic hyperuricemia, yet the impact of hyperuricemia on tendon homeostasis and associated repercussions is largely unknown. Here, we investigated whether asymptomatic hyperuricemia was associated with spontaneous ruptures in the Achilles tendon and the pathological effect of hyperuricemia on the tendon stem/progenitor cells (TSPCs). Significantly higher serum uric acid (SUA) levels were found in 648 closed Achilles tendon rupture (ATR) patients comparing to those in 12559 healthy volunteers. In vitro study demonstrated that uric acid (UA) dose dependently reduced rat Achilles TSPC viability, decreased the expressions of tendon collagens, and deformed their structural organization while significantly increased the transcript levels of matrix degradative enzymes and proinflammatory factors. Consistently, marked disruptions in Achilles tendon tissue structural and functional integrity were found in a rat model of hyperuricemia, together with enhanced immune cell infiltration. Transcriptome analysis revealed a significant elevation in genes involved in metabolic stress and tissue degeneration in TSPCs challenged by hyperuricemia. Specifically, reduced activity of the AKT-mTOR pathway with enhanced autophagic signaling was confirmed. Our findings indicate that asymptomatic hyperuricemia may be a predisposition of ATR by impeding the normal functions of TSPCs. This information may provide theoretical and experimental basis for exploring the early prevention and care of ATR.
Morphoagronomical and Nutritive Performance of Brachiaria Grasses Affected by Soil Type and Fertilizer Application Grown under Rainfed Condition in Ethiopia
Authors: Hunegnaw Beyadglign , Mekuriaw Yeshambel , Asmare Bimrew , Mekuriaw Shigdaf
Published: December 2022

The objective of the field experiment was to evaluate the agronomic performance and nutritive values of brachiaria grass in response to cultivars, soil type, and fertilizer application. A randomized complete block design containing three replications with three factors (fertilizer, cultivars, and soil types) was used. The cultivars were Brachiaria mutica, Brachiaria hybrid Mulato-II, Brachiaria hybrid Mulato-I, Brachiaria birzantha Marandu, and Brachiaria birzantha La liberated. The root splits were means of propagation for all cultivars. The spacing between blocks and plots was 1 meter while between plants and rows was 0.5 meter. Agronomic performance such as plant height (PH), number of tillers (NT), number and length of leaves, forage dry matter (DM) yield, and nutritive values of the cultivars were measured and analyzed. Forage samples were taken at 90 days harvesting age. A general linear model of statistical analysis system (SAS) version 9.0 is used as a statistical method. The results revealed that all three factors interaction was highly significant (

p
<
0.001

) on all agronomic and nutritive values of Brachiaria grass cultivars. The agronomic performance and most of its nutritive values of brachiaria cultivars were higher (

p
<
0.05

) at black soil than in red soil; except for crude protein. The Brachiria mutica cultivar had a higher agronomic performance at both soil types than hybrid Mulato-II and hybrid Mulato-I. Based on the response recorded, it can be concluded that hybrid Mulato-II, B. mutica, and hybrid Mulato-I cultivars were performing better in the study areas. As a recommendation, farmers should consider cultivar, soil type, and presence of fertilizer in establishing brachiaria grass in the production system.
Automated Decision Technique for the Crowd Estimation Method Using Thermal Videos
Authors: Negied Nermin K. , El-Sayed Ayman , Hassaan Asmaa S.
Published: December 2022

Counting and detecting the pedestrians is an important and critical aspect for several applications such as estimation of crowd density, organization of events, individual’s flow control, and surveillance systems to prevent the difficulties and overcrowding in a huge gathering of pedestrians such as the Hajj occasion, which is the annual event for Muslims with the growing number of pilgrims every year. This paper is based on applying some enhancements to two different techniques for automatically estimating the crowd density. These two approaches are based on individual motion and the body’s thermal features. Theessential characteristic of crowd counting techniques is that they do not require a previously stored and trained data; instead they use a live video stream as input. Also, it does not require any intervention from individuals. So, this feature makes it easy to automatically estimate the crowd density. What makes this work special than other approaches in literature is the use of thermal videos, and not just relying on a way or combining several ways to get the crowd size but also analyzing the results to decide which approach is better considering different cases of scenes. This work aims at estimating the crowd density using two methods and decide which method is better and more accurate depending on the case of the scene; i.e., this work measures the crowd size from videos using the heat signature and motion analysis of the human body, plus using the results analysis of both approaches to decide which approach is better. The better approach can vary from video-to-video according to many factors such as the motion state of humans in this video, the occlusion amount, etc. Both approaches are discussed in this paper. The first one is based on capturing the thermal features of an individual and the second one is based on detecting the features of an individual motion. The result of these approaches has been discussed, and different experiments were conducted to prove and identify the most accurate approach. The experimental results prove the advancement of the approach proposed in this paper over the literature as indicated in the result section.
Searching, Navigating, and Recommending Movies through Emotions: A Scoping Review
Authors: Piçarra Nuno , Reis Eduardo , Chambel Teresa , Arriaga Patrícia
Published: December 2022

Movies offer viewers a broad range of emotional experiences, providing entertainment, and meaning. Following the PRISMA-ScR guidelines, we reviewed the literature on digital systems designed to help users search and browse movie libraries and offer recommendations based on emotional content. Our search yielded 83 eligible documents (published between 2000 and 2021). We identified 22 case studies, 34 empirical studies, 26 proof of concept, and one theoretical paper. User transactions (e.g., ratings, tags) were the preferred source of information. The documents examined approached emotions from both a categorical (n=35) and dimensional (n=18) perspectives, and nine documents offer a combination of both approaches. Although there are several authors mentioned, the references used are frequently dated, and 12 documents do not mention author or model used. We identified 61 words related to emotion or affect. Documents presented on average 1.36 positive terms and 2.64 negative terms. Sentiment analysis (n=31) is frequently used for emotion identification, followed by subjective evaluations (n=15), movie low-level audio and visual features (n = 11), and face recognition technologies (n=8). We discuss limitations and offer a brief review of current emotion models and research.
Abstract A030: Deciphering the micro-RNA landscape of AKT isoforms and its clinical impact in patients with lung adenocarcinoma
Authors: Laliotis George , Lin Pauline
Published: December 2022

Over the last 25 years, AKT kinase has been thoroughly investigated and characterized as a crucial regulator of cellular homeostasis, affecting a plethora of essential molecular functions. The three identified isoforms of this kinase, namely AKT1, AKT2 and AKT3, often display opposing and antagonizing cellular functions. One of these important cellular functions is the expression and activation of micro-RNAs (miRNAs), an important RNA process that epigenetically regulates the human transcriptome. In the context of human cancer and based on several reports, AKT kinase has been associated with aberrant expression of oncogenic miRNAs, that in turn hijack oncogenic pathways, leading to tumor progression, metastasis and resistance to therapy, especially in lung adenocarcinoma (LUAD). Nevertheless, a comprehensive analysis of the impact of each AKT isoform on the regulation and enrichment of a specific miRNA signature in lung adenocarcinoma has yet to be performed. Here, we were willing to elucidate the miRNA epigenetic landscape and downstream targets, driven by each AKT isoform, and its clinical importance in patients with lung adenocarcinoma. To this extent, we utilized RNA-Seq and Small RNA-Seq data from The Cancer Genome Atlas (TCGA-LUAD) to identify the miRNA signatures related with the expression of each AKT isoform in LUAD. Gene Set Enrichment Analysis from RNA-Seq and miRNA levels analysis from Small RNA-Seq, identified a unique miRNA signature for each AKT isoform, demonstrating their largely opposing effect in miRNA profiling. In parallel analysis, in silico target analysis of the top 50 regulated miRNAs, demonstrated another set of unique targets for each isoform-dependent miRNA signature, which is involved in metabolism, DNA damage, RNA processing, cell survival, immune response and metastasis. More importantly, clinical and survival analysis revealed that the top 50 Differentially regulated miRNAs, ranked by q-value, for each isoform correlated with poor progression free survival in patients with LUAD. Collectively, our atlas of AKT isoform-driven miRNA landscapes implicates AKT as a global effector of miRNA landscape in lung adenocarcinoma. Due to the lack of reliable isoform-specific AKT inhibitors, the identification of the oncogenic miRNA networks regulated by each isoform, acts as an important transnational resource for the design and testing of inhibitors that bypass AKT inhibition toxicity, sparing its impactful physiological functions.

Citation Format: George Laliotis, Pauline Lin. Deciphering the micro-RNA landscape of AKT isoforms and its clinical impact in patients with lung adenocarcinoma. [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 A030.
Abstract B003: Inactivation mutations of Kmt2c/d license a molecular “field effect” and prime the urothelium for tumorigenesis
Authors: Wang Naitao , Pachai Mohini R. , Li Dan , Lee Cindy , Warda Sarah , Xie Guojia , Qian Cheng , Wong Wai Pung E. , Yan Juan , Hu Wenhuo , Smith Alison , Ge Kai , Chandarlapaty Sarat , Iyer Gopakumar V. , Rosenberg Jonathan E. , Solit David B. , AI-Ahmadie Hikmat A. , Chi Ping , Chen Yu
Published: December 2022

Urothelial carcinoma (UC) is widely recognized to arise from a “field” of precancerous but histologically normal urothelium (HNU). The molecular mechanism that licenses the “field effect” remains elusive. Recent studies revealed prevalent KMT2C and KMT2D loss-of-function (LOF) mutations in HNU and cancer adjacent urothelium, suggesting their potential involvement in UC initiation. Here, we demonstrated that knockout (KO) of Kmt2c and/or Kmt2d in murine urothelial cells induced drastic alterations of cellular states by single cell RNA analysis, but was insufficient to induce robust histological changes. Kmt2c/d loss enhanced organoid formation efficiency, induced epithelial-mesenchymal transition (EMT), and impaired urothelial differentiation, indicating the augmented lineage plasticity after Kmt2c/d KO. Additionally, we identified that Kmt2c/d KO induced a pre-tumorigenic transcriptome with increased enrichments of gene sets associated with inflammation and decreased enrichments of gene sets associated with differentiation. Consequently, loss of Kmt2c/d sensitized urothelial cells to common oncogenic mutations to initiate UC in mouse models. We further observed that KO of Kmt2c/d increased tumorigenic susceptibility in carcinogen-induced UC model. Mechanistically, we observed decreased H3K4me1, H3K27Ac histone marks and decreased enhancer RNA production at the majority of enhancers that correlate with downregulation of urothelial specific lineage gene expression after Kmt2c/d KO. Furthermore, we observed increased Menin deposition on promoters of up-regulated genes. Blockade of Menin-KMT2A complex by small molecule inhibitor partially rescued the EMT and basal differentiation induced by Kmt2c/d KO. Together, our data posit that Kmt2c/d represents a key molecular determinant and their functional loss licenses a molecular “field effect” which primes the urothelium for oncogenic transformation.

Citation Format: Naitao Wang, Mohini R. Pachai, Dan Li, Cindy Lee, Sarah Warda, Guojia Xie, Cheng Qian, Wai Pung E. Wong, Juan Yan, Wenhuo Hu, Alison Smith, Kai Ge, Sarat Chandarlapaty, Gopakumar V. Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat A. AI-Ahmadie, Ping Chi, Yu Chen. Inactivation mutations of Kmt2c/d license a molecular “field effect” and prime the urothelium for tumorigenesis. [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 B003.
Abstract B012: Defining the role of the BAF complex in primary liver cancers
Authors: Dzama Margarita M. , Scoville Deena M. , Bucklan Emma D. , Raab Jesse R.
Published: December 2022

Incidence and mortality from primary liver cancer are increasing and few effective therapies exist for this deadly disease. Mutations in genes important for chromatin mediated gene regulation commonly occur in both hepatocellular carcinoma and cholangiocarcinoma, the two most common primary liver cancers. Chromatin regulators have been shown to be key modulators of both sensitivity and resistance to therapy response, and therapeutic targeting of chromatin regulators is under development for a wide range of cancers. To uncover chromatin genes that modulate therapy response, we performed epigenome-focused CRISPR screening in the presence of multiple kinases inhibitors (sorafenib, donafenib, cabozantinib). We found that disruption of a specific form of the SWI/SNF chromatin remodeling complex, called BAF, led to therapy resistance. The BAF complex is frequently mutated in both hepatocellular carcinoma and cholangiocarcinoma. Recent studies show that loss of ARID1A and ARID1B, members of the BAF complex, gives rise to liver tumors with morphologies of both hepatocellular carcinoma and cholangiocarcinoma. Critically, because multikinase inhibitors are the most common treatments for advanced hepatocellular carcinoma, our findings suggest patients with BAF mutations would not respond well to these drugs. Using gene expression analysis, genome-wide chromatin localization, and chromatin accessibility assays we are uncovering how altered chromatin state underlies multikinase inhibitor response in BAF mutant tumors. Using high-throughput epigenome focused CRISPR screens we will identify novel modulators of therapy response in liver cancer.

Citation Format: Margarita M. Dzama, Deena M. Scoville, Emma D. Bucklan, Jesse R. Raab. Defining the role of the BAF complex in primary liver cancers. [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 B012.
Abstract B022: CHD1 promotes sensitivity to aurora kinase inhibitors by modulating the interaction of AURKA with TPX2
Authors: Li Haoyan , Wang Yin , Lin Kevin , Venkadakrishnan Varadha Balaji , Bakht Martin , Tremble Kaitlyn , Lu Yue , Beltran Himisha , Zhao Di
Published: December 2022

Clinical studies have shown that subsets of cancer patients achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain-helicase-DNA-binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the co-activator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies.

Citation Format: Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Kaitlyn Tremble, Yue Lu, Himisha Beltran, Di Zhao. CHD1 promotes sensitivity to aurora kinase inhibitors by modulating the interaction of AURKA with TPX2. [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 B022.
Abstract IA011: Transcriptional dependencies of tuft cell lung tumors
Authors: Vakoc Christopher R.
Published: December 2022

Using genetic screens performed in cancer cell lines, we previously identified a tuft cell variant of small cell lung cancer. This novel tumor entity is characterized by high expression of, and addiction to, POU2F3, which encodes a POU homeodomain transcription factor. Subsequent work by several laboratories has revealed tuft cell tumors exist in several different anatomical sites (e.g., thymus, prostate, GI tract), indicating a broader relevance of this cell lineage in human cancer. In my presentation, I will present our efforts to reveal transcriptional mechanisms in tuft cell lung tumors, focusing on the identification of OCA-T1 and OCA-T2 as coactivators of POU2F3.

Citation Format: Christopher R. Vakoc. Transcriptional dependencies of tuft cell lung tumors. [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 IA011.
Abstract IA018: Reading and writing extrachromosomal DNA
Authors: Chang Howard Y.
Published: December 2022

Cancer patients face an extraordinary challenge when oncogenes unleash themselves from chromosomes. Extrachromosomal DNA (ecDNA) are large, megabase-sized circular episomes containing oncogenes and regulatory DNA elements. EcDNAs have a remarkable transcriptional advantage and rapidly change copy number–a moving target driving accelerated evolution in cancer. We present a method for targeted purification of megabase-sized ecDNA by combining in-vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis of agarose-entrapped genomic DNA (CRISPR-CATCH). Targeted purification of ecDNA versus chromosomal DNA enabled phasing of genetic variants and provided definitive proof of oncogenic mutations exclusively on ecDNAs, discovery of ecDNA-specific demethylation with single molecule resolution, and accurate reconstruction of megabase- sized ecDNA structures with base-pair resolution. We model and test the impact of non-chromosomal oncogene inheritance—random identity by descent—on ecDNA on variation and selection. Integrating mathematical modeling, unbiased image analysis, CRISPR-based ecDNA generation, and live-cell imaging, we identify a set of basic “rules” for how random ecDNA inheritance drives oncogene copy number and distribution, resulting in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted cancer treatment. These new tool kits for reading and writing ecDNAs promise to unravel the genetic and epigenetic landscapes of ecDNA biogenesis, dynamics, and function.

Citation Format: Howard Y. Chang. Reading and writing extrachromosomal DNA. [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 IA018.
Abstract IA021: Targeting epigenetic regulators of oncogenic transcription factors
Authors: Chinnaiyan Arul M.
Published: December 2022

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodeling and is altered in over 20% of cancers. We recently developed and evaluated a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supraphysiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumor growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

Citation Format: Arul M. Chinnaiyan. Targeting epigenetic regulators of oncogenic transcription factors. [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 IA021.
Abstract A006: Associations of BMI and albumin with colorectal cancer risk: A prospective cohort study
Authors: Andersen Shaneda Warren , Walts Zoe , Brent Ronni , Parlato Lisa
Published: December 2022

Background: Obesity may increase colorectal cancer (CRC) risk, primarily through mechanisms of increased inflammation. BMI is the most commonly used measure of adiposity; however, it may less accurately measure adiposity in Black populations, highlighting the need for biomarkers of inflammation to evaluate risk. Herein, we investigate the associations between BMI, albumin as a biomarker of inflammation, and CRC risk. Methods: Participant data arise from 71,141 participants of the Southern Community Cohort Study, of which 724 were diagnosed with incident CRC; 69% of the cohort are Black, and 56% have household income <$15,000. A subset of 277 cases and 642 controls had serum albumin concentration measured from blood samples taken at enrollment. Controls were selected through incidence density sampling of the cohort and individually matched to cases by age, sex, and race. Cox proportional hazards were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and CRC risk. Conditional logistic regression was used to calculate odds ratios (ORs) and 95%CIs for associations between albumin concentrations and CRC risk. WHO categories of BMI and albumin concentration tertiles determined through the control’s distribution were used. Results: Participants with underweight (<18.5) compared to normal (18.5-24.9) BMI had increased CRC risk (HR:1.69, 95%CI:0.95-2.98). Null associations were observed between overweight and obese BMI and CRC risk compared to normal BMI participants. Associations between BMI and CRC risk did not vary by sex or race (p-interactions>0.05). Albumin concentration was lower in Black participants and inversely associated with CRC risk (per-standard-deviation increase: OR:0.86, 95%CI:0.74,0.99). Associations were most apparent in participants who self-identified as Black race (OR 0.81, 95%CI:0.68,0.97), or female (OR:0.80, 95%CI:0.65,0.98). There was no evidence that albumin mediated the association between BMI and CRC risk, however BMI modified the association between albumin and CRC (BMI <30: OR: 0.90 95%CI:0.73,1.11; BMI ≥30: OR:0.75, 95%CI:0.60,0.95; p-interaction=0.07). Conclusions: Our results support the role of an inflammatory mechanism to increase CRC risk. The null associations between overweight and obese BMI with CRC risk displays the limited predictive utility of BMI in Black populations. Lower albumin concentrations and increased inflammation in Black populations, particularly in the presence of increased adiposity, may represent a contributing factor to racial disparity in CRC incidence.

Citation Format: Shaneda Warren Andersen, Zoe Walts, Ronni Brent, Lisa Parlato. Associations of BMI and albumin with colorectal cancer risk: A prospective cohort study [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 A006.
Abstract A023: Influence of pre-diagnosis obesity and post-diagnosis aspirin use on survival from stage IV colorectal cancer
Authors: Davis Jennifer S. , Chavez Janelle C. , Kok Melissa , Miguel Yazmin San , Lee Hwa Young , Henderson Henry , Overman Michael J. , Morris Van Karlyle , Kee Bryan , Fogelman David , Advani Shailesh M. , Johnson Benny , Parseghian Christine , Shen John Paul , Dasari Arvind , Shaw Kenna R. , Vilar Eduardo , Raghav Kanwal P. , Shureiqi Imad , Wolff Robert A. , Meric-Bernstam Funda , Maru Dipen , Menter David G. , Kopetz Scott , Chang Shine
Published: December 2022

Background: The relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in late-stage patients. Increased body mass may negate aspirin use for cancer prevention, but the influence of body mass index (BMI) on post-diagnosis aspirin use is unclear. This study aims to evaluate impacts of pre-diagnosis BMI and post-diagnosis aspirin use on overall survival in late-stage CRC patients on the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) clinical protocol. Methods: Patients with metastatic or treatment refractory disease were consented on the ATTACC protocol at MD Anderson Cancer Center and invited to complete a survey on risk factors relevant to CRC etiology. Using survey data, BMI was calculated from the decade prior to initial CRC diagnosis for 656 patients. Survival was measured from stage IV diagnosis until death or last follow-up. Cox Proportional Hazards models were constructed to estimate associations of pre-diagnosis obesity and post-diagnosis aspirin use with overall survival. Results: Controlling for age, sex, race, stage at initial diagnosis, and weight change between pre-diagnosis and survey date, patients with pre-diagnosis obesity had significantly higher likelihood of death (HR 1.45, 95% CI: 1.11, 1.91) compared to those with normal pre-diagnosis BMI. Further, only patients with normal weight pre-diagnosis experienced a survival benefit with post-diagnosis aspirin use (HR 0.59, 95% CI: 0.39, 0.90). Conclusions: Our findings suggest potentially differential tumor development resulting from the long-term physiologic host environment, here obesity. Confirmation and further evaluation are needed to determine whether pre-diagnosis BMI may predict benefit from post-diagnosis aspirin use.

Citation Format: Jennifer S. Davis, Janelle C. Chavez, Melissa Kok, Yazmin San Miguel, Hwa Young Lee, Henry Henderson, Michael J. Overman, Van Karlyle Morris, Bryan Kee, David Fogelman, Shailesh M. Advani, Benny Johnson, Christine Parseghian, John Paul Shen, Arvind Dasari, Kenna R. Shaw, Eduardo Vilar, Kanwal P. Raghav, Imad Shureiqi, Robert A. Wolff, Funda Meric-Bernstam, Dipen Maru, David G. Menter, Scott Kopetz, Shine Chang. Influence of pre-diagnosis obesity and post-diagnosis aspirin use on survival from stage IV colorectal cancer [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 A023.
Abstract A028: Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images
Authors: Lin Jia-Ren , Chen Yu-An , Campton Daniel , Cooper Jeremy , Coy Shannon , Yapp Clarence , McCarty Erin , Ligon Keith L. , Reese Steven , George Tad , Santagata Sandro , Sorger Peter
Published: December 2022

Histopathology using Hematoxylin and Eosin (H&E) stained tissue sections plays a central role in the diagnosis and staging of diseases. The transition to digital H&E pathology affords an opportunity for integration with recently developed, highly multiplexed tissue imaging methods. Here we describe an approach (and instrument) for collecting and analyzing H&E and high-plex immunofluorescence (IF) images from the same cells at subcellular-resolution in a whole-slide format suitable for translational and clinical research and eventual deployment in a diagnostic setting. IF and H&E images provide highly complementary information for analysis by human experts and machine learning algorithms. Using images of 40 human colorectal cancer resections, we demonstrate the automated generation and ranking of computational models, based either on immune infiltration or tumor-intrinsic features, that are highly predictive of progression-free survival. When these models are combined, a hazard ratio of ~0.045 can be achieved, suggesting the potential of integrated H&E and high-plex imaging in the generation of high performance prognostic biomarkers.

Citation Format: Jia-Ren Lin, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Erin McCarty, Keith L. Ligon, Steven Reese, Tad George, Sandro Santagata, Peter Sorger. Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images [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 A028.
Abstract B019: APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer
Authors: Lengner Christopher
Published: December 2022

Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector b-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive b-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.

Citation Format: Christopher Lengner. APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [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 B019.
Abstract IA012: Risk factors for early-onset colorectal cancer
Authors: Hayes Richard B.
Published: December 2022

Colorectal cancer (CRC) incidence has been declining in the U.S. overall; however, the incidence of CRC in individuals less than 50 years of age (early-onset disease) has been increasing over the last several decades in the U.S. and elsewhere. Furthermore, cancers diagnosed in people less than 50 years of age tend to be characterized by advanced stage and greater propensity for recurrence, increasing the urgency of this emerging public health problem. Responding to the rapid rise in early-onset CRC, some CRC screening guidelines have changed to lower the screening age from 50 to 45, for average risk individuals. Our purpose was to identify genetic, environmental and lifestyle risk factors for early-onset CRC which could be used in predictive modelling to identify the younger individuals who would most benefit from screening. This research, which included more than 3,500 early-onset CRC and 3,500 comparison controls, serves to comprehensively assess genetic, environmental and lifestyle risks in early-onset CRC, as well as to develop a risk prediction tool specifically for this age group. We found that a polygenic risk score is associated with early-onset CRC, particularly for those without a family history of CRC. Several known CRC environmental and lifestyle risk factors are also linked with early-onset disease. In summary, the absolute risk for CRC in young people is low; however, genetic, environmental and lifestyle information provides initial stratification into low and high-risk groups. These findings may contribute to the identification of individuals susceptible to early-onset CRC for tailored early detection or other preventive interventions.

Citation Format: Richard B. Hayes. Risk factors for early-onset colorectal cancer [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 IA012.
A Deep Dive into the Circulating ctDNA Cosmos to Vanquish Neuroblastoma
Authors: Deubzer Hedwig E. , Astrahantseff Kathy , Lodrini Marco
Published: December 2022

Single biopsies fail to reflect intratumor heterogeneity and tumor evolution. In this issue of Cancer Discovery, Bosse and colleagues show an important role for circulating cell-free tumor DNA sequencing to detect the genomic evolution of neuroblastoma under ALK inhibitor therapy and identify novel (sub)clonal pathogenic variants involved in disease progression under conventional therapy.

See related article by Bosse et al., p. 2800 (5).
Abstract A26: Tetravalency endows anti-CD27 antibodies with enhanced co-stimulatory activity and anti-tumour immune responses
Authors: Widdess Marcus A , Chan H. T. Claude , Penfold Christine A , Mockridge C Ian , Inzhelevskaya Tatyana , Metcalfe Hannah J , Cragg Mark S , Al-Shamkhani Aymen
Published: December 2022

Immunostimulatory antibodies targeting co-stimulatory TNFRSF members have shown promise in pre-clinical cancer models, but this has not translated into clinical success, primarily due to lack of efficacy. Oligomerisation of the co-stimulatory molecule CD27 by its trimeric membrane-bound ligand activates NF-κB and AP1 signalling leading to enhanced CD8 T cell responses in both humans and mice. Targeting CD27 with bivalent mAb may lead to sub-optimal receptor oligomerisation and inefficient T cell activation. Here we present a general approach to improve the potency of anti-CD27 mAb. We engineered tetravalent forms of anti-CD27 antibodies targeting both mouse and human CD27 by attaching two additional Fab fragments to the N-terminus of the of the IgG VH domain. These tetravalent mAb had greater avidity to CD27 and were more potent than their bivalent counterparts in stimulating NF-κB activation and T cell proliferation in vitro, with optimal responses requiring antibody crosslinking by FcγRIIb. In addition, confocal microscopy of hCD27-GFP fusion protein expressing Jurkat T cells showed that tetravalent anti-hCD27 mAb triggered receptor clustering more efficiently than the equivalent bivalent mAb, as evidenced by the increased number of receptor clusters on the cell surface. Importantly, tetravalent anti-CD27 mAb induced greater CD8 T cell responses than the bivalent mAb in a vaccination model and was more efficacious in suppressing tumour growth in vivo. This work demonstrates that the agonistic activity of anti-CD27 mAb can be significantly improved by tetravalency and suggest that this approach could be utilised to enhance the therapeutic activity of mAb targeting other members of the TNFRSF.

Citation Format: Marcus A Widdess, H. T. Claude Chan, Christine A Penfold, C Ian Mockridge, Tatyana Inzhelevskaya, Hannah J Metcalfe, Mark S Cragg, Aymen Al-Shamkhani. Tetravalency endows anti-CD27 antibodies with enhanced co-stimulatory activity and anti-tumour immune responses [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 A26.
Abstract A53: Intranasal nanoparticulate PLGA cancer vaccine administration prevents secondary lung metastasis
Authors: Donkor Michael A , Choe Jamie , Quinn Byron , Jones Harlan P
Published: December 2022

The lung is one of the most frequent sites of cancer metastasis. Because metastatic lung disease is usually associated with poor survivorship, decreasing secondary lung metastasis will decrease morbidity and mortality associated with cancer. Mitigating tumor immunosurveillance at metastatic sites such as the lung is essential for tumor progression and metastasis. As such, tumors developing elsewhere in the body take advantage of the natural tolerogenicity of the lung to establish immunosuppressive niches via tumor burden induce pre-metastatic niche formation to support lung metastasis. Here we tested the ability of an intranasal nano-vaccine administration to prevent the seeding of tumor cells in the lungs by pre-emptying tumor burden induced immunosuppression. Our hypothesis is that intranasal administration of cancer nano-vaccine will prevent secondary lung metastasis from an existing primary tumor. Because breast cancer is the one of the primary tumors with high propensity to metastasize to the lung, we used the syngeneic mouse breast tumor model to test our hypothesis. Our results showed that intranasal administration of our engineered nano-vaccine protected the lungs of female BALB/c mice from secondary lung metastasis after orthotopic implantation of murine 4T1 tumors. The protection was as a result of nano-vaccine induced antitumor immunity in the lungs. Mice that received the intranasal nano-vaccine had increased frequency of effector T-cells and increase accumulation of lung resident memory T-cell in their lungs. This coincided with increased frequency of IFN-g and granzyme B producing CD8+ T-cells following ex-vivo restimulation of lymphocytes from the lungs of previously immunized mice with tumor cell. These results demonstrate that cancer vaccines can still be part of an integrated cancer therapy where they can be used as a prophylactic approach to prevent secondary lung metastasis.

Citation Format: Michael A Donkor, Jamie Choe, Byron Quinn, Harlan P Jones. Intranasal nanoparticulate PLGA cancer vaccine administration prevents secondary lung metastasis [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 A53.