bluuebunny/crossref_metadata_2025 huggingface dataset:
Error Calibration of Cross Magnetic Gradient Tensor System with Total Least‐Squares Method
Authors: Chi Cheng , Wang Dan , Tao Ronghua , Yu Zhentao
Published: January 2023

The magnetic gradient tensor system configured by fluxgate magnetometers is subjected to different scale factors, three‐axis nonorthogonality, bias, and misalignment errors. All those errors above will influence the measurement precision directly, so the magnetic gradient tensor system must be calibrated before use. In this paper, an error calibration method of the magnetic gradient tensor system is proposed. The procedure of the proposed method is as follows. Firstly, the error calibration model of the single fluxgate magnetometer is established and generated an ellipsoid mathematical expression. To simplify the calculation, the ellipsoid mathematical expression is transformed into a linear model of intermediate variables, and then, error parameters are estimated by the total least‐squares method. Secondly, the orthogonal procrustes problem is adopted to calibrate misalignment errors. Finally, simulations and experiments with a cross magnetic gradient tensor system are carried out for verification of the proposed error calibration method. Results show that compared with the original least‐squares method, the proposed method can increase the measurement accuracy of the cross magnetic gradient tensor system greatly.
Global Trends in Research of Mitochondrial Biogenesis over past 20 Years: A Bibliometric Analysis
Authors: Song Lei , Liang Jiaqi , Wang Wenting , Gao Jie , Chai Hua , Tan Yu , Zheng Liying , Xue Mei , Shi Dazhuo
Published: January 2023

Background. Mitochondrial biogenesis-related studies have increased rapidly within the last 20 years, whereas there has been no bibliometric analysis on this topic to reveal relevant progress and development trends. Objectives. In this study, a bibliometric approach was adopted to summarize and analyze the published literature in this field of mitochondrial biogenesis over the past 20 years to reveal the major countries/regions, institutions and authors, core literature and journal, research hotspots and frontiers in this field. Methods. The Web of Science Core Collection database was used for literature retrieval and dataset export. The CiteSpace and VOSviewer visual mapping software were used to explore research collaboration between countries/regions, institutions and authors, distribution of subject categories, core journals, research hotspots, and frontiers in this field. Results. In the last 20 years, the annual number of publications has shown an increasing trend yearly. The USA, China, and South Korea have achieved fruitful research results in this field, among which Duke University and Chinese Academy of Sciences are the main research institutions. Rick G Schnellmann, Claude A Piantadosi, and Hagir B Suliman are the top three authors in terms of number of publications, while RC Scarpulla, ZD Wu, and P Puigserver are the top three authors in terms of cocitation frequency. PLOS One, Biochemical and Biophysical Research Communications, and Journal of Biological Chemistry are the top three journals in terms of number of articles published. Three papers published by Richard C Scarpulla have advanced this field and are important literature for understanding the field. Mechanistic studies on mitochondrial biosynthesis have been a long-standing hot topic; the main keywords include skeletal muscle, oxidative stress, gene expression, activation, and nitric oxide, and autophagy and apoptosis have been important research directions in recent years. Conclusion. These results summarize the major research findings in the field of mitochondrial biogenesis over the past 20 years in various aspects, highlighting the major research hotspots and possible future research directions and helping researchers to quickly grasp the overview of the developments in this field.
Predicting Antecedents of Employee Smart Work Adoption Using SEM-Multilayer Perceptron Approach
Authors: Wang Wen-Bao , Shieh Chich-Jen , Al-Khafaji Hamza Mohammed Ridha , Sevbitov Andrei , Ismael Aras Masood , Chetthamrongchai Paitoon , Suksatan Wanich , Bahrami Parvaneh
Published: January 2023

The COVID-19 pandemic forced many organizations to move to telework and smart work (SW), and this practice is expected to continue even later in the postpandemic period. Hence, it is very important for managers and organizations to identify the motivating and deterrent factors in adopting smart work and plan to manage them. Therefore, the present study using an innovative methodology tried to identify and prioritize the factors influencing employee SW adoption. In the first stage, the conceptual model of the research was designed, inspired by the literature. In the next step, using structural equation modeling (SEM), antecedents whose effects on employee SW adoption were confirmed were identified. Finally, the output of the SEM model was considered as the input of the multilayer perceptron (MLP) model, which is an artificial neural network model, to determine the importance of each antecedent in the prediction of employee behavior. The present study provides quantitative empirical evidence that perceived value, institutional and technological support, perceived limited communication, and perceived cost are antecedents of employee SW adoption that are, respectively, important in predicting the behavioral intentions of employees in acceptance of SW. The findings of this study contribute to both the SW and the behavioral intention theory literature.
Improved Medication Adherence with the Use of Extended-Release Tacrolimus in Liver Transplant Recipients: A Pilot Randomized Controlled Trial
Authors: Verma Manisha , Zaki Radi , Sadeh Johnathan , Knorr John P. , Gallagher Mark , Parsikia Afshin , Navarro Victor
Published: January 2023

Background. Nonadherence to immunosuppression in liver transplant recipients (LTRs) leads to deterioration in health outcomes. Once-dailyextended-release tacrolimus (TAC-ER) may improve adherence when compared to twice-dailyimmediate-release tacrolimus (TAC-IR). Methods. We conducted a randomized controlled study to evaluate medication adherence, clinical efficacy, and safety of TAC-ER in stable LTR. All patients >18 years who underwent liver transplantation before 6 months were eligible. Patients were randomized 1 : 1 to continued TAC-IR or conversion to TAC-ER. The primary outcome was change in medication adherence from baseline to 9 months, assessed using BAASIS. Secondary outcomes were tacrolimus trough levels, safety, and quality of life. Results. Thirty-one patients were consented and randomized to either of the two groups: conversion to TAC-ER (n = 15) or continued TAC-IR (n = 16). Six patients in the TAC-ER group withdrew after randomization due to apprehension about switching medication (n = 2), unwillingness to travel (n = 2), and increased liver tests after conversion (n = 2, both were acute rejections despite therapeutic tacrolimus levels and were considered unrelated to TAC-ER). We compared the results of nine patients in the TAC-ER group that completed the study with those of sixteen in the TAC-IR group. At baseline, there was no difference in tacrolimus trough levels between groups. Improved adherence was observed in the TAC-ER group as 100% of patients reported at least one period of full adherence during the study period (100% vs. 62.6%,

p
=
0.035

). Tacrolimus trough levels and liver tests were comparable between groups throughout the study. There were no differences in eGFR, HbA1c, or QoL between the groups. Conclusion. TAC-ER improved medication adherence while maintaining comparable trough levels, liver function, and QoL as TAC-IR in LTR.
YAP-Activated SATB2 Is a Coactivator of NRF2 That Amplifies Antioxidative Capacity and Promotes Tumor Progression in Renal Cell Carcinoma
Authors: Jin Juan , Chen Fen , He Wenfang , Zhao Li , Lin Bo , Zheng Danna , Chen Li , He Hongchao , He Qiang
Published: January 2023

Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein, special AT-rich binding protein-2 (SATB2), in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin using sequencing analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer–promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Finally, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC.

Significance:

A YAP-SATB2-NRF2 regulatory axis amplifies antioxidative stress signaling and provides potential therapeutic targets to enhance response to chemotherapy in renal cell carcinoma.
HAND2 Assists MYCN Enhancer Invasion to Regulate a Noradrenergic Neuroblastoma Phenotype
Authors: Xu Man , Sun Ming , Zhang Xiyuan , Nguyen Rosa , Lei Haiyan , Shern Jack F. , Thiele Carol J. , Liu Zhihui
Published: January 2023

Noradrenergic neuroblastoma is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TF) such as PHOX2B, HAND2, and GATA3, which form a network with MYCN. At normal physiologic levels, MYCN mainly binds to promoters but when aberrantly upregulated as in neuroblastoma, MYCN also binds to enhancers. Here, we investigated how MYCN invades enhancers and whether CRC TFs play a role in this process. HAND2 was found to regulate chromatin accessibility and to assist MYCN binding to enhancers. Moreover, HAND2 cooperated with MYCN to compete with nucleosomes to regulate global gene transcription. The cooperative interaction between MYCN and HAND2 could be targeted with an Aurora A kinase inhibitor plus a histone deacetylase inhibitor, resulting in potent downregulation of both MYCN and the CRC TFs and suppression of MYCN-amplified neuroblastoma tumor growth. This study identifies cooperation between MYCN and HAND2 in neuroblastoma and demonstrates that simultaneously targeting MYCN and CRC TFs is an effective way to treat this aggressive pediatric tumor.

Significance:

HAND2 and MYCN compete with nucleosomes to regulate global gene transcription and to drive a malignant neuroblastoma phenotype.
Stepped Behavioral and Biological Screening for Oral Oncogenic HPV DNA in Middle-aged and Elderly Adults: A Feasibility Study
Authors: Day Andrew T. , Sample Reilly A. , Salley Jordan R. , Oliver Dwight , Dahlstrom Kristina R. , Sturgis Erich M. , Tiro Jasmin A.
Published: January 2023

Novel preventive interventions are needed to address the rising incidence of human papillomavirus (HPV)-mediated oropharyngeal cancer (HPV+ OPC). This pilot study evaluated the feasibility of a stepped, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate HPV+ OPC outcome.

This was a cross-sectional, feasibility study. Eligible 45–74 years old adults identified from three clinical research registries were administered a behavioral risk survey (step 1). Participant tobacco use and sexual behavior history were translated into a quantifiable risk of oral oncogenic HPV DNA, according to prior National Health and Nutrition Examination Survey analyses. Females with >2% risk and males with >7% risk were offered biological screening for oral oncogenic HPV DNA (step 2) via an oral rinse and gargle specimen.

A total of 292 individuals were contacted, but only 144 (49%) were reached. Among these, 56 individuals (19%) were uninterested and 18 (13%) were ineligible. Seventy individuals began the survey and 66 completed it (step 1), among whom 46 were classified as low-risk. Among the remaining 20 participants classified as high-risk for an oral oncogenic HPV infection, 5% were current smokers and the median participant had performed oral sex on 10 unique partners. During step 2 (biological screening), 45% (9/20) completed testing, all of whom tested negative for oral oncogenic HPV DNA.

In this pilot of a stepped, oral oncogenic HPV screening program, enrollment and study completion were suboptimal. These barriers to screening should be characterized and addressed before reevaluating the feasibility of this program.

Prevention Relevance:

Novel preventive interventions are needed to address the rising incidence of HPV+ OPC. In this feasibility study, we characterized barriers to a two-step, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate outcome for HPV+ OPC.
Abstract IA001: Innovation and equity in cancer prevention and screening
Authors: Lowy Douglas R.
Published: January 2023

This presentation will highlight some of the opportunities for improving cancer prevention and screening of asymptomatic individuals, which includes increasing the uptake of current standard of care and research for new interventions that can become standard of care. It is important to strive to address cancer disparities in the US and globally, as the greatest population-wide benefit for current and new interventions will be derived from equitable access to them. To increase the likelihood that uptake of new interventions will be equitable, this parameter should be considered throughout the development and evaluation of the candidate interventions, rather than waiting until after they have been approved. The main goals of prevention and screening are to enable people to live longer healthier lives, and approved interventions should ultimately be held to this standard, although initial approval, especially for primary prevention, may be based on surrogate endpoints. For example, initial HPV vaccine approval, in 2006, was based on its reduction in cervical dysplasia rates. Reduced cancer risk was not observed until more than a decade after that, and the vaccine has still not been formally shown to reduce mortality rates from HPV-associated cancer. The global equitable uptake of the HPV vaccine lags considerably, although the vast majority of HPV-associated cancers occur in low- and middle-income countries. We and others are conducting research to address this important gap. For cancer screening, a much shorter interval is usually needed to determine if the intervention does reduce cancer-specific mortality rates. This parameter is highly relevant for multicancer detection tests, which have considerable potential. While these tests can detect asymptomatic cancer earlier than if one waited for symptoms to develop, it remains to be demonstrated whether cancer detected by this approach will reduce cancer-specific mortality rates. It is also critical to develop equitable approaches for cancer diagnosis and treatment triggered by a positive test.

Citation Format: Douglas R. Lowy. Innovation and equity in cancer prevention and screening. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA001.
Abstract IA014: Precision public health approaches to health equity
Authors: Griffith Derek M.
Published: January 2023

Since President Barack Obama announced the “Precision Medicine Initiative” during his state of the union address in January 2015, the sciences of precision medicine and health equity have largely grown in parallel, though there have been some efforts to bring the two together. As research on health equity has evolved to name and consider structural racism, the penultimate goal of research in this area also as moved from efforts to identify and describe gaps between racial and ethnic groups to characterizing the context creates and perpetuates racial inequities and how best to mitigate them. In this presentation, I will briefly describe how syndemics, intersectionality, and individual tailoring may complement downstream efforts to characterize epigenetic and genomic efforts to develop biomedical interventions to achieve healthcare equity and health equity. After noting how the principles of precision medicine may be applied more broadly than the most common way it is operationalized through genomic medicine, I argue that that creating racial justice in health will require defining health equity more clearly and precisely. Consequently, I utilize the example of Black men and the context of COVID-19 to highlight how more precisely defining the structural context of the population of interest by using tools such as intersectionality and syndemics is fundamental to achieving equity. I highlight how achieving health equity will require creating, resisting, undoing, and mitigating structural racism and note what that means for cancer research. Precision medicine may help to mitigate the health effects of structural racism, and it will remain an important tool to promote population health; however, efforts to achieve health equity and racial justice will require interventions that change the contexts and conditions that create, exacerbate, and perpetuate structural inequities and the racial inequities in health outcomes that they produce and maintain.

Citation Format: Derek M. Griffith. Precision public health approaches to health equity. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA014.
Abstract IA017: Targeting the mTOR pathway for the prevention of triple-negative breast cancer
Authors: Brown Powel H. , Mazumdar Abhijit , Tahaney William , Hill Jamal , Zhang Yun , Ramachandran Sumankalai , Kawedia Jitesh , Qian Jing , Contreras Alejandra , Savage Michelle , Vornik Lana
Published: January 2023

Phase III cancer prevention clinical trials have shown that breast cancer prevention is feasible using anti-estrogen drugs. However, these drugs have not been widely accepted because of concerns about toxicity. In addition, anti-estrogen drugs do not prevent estrogen-negative breast cancers, including the most aggressive form of breast cancer, triple-negative breast cancer (TNBC), that does not express the estrogen receptor (ER), progesterone receptor, or the human epidermal growth factor receptor 2 (HER2). Our laboratory is focused on identifying growth-regulatory molecules that are essential for the growth of TNBCs. For this study, we identified mTOR as an essential growth-regulatory molecule that is highly expressed in TNBCs. We then investigated whether the mTOR inhibitor everolimus can prevent mammary tumors in transgenic mouse models including 4 models of TNBC and one model of ER-negative/HER2-positive breast cancer. Everolimus treatment significantly delayed mammary tumor formation but with a varying degree in all five mouse models. Everolimus treatment for up to 1 year was well tolerated with no observable toxicity. These results suggest that mTOR inhibitors may be promising drugs for the prevention of ER-negative and triple-negative breast cancers in women at risk of these aggressive breast cancers. Grant support: This research was supported by an NCI-PREVENT contract to P. Brown and A. Mazumdar (HHSN261201500018I/HHSN26100006).

Citation Format: Powel H. Brown, Abhijit Mazumdar, William Tahaney, Jamal Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh Kawedia, Jing Qian, Alejandra Contreras, Michelle Savage, Lana Vornik. Targeting the mTOR pathway for the prevention of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA017.
Abstract IA021: Contribution of biomarker-based risk profiles to cancer early detection
Authors: Hanash Samir
Published: January 2023

The potential of blood tests for multi-cancer early detection (MCED) to reduce cancer mortality has elicited both optimism and concern about their generalized applicability. Identifying in the general population individuals at increased risk, through the use of biomarkers together with subject characteristics, has the potential to trigger preventive intervention and to improve effectiveness of early detection through a tailored approach to screening based on a personalized risk profile. The contribution of blood-based biomarkers for personalized lung cancer risk assessment will be highlighted.

Citation Format: Samir Hanash. Contribution of biomarker-based risk profiles to cancer early detection. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA021.
Abstract IA025: Rethinking risk assessment in the era of multi-cancer early detection
Authors: Patel Alpa V.
Published: January 2023

Cancer screening is a critical component of cancer control and reducing cancer mortality as it increases the likelihood of identifying cancers earlier when there is a greater opportunity for therapeutic intervention. Current cancer screening tests, such as mammography, focus on detection of a single cancer type, and screening recommendations for these tests are based on risk of that single cancer. Unfortunately, recommended screening tests are available only for a few cancers that collectively account for approximately one-third of cancer-related deaths, leaving opportunity for enhanced screening that would potentially include additional cancer types. Newer technologies that are under development have the potential to reduce the overall cancer burden because they are focused on the early detection of multiple cancers in a single screening test (called multi-cancer early detection, or MCED, tests). Given existing screenings are cancer-specific, the introduction of MCED tests, which simultaneously target detection of several cancers, will require a new approach to risk assessment and screening guidelines development. Specifically, MCED screening guidelines will require that we understand the populations who will most benefit from using MCED tests; identify the risk factors, other than age, that are associated with risk of developing any cancer; and determine the frequency of screening intervals. In this presentation, we will explore strategies for rethinking risk assessment related to MCED tests to begin informing future multi-cancer screening guidelines.

Citation Format: Alpa V. Patel. Rethinking risk assessment in the era of multi-cancer early detection. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA025.
Abstract P006: Targeting the zymogen granule protein 16B (ZG16B) to suppress breast cell growth and invasiveness
Authors: Lengyel Máté , Uray Iván P.
Published: January 2023

The induction of tumor suppressing effects by retinoid X receptor-selective agonists in premalignant breast cells may become ineffective in the course of malignant transformation. Therefore, this study aimed to identify pro-tumorigenic factors suppressed in a rexinoid-dependent manner, hypothesizing that such a mechanism may remain active and relevant for cancer interception throughout the various stages of breast cell transformation. To minimize toxicity due to long-term rexinoid treatment in the prevention setting, an additional goal was to identify synergistic growth suppressive combinations of bexarotene (Bex) in normal mammary epithelial cells. The selected combination of Bex and a non-selective beta-adrenergic inhibitor carvedilol (Carv) from an unbiased high throughput screen demonstrated marked cancer preventive activity in a mouse model of Her2-induced ER-negative breast cancer at subtherapeutic doses. To elucidate the molecular underpinnings of this chemopreventive activity, genes selectively suppressed by the drug combination over the individual agents were sought. We determined that the zymogen granule protein 16B (ZG16B), a secreted prognostic marker in breast cancer, was suppressed in normal breast cells by the combination of Bex and Carv. Chromatin immunoprecipitation following Bex+Carv treatment revealed enrichment of the chromatin remodeler protein ARID1A at sites of decreased H3K27 acetylation within the enhancer of the ZG16B gene, resulting in a marked down-regulation of ZG16B. Cell-free supernatant containing overexpressed recombinant ZG16B triggered Erk phosphorylation, increased the proliferation and migration of immortalized HME-hTert cells and induced the expression of extracellular matrix proteins. Furthermore, ZG16B promoted mesenchymal characteristics similar to TGF-b, which was inhibited by an antibody against ZG16B. When administered in tandem, ZG16B neutralized the effects of Bex+Carv. In breast cancer cells, ZG16B stimulated the migration of all tested cell lines, but enhanced proliferation only in ER-positive MCF-7 and T47D cells. Anchorage independent 3D growth of both ER-positive T47D and ER-negative MDA-MB231 cells was stimulated by ZG16B, while Bex+Carv reduced colony formation and suppressed ZG16B levels. Taken together, ZG16B is a potent factor in the growth, mesenchymal transition and invasiveness of breast epithelial cells at all stages of transformation. Our data further suggest that ZG16B may represent a relevant target of the tumor suppressing activity of rexinoids and the combination of Bex+Carv.

Citation Format: Máté Lengyel, Iván P. Uray. Targeting the zymogen granule protein 16B (ZG16B) to suppress breast cell growth and invasiveness. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P006.
Abstract P007: Short-term PI3K inhibition prevents breast cancer in preclinical models
Authors: Ku Amy T. , Young Adelaide , Ibrahim Ahmed A. , Bu Wen , Jiang Weiyu , Lin Meng , Williams Laterrica C. , McCue Bryant , Miles George , Nagi Chandandeep , Behbod Fariba , Li Yi
Published: January 2023

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of breast precancerous lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.

Citation Format: Amy T. Ku, Adelaide Young, Ahmed A. Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C. Williams, Bryant McCue, George Miles, Chandandeep Nagi, Fariba Behbod, Yi Li. Short-term PI3K inhibition prevents breast cancer in preclinical models. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P007.
Abstract P016: Endomembranes accumulate unesterified cholesterol in Apc mutant models and humans with CRC as assessed by RNAseq and confocal microscopy
Authors: Munoz-Vega Monica , Erazo-Oliveras Alfredo , Salinas Michael L. , Wang Xiaoli , Goldsby Jennifer S. S , Chapkin Robert S.
Published: January 2023

Background: Increased rates of cholesterol synthesis have been recognized as an important aspect of the metabolism of transformed cells. However, precisely how cholesterol dysmetabolism affects membrane homeostasis is not yet fully understood. Since free cholesterol can be transported from the plasma membrane to other organelles in a dynamic and bidirectional fashion, there is an urgent need to determine to what extent endomembranes are affected by driver oncogene-mediated distortions in cholesterol homeostasis. Aim: Determine if cholesterol is increased in endomembranes, relative to the plasma membrane in Apc mutant cell lines and primary Apc null mouse colonocytes amd CRC samples. Methods: Three mouse epithelial isogenic wild type and mutant Apc colonic cell lines (YAMC (Apc +/+), IMCE (Apc +/-), IMCE βcat (Apc +/- + ΔN89 βcat) were used. In addition, primary colonocytes from Apc wildtype and null mice were examined. mRNA was sequenced using a TruSeq Illumina Stranded mRNA kit. Data analysis was conducted as follows: EdgeR was used to identify differentially expressed genes. Human CRC RNAseq data was obtained from a public reservoir and analyzed. A gene target list (~ 290 genes) related to organelle cholesterol transport was subsequently queried. Membranes from the endoplasmic reticulum (ER), mitochondria and lysosomes were assessed using fluorescent probes: ERTracker, MitoTracker and LysoTracker, respectively. Cells were fixed and stained with Filipin III and imaged using confocal microscopy. Fluorescence colocalization was calculated and statistical analysis was performed using a one-way ANOVA. Results: Apc mutant colonocyte cell lines and Apc null mouse models and human CRC samples exhibited differential expression of cholesterol trafficking genes including Acaa1b, Acaa2, Pcsk9, Stard5. Genes related to mitochondrial cholesterol metabolism, transport, and accumulation, e.g., Tspo, Ppargc1a and Cyp27a, were also found differentially expressed in the three models. Imaging experiments revealed that mitochondrial cholesterol was 17% higher in IMCE and IMCE βcat cell lines. Lysosomal cholesterol was 21% higher in IMCE cells. ER cholesterol levels were unaffected. Conclusions: Our preliminary findings indicate dysregulation of mitochondrial and lysosomal unesterified cholesterol levels in colonocytes expressing mutant APC.

Citation Format: Monica Munoz-Vega, Alfredo Erazo-Oliveras, Michael L. Salinas, Xiaoli Wang, Jennifer S. S Goldsby, Robert S. Chapkin. Endomembranes accumulate unesterified cholesterol in Apc mutant models and humans with CRC as assessed by RNAseq and confocal microscopy. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P016.
Abstract P043: A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting
Authors: Schrock-Kelley Suzanne , Souter Vivienne , Hall Michael , Weitzel Jeffrey N.
Published: January 2023

Background: Germline testing for hereditary colorectal cancer (CRC) has traditionally been offered to patients with strong cancer family histories, whose colon tumors revealed mismatch repair deficiency (dMMR), and/or individuals diagnosed with CRC under age 50. Underdiagnosis of hereditary cancer syndromes is often attributed to the complexity or unawareness of family history or phenotypic criteria.1,2 The National Comprehensive Cancer Network (NCCN) guidelines for CRC were recently updated (v. 1.2022) to consider germline multigene panel testing (MGPT) evaluation for all individuals with CRC.3,4 Our goal was to evaluate documentation of MGPT in CRC patients referred for molecular residual disease (MRD) testing. Methods: This retrospective cohort study reviewed clinical data submitted to a commercial laboratory for consecutive CRC patients referred from non-academic medical facilities for MRD testing during a two-month study period. Medical diagnoses, treatment history, family history and germline genetic evaluation status were obtained from the test requisition form and pathology reports. Clinical notes were reviewed in 77/80 cases. Results: Of the 80 patients who met criteria for inclusion, 65/80 (81%) had documented MMR testing of their colorectal tumor. Whereas five had abnormal immunohistochemistry, only two (40%) had documented germline results. 19/80 (24%) met NCCN criteria solely based on a personal CRC diagnosis <50 years, but only 1/19 (5.3%) had documented MGPT. Only 5/80 (6%) of all CRC patients had documented MGPT. Conclusion: Our real-world data from the community oncology precision medicine setting suggests that a majority of CRC patients who received MRD testing and met the prior NCCN criteria for MGPT may not have received evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing in CRC patients regardless of age at diagnosis or MMR status.

Citation Format: Suzanne Schrock-Kelley, Vivienne Souter, Michael Hall, Jeffrey N. Weitzel. A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P043.
Abstract P048: Development of the diagnostic method for pancreatic cancer using novel isolation technology of extracellular vesicles
Authors: Shimizu Yuta , Takahashi Kenji , Asai Fumi , Inuzuka Tatsutoshi
Published: January 2023

Background: Extracellular vesicles (EVs) are secreted by all cells into extracellular fluids and are found in most body fluids, including blood and urine. EVs contain many bioactive molecules, including proteins, RNA, DNA, and phospholipids. EVs have been reported to be associated with various diseases, including cancer metastasis and progression, suggesting that they play an important role in cell-to-cell communication. EVs are a promising modality for liquid biopsy and their clinical applications are desired, but methods for EVs isolation and quantification are still controversial. Traditionally used methods include ultracentrifugation (UC), polymer-based precipitation, and immunoprecipitation (IP) against surface marker antigens, but they are often inadequate in recovery efficiency and purity and are not standardized. In addition, it is very difficult to separate and recover EVs from body fluids that contain many contaminants. Therefore, we developed the original IP method (EViSTEPTM) in which a chelating agent-based reagent combined with in-house antibodies (CD9 and CD63) separate EVs with high purity and high recovery from body fluids such as serum and plasma for clinical applications. In this study, we evaluated whether EViSTEPTM in combination with expression levels of a newly identified long non-coding RNA (lncRNA), LOC100507412 (HEVEPA), could be used for stratification of pancreatic ductal adenocarcinoma (PDAC). Methods: EVs were isolated from serum of PDAC (22 cases), intraductal papillary mucinous neoplasm (IPMN) (23 cases), and healthy controls (HC) (21 cases) using EViSTEPTM, and HEVEPA expression analysis was performed by digital droplet PCR. Results: In the analysis of HC, IPMN, and PDAC samples, HEVEPA was significantly more highly expressed in PDAC compared to HC and IPMN. In ROC analysis between PDAC versus non-PDAC (IMPN and HC), the AUC of HEVEPA (0.80) was comparable to other tumor makers such as CEA (0.48) and CA19-9 (0.89). Furthermore, the AUC improved to 0.99 when HEVEPA was combined with CA19-9 but was not significantly different from that of CA19-9 alone. Conclusion: EViSTEPTM enables us to analyze HEVEPA in EVs, and the combination of HEVEPA and CA19-9 is expected to improve the diagnostic performance of PDAC. The combination of the EViSTEPTM method of EVs isolation and HEVEPA expression levels was suggested to be useful for the stratification of PDAC.

Citation Format: Yuta Shimizu, Kenji Takahashi, Fumi Asai, Tatsutoshi Inuzuka. Development of the diagnostic method for pancreatic cancer using novel isolation technology of extracellular vesicles. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P048.
Abstract P052: Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth
Authors: Korac Ksenija , Bhutia Yangzom D , Rajasekaran Devaraja
Published: January 2023

IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift about IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson’s disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.

Citation Format: Ksenija Korac, Yangzom D Bhutia, Devaraja Rajasekaran. Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P052.
Abstract P059: A case of stage I esophageal adenocarcinoma diagnosed using a multi-cancer early detection test
Authors: Jr David DeAtkine
Published: January 2023

Introduction: There is no guideline-recommended screening test for esophageal cancer, a cancer that occurs in approximately 1 in 125 men and 1 in 417 women in the US. Risk factors for esophageal adenocarcinoma include gastroesophageal reflux disease, Barrett’s esophagus, obesity, and smoking. A multi-cancer early detection (MCED) test that analyzes methylation patterns of cell-free DNA in the blood using sequencing assays and machine-learning classifiers is available as a complement to existing single-cancer screening tests. The MCED test reports either (1) ‘cancer signal detected’ with 1 or 2 cancer signal origin (CSO) prediction(s) or (2) ‘cancer signal not detected’. A case of esophageal adenocarcinoma is presented here to demonstrate early detection using the MCED test and to review the diagnostic journey following a cancer signal detected (positive) test result. Case Description/Methods: An asymptomatic 63-year-old White male (BMI: 27 kg/m2) with history of peptic ulcer disease was screened using the MCED test. He reported moderate alcohol use (6/week) and no tobacco use. His last colonoscopy was 5 years prior to using the test. Nine days after a blood sample was collected for analysis by the MCED test, a positive test result (CSO prediction=Stomach/Esophagus) was reported and communicated to the patient (Day 1). Computed tomography (CT) of the chest, abdomen, and pelvis with contrast showed no significant findings (Day 13). A submucosal bulge just below the gastroesophageal junction (GEJ) was noted on upper endoscopy. The lesion, and area above the GEJ were extensively biopsied (Day 15). Pathologic evaluation confirmed diagnosis of Clinical Stage I esophageal adenocarcinoma with superficial focally invasive adenocarcinoma arising in a background of intestinal metaplasia with high grade dysplasia (Day 29). The patient underwent total gastrectomy without complications (Day 104). He will undergo appropriate follow-up 6 months post-op. Discussion: The MCED test detected a cancer signal and predicted a gastrointestinal CSO for an asymptomatic individual with Clinical Stage I esophageal cancer. Diagnostic resolution was achieved within 1 month and treatment was provided with curative intent. Given that there is no guideline-recommended screening test available for esophageal cancer, the use of this MCED test detected cancer early, directed diagnostic workup, and potentially improved outcomes for this asymptomatic patient.

Citation Format: David DeAtkine Jr. A case of stage I esophageal adenocarcinoma diagnosed using a multi-cancer early detection test. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P059.
Abstract P067: Evaluating the risk of clinically significant prostate cancer in lesions detected on multiparametric MRI of the prostate
Authors: Molokwu Chidi N. , Gkikas Christos , Lee Nicola , Lesniak-Buzon Joanna , Ali Faisal , Bardgett Harry
Published: January 2023

Introduction: Multiparametric Magnetic Resonance Imaging (mpMRI) is a valuable tool in the prostate cancer diagnostic pathway. mpMRI has a negative predictive value (NPV) of approximately 90% for detecting clinically significant prostate cancer (csPCa), defined as the presence of any Gleason Grade (GG) 4 or 5. Lesions detected on mpMRI are scored using the PIRADS scoring system from 1 to 5. PIRADS-3, 4 and 5 lesions are recommended for biopsy. The use of mpMRI to guide prostate biopsy has been shown to be superior to systematic biopsy alone for detecting early csPCa as small lesions can be identified and accurately targeted. We analysed the outcome of targeted biopsy of prostate lesions detected on mpMRI, and systematic biopsy when no lesions were detected, to determine the risk of csPCa based on mpMRI findings. Methods: Men attending our prostate diagnostic pathway were offered mpMRI before biopsy. The criteria for pre-biopsy mpMRI were any man suitable for radical surgery or radiotherapy, plus one or more of PSA > 3, palpable lesion on digital rectal examination, or family history of PCa in a first degree relative (father or brother). mpMRI was performed with a 1.5-Tesla magnet and included T2, DWI and DCE sequences. Men with PIRADS 3, 4, and 5 lesions were offered targeted biopsy with 2-4 biopsy cores per lesion, and men with no lesion on MRI were offered systematic prostate biopsy with 8-16 biopsy cores. Results: 546 targeted lesions were biopsied in 349 men. 159 lesions were PIRADS-3, 226 were PIRADS-4, and 161 were PIRADS-5. 141 men with negative mpMRI had systematic prostate biopsy. Of the PIRADS-3 lesions, 84% were benign, 5% had GG 3, 11% had GG 4 and none had GG 5. Of the PIRADS-4 lesions, 44% were benign, 12% had GG 3, 42% had GG 4, and 2% had GG 5. Of the PIRADS-5 lesions, 23% were benign, 2% had GG 3, 62% had GG 4, and 13% had GG 5. Of the men with no lesion on mpMRI, 9% had GG 3, 4% had GG 4, and none had GG 5. Conclusion: Most men with negative mpMRI or PIRADS-3 lesions have benign tissue on biopsy or early PCa and are unlikely to have csPCa. A decision for biopsy vs PSA monitoring in these men should weigh the risks and benefits of biopsy and should be a shared decision taking into consideration individual risk factors for PCa, age and co-morbidities.

Citation Format: Chidi N. Molokwu, Christos Gkikas, Nicola Lee, Joanna Lesniak-Buzon, Faisal Ali, Harry Bardgett. Evaluating the risk of clinically significant prostate cancer in lesions detected on multiparametric MRI of the prostate. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P067.