bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5824: Fully-humanized, bioengineered miR-1291 modulates key nutrient transport and metabolism to control tumor metabolism
Authors: Tu Mei-Juan , Gonzalez Frank J. , Yu Ai-Ming 
Published: June 2022

Abstract
Tumor progression is accompanied by metabolic reprogramming to allow carcinoma cells to access essential nutrients under the tumor microenvironment. To meet energetic and material needs for high-rate proliferation and tumorigenesis, cancer cells generally rely more heavily on vital nutrients (e.g., glucose, amino acids, and vitamins) than normal cells. Therefore, controlling nutrient transport and metabolism in cancer cells is a promising therapeutic strategy. Our previous studies have suggested that microRNA-1291-5p (miR-1291-5p or miR-1291) is downregulated in pancreatic cancer (PC) cells and acts as a tumor suppressor. The current study is to delineate the role of miR-1291 in the control of PC cell metabolism and develop miR-1291 therapy. We first employed our newly-invented RNA bioengineering technology to achieve high-level and large-scale, in vivo fermentation production of a fully-humanized biologic miR-1291 agent at a high degree of homogeneity (&gt; 4 mg BioRNA per liter of culture and &gt; 97% purity). RNA sequencing studies revealed that BioRNA/miR-1291 was selectively processed to target miR-1291-5p to modulate the transcriptome in PC cells. Proteomics study showed that a number of proteins were reduced remarkably in AsPC-1 cells by biologic miR-1291-5p, among which PNPO, an enzyme that mediates the synthesis of essential nutrient vitamin B6 (VB6), was revealed as a leading target of miR-1291-5p. Besides PNPO and the previously-reported glucose transporter SLC2A1/GLUT1, amino acid transporter SLC7A5/LAT1 was verified as a direct target for miR-1291-5p. Downregulation of PNPO, LAT1, GLUT1 protein expression by biological miR-1291 led to sharp alteration of homeostasis of glucose, amino acids, and VB6 in human PC cells, and subsequent suppression of glycolysis capacity and mitochondrial function as well as the increase of oxidative stress. Combination treatment with bioengineered miR-1291 and 5-FU exerted strong synergism in the inhibition of PC cell and organoid proliferation in vitro. In addition, miR-1291 mono- and combination therapy were effective to control tumor growth in pancreatic cancer patient-derived xenograft (PDX) mouse models. These results demonstrate a critical role for miR-1291 in the regulation of PC cell metabolism which provides insight in developing new therapeutic strategies for PC.
Citation Format: Mei-Juan Tu, Frank J. Gonzalez, Ai-Ming Yu. Fully-humanized, bioengineered miR-1291 modulates key nutrient transport and metabolism to control tumor metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5824.
Abstract 5829: Characterizing cargoes of extracellular vesicles in promoting breast cancer growth and chemotherapy resistance
Authors: Ngue Harrison , Kim Hyejin , Vasudevan Shobha 
Published: June 2022

Abstract
Cancer cells employ bidirectional cell communication to maintain growth and metastasis in the tumor microenvironment. One mechanism of communication that has become increasingly appreciated is the secretion of extracellular vesicles (EVs), heterogeneous multi-signal messengers that support cancer dissemination through the transfer of biomolecules such as oncoproteins and noncoding RNA species. However, little is understood about EVs in relation to chemotherapy resistance. In this study, we profiled two different breast cancer cell lines: 1) BT549 (triple negative), treated with gemcitabine and paclitaxel chemotherapy, and 2) MCF7 (estrogen receptor-positive), treated with palbociclib and fulvestrant, compared to their wild-type states. EVs were collected from these cells using tangential flow filtration and quantified with Brownian motion-based nanoparticle tracking analysis and microfluidic resistive pulse sensing, and profiling of RNA and peptide markers was completed through RT-qPCR and Western blotting, respectively. Initial data showed that representative mitochondrial ribosomal genes mt12S and MRPS14 were among the most upregulated RNAs in our drug-exposed EV samples, indicating that extracellular transfer of mitochondrial materials plays a role in cancer growth under chemotherapy stress. These findings were supported by prior genetic research at the Vasudevan laboratory, in which a set of mitochondrial ribosomal RNAs was found to be upregulated in cytosine arabinoside-induced chemoresistant acute monocytic leukemia cells, as well as by the recent discovery of mitovesicles, a novel population of EVs that originate from mitochondria. Through additional efforts to isolate further subtypes of EVs, the mechanisms by which these mitochondrial cargoes promote chemoresistant phenotypes will be uncovered.
Citation Format: Harrison Ngue, Hyejin Kim, Shobha Vasudevan. Characterizing cargoes of extracellular vesicles in promoting breast cancer growth and chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5829.
Abstract 5843: Truncated APC & AXIN2 expression contribute to maintaining β-catenin/WNT signaling at the “Just Right” level for CRC cell proliferation
Authors: Zhang Chi , Facey Caroline O. , Funk Katherine , Opdenaker Lynn M. , Boman Bruce M. 
Published: June 2022

Abstract
Adenomatous polyposis coli (APC) mutation leads to increased WNT signaling and stem cell overpopulation, which drives development of colorectal cancer (CRC). APC mutations often encode a truncated protein that has loss of APC’s domains that mediate APC interaction with AXIN2. A substantial body of scientific evidence indicates that truncated APC is essential for CRC cell proliferation by maintaining beta-catenin levels and WNT signaling at the “just right” level (known as the “Just Right” Hypothesis). Thus, AXIN2 is of particular interest because both wild-type APC and AXIN2 are part of the beta-catenin destruction complex, which is essential for tumor-suppressing ability.
Hypothesis: the degree of AXIN2 expression, in the context of truncated APC, is critical to maintain WNT-signaling activity at the “just right” level which is optimal for CRC cell proliferation. Accordingly, we evaluated the effect of AXIN2 levels in CRC cells that contain APC protein-truncating mutations on WNT signaling (Top Flash assay), expression of WNT-targeted genes, and CRC cell proliferation and differentiation. We found that modulating AXIN2 expression altered WNT signaling, expression of WNT-targeted genes, and CRC cell proliferation in CRC cell lines with different APC-truncation causing mutations. Indeed, western blot results showed that knock down of AXIN2 gene expression increased truncated-APC and AXIN1 protein expression, and decreased expression of several WNT-target genes (e.g. LGR5, CD44, c-Jun, c-Myc, Cyclin D1), particularly genes that have reported roles in cell cycle regulation. These findings were consistent with our independent bioinformatics analyses of NCI TCGA RNA-seq data on CRC patients. Overall, our study suggests that i) The beta-catenin destruction complex is still functional at a certain level despite APC-truncating mutations; ii) Perturbing AXIN2 expression leads to changes in WNT-signaling activity that deviate from a level that is “just right” for malignant cell proliferation, likely by affecting the function of the destruction complex; iii) Deviation from “just right” WNT signaling levels alters WNT-target gene expression and diminishes the ability of APC-mutant CRC cells to maintain uncontrolled proliferation.
Citation Format: Chi Zhang, Caroline O. Facey, Katherine Funk, Lynn M. Opdenaker, Bruce M. Boman. Truncated APC & AXIN2 expression contribute to maintaining β-catenin/WNT signaling at the “Just Right” level for CRC cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5843.
Abstract 5846: Comprehensive genomics-based screening of novel therapeutic targets and biomarkers for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: June 2022

Abstract
As the number of patients with lung cancer who show good response to standard therapies is limited, new molecular targeted therapies and biotherapies with predictive biomarkers are urgently required. We have been developing molecular therapies targeting oncoproteins with their companion diagnostics as follows, i) To identify overexpressed genes in 120 lung cancers by gene expression microarray analysis of 27,648 genes, ii) To verify the candidate genes for their scarce expression in 23 normal organs, iii) To validate the clinicopathologic significance of their protein expression by tissue microarray covering hundreds of lung cancers including non-small cell lung cancers (NSCLCs), and iv) To examine whether they are important for the growth or invasion of cancer cells by using siRNAs and/or small molecule inhibitors. By this screening system, we identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis for lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Our comprehensive genomics-based screening might be useful to select the novel biomarkers and therapeutic targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies against lung cancer.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Comprehensive genomics-based screening of novel therapeutic targets and biomarkers for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5846.
Abstract 5854: Therapeutic targeting of p73-activated c-FLIP switches cell fate from growth arrest and survival to apoptosis in p53-deficient cancer cells
Authors: Zhang Shengliang , El-Deiry Wafik S. 
Published: June 2022

Abstract
The tumor suppressor p73, a member of the p53 family, transcriptionally activates numerous p53-target genes in cell cycle regulation and apoptosis. Therapeutic activation of p73 can restore p53-signaling in mutant p53-expressing cancer cells effectively bypassing the p53 deficiency. In addition to pro-apoptotic signaling, outcomes of p73 activation contain survival signals and this may provide insights in cell fate outcomes between cell survival and apoptosis after cellular stress. We report that cellular FLICE inhibitory protein (c-FLIP), a master antiapoptotic factor, is a novel transcriptional target of p73. To test if p73 regulates c-FLIP expression in p53-deficient cancer cells, we overexpressed p73 in p53-deficient cancer cells using p73-adenovirus. Overexpression of p73 dramatically increased c-FLIP at the protein and RNA levels. The effect of p73 on c-FLIP upregulation was blocked by knock-down of p73. ChIP assay showed that p73 binds to the c-FLIP promoter in a p73-level dependent manner. Furthermore, a luciferase reporter assay showed that p73 increased the c-FLIP-L-promoter-mediated luciferase reporter expression in p53-deficient cancer cells. To test the effect of the outcomes of p73 signaling on cell survival or death, we performed cell viability assay and found that p73 reduces cell viability in a p73-level dependent manner. We found an increase of both p21 and c-FLIP at the protein levels in response to overexpression of p73 in p53-deficient cancer cells, but no cleaved-PARP was detected and flow cytometric analysis showed the cells were arrested in G1 phase. These results suggest that p73 arrests the cell cycle and prevents apoptosis at the tested levels of p73. We knocked down c-FLIP using siRNA in p53-deficient cancer cells, and found that knockdown of c-FLIP enhanced cleaved-PARP, cleaved caspase- 3 and -8 correlated to high level of apoptotic signaling with Noxa and puma upregulation in response to the overexpression of p73. Our results suggest that the depletion of c-FLIP primes cellular apoptosis switching from p73-induced cell cycle arrest (cell survival) and sensitizes cells to p73-induced apoptotic signals in p53-deficient cells. The cell fate decision following p73 activation is determined by the adjustment of the balance of outcomes of p73 activation between p73-induced pro-apoptotic signaling and c-FLIP expression in p53-deficent cancer cells. Our discovery of the new function of p73 to upregulate c-FLIP provides a rationale for depleting c-FLIP to improve antitumor efficacy of p73-targeting cancer therapy.
Citation Format: Shengliang Zhang, Wafik S. El-Deiry. Therapeutic targeting of p73-activated c-FLIP switches cell fate from growth arrest and survival to apoptosis in p53-deficient cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5854.
Abstract 5860: Five-year survival of patients with late stage prostate cancer: Comparison of the military health system with the US general population
Authors: Lin Jie , Nousome Darryl , Jiang Jiji , Chesnut Gregory , Shriver Craig , Zhu Kangmin 
Published: June 2022

Abstract
While the five-year survival for local and regional prostate cancer is nearly 100%, it decreases dramatically for advanced (stages III and IV) prostate cancer. Access to health care is an important factor that affects cancer prognosis. The Military Health System (MHS) provides universal health care to beneficiaries. However, it is unclear whether the universal care translates into improved survival among patients with advanced prostate cancer. We compared survival of patients with advanced prostate cancer between the MHS and the U.S. general population. The MHS patients (N= 5,379) were identified from the Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR). Patients in the U.S. general population (N=21,516) were identified from the Surveillance, Epidemiology, and End Results (SEER) program. All patients were diagnosed between January 1, 1987 and December 31, 2013. The two populations were matched on age (within 5 years), race, and diagnosis year. Multivariable Cox regression hazard model was used to estimate hazard ratios (HRs) for ACTUR compared to SEER. ACTUR patients exhibited longer 5-year survival than matched SEER patients (HR=0.74, 95% CI=0.67-0.83), after adjustment for the potential confounders. In stratified analysis, the improved survival was observed for ages 50 years or older, both white and black races, all tumor stages, and grades. In stratified analysis by treatment receipt, the improved survival of ACTUR patients compared to SEER patients remained regardless of the receipt of surgery or radiation treatment. Our results suggested that MHS beneficiaries with advanced prostate cancer had longer survival than their counterparts in the U.S. general population. Universal health care in the MHS might translate into improved survival for advanced prostate cancer.
Disclaimers: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions, or policies of the USUHS, HJF, the DoD or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.
Citation Format: Jie Lin, Darryl Nousome, Jiji Jiang, Gregory Chesnut, Craig Shriver, Kangmin Zhu. Five-year survival of patients with late stage prostate cancer: Comparison of the military health system with the US general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5860.
Abstract 5862: Racial disparities in pancreatic cancer: A quantitative proteo-genomic analysis
Authors: Chatterjee Digonto , Hester Jack , Srivastava Meera , Bera Alakesh 
Published: June 2022

Abstract
Pancreatic cancer remains a major health concern, being among the most deadly forms of cancer. It is the seventh most common cancer, yet it is the third leading cause of cancer deaths in the United States. It is estimated that in 2021, 48,220 patients will die from pancreatic cancer. Risk factors for pancreatic cancer include smoking, diabetes, obesity, chronic pancreatitis, and family history. Over 80% of the patients present with metastatic disease. Despite advances in chemotherapy, the average survival remains less than 5 years even after surgery. Genetic research on pancreatic cancer has generally only focused on familial pancreatic cancer, which is only 10% of all pancreatic cancer patients. This study focuses on finding genes that impact the survival of pancreatic cancer patients based on race, with the goal of finding genes that are race specific and can be used as biomarkers and potential targets to develop personalized treatment options. All datasets for pancreatic cancer in cBioPortal were used for this study. The data were then stratified based on race information for the patients. Three (3) racial categories, 1) White 2) African American and Black, and 3) Asian were chosen. Our analysis finds that White, African Americans and Asians have distinct copy number alterations, more specifically amplifications in specific genes, with GATA6, RECQL4, and MIB1 being only altered in White patients, PKD1L1, GARS1, and NEUROD6 only altered in Black & African American patients, and the entire 4p16.3 cytoband of genes (39 in total), only altered in Asian patients. Patients with alterations in these unique genes also had poor survival. Using the Protein Atlas, MD Anderson Cell Lines Project (MCLP) dataset and genecards.org data, we identified potential drug candidates that target the proteins encoded by these genes. Our study clearly demonstrates that race specific genetic alterations exist in pancreatic cancer and provides a foundation for the development of race specific diagnostic/prognostic biomarkers and targeted therapeutic options with better survival outcomes.
Citation Format: Digonto Chatterjee, Jack Hester, Meera Srivastava, Alakesh Bera. Racial disparities in pancreatic cancer: A quantitative proteo-genomic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5862.
Abstract 5895: Examining the association between arsenic exposure and cancer risk among Canadian adults
Authors: Pullella Katherine , Chang Vicky C. , Harris Shelley A. , Hanley Anthony J. , McLaughlin John R. , Lubinski Jan , Narod Steven A. , Kotsopoulos Joanne 
Published: June 2022

Abstract
Background: Arsenic is a highly prevalent environmental toxin and an established carcinogen for cancers of the skin, bladder, and lung. Emerging evidence also suggests that arsenic exposure may be a risk factor for breast and other cancers. Previous studies have been conducted in populations with endemically high levels of arsenic; however, the impact of chronic exposure to low levels is not known. Thus, the purpose of this study was to describe the arsenic exposure in Canadian adults and to evaluate the association between arsenic status and cancer risk.
Methods: The Canadian Health Measures Survey (CHMS) is an ongoing, nationally representative survey that collects self-reported and objective health measures, including biomonitoring data, from participants in biennial cycles. This analysis utilized total, inorganic and organic urinary arsenic biomarkers (µg/L) from Cycles 1-5 (2007-2017) of the CHMS. Incident cancers were ascertained through a linkage to the Canadian Cancer Registry. Arsenic exposure was described using weighted percentiles, and Cox proportional hazards regression models were used to estimate the association between arsenic exposure and cancer risk (overall and site-specific).
Results: This analysis included 10,000 individuals, aged 18-80. The median total urinary arsenic level was 7.5 ug/g of creatinine. Preliminary models showed that levels of inorganic arsenic exposure above the geometric mean (&gt; 4.5 µg/L) were associated with a 3-fold increased risk of developing any cancer (HR = 3.58; 95%CI 1.63-7.85), compared to those with lower levels. Site-specific risk modelling is ongoing and preliminary results will be presented.
Significance: This study found inorganic arsenic exposure may be associated with an increased risk of developing cancer. To our knowledge, this study is the first to ascertain national estimates of arsenic exposure and provide insight on the relationship between arsenic exposure and cancer risk in Canadian adults. These findings are critical for developing population-level interventions to reduce the Canadian, and global, cancer burden.
Citation Format: Katherine Pullella, Vicky C. Chang, Shelley A. Harris, Anthony J. Hanley, John R. McLaughlin, Jan Lubinski, Steven A. Narod, Joanne Kotsopoulos. Examining the association between arsenic exposure and cancer risk among Canadian adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5895.