bluuebunny/crossref_metadata_2025 huggingface dataset:
Hadoop Small Image Processing Technology Based on Big Data Processing and Its Application Effect in Face Feature Extraction and Face Recognition System Design
Authors: Zhang Yidi
Published: June 2022

From standard software to crucial applications, face recognition (FR) is always at the core of many unique advances over the past 20 years. Big data is a rapidly growing collection of data. It is important in many applications such as medical, academic, and industries, and it refers to vast data sources that are hard to analyze, store, and interpret for subsequent procedures. Hadoop is an open-source large data processing platform that stores and analyses data in scalable computer clusters. FR technology is built on Hadoop processing to boost the effectiveness of recognition using MapReduce computing. This paper presents a novel adaptive fine-tuned AdaBoost (AFTA) algorithm to enhance the FR in the Hadoop processing. Collected face data sets are employed in preprocessing stage to normalize and enhance the superiority through the median filter (MF) and contour-based image enhancement (CIE), correspondingly. To handle vast quantities of the data, boosted k-means clustering (BKC) approach is used over the Hadoop servers for the MapReduce process. The binary partition tree (BPT) approach is employed in the segmentation stage to split the data into many subgroups. To lessen the dimension of the data, we use the Gabor filter. To select the consistent features, threshold-based binary particle swarm optimization (T-BPSO) is applied. Then, our proposed technique is utilized in the FR process. Finally, the performance metrics of the proposed technique are examined and compared with existing techniques to accomplish our research with the greatest effectiveness. For accuracy, precision, recall, and F-score, we attained the proposed (AFTA) values of 99.67, 97.13, 95.21, and 94.11, respectively. The outcomes are depicted in graphical representation by employing the MATLAB tool.
Circular RNA circ-ABCB10 Promotes Proliferation and Inhibits Apoptosis of Laryngeal Carcinoma by Inhibiting KLF6
Authors: Chen Zhuxiang , Zhang Zhimin , Zhao Zhang
Published: June 2022

Objective. To explore the effect of circular RNA circ-ABCB10 on the proliferation and apoptosis of laryngeal carcinoma via inhibiting KLF6. Methods. RT-qPCR assay was adopted to detect the expression of circ-ABCB10 and KFL6 in laryngeal carcinoma tissues and cell lines. Cell counting kit-8 (CCK-8) and clone formation assay were employed to detect laryngeal cancer cell viability and proliferation when circ-ABCB10 was silenced or upregulated. In this study, the apoptosis rate was detected by flow cytometry and the protein expression was detected by Western blotting. Wound healing and cross-hole invasion were used to study the migration and invasion of laryngeal cancer cells when circ-ABCB10 was silenced or upregulated. Results. The results of RT-qPCR detection indicated that the expression of circ-ABCB10 in all three laryngeal carcinoma cells was downregulated by 3.2 times compared with that of HaCat cells. There is low expression of circ-ABCB10 in most laryngeal carcinoma tissues, the diagnostic cutoff value of circ-ABCB10 is 0.0008, the area under the curve is 0.718, the sensitivity is 0.981, and the specificity is 0.556. The expression level of KLF6 in laryngeal carcinoma is on the rise, which is significantly higher compared to healthy tissues (

P
<
0.05

); 48 hours after transfection, RT-qPCR analysis confirmed the transfection efficiency, and upregulation of circ-ABCB10 could significantly promote cell proliferation. Compared with the control group, silencing circ-MTCL1 could inhibit cell proliferation, overexpression of circ-ABCB10 promoted cell migration, and downregulation of circ-ABCB10 significantly inhibited cell movement (

P
<
0.001

). Upregulation of circ-ABCB10 significantly enhanced the invasiveness and motility of laryngeal cancer cells, while downregulation of circ-ABCB10 was the opposite. Compared with the KLF6 NC group, KLF6 level increased significantly in the KLF6 group, while cell viability, colony formation, scratch healing rate, invasive cell number, and Bcl-2 expression level decreased significantly in the KLF6 group, while apoptosis rate and Bax expression level increased significantly (

P
<
0.05

). KLF6 level in the si-circ-ABCB10+anti-KLF6 group was significantly lower than that in the si-circ-ABCB10+anti-KLF6-NC group (

P
<
0.05

). Meanwhile, the cell activity, colony formation number, cell scratch healing rate, number of invaded cells, and Bcl-2 all indicated an upward trend, while the cell apoptosis rate and Bax expression indicated a downward trend (

P
<
0.05

). Conclusion. The expression of circ-ABCB10 in laryngeal carcinoma was significantly higher compared to that in paracancerous tissues. Silencing circ-ABCB10 could significantly inhibit the growth and proliferation of laryngeal adenocarcinoma cells, while overexpression of circ-ABCB10 could significantly promote the growth of laryngeal adenocarcinoma cells, probably by inhibiting KLF6 to enhance the proliferation of laryngeal carcinoma and inhibit apoptosis.
Interactive Design and Management Method of Art Teaching System in Colleges and Universities under the Background of Big Data
Authors: Huang Zejun
Published: June 2022

Now, there are some problems in the art teaching system of colleges and universities, such as low management efficiency. However, with the development of big data technology, big data has been applied to the design and management of art teaching systems in colleges. Firstly, a model of art teaching system through the relevant big data was established; then the process of establishing the model was also discussed. Subsequently, based on the interactive design method and Hyperlink-Induced Topic Search (HITS) algorithm as the web design mode, this paper establishes the teaching system management platform and applies it to the art teaching in colleges and universities. The teaching evaluations of students and teachers of different grades were analyzed, and the application prospect of the teaching system design and management platform was obtained. In general, this paper indicates a theoretical reference for optimizing the effect of art teaching and realizing the design and management method of art teaching system under the background of big data.
[Retracted] Dioscorea nipponica Makino Relieves Ovalbumin‐Induced Asthma in Mice through Regulating RKIP‐Mediated Raf‐1/MEK/MAPK/ERK Signaling Pathway
Authors: Wang Weiyi , Xu Liying , Zhou Lingming , Wan Shanhong , Jiang Libin
Published: June 2022

Purpose. Dioscorea nipponica Makino (DNM) is a traditional herb with multiple medicinal functions. This study is aimed at exploring the therapeutic effects of DNM on asthma and the underlying mechanisms involving RKIP‐mediated MAPK signaling pathway. Methods. An ovalbumin‐induced asthma model was established in mice, which was further administrated with DNM and/or locostatin (RKIP inhibitor). ELISA was performed to detect the serum titers of OVA‐IgE and OVA‐IgG1, bronchoalveolar lavage fluid (BALF) levels of inflammation‐related biomarkers, and tissue levels of oxidative stress‐related biomarkers. The expression of RKIP was measured by quantitative real‐time PCR, Western blot, immunohistochemistry, and immunofluorescence. HE staining was used to observe the pathological morphology of lung tissues. The protein expression of MAPK pathway‐related proteins was detected by Western blot. Results. Compared with the controls, the model mice exhibited significantly higher serum titers of OVA‐IgE and OVA‐IgG1, BALF levels of IL‐6, IL‐8, IL‐13, TGF‐β1, and MCP‐1, tissue levels of MDA and ROS, lower BALF levels of IL‐10 and IFN‐γ, and tissue level of GSH. DNM relieved the allergic inflammatory response and oxidative stress in the model mice. DNM also recovered the downregulation of RKIP and the pathological injury of lung tissues in asthma mice. In addition, the Raf‐1/MEK/MAPK/ERK pathway in the model mice was blocked by DNM. Silencing of RKIP by locostatin weakened the relieving effects of DNM on asthma through activating the Raf‐1/MEK/MAPK/ERK pathway. Conclusion. DNM relieves asthma via blocking the Raf‐1/MEK/MAPK/ERK pathway that mediated by RKIP upregulation.
Inhibition of miR-let-7i Induces DC Immature Cells and Improves Skin Graft Tolerance
Authors: Zheng Zhibin , Yang Yurou , Liu Hai , Hu Mingdao , Chen Peng
Published: June 2022

Dendritic cells (DC) initiate the immune response in the body. They can stimulate T cell activation, proliferation, and differentiation and ultimately participate in the immune response and the immune tolerance response. The purpose of this study was to coculture DCs and T cells and subcutaneously inject DCs transfected with miR-let-7i into rhesus monkey transplantations to verify the role of miR-let-7i in allograft immune tolerance. In vitro studies found that the expression of miR-let-7i was upregulated after inducing the maturation of DCs. The low expression of miR-let-7i inhibited the maturation of DCs, promoted the differentiation of T cells into T helper T cells 2 (Th2), and inhibited T helper T cell 1- (Th1-) driven rejection. In vivo studies also obtained similar results, and subcutaneous injection of DCs transfected with miR-let-7i inhibitor prolonged the survival time of allogeneic skin transplantation. Therefore, we conclude that inhibition of miR-let-7i inhibits DC maturation and improves the tolerance of grafted skin.
Poricoic Acid A Inhibits the NF-κB/MAPK Pathway to Alleviate Renal Fibrosis in Rats with Cardiorenal Syndrome
Authors: Chen Wenzhong , Fan Zhiwen , Huang Canhui , Liu Junying
Published: June 2022

Objective. To explore the potential and mechanism of action of poricoic acid A (PAA) in treatment of cardiorenal injury and fibrosis due to cardiorenal syndrome (CRS). Materials and Methods. A CRS rat model was established by transabdominal subtotal nephrectomy (STNx). The experimental group was treated by gavage of PAA (10 mg/kg/day). After 8 weeks of treatment, echocardiography was utilized for detecting heart-related indexes in rats. HE and Masson staining were conducted to detect the degree of pathological damage and fibrosis in rat kidney tissue, respectively. In addition, serum blood urea nitrogen (BUN), serum creatinine (SCr), and 24-hour urine protein were measured biochemically. Also, the levels of inflammatory factors (IL-1β, IL-6, and IL-10) in rat kidneys were measured using ELISA. Western blot was used to examine the expression of NF-κB/MAPK pathway-related proteins. Results. In this study, a CRS rat model was successfully established by STNx surgery. PAA treatment could significantly alleviate the damage of heart and kidney function in CRS rats and reduce the pathological damage of kidney tissue and renal fibrosis. Meanwhile, PAA could also inhibit the renal inflammatory response through downregulating IL-1β and IL-6 levels in the kidney tissue and upregulating IL-10 level. Further mechanism exploration showed that the NF-κB/MAPK signaling pathway was significantly activated in CRS rats, while PAA treatment could markedly inhibit the NF-κB/MAPK signaling pathway activity in CRS rats. Conclusion. PAA can obviously improve the pathological damage and fibrosis of renal tissue in CRS rats and maintain the function of the heart and kidney. The above functions of PAA may be achieved by inhibiting the NF-κB/MAPK signaling pathway activity. Briefly speaking, PAA can serve as a potential drug for CRS treatment.
[Retracted] Surgical Strategy and Prognosis of Pancreatic Neuroendocrine Tumors Based on Smart Medical Imaging
Authors: Huang Ming , Li Jian , Yin Qinghua , Xiong Lixin
Published: June 2022

It is imperative to seize the “golden rescue time” and implement new concepts and new skills in modern trauma rescue. Combining with the development background of smart medical image analysis, this topic focuses on surgical strategies and prognostic measures and studies a serious and difficult disease frequently occurring in middle‐aged and elderly people: pancreatic neuroendocrine tumors. This article uses the comparative test method and sample collection method to collect the medical records of patients with neuroendocrine tumors diagnosed by pathology from July 2010 to January 2018 in the First Affiliated Hospital of X City and analyze the samples with gender and age. At the same time, routine tumor marker examination and the location of NEN in the digestive system were performed. The distribution analysis of EUS characteristics of neuroendocrine tumor mucosa in each site was performed after operation, and the analysis of survival‐related factors was performed during postoperative follow‐up. The experimental data showed that among the tumor causes, WHO tumor grade (p < 0.05) and whether the surgical method was R0 resection (p < 0.05) were associated with prognosis. However, factors such as gender, age, and functional status were associated with prognosis. It has successfully completed the subject of surgical strategy and prognosis of pancreatic neuroendocrine tumors based on smart medical image analysis.
Analytical Solution for the Cubic‐Quintic Duffing Oscillator Equation with Physics Applications
Authors: Salas Alvaro H. , Martínez H Lorenzo J. , Ocampo R David L.
Published: June 2022

The nonlinear differential equation governing the periodic motion of the one‐dimensional, undamped, and unforced cubic‐quintic Duffing oscillator is solved exactly by obtaining the period and the solution. The period is given in terms of the complete elliptic integral of the first kind and the solution involves Jacobian elliptic functions. We solve the cubic‐quintic Duffing equation under arbitrary initial conditions. Physical applications are provided. The solution to the mixed parity Duffing oscillator is also formally derived. We illustrate the obtained results with concrete examples. We give high accurate trigonometric approximations to the Jacobian function cn.
Research on the Construction of Financial Supervision Information System Based on Machine Learning
Authors: Lin Ge , Shangle Ai , Haoxiang Zhao , Jingyue Yu , Junyao Yang
Published: June 2022

In order to fully implement systematic, continuous and effective supervision of financial institutions and promote the safe, steady, and efficient operation of China’s financial system, this research needs to develop a fully intelligent financial supervision information system, so as to take measures to effectively prevent and resolve financial risks. In this paper, based on ML (machine learning), an LSTM (long short-term memory) model with good comprehensive performance is built. This model is different from the existing scorecard model which relies on statistical learning. It not only further reduces the dependence on financial experts, but also has the ability of rapid iteration. The post-loan risk early warning model based on RF (random forest) algorithm is designed. The model parameters are optimized, which makes the risk early warning model have higher accuracy. The results show that when the data amount is 10,000 to 50,000, the accuracy of the model is relatively high when it is input into the model. When the amount of data is low, the overall throughput of the model is still very high. It shows that the pre-warning model of post-lending risk constructed in this paper has a strong risk prediction ability.
Abstract 1019: Address breast cancer equity through virtual community oncology navigation and engagement (vCONET)
Authors: Salinas Manisha
Published: June 2022

The objective of this study is to develop and test a culturally sensitive, inclusive, and accessible virtual navigation model for Black women to promote and improve breast cancer screening behaviors. Breast cancer is among the leading causes of cancer morbidity and mortality globally, and there is a wide range of racial and ethnic disparities across the cancer continuum. Black women continue to have disproportionately high mortality rates compared to Whites, and are more impacted by triple-negative breast cancer and inflammatory breast cancer earlier in their lives and at more advanced stages. Patient navigation, particularly when culturally tailored to the intended population, is highly effective in reducing the complexity of access to care for cancer prevention and treatment. The growing momentum and usage of telehealth and virtual care has significant potential to reach Black women, to promote higher mammography screening and early detection of breast cancer. Virtual patient navigation can provide a safe, engaging, and accessible space to accelerate the application of practical approaches to address health disparities and increase preventive behaviors in underrepresented community. However, limited information exists on specific factors which impact the design, implementation, and receptivity of virtual navigation in Black communities. This study aims to: 2) Develop and test a culturally-adapted prototype of a virtual patient navigation intervention tool for increasing access to breast cancer screening education and promotion for Black women. 1) Use qualitative focus group methodology to explore the beliefs, attitudes, perceptions, and receptivity of community members of program usability and breast cancer awareness, prevention and screening behaviors among Black women. The study will examine social determinants of health that impact potential challenges to access utilization of mammography screening services. Qualitative focus group discussions will be conducted to guide the details of the virtual patient navigation, such as communication channels, specific messaging approaches, and sociocultural factors to integrate, as well as addressing current challenges and needs faced by the community. The results of this study can provide valuable insight to specific needs regarding outreach and access to screening mammography services to underrepresented communities of color to ultimately reduce breast cancer rates. Data collection is ongoing and preliminary results will be presented.

Citation Format: Manisha Salinas. Address breast cancer equity through virtual community oncology navigation and engagement (vCONET) [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 1019.
Abstract 1043: Advances in cystine-dense peptide (CDP) screening and therapeutic applications
Authors: Crook Zachary R. , Girard Emily J. , Sevilla Gregory P. , Brusniak Mi-Youn , Rupert Peter B. , Friend Della J. , Gewe Mesfin M. , Clarke Midori , Lin Ida , Ruff Raymond , Phi Doan , Bandaranayake Ashok , Correnti Colin E. , Mhyre Andrew J. , Nairn Natalie W. , Strong Roland K. , Olson James M.
Published: June 2022

Cystine-dense peptides (CDPs) are a class of drug-like miniproteins that marry many of the advantages of biologics (high affinity and specificity) and small molecule therapeutics (high tissue permeability and low immunogenicity). The beneficial properties of CDPs, and miniproteins in general, have driven interest in therapeutic applications. However, CDP diversity is vast from every clade of life, and properly interrogating “CDP space” requires specialized screening and modeling tools.

With this in mind, we have created an optimized mammalian surface display platform to screen for CDPs of clinical interest using libraries of structurally-diverse native scaffolds optimized for stability. These native CDPs can be structurally modeled, which we did in determining the structures of over 4200 native CDPs. This modeling permits further selection in silico as well as targeted mutagenesis for favorable target-binding capabilities. Hits from these screens are routinely matured to sub-nM affinity. These CDPs can play numerous roles in a drug design pipeline, from an independent drug candidate to a delivery agent for tissue-targeting to a module in a polyspecific biologic. Recent novel CDP candidates have shown promise in immune-oncology space as part of a bispecific T-cell engager targeting PD-L1, where a single 2-week treatment was capable of eliminating subcutaneous PC3 prostate cancer xenograft tumors in 27/30 mice.

Besides bispecifics, future directions for the platform include exploring targeted protein degradation. Additionally, we are expanding upon our previous work on CDPs to explore CNS or tumor delivery of therapeutic cargo. The versatility of CDPs and novel screening tools to rapidly identify and mature candidates of interest can facilitate rapid advancement of CDP therapeutics to address difficult targets in oncology.

Citation Format: Zachary R. Crook, Emily J. Girard, Gregory P. Sevilla, Mi-Youn Brusniak, Peter B. Rupert, Della J. Friend, Mesfin M. Gewe, Midori Clarke, Ida Lin, Raymond Ruff, Doan Phi, Ashok Bandaranayake, Colin E. Correnti, Andrew J. Mhyre, Natalie W. Nairn, Roland K. Strong, James M. Olson. Advances in cystine-dense peptide (CDP) screening and therapeutic applications [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 1043.
Abstract 1049: Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect
Authors: Al Saeedy Dalia , Abuhijjleh Reham K. , Gouda Ahmed , El-Khamisy Sherif F. , Al-Abd Ahmed M.
Published: June 2022

Several semisynthetic analogs of camptothecin (CPT) are used clinically for the treatment of various types of cancers, including colorectal (CRC) cancer, despite their severe, potentially life-threatening toxicities. Studies defined key mutations in the UDP-glycosyltransferase 1 polypeptide A1 (UGT1A1) gene in CRC which play a role in the toxicity and resistance of a broad class of anti-cancer drugs that target DNA topoisomerases. UGT-1A1 is responsible for the glucuronidation and detoxification of the active/toxic metabolite of the topoisomerase I poison, CPT and its analogues, SN-38. Herein, we investigated the potential chemomodulatory effects of a UGT1A1-gene inducer, phenytoin, to the anticancer properties of CPT. The cytotoxic effects of CPT, phenytoin and their combination were evaluated against various colorectal cancer cell lines (SW620, HT29 and HCT116) using sulforhodamine-B assay under normoxic and hypoxic conditions. In HT29, CPT alone and after combination treatment had IC50’s of 0.1235 µM and 0.0269 µM, respectively, under normoxic conditions; and 0.1352 µM and 0.0476 µM, respectively, under hypoxic conditions. In SW620, CPT alone and after combination treatment had IC50’s of 1.9861 µM and 0.0087 µM, respectively, under normoxic conditions; and 1.9549 µM and 0.0024 µM, respectively, under hypoxic conditions. In HCT116, CPT alone and after combination treatment had IC50’s of 0.163 µM and 0.0157 µM, respectively, under normoxic conditions; and 0.1013 µM and 0.0766 µM, respectively, under hypoxic conditions. Flow cytometric analysis after annexin-V/FITC staining showed that the combination treatment significantly induced total apoptosis in all cell lines under investigation. In both HT29 and SW620, the combination treatment significantly suppressed the autophagy compared to CPT treatment alone using acridine orange staining coupled with flowcytometry. Cell cycle analysis using DNA content flowcytometry after PI staining showed significant S-phase arrest in the combination treatment when compared to the control across all cell lines under investigation. This indicates that sub-molecular mechanisms of phenytoin induced chemomodulatory effect to CPT anticancer properties is oxygen tension dependent. Further investigation for the intratumoral metabolism of CPT under hypoxic as well as normoxic conditions and particularly those attributed to UGT-1A1 is currently undergoing.

Citation Format: Dalia Al Saeedy, Reham K. Abuhijjleh, Ahmed Gouda, Sherif F. El-Khamisy, Ahmed M. Al-Abd. Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect [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 1049.
Abstract 1069: OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models
Authors: Bisht Arnima , Cox Murray , Peddaboina Chander Sekhar , Crocamo Michael , Fandi Abderrahim , Rohlff Christian
Published: June 2022

CD205 is a transmembrane glycoprotein, robustly expressed in malignancies from varied histotypes, making it an ideal target for Antibody Drug Conjugate (ADC) therapy. OBT076 is a novel and selective clinical stage ADC with potent activity against CD205-positive liquid and solid tumors. We explored the cellular cytotoxicity profile of combination chemotherapy with OBT076 and two standard-of-care platinum-based compounds, Oxaliplatin (Ox) and Cisplatin (Cis), in preclinical gastric, pancreatic and colorectal cancer models.

A panel of gastric cancer and other solid tumor cell lines were selected, based on mRNA data, for CD205 expression. This was confirmed using flow cytometry. The cell lines were assessed for susceptibility to monotherapy with OBT076, Ox and Cis. Cells lines displaying positive cytotoxic responses were assessed for susceptibility to combination chemotherapy by first treating cells with a single dose of OBT076 for 72 hours, leading to 20% growth inhibition (IC20), and subsequently with either Ox or Cis for 48 hours (OBT-Ox and OBT-CIS, respectively). The ATP-dependent fluorescence-based cellular viability system cell titer-glo was used as the cytotoxic readout.

In our preclinical gastric cancer model, pre-treatment with OBT076 followed by either Ox or Cis displayed synergistic combination effects, reducing the half-maximal inhibitory concentration (IC50) of Ox and Cis by 40- and 10-fold respectively. The resultant cellular cytotoxicity of OBT-Ox and OBT-Cis combination therapy was higher compared to monotherapy with either agent. Moreover, while monotherapy with Ox was less potent than with Cis, OBT-Ox achieved similar potency to OBT076-Cis. For colorectal and pancreatic cancer models, the effects were less pronounced: OBT076-combination therapy increased Platinum sensitivity by 2 to 5 times. No synergistic effects were observed when the treatment order was reversed. These results and those from ongoing in vivo studies in gastric cancer models will be discussed.

In summary OBT076, a clinical stage ADC displays synergistic anti-tumor effects in preclinical gastric cancer models, when used in combination with Ox or Cis. OBT076 is currently being evaluated in the gastric clinical population where Platinum-based therapies remain the mainstay of treatment.

Citation Format: Arnima Bisht, Murray Cox, Chander Sekhar Peddaboina, Michael Crocamo, Abderrahim Fandi, Christian Rohlff. OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models [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 1069.
Abstract 119: Pan-cancer analysis of HIF pathways defines a robust molecular signature that reflects tissue and cellular hypoxia in bulk and single-cell RNA-seq analyses
Authors: Lombardi Olivia , Li Ran , Halim Silvia , Ratcliffe Peter J. , Mole David R.
Published: June 2022

Low levels of tissue oxygen, or intra-tumor hypoxia, is a common feature of many solid cancers in which dysregulated cell proliferation often outstrips the ability to develop new functional blood vessels. Furthermore, hypoxia pathways may also be activated in response to mutation in key tumor suppressor genes or oncogenes. Importantly, in many types of cancer, activation of hypoxia pathways is associated with a clinically aggressive phenotype as well as with resistance to therapy. Indeed, hypoxia drives many of the “hallmarks” of cancer, including cell proliferation, apoptosis, metabolism, immune responses, genomic instability, vascularization, invasion and metastasis. However, the full-range of genes activated by hypoxia varies greatly between cell-types and for many this remains uncharacterized. The key mediator of the cellular transcriptional response to hypoxia is the HIF (hypoxia-inducible factor) family of transcription factors. Here, we generate pan-genomic datasets encompassing HIF ChIP-seq and RNA-seq across cancer cell lines from diverse common tumor types. We then employ integrated analysis of our 72 transcriptome and whole-genome-binding datasets to define a core set of HIF-target genes that are conserved across multiple cell types. We show that these genes can be used to identify HIF activation and tumor hypoxia in bulk RNA-seq analysis of solid tumors, and that this can be applied to large tumor databases (TCGA). We then leverage this analysis to identify tumor-type-specific HIF-associated genes in 32 different cancer types, including those lacking cell-culture models. We further show that these conserved HIF-target genes can be applied to single cell RNA-seq datasets from solid tumors and used to examine intra-tumor heterogeneity in HIF-pathway activation within individual cancer samples. Importantly, using a panel of genes reduces the phenomenon of “drop-out” typically observed in gene-level expression in these datasets. Lastly, applying this gene signature to single cell data allows the hypoxia response to be deconvoluted across diverse cell-types in heterogenous tumor samples. This includes not only the identification of HIF-activity in cancer cells, but also in non-cancer cells within the tumor, thereby allowing the effects of intra-tumor hypoxia on stromal responses (such as tumor angiogenesis) to be studied in vivo in solid tumors.

Citation Format: Olivia Lombardi, Ran Li, Silvia Halim, Peter J. Ratcliffe, David R. Mole. Pan-cancer analysis of HIF pathways defines a robust molecular signature that reflects tissue and cellular hypoxia in bulk and single-cell RNA-seq analyses [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 119.
Abstract 1190: MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer
Authors: Begley Dale A. , Krupke Debbie M. , Neuhauser Steven , Sundberg John , Bult Carol J.
Published: June 2022

The laboratory mouse is the premier mammalian model organism for interrogating the genetic and molecular basis of human cancer and for preclinical investigations into targets for the prevention and treatment of cancer. The distributed and heterogenous nature of information about these model systems makes it difficult for researchers to integrate and interpret the information to determine the state of the field and to identify the most relevant models for basic and preclinical research. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated knowledgebase about genetically defined mouse strains and Patient Derived Xenograft (PDX) models of human cancer. Data in MMHCdb are obtained from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. MMHCdb is built on FAIR data management principles (Findable, Accessible, Interoperable, Reusable). The enforcement of metadata standards and official gene, allele and strain nomenclature ensure accurate and comprehensive search results for cancer models. MMHCdb has long represented data from spontaneous or endogenously induced tumors from genetically defined mice and for PDXs which have been the foundation of basic cancer research and preclinical studies for decades. MMHCdb has expanded to include cancer models such as Diversity Outbred and Collaborative Cross mice which are ideally suited for research into the relationship of genetic variation with cancer susceptibility and for modeling the genetics of variability in treatment responses. The MMHCdb contains over 109,266 curated tumor frequency records for over 8,275 mouse strains. Tumor types in the database have been indexed to over 21,000 literature citations. PDX models and data available in MMHCdb are also accessible from the Patient Derived Cancer Models resource at EMBL-EBI which currently provides information for over 4,000 PDXs (https://cancermodels.org).MMHCdb is supported by NCI R01 CA089713

Citation Format: Dale A. Begley, Debbie M. Krupke, Steven Neuhauser, John Sundberg, Carol J. Bult. MMHCdb: A knowledgebase for the evolving landscape of mouse models of human 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 1190.
Abstract 122: Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy resistance
Authors: Qin Liang , Chung Yoon-Mi , Berk Michael , Naelitz Bryan , Klein Eric , Chakraborty Abhishek A , Sharifi Nima
Published: June 2022

Androgen deprivation therapy depletes circulating testosterone and is the mainstay treatment for advanced prostate cancer by suppressing tumor androgen receptor signaling. Despite initial treatment response, castration-resistant prostate cancer nearly always develops and remains driven primarily by the androgen axis. We investigated how changes in oxygenation affect androgen synthesis. Our study indicates that when chronic hypoxia is coupled to reoxygenation, prostate cancer cells efficiently metabolize androgen precursors to produce androgens and activate AR. Hypoxia induces 3βHSD1, the rate-limiting androgen synthesis regulator, and reoxygenation replenishes necessary cofactors. Therefore, hypoxia and reoxygenation are both essential for potent androgen synthesis. The EGLN1/VHL/HIF2α pathway promoted transcription of HSD3B1 by directly binding the 5’ regulatory region of HSD3B1. HIF2α overexpression facilitated prostate cancer progression, which largely depends on 3βHSD1. PT2399, a specific HIF2α inhibitor, prevented prostate cancer cell proliferation. Our study indicates HIF2α is a potential therapeutic target in prostate cancer.

Citation Format: Liang Qin, Yoon-Mi Chung, Michael Berk, Bryan Naelitz, Eric Klein, Abhishek A Chakraborty, Nima Sharifi. Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy 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 122.
Abstract 1220: Accurately genotyping HLA and KIR alleles using cfDNA assay and k-mer based algorithm for immunotherapy
Authors: Gnerre Sante , Tsui Brian Yik Tak , Jiang Tingting , Kim Yvonne , Ma Dustin , Wu Indira , Nagy Rebecca , Chuang Han-Yu
Published: June 2022

Background: HLA and KIR genotypes show great promise as emerging biomarkers for immune checkpoint inhibitors (ICIs) and understanding patient prognosis. Multiple studies have shown that HLA-I heterozygosity and high sequence divergence across alleles positively correlates with response to ICIs. However the high degree of polymorphism and allele sequence similarities in HLA and KIR present a challenge to accurate allele calling. To address these difficulties we developed kmerizer, a novel allele caller optimized for short fragments, such as reads from a cfDNA assay.

Methods: We tested kmerizer on MHC class1 and class2 genes, and on KIR genes, on both simulated datasets and real samples (cell lines and plasma samples). To assess the capability of the algorithm to distinguish highly homologous allele pairs, we simulated cfDNA-like fragments with errors on randomly selected allele pairs, and on allele pairs with a high level of homology. Twelve plasma samples and 19 reference cell lines fragmented to cfDNA size were analyzed using a NGS cfDNA assay. For plasma samples, paired buffy coats were sent to an external vendor for HLA typing using multiplex PCR-based amplicon and sequenced by 300bp paired-end reads.

Results: Of the 19 cell lines and 12 plasma samples for HLA typing (A, B, C, and DQB1 loci), kmerizer delivered 100% sensitivity with 98% specificity. On the simulated dataset, kmerizer achieved 99% sensitivity and specificity on all the MHC class1 and class 2 loci, and 90% sensitivity and specificity on all KIR loci, for both homozygous and heterozygous pairs. The novel allele caller kmerizer also demonstrated a lighter footprint on computational resource need: one deep-sequencing plasma sample on average can be processed in less than 2 minutes which is about 15 times faster than the most commonly used HLA typing tool HISAT21, which does not support KIR typing.

Conclusions: As utilization of ICIs increases, the use of genetic and genomic information to accurately identify patients more likely to respond to ICIs will be critical. kmerizer is a fast and highly sensitive and specific allele caller, and it can effectively call alleles on both HLA and KIR.

References: [1] Kim, D., Paggi, J. M., Park, C., Bennett, C., & Salzberg, S. L. (2019). Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nature biotechnology, 37(8), 907-915.

Citation Format: Sante Gnerre, Brian Yik Tak Tsui, Tingting Jiang, Yvonne Kim, Dustin Ma, Indira Wu, Rebecca Nagy, Han-Yu Chuang. Accurately genotyping HLA and KIR alleles using cfDNA assay and k-mer based algorithm for immunotherapy [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 1220.
Abstract 125: The role of oxidative stress on the polyaneuploid cancer cell state in metastatic cancer
Authors: Li Melvin , Amend Sarah R. , Pienta Kenneth J.
Published: June 2022

Metastatic cancer is responsible for 90% of cancer deaths and is currently incurable due to resistance to all systemic anticancer therapies. Our lab hypothesizes that this resistance is driven by a subpopulation of cells in the tumor that enter the polyaneuploid cancer cell (PACC) state by undergoing a polyaneuploid transition (PAT). Cells in the PACC state are found in cell culture, xenograft, and genetically engineered mouse models, as well as in clinical samples. We have shown that cancer cells are induced to undergo a PAT upon exposure to external stress, such as chemotherapeutic treatments that include platinum-based therapy, etoposide, and taxane drugs. In addition, cells that enter the PACC state are resistant to that stress. One mechanism of therapy-induced cancer cell death is due to the resultant oxidative stress. We hypothesize that this oxidative stress drives a subset of cancer cells to undergo the PAT, thus enabling them to persist following treatment. To test the effects of oxidative stress on the PACC state, we treated cancer cells with cisplatin to induce the PAT and measured mitochondrial function and levels of reactive oxygen species (ROS). Using fluorescence microscopy with live-cell mitochondrial and ROS dyes, we showed that cells in the PACC state have higher mitochondrial mass, exhibit two to three times more mitochondrial activity per total mitochondria, and have over a five-fold increase in intracellular ROS levels per unit area when compared to typical cancer cell populations that they arise from. Moreover, PACCs exhibit a three-fold increase in their oxygen consumption rate and have higher expression of genes related to mitochondrial respiration and antioxidant pathways when compared to cells that did not undergo the PAT. Taken together, this suggests that cells in the PACC state may have a higher tolerance for stress since they can withstand higher amounts of ROS that result from both therapy and mitochondrial activity without exhibiting cell death. Our goal is to investigate how oxidative stress affects PACC formation and identify mechanisms of how PACCs manage stress to ultimately target these cells. If we can prevent PACC formation or find a method to eliminate cells in the PACC state, we can attack and resolve the issue of therapeutic resistance and incurability of metastatic cancer.

Citation Format: Melvin Li, Sarah R. Amend, Kenneth J. Pienta. The role of oxidative stress on the polyaneuploid cancer cell state in metastatic 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 125.
Abstract 1305: Tumor Treating Fields (TTFields) promote a pro-inflammatory phenotype in macrophages
Authors: Barsheshet Yiftah , Brant Boris , Voloshin Tali , Volodin Alexandra , Koren Lilach , Koltun Bella , Klein-Goldberg Anat , Zemer-Tov Efrat , Kan Tal , Paz Rom , Giladi Moshe , Weinberg Uri , Palti Yoram
Published: June 2022

Introduction: Tumor Treating Fields (TTFields) are low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields that are delivered non-invasively to tumors. TTFields therapy is approved in the US and Europe for the treatment of patients with glioblastoma or mesothelioma. In addition to an established anti-mitotic mechanism of action, previous studies have shown that TTFields-induced cell death stimulates anti-tumor immunity and promotes the maturation of dendritic cells. In the current research, the effect of TTFields on the polarization of unstimulated macrophages and the phenotypic regulation of M1 and M2 macrophages was investigated.

Methods: Bone marrow-derived macrophages (BMDMs) were generated from the femurs and tibias of 5-8-week-old Balb\C mice. TTFields (150 kHz) were applied for 24 h to unstimulated (M0 phenotype) BMDMs and BMDMs stimulated with LPS+IFN-γ (M1 polarization) or IL-4 (M2 polarization). Flow cytometry was used to identify surface expression of the macrophage biomarker F4/80 and activation markers CD80, major histocompatibility complex class II (MHC II), inducible nitric oxide synthase (iNOS), CD206, and ARG-1. Multiplexed secretion assays were conducted to quantify CXCL1 (KC), IL-18, IL-23, IL-12p70, IL6, TNF-α, IL-12p40, free active TGF-β1, CCL22 (MDC), IL-10, IL-6, G-CSF, CCL17 (TARC), and IL-1β as to examine the heterogeneity of the stimulated macrophages.

Results: The percentage of cells expressing the pro-inflammatory M1 markers CD80+ and MHC IIhigh was significantly increased following application of TTFields to polarized (M1 or M2) or unpolarized BMDMs, while expression of the M2 markers CD206 and ARG-1 was significantly decreased. A pro-inflammatory secretion pattern, with increased levels of CXCL1, IL-18, IL-23, IL-12p70, TNF-α, IL-12p40, CCL22, G-CSF, CCL17 and IL-1β was observed in cell supernatants of M1 and M2 stimulated BMDMs, and unstimulated M0 BMDMs, following delivery of TTFields. Taken together, TTFields polarized unstimulated BMDMs to the M1 phenotype, and induced phenotype skewing of M2 polarized BMDMs to the M1 phenotype.

Conclusions: TTFields therapy displays a novel immunoregulatory role in macrophage polarization and promotes a pro-inflammatory phenotype. Future investigations will focus on defining the underlying mechanism of this phenotypic skewing.

Citation Format: Yiftah Barsheshet, Boris Brant, Tali Voloshin, Alexandra Volodin, Lilach Koren, Bella Koltun, Anat Klein-Goldberg, Efrat Zemer-Tov, Tal Kan, Rom Paz, Moshe Giladi, Uri Weinberg, Yoram Palti. Tumor Treating Fields (TTFields) promote a pro-inflammatory phenotype in macrophages [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 1305.
Abstract 1317: The role of PAX8 in copy number-high uterine cancers: Inflammatory cytokine modulation
Authors: Karnolt Lauren , Okuka Maja , Read Susan , Dou Yongchao , Zhang Bing , Rutherford Thomas J. , Anderson Matthew L.
Published: June 2022

Paired Box 8 (PAX8) is a transcription factor clinically utilized as a histologic biomarker for cancers arising in tissues derived from the embryonic Mullerian tract. Although dysregulated PAX8 expression has recently been shown to promote the growth of ovarian and renal cancers, its role in uterine cancer remains poorly understood. Here, we hypothesized that overexpression of PAX8 promotes uterine cancer growth and metastasis. When 108 uterine cancer specimens were evaluated by mass spectroscopy, the highest levels of PAX8 were found in TP53-mutated, copy number (CN)-high specimens. In vitro, we found that targeting PAX8 expression resulted in decreased rates of both proliferation and apoptosis in multiple representative cell lines (ARK2 and ARK4). PAX8 knockdown also negatively impacted rates of in vitro migration and invasion assessed using commercially available Boyden chamber assays. Using whole-exome and transcriptomic profiling performed by Next Generation Sequencing, we found that PAX8 knockdown resulted in increased expression of 268 gene products by >1.5-fold, and decreased expression of 179 gene products (adj p<0.01; FDR<1%). Specific gene products whose expression was altered by targeting PAX8 expression included IL-1β, IL-11, and MUC1. With qPCR, we confirmed that levels of IL-1β were 13.8-fold and 3.4-fold higher in cultures of ARK2 and ARK4 cells transfected with PAX8-specific siRNA, respectively, when compared to cultures transfected with a nontargeting control (p<0.01). Using these transfections, we also confirmed increased expression of IL-11 in ARK2 cells (RQ=3.22, p<0.01) and ARK4 cells (RQ = 2.28, p<0.01), and increased expression of MUC1 in ARK2 cells (RQ=1.13, p<0.01). Collectively, our findings demonstrate that PAX8 regulates the proliferation of CN-high uterine cancers, potentially through the regulation of IL-1β expression. Notably, our data also implicates PAX8 expression as a key mediator of the inflammatory response to these aggressive cancers. Key differences in PAX8’s relationship with proliferation and these select few signaling molecules, compared to what is seen in other PAX8-dependent cancers, suggest unique roles for PAX8 as an oncogene in uterine cancers.

Citation Format: Lauren Karnolt, Maja Okuka, Susan Read, Yongchao Dou, Bing Zhang, Thomas J. Rutherford, Matthew L. Anderson. The role of PAX8 in copy number-high uterine cancers: Inflammatory cytokine modulation [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 1317.
Abstract 1332: Adar1 impacts pancreatic homeostasis and pancreatic tumor biology
Authors: Rupani Dhwani , Cowan Robert , Gates Chris , McAllister Florencia , Rhim Andrew
Published: June 2022

Adenosine-to-Inosine (A-to-I) RNA editing is mediated by Adenosine deaminase acting on RNA (Adar) enzymes. The resulting A-to-I edit in RNA alters its post-transcriptional processing making Adar1 a critical regulator of gene expression. In line with its role in gene regulation, Adar1 has been implicated in development and organogenesis. We investigated the role of Adar1 in pancreatic development and homeostasis, and observed that though Adar1 is not required for pancreatic development, it is essential for pancreatic homeostasis. We observed that loss of Adar1 can stimulate a Mavs-mediated innate immune pathway and results in influx of immune cells in the pancreas. Pancreatic tumors are notorious for their immunosuppressive microenvironment. Since loss of Adar1 can activate a Mavs-mediated innate immune pathway, we next investigated the role of ADAR1 in human pancreatic ductal adenocarcinoma cell lines. We developed a bioinformatics pipeline, Cancer RSNV (RNA Single Nucleotide Variant) Identifier and Annotator (CRIDA) to identify A-to-I RNA edits in pancreatic cancer and observed wide-spread ADAR1-mediated RNA editing in pancreatic cancer cells. We analyzed genes that are differentially regulated between ADAR1 knockdown and control cells, and observed a differential immune signaling. Together, our data suggests that Adar1 is important for pancreatic homeostasis and tumor biology.

Citation Format: Dhwani Rupani, Robert Cowan, Chris Gates, Florencia McAllister, Andrew Rhim. Adar1 impacts pancreatic homeostasis and pancreatic tumor biology [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 1332.