Publications by authors named "Surinder K Batra"

420 Publications

Endothelin-axis antagonism enhances tumor perfusion in pancreatic cancer.

Cancer Lett 2022 Jun 19:215801. Epub 2022 Jun 19.

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address:

Delivery of therapeutic agents in pancreatic cancer (PC) is impaired due to its hypovascular and desmoplastic tumor microenvironment. The Endothelin (ET)-axis is the major regulator of vasomotor tone under physiological conditions and is highly upregulated in multiple cancers. We investigated the effect of dual endothelin receptor antagonist bosentan on perfusion and macromolecular transport in a PC cell-fibroblast co-implantation tumor model using Dynamic Contrast Enhancement Magnetic Resonance Imaging (DCE-MRI). Following bosentan treatment, the contrast enhancement ratio and wash in rates in tumors were two- and nine times higher, respectively, compared to the controls, whereas the time to peak was significantly shorter (7.29 ± 1.29 min v/s 22.08 ± 5.88 min; p = 0.04). Importantly, these effects were tumor selective as magnitude of change for these parameters was much lower in muscles. Bosentan treatment also reduced desmoplasia and improved intratumoral distribution of high molecular weight FITC-dextran. Overall, these findings support that targeting the ET-axis can serve as a potential strategy to selectively enhance tumor perfusion and improve the delivery of therapeutic agents in pancreatic tumors.
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http://dx.doi.org/10.1016/j.canlet.2022.215801DOI Listing
June 2022

Anti-mucin 4 fluorescent antibody brightly targets colon cancer in patient-derived orthotopic xenograft mouse models: A proof-of-concept study for future clinical applications.

Am J Surg 2022 May 31. Epub 2022 May 31.

Department of Surgery, University of California San Diego, 9300 Campus Point Dr, La Jolla, CA, 92037, USA; VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA, 92161, USA. Electronic address:

Background: There is a high rate of positive surgical margins with resection of liver metastases in colorectal cancer (CRC). The present study reports using a fluorescent anti-mucin 4 (MUC4) antibodies to label primary CRC and liver metastases to better visualize tumor margins in mouse models.

Methods: Western blotting for MUC4 protein expression of normal colon and CRC tumor lysates was performed. Orthotopic primary and liver metastatic CRC mouse models received anti-MUC4 antibody conjugated to IR800 (MUC4-IR800). Mice were sacrificed and imaged after 48 hours.

Results: Western blotting demonstrated increased MUC4 expression in a human CRC cell line and patient-derived primary and liver-metastatic CRCs. The LS174T orthotopic primary CRC model tumor to background ratio (TBR) was 2.04 (±0.35). The patient-derived orthotopic xenograft (PDOX) primary CRC model TBR was 2.17 (±0.35). The PDOX liver metastasis model TBR was 1.56 (±0.53).

Conclusion: MUC4-IR800 provided bright labeling of primary and liver tumors in CRC orthotopic mouse models, demonstrating their future clinical potential for margin visualization in fluorescence guided surgery.
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http://dx.doi.org/10.1016/j.amjsurg.2022.05.036DOI Listing
May 2022

The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights.

Biochim Biophys Acta Rev Cancer 2022 Jun 6;1877(4):188737. Epub 2022 Jun 6.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. Electronic address:

The dysregulation of leukemia inhibitory factor (LIF) and its cognate receptor (LIFR) has been associated with multiple cancer initiation, progression, and metastasis. LIF plays a significant tumor-promoting role in cancer, while LIFR functions as a tumor promoter and suppressor. Epithelial and stromal cells secrete LIF via autocrine and paracrine signaling mechanism(s) that bind with LIFR and subsequently with co-receptor glycoprotein 130 (gp130) to activate JAK/STAT1/3, PI3K/AKT, mTORC1/p70s6K, Hippo/YAP, and MAPK signaling pathways. Clinically, activating the LIF/LIFR axis is associated with poor survival and anti-cancer therapy resistance. This review article provides an overview of the structure and ligands of LIFR, LIF/LIFR signaling in developmental biology, stem cells, cancer stem cells, genetics and epigenetics of LIFR, LIFR regulation by long non-coding RNAs and miRNAs, and LIF/LIFR signaling in cancers. Finally, neutralizing antibodies and small molecule inhibitors preferentially blocking LIF interaction with LIFR and antagonists against LIFR under pre-clinical and early-phase pre-clinical trials were discussed.
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http://dx.doi.org/10.1016/j.bbcan.2022.188737DOI Listing
June 2022

Editorial: Metastatic Castration Resistant Prostate Cancer: Prognosis and Treatment.

Front Oncol 2022 13;12:913630. Epub 2022 May 13.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States.

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http://dx.doi.org/10.3389/fonc.2022.913630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136391PMC
May 2022

DNA-gold nanoprobe-based integrated biosensing technology for non-invasive liquid biopsy of serum miRNA: A new frontier in prostate cancer diagnosis.

Nanomedicine 2022 07 13;43:102566. Epub 2022 May 13.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

The low specificity of prostate-specific antigen contributes to overdiagnosis and ov ertreatment of prostate cancer (PCa) patients. Hence, there is an urgent need for inclusive diagnostic platforms that could improve the diagnostic accuracy of PCa. Dysregulated miRNAs are closely associated with the progression and recurrence and have emerged as promising diagnostic and prognostic biomarkers for PCa. Nevertheless, simple, rapid, and ultrasensitive quantification of serum miRNAs is highly challenging. This study designed, synthesized, and demonstrated the practicability of DNA-linked gold nanoprobes (DNA-AuNPs) for the single-step quantification of miR-21/miR-141/miR-375. In preclinical study, the assay differented PCa Pten conditional knockout (Pten) mice compared to their age-matched Pten wild-type (Pten) control mice. In human sera, receiver operating characteristic (ROC) curve-based correlation analyses revealed clear discrimination between PCa patients from normal healthy controls using training and validation sets. Overall, we established integrated nano-biosensing technology for the PCR-free, non-invasive liquid biopsies of multiple miRNAs for PCa diagnosis.
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http://dx.doi.org/10.1016/j.nano.2022.102566DOI Listing
July 2022

Liquid biopsies to occult brain metastasis.

Mol Cancer 2022 05 10;21(1):113. Epub 2022 May 10.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA.

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the uniquely distinct brain microenvironment. Keeping abreast with the recent breakthroughs in the context of various biomolecules detections and identifications, the circulating tumor cells (CTC), cell-free nucleotides, non-coding RNAs, secretory proteins, and metabolites can be pursued in human body fluids such as blood, serum, cerebrospinal fluid (CSF), and urine to obtain potential candidates for biomarker development. The liquid biopsy-based biomarkers can overlay with current imaging techniques to amplify the signal viable for improving the early detection and treatments of occult BrM.
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http://dx.doi.org/10.1186/s12943-022-01577-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088117PMC
May 2022

MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2 Associated Cell Adhesion.

Mol Cancer Res 2022 May 9. Epub 2022 May 9.

University of Nebraska Medical Center, Omaha, NE, United States.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal types of cancer, commonly metastasizes to the liver resulting in an overall poor prognosis. However, the molecular mechanism involved in liver metastasis remains poorly understood. Here, we aimed to identify the MUC16-mediated molecular mechanism of PDAC-liver metastasis. Previous studies demonstrated that MUC16 and its C-terminal (Cter) domain are involved in the aggressiveness of PDAC. In the present study, we observed MUC16 and its Cter expression significantly high in human PDAC tissues, PDAC organoids, and metastatic liver tissues, while no expression was observed in normal pancreatic tissues using immunohistochemistry (IHC) and immunofluorescence (IFC) analyses. MUC16 knockdown in SW1990 and CD18/HPAF PDAC cells significantly decreased the colony formation, migration, and endothelial/p-selectin binding. In contrast, MUC16-Cter ectopic overexpression showed significantly increased colony formation and motility in MiaPaCa2 PC cells. Interestingly, MUC16 promoted cell survival and colonization in the liver, mimicking an ex vivo environment. Furthermore, MUC16 enhanced liver metastasis in the in vivo mouse model. Our integrated analyses of RNA-seq suggested that MUC16 alters Neuropilin-2 (NRP2) and cell adhesion molecules in PC cells. Furthermore, we identified that MUC16 regulated NRP2 via JAK2/STAT1 signaling in PDAC. NRP2 knockdown in MUC16 overexpressed PDAC cells showed significantly decreased cell adhesion and migration. Overall, the findings indicate that MUC16 regulates NRP2 and induces metastasis in PDAC. Implications: This study shows that MUC16 plays a critical role in PDAC liver metastasis by mediating NRP2 regulation by JAK2/STAT1 axis, thereby paving the way for future therapy efforts for metastatic PDAC.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0888DOI Listing
May 2022

Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review.

Cell Mol Life Sci 2022 Apr 29;79(5):266. Epub 2022 Apr 29.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Hedgehog (Hh) signaling is evolutionarily conserved and plays an instructional role in embryonic morphogenesis, organogenesis in various animals, and the central nervous system organization. Multiple feedback mechanisms dynamically regulate this pathway in a spatiotemporal and context-dependent manner to confer differential patterns in cell fate determination. Hh signaling is complex due to canonical and non-canonical mechanisms coordinating cell-cell communication. In addition, studies have demonstrated a regulatory framework of Hh signaling and shown that cholesterol is vital for Hh ligand biogenesis, signal generation, and transduction from the cell surface to intracellular space. Studies have shown the importance of a specific cholesterol pool, termed accessible cholesterol, which serves as a second messenger, conveying signals between smoothened (Smo) and patched 1 (Ptch1) across the plasma and ciliary membranes. Remarkably, recent high-resolution structural and molecular studies shed new light on the interplay between Hh signaling and cholesterol in membrane biology. These studies elucidated novel mechanistic insight into the release and dispersal of cholesterol-anchored Hh and the basis of Hh recognition by Ptch1. Additionally, the putative model of Smo activation by cholesterol binding and/or modification and Ptch1 antagonization of Smo has been explicated. However, the coupling mechanism of Hh signaling and cholesterol offered a new regulatory principle in cell biology: how effector molecules of the Hh signal network react to and remodel cholesterol accessibility in the membrane and selectively activate Hh signaling proteins thereof. Recognizing the biological importance of cholesterol in Hh signaling activation and transduction opens the door for translational research to develop novel therapeutic strategies. This review looks in-depth at canonical and non-canonical Hh signaling and the distinct proposed model of cholesterol-mediated regulation of Hh signaling components, facilitating a more sophisticated understanding of the Hh signal network and cholesterol biology.
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http://dx.doi.org/10.1007/s00018-022-04233-1DOI Listing
April 2022

Macrophage inhibitory cytokine-1 in cancer: Beyond the cellular phenotype.

Cancer Lett 2022 06 26;536:215664. Epub 2022 Mar 26.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address:

Despite technological advances in diagnostic abilities and improved treatment methods, the burden of cancers remains high, leading to significant morbidity and mortality. One primary reason is that cancer cell secretory factors modulate the tumor microenvironment, supporting tumor growth and circumvents anticancer activities of conventional therapies. Macrophage inhibitory cytokine-1 (MIC-1) is a pleiotropic cytokine elevated in various cancers. MIC-1 regulates various cancer hallmarks, including sustained proliferation, tumor-promoting inflammation, avoiding immune destruction, inducing invasion, metastasis, angiogenesis, and resisting cell death. Despite these facts, the molecular regulation and downstream signaling of MIC-1 in cancer remain elusive, partly because its receptor (GFRAL) was unknown until recently. Binding of MIC-1 to GFRAL recruits the coreceptor tyrosine kinase RET to execute its downstream signaling. So far, studies have shown that GFRAL expression is restricted to the brain stem and is responsible for MIC-1/GFRAL/RET-mediated metabolic disorders. Nevertheless, abundant levels of MIC-1 expression have been reported in all cancer types and have been proposed as a surrogate biomarker. Given the ubiquitous expression of MIC-1 in cancers, it is crucial to understand both upstream regulation and downstream MIC-1/GFRAL/RET signaling in cancer hallmark traits.
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http://dx.doi.org/10.1016/j.canlet.2022.215664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088220PMC
June 2022

Chemokine-mucinome interplay in shaping the heterogeneous tumor microenvironment of pancreatic cancer.

Semin Cancer Biol 2022 Mar 26. Epub 2022 Mar 26.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

Pancreatic cancer (PC) is exemplified by a complex immune-suppressive, fibrotic tumor microenvironment (TME), and aberrant expression of mucins. The constant crosstalk between cancer cells, cancer-associated fibroblasts (CAFs), and the immune cells mediated by the soluble factors and inflammatory mediators including cytokines, chemokines, reactive oxygen species (ROS) promote the dynamic temporal switch towards an immune-escape phenotype in the neoplastic cells and its microenvironment that bolsters disease progression. Chemokines have been studied in PC pathogenesis, albeit poorly in the context of mucins, tumor glycocalyx, and TME heterogeneity (CAFs and immune cells). With correlative analysis from PC patients' transcriptome data, support from available literature, and scientific arguments-based speculative extrapolations in terms of disease pathogenesis, we have summarized in this review a comprehensive understanding of chemokine-mucinome interplay during stromal modulation and immune-suppression in PC. Future studies should focus on deciphering the complexities of chemokine-mediated control of glycocalyx maturation, immune infiltration, and CAF-associated immune suppression. Knowledge extracted from such studies will be beneficial to mechanistically correlate the mucin-chemokine abundance in serum versus pancreatic tumors of patients, which may aid in prognostication and stratification of PC patients for immunotherapy.
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http://dx.doi.org/10.1016/j.semcancer.2022.03.022DOI Listing
March 2022

Cytokines chattering in pancreatic ductal adenocarcinoma tumor microenvironment.

Semin Cancer Biol 2022 Mar 26. Epub 2022 Mar 26.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Omaha, NE, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) consists of multiple cell types interspersed by dense fibrous stroma. These cells communicate through low molecular weight signaling molecules called cytokines. The cytokines, through their receptors, facilitate PDAC initiation, progression, metastasis, and distant colonization of malignant cells. These signaling mediators secreted from tumor-associated macrophages, and cancer-associated fibroblasts in conjunction with oncogenic Kras mutation initiate acinar to ductal metaplasia (ADM), resulting in the appearance of early preneoplastic lesions. Further, M1- and M2-polarized macrophages provide proinflammatory conditions and promote deposition of extracellular matrix, whereas myofibroblasts and T-lymphocytes, such as Th17 and T-regulatory cells, create a fibroinflammatory and immunosuppressive environment with a significantly reduced cytotoxic T-cell population. During PDAC progression, cytokines regulate the expression of various oncogenic regulators such as NFκB, c-myc, growth factor receptors, and mucins resulting in the formation of high-grade PanIN lesions, epithelial to mesenchymal transition, invasion, and extravasation of malignant cells, and metastasis. During metastasis, PDAC cells colonize at the premetastatic niche created in the liver, and lung, an organotropic function primarily executed by cytokines in circulation or loaded in the exosomes from the primary tumor cells. The indispensable contribution of these cytokines at every stage of PDAC tumorigenesis makes them exciting candidates in combination with immune-, chemo- and targeted radiation therapy.
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http://dx.doi.org/10.1016/j.semcancer.2022.03.021DOI Listing
March 2022

Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments.

Mol Cancer 2022 03 18;21(1):79. Epub 2022 Mar 18.

Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, (IUST), 192122, Awantipora, Jammu & Kashmir, India.

Over the past decade, invasive techniques for diagnosing and monitoring cancers are slowly being replaced by non-invasive methods such as liquid biopsy. Liquid biopsies have drastically revolutionized the field of clinical oncology, offering ease in tumor sampling, continuous monitoring by repeated sampling, devising personalized therapeutic regimens, and screening for therapeutic resistance. Liquid biopsies consist of isolating tumor-derived entities like circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc., present in the body fluids of patients with cancer, followed by an analysis of genomic and proteomic data contained within them. Methods for isolation and analysis of liquid biopsies have rapidly evolved over the past few years as described in the review, thus providing greater details about tumor characteristics such as tumor progression, tumor staging, heterogeneity, gene mutations, and clonal evolution, etc. Liquid biopsies from cancer patients have opened up newer avenues in detection and continuous monitoring, treatment based on precision medicine, and screening of markers for therapeutic resistance. Though the technology of liquid biopsies is still evolving, its non-invasive nature promises to open new eras in clinical oncology. The purpose of this review is to provide an overview of the current methodologies involved in liquid biopsies and their application in isolating tumor markers for detection, prognosis, and monitoring cancer treatment outcomes.
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http://dx.doi.org/10.1186/s12943-022-01543-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932066PMC
March 2022

Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer.

Aging (Albany NY) 2022 03 7;14(5):2025-2046. Epub 2022 Mar 7.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4) CRC mouse model by crossing with Muc4 and mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. Further, the absence of Muc4 was associated with goblet cell dysfunction where the expression of intestinal homeostasis molecules (Muc2 and Fam3D) was downregulated. Next, we also observed that loss of Muc4 showed reduced thickness of mucus layer, leading to infiltration of bacteria, reduction in anti-microbial peptides, and upregulation of pro-inflammatory cytokines. Further, gene mutation results in activation of the Wnt/β-catenin signaling pathway that corroborated with an increased nuclear accumulation of β-catenin and activation of its target genes: cyclin D1 and c-Myc in Muc4 mice was observed. We conclude that the presence of Muc4 is essential for intestinal homeostasis, reduces tumor burden, and improves overall survival.
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http://dx.doi.org/10.18632/aging.203935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954958PMC
March 2022

Mucin 5AC-Mediated CD44/ITGB1 Clustering Mobilizes Adipose-Derived Mesenchymal Stem Cells to Modulate Pancreatic Cancer Stromal Heterogeneity.

Gastroenterology 2022 Jun 24;162(7):2032-2046.e12. Epub 2022 Feb 24.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address:

Background & Aims: Secreted mucin 5AC (MUC5AC) promotes pancreatic cancer (PC) progression and chemoresistance, suggesting its clinical association with poor prognosis. RNA sequencing analysis from the autochthonous pancreatic tumors showed a significant stromal alteration on genetic ablation of Muc5ac. Previously, depletion or targeting the stromal fibroblasts showed an ambiguous effect on PC pathogenesis. Hence, identifying the molecular players and mechanisms driving fibroblast heterogeneity is critical for improved clinical outcomes.

Methods: Autochthonous murine models of PC (Kras, Pdx1-Cre [KC] and Kras, Pdx1-Cre, Muc5ac [KCM]) and co-implanted allografts of murine PC cell lines (Muc5ac wild-type and CRISPR/Cas knockout) with adipose-derived mesenchymal stem cells (AD-MSCs) were used to assess the role of Muc5ac in stromal heterogeneity. Proliferation, migration, and surface expression of cell-adhesion markers on AD-MSCs were measured using live-cell imaging and flow cytometry. MUC5AC-interactome was investigated using mass-spectrometry and enzyme-linked immunosorbent assay.

Results: The KCM tumors showed a significant decrease in the expression of α-smooth muscle actin and fibronectin compared with histology-matched KC tumors. Our study showed that MUC5AC, carrying tumor secretome, gets enriched in the adipose tissues of tumor-bearing mice and patients with PC, promoting CD44/CD29 (integrin-β1) clustering that leads to Rac1 activation and migration of AD-MSCs. Furthermore, treatment with KC-derived serum enhanced proliferation and migration of AD-MSCs, which was abolished on Muc5ac-depletion or pharmacologic inhibition of CXCR2 and Rac1, respectively. The AD-MSCs significantly contribute toward α-smooth muscle actin-positive cancer-associated fibroblasts population in Muc5ac-dependent manner, as suggested by autochthonous tumors, co-implantation xenografts, and patient tumors.

Conclusion: MUC5AC, secreted during PC progression, enriches in adipose and enhances the mobilization of AD-MSCs. On recruitment to pancreatic tumors, AD-MSCs proliferate and contribute towards stromal heterogeneity.
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http://dx.doi.org/10.1053/j.gastro.2022.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117481PMC
June 2022

Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies.

Theranostics 2022 1;12(3):1030-1060. Epub 2022 Jan 1.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE.

Pancreatic tumors are highly desmoplastic and immunosuppressive. Delivery and distribution of drugs within pancreatic tumors are compromised due to intrinsic physical and biochemical stresses that lead to increased interstitial fluid pressure, vascular compression, and hypoxia. Immunotherapy-based approaches, including therapeutic vaccines, immune checkpoint inhibition, CAR-T cell therapy, and adoptive T cell therapies, are challenged by an immunosuppressive tumor microenvironment. Together, extensive fibrosis and immunosuppression present major challenges to developing treatments for pancreatic cancer. In this context, nanoparticles have been extensively studied as delivery platforms and adjuvants for cancer and other disease therapies. Recent advances in nanotechnology have led to the development of multiple nanocarrier-based formulations that not only improve drug delivery but also enhance immunotherapy-based approaches for pancreatic cancer. This review discusses and critically analyzes the novel nanoscale strategies that have been used for drug delivery and immunomodulation to improve treatment efficacy, including newly emerging immunotherapy-based approaches. This review also presents important perspectives on future research directions that will guide the rational design of novel and robust nanoscale platforms to treat pancreatic tumors, particularly with respect to targeted therapies and immunotherapies. These insights will inform the next generation of clinical treatments to help patients manage this debilitating disease and enhance survival rates.
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http://dx.doi.org/10.7150/thno.64805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771545PMC
April 2022

Differential expression profile of CXC-receptor-2 ligands as potential biomarkers in pancreatic ductal adenocarcinoma.

Am J Cancer Res 2022 15;12(1):68-90. Epub 2022 Jan 15.

Department of Pathology and Microbiology, 985950 Nebraska Medical Center Omaha, NE 68198-5900, USA.

The discovery of early detection markers of pancreatic cancer (PC) disease is highly warranted. We analyzed the expression profile of different CXC-receptor-2 (CXCR2) ligands in PC cases for the potential of biomarker candidates. Analysis of different PDAC microarray datasets with matched normal and pancreatic tumor samples and next-generation sequenced transcriptomics data using an online portal showed significantly high expression of CXCL-1, 3, 5, 6, 8 in the tumors of PC patients. High CXCL5 expression was correlated to poor PC patient survival. Interestingly, mRNA and protein expression analysis of human PC cell lines showed higher CXCL2, 3, and 5 expressions in cell lines derived from metastatic sites than primary tumors. Furthermore, we utilized immunohistochemistry (IHC) to evaluate the expression of CXCR2 ligands in the human PC tumors and observed positive staining for CXCL1, 3, and 8 with a higher average IHC composite score of CXCL3 in the PC tissue specimens than the normal pancreas. We also observed an increase in the expression of mouse CXCL1, 3, and 5 in the pre-cancerous lesions of tumors and metastasis tissues derived from the PDX-cre-LSL-Kras mouse model. Together, our data suggest that different CXCR2 ligands show the potential of being utilized as a diagnostic biomarker in PC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822283PMC
January 2022

Reply.

Cancer Lett 2022 02;527:193-194

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2021.12.020DOI Listing
February 2022

The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells.

Neoplasia 2022 03 31;25:28-40. Epub 2022 Jan 31.

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.. Electronic address:

Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed.
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http://dx.doi.org/10.1016/j.neo.2022.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8814762PMC
March 2022

A p130Cas-Mediated Mechanism Governs Acinar to Ductal Metaplasia and the Initiation of Pancreatic Ductal Adenocarcinoma.

Gastroenterology 2022 04 1;162(4):1037-1040. Epub 2022 Feb 1.

Department of Biochemistry and Molecular Biology, College of Medicine and, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2022.01.042DOI Listing
April 2022

Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma.

Metabolites 2022 Jan 7;12(1). Epub 2022 Jan 7.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the significance of the de novo cholesterol synthesis pathway has been controversial in PC, indicating the need to reassess this pathway in PC. We utilized preclinical models and clinical specimens of PC patients and cell lines and utilized mass spectrometry-based sterol analysis. Further, we also performed in silico analysis to corroborate the significance of de novo cholesterol synthesis pathway in PC. Our results demonstrated alteration in free sterol levels, including free cholesterol, across in vitro, in vivo, and clinical specimens of PC. Especially, our sterol analyses established consistent alterations in free cholesterol across the different PC models. Overall, this study demonstrates the significance and consistency in deviation of cholesterol synthesis pathway in PC while showing the aberrations in sterol metabolite intermediates and the related genes using preclinical models, in silico platforms, and the clinical specimens.
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http://dx.doi.org/10.3390/metabo12010047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779872PMC
January 2022

Substituent Effects Impact Surface Charge and Aggregation of Thiophenol-Labeled Gold Nanoparticles for SERS Biosensors.

Biosensors (Basel) 2022 Jan 5;12(1). Epub 2022 Jan 5.

Sanguine Diagnostics and Therapeutics Inc., Omaha, NE 68106, USA.

SERS immunoassay biosensors hold immense potential for clinical diagnostics due to their high sensitivity and growing interest in multi-marker panels. However, their development has been hindered by difficulties in designing compatible extrinsic Raman labels. Prior studies have largely focused on spectroscopic characteristics in selecting Raman reporter molecules (RRMs) for multiplexing since the presence of well-differentiated spectra is essential for simultaneous detection. However, these candidates often induce aggregation of the gold nanoparticles used as SERS nanotags despite their similarity to other effective RRMs. Thus, an improved understanding of factors affecting the aggregation of RRM-coated gold nanoparticles is needed. Substituent electronic effects on particle stability were investigated using various para-substituted thiophenols. The inductive and resonant effects of functional group modifications were strongly correlated with nanoparticle surface charge and hence their stability. Treatment with thiophenols diminished the negative surface charge of citrate-stabilized gold nanoparticles, but electron-withdrawing substituents limited the magnitude of this diminishment. It is proposed that this phenomenon arises by affecting the interplay of competing sulfur binding modes. This has wide-reaching implications for the design of biosensors using thiol-modified gold surfaces. A proof-of-concept multiplexed SERS biosensor was designed according to these findings using the two thiophenol compounds with the most electron-withdrawing substitutions: NO and CN.
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http://dx.doi.org/10.3390/bios12010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773556PMC
January 2022

Fluorescent Anti-MUC5AC Brightly Targets Pancreatic Cancer in a Patient-derived Orthotopic Xenograft.

In Vivo 2022 Jan-Feb;36(1):57-62

Department of Surgery, University of California San Diego, La Jolla, CA, U.S.A.;

Background: Overexpression of mucin-5AC (MUC5AC) makes it a targetable biomarker in pancreatic cancer. The present study evaluated tumor targeting with a MUC5AC antibody conjugated to a near-infrared dye in a patient-derived orthotopic xenograft (PDOX) mouse model.

Materials And Methods: MUC5AC monoclonal antibody was conjugated to the near-infrared dye IRDye800CW to synthesize MUC5AC-IR800. PDOX models were established by implanting a high-MUC5AC-expressing patient-derived pancreatic tumor on the pancreas of nude mice. After 4 weeks of PDOX tumor growth, mice were imaged after receiving MUC5AC-IR800 (75 μg) intravenously.

Results: In the PDOX models, MUC5AC-IR800 selectively and brightly targeted the pancreatic tumor (tumor to background ratio: 2.46±0.465).

Conclusion: MUC5AC-IR800 provides distinct visualization of pancreatic tumors. MUC5AC-IR800 may be used clinically in the future to improve pancreatic cancer resection. This novel fluorescent probe is also promising for targeting of pre-malignant pancreatic lesions with subsequent resection under fluorescence guidance.
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http://dx.doi.org/10.21873/invivo.12676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765132PMC
January 2022

Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling.

EBioMedicine 2022 Jan 28;75:103772. Epub 2021 Dec 28.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

Background: Radiation therapy (RT) has a suboptimal effect in patients with pancreatic ductal adenocarcinoma (PDAC) due to intrinsic and acquired radioresistance (RR). Comprehensive bioinformatics and microarray analysis revealed that cholesterol biosynthesis (CBS) is involved in the RR of PDAC. We now tested the inhibition of the CBS pathway enzyme, farnesyl diphosphate synthase (FDPS), by zoledronic acid (Zol) to enhance radiation and activate immune cells.

Methods: We investigated the role of FDPS in PDAC RR using the following methods: in vitro cell-based assay, immunohistochemistry, immunofluorescence, immunoblot, cell-based cholesterol assay, RNA sequencing, tumouroids (KPC-murine and PDAC patient-derived), orthotopic models, and PDAC patient's clinical study.

Findings: FDPS overexpression in PDAC tissues and cells (P < 0.01 and P < 0.05) is associated with poor RT response and survival (P = 0.024). CRISPR/Cas9 and pharmacological inhibition (Zol) of FDPS in human and mouse syngeneic PDAC cells in conjunction with RT conferred higher PDAC radiosensitivity in vitro (P < 0.05, P < 0.01, and P < 0.001) and in vivo (P < 0.05). Interestingly, murine (P = 0.01) and human (P = 0.0159) tumouroids treated with Zol+RT showed a significant growth reduction. Mechanistically, RNA-Seq analysis of the PDAC xenografts and patients-PBMCs revealed that Zol exerts radiosensitization by affecting Rac1 and Rho prenylation, thereby modulating DNA damage and radiation response signalling along with improved systemic immune cells activation. An ongoing phase I/II trial (NCT03073785) showed improved failure-free survival (FFS), enhanced immune cell activation, and decreased microenvironment-related genes upon Zol+RT treatment.

Interpretation: Our findings suggest that FDPS is a novel radiosensitization target for PDAC therapy. This study also provides a rationale to utilize Zol as a potential radiosensitizer and as an immunomodulator in PDAC and other cancers.

Funding: National Institutes of Health (P50, P01, and R01).
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http://dx.doi.org/10.1016/j.ebiom.2021.103772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718746PMC
January 2022

Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications.

Semin Cancer Biol 2021 Dec 27. Epub 2021 Dec 27.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68108, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68108, USA. Electronic address:

Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.
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http://dx.doi.org/10.1016/j.semcancer.2021.12.009DOI Listing
December 2021

Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers.

Pharmaceutics 2021 Nov 23;13(12). Epub 2021 Nov 23.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.
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http://dx.doi.org/10.3390/pharmaceutics13121987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707074PMC
November 2021

MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB).

Acta Neuropathol Commun 2021 12 18;9(1):195. Epub 2021 Dec 18.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.
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http://dx.doi.org/10.1186/s40478-021-01299-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684142PMC
December 2021

Acinar to ductal cell trans-differentiation: A prelude to dysplasia and pancreatic ductal adenocarcinoma.

Biochim Biophys Acta Rev Cancer 2022 01 13;1877(1):188669. Epub 2021 Dec 13.

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

Pancreatic cancer (PC) is the deadliest neoplastic epithelial malignancies and is projected to be the second leading cause of cancer-related mortality by 2024. Five years overall survival being ~10%, mortality and incidence rates are disturbing. Acinar to ductal cell metaplasia (ADM) encompasses cellular reprogramming and phenotypic switch-over, making it a cardinal event in tumor initiation. Differential cues and varied regulatory factors drive synchronous functions of metaplastic cell populations leading to multiple cell fates and physiological outcomes. ADM is a precursor for developing early pre-neoplastic lesions further progressing into PC due to oncogenic signaling. Hence delineating molecular events guiding tumor initiation may provide cues for regenerative medicine and precision onco-medicine. Therefore, understanding PC pathogenesis and early diagnosis are crucial. We hereby provide a timely overview of the current progress in this direction and future perspectives we foresee unfolding in the best interest of patient well-being and better clinical management of PC.
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http://dx.doi.org/10.1016/j.bbcan.2021.188669DOI Listing
January 2022

Characterization of recombinant β subunit of human MUC4 mucin (rMUC4β).

Sci Rep 2021 12 9;11(1):23730. Epub 2021 Dec 9.

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA.

MUC4 is a transmembrane mucin expressed on various epithelial surfaces, including respiratory and gastrointestinal tracts, and helps in their lubrication and protection. MUC4 is also aberrantly overexpressed in various epithelial malignancies and functionally contributes to cancer development and progression. MUC4 is putatively cleaved at the GDPH site into a mucin-like α-subunit and a membrane-tethered growth factor-like β-subunit. Due to the presence of several functional domains, the characterization of MUC4β is critical for understanding MUC4 biology. We developed a method to produce and purify multi-milligram amounts of recombinant MUC4β (rMUC4β). Purified rMUC4β was characterized by Far-UV CD and I-TASSER-based protein structure prediction analyses, and its ability to interact with cellular proteins was determined by the affinity pull-down assay. Two of the three EGF-like domains exhibited typical β-fold, while the third EGF-like domain and vWD domain were predominantly random coils. We observed that rMUC4β physically interacts with Ezrin and EGFR family members. Overall, this study describes an efficient and simple strategy for the purification of biologically-active rMUC4β that can serve as a valuable reagent for a variety of biochemical and functional studies to elucidate MUC4 function and generating domain-specific antibodies and vaccines for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41598-021-02860-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660890PMC
December 2021

Correction: Kaushal et al. Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β. 2021, , 3105.

Cancers (Basel) 2021 Nov 9;13(22). Epub 2021 Nov 9.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

The authors would like to make a correction to their published paper [...].
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http://dx.doi.org/10.3390/cancers13225591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616051PMC
November 2021
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