Browsing by Author "Ma, Yan"

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    A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy.
    (Theranostics, 2015) Liu, Yang; Ashton, Jeffrey R; Moding, Everett J; Yuan, Hsiangkuo; Register, Janna K; Fales, Andrew M; Choi, Jaeyeon; Whitley, Melodi J; Zhao, Xiaoguang; Qi, Yi; Ma, Yan; Vaidyanathan, Ganesan; Zalutsky, Michael R; Kirsch, David G; Badea, Cristian T; Vo-Dinh, Tuan
    Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.
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    Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice.
    (Front Oncol, 2013) Perez, Bradford A; Ghafoori, A Paiman; Lee, Chang-Lung; Johnston, Samuel M; Li, Yifan; Moroshek, Jacob G; Ma, Yan; Mukherjee, Sayan; Kim, Yongbaek; Badea, Cristian T; Kirsch, David G
    PURPOSE: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT). MATERIALS AND METHODS: Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic Kras(G12D) and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy10. Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis. RESULTS: Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARF(FL/FL) mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53(FL/FL) mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53. CONCLUSION: Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations.
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    Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D.
    (Scientific reports, 2019-11-20) Huang, Jianguo; Chen, Mark; Xu, Eric S; Luo, Lixia; Ma, Yan; Huang, Wesley; Floyd, Warren; Klann, Tyler S; Kim, So Young; Gersbach, Charles A; Cardona, Diana M; Kirsch, David G
    Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in Kras and transformation-related protein 53 (Trp53) are known to transform a variety of mesenchymal and epithelial cells in vitro and in vivo. Identifying other genes that can cooperate with oncogenic Kras and substitute for Trp53 mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in KrasG12D immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic Kras to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with KrasG12D to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A (Cdkn2a), whose alternative reading frame product p19 activates Trp53, we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 (Fbxw7) and solute carrier family 9 member 3 (Slc9a3). Remarkably, the TCGA database indicates that both FBXW7 and SLC9A3 are commonly co-mutated with KRAS in human cancers. However, we found that only mutation of Trp53 or Cdkn2a, but not Fbxw7 or Slc9a3 can cooperate with KrasG12D to generate primary sarcomas in mice. These results show that mutations in oncogenic Kras and either Fbxw7 or Slc9a3 are sufficient for transformation in vitro, but not for in vivo sarcomagenesis.
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    Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
    (Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian T
    This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
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    Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.
    (Molecular cancer therapeutics, 2023-01) Patel, Rutulkumar; Mowery, Yvonne M; Qi, Yi; Bassil, Alex M; Holbrook, Matt; Xu, Eric S; Hong, Cierra S; Himes, Jonathon E; Williams, Nerissa T; Everitt, Jeffrey; Ma, Yan; Luo, Lixia; Selitsky, Sara R; Modliszewski, Jennifer L; Gao, Junheng; Jung, Sin-Ho; Kirsch, David G; Badea, Cristian T
    This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.
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    Risk stratification with video capsule endoscopy leads to fewer hospital admissions in emergency department patients with low-risk to moderate-risk upper gastrointestinal bleed: A multicenter clinical trial.
    (J Am Coll Emerg Physicians Open, 2021-10) Meltzer, Andrew C; Limkakeng, Alexander T; Gentile, Nina T; Freeman, Jincong Q; Hall, Nicole C; Vargas, Nataly Montano; Fleischer, David E; Malik, Zubair; Kallus, Samuel J; Borum, Marie L; Ma, Yan; Kumar, Anita B
    Objective: In US emergency departments (EDs), the physician has limited ability to evaluate for common and serious conditions of the gastrointestinal (GI) mucosa such as a bleeding peptic ulcer. Although many bleeding lesions are self-limited, the majority of these patients require emergency hospitalization for upper endoscopy (EGD). We conducted a clinical trial to determine if ED risk stratification with video capsule endoscopy (VCE) reduces hospitalization rates for low-risk to moderate-risk patients with suspected upper GI bleeding. Methods: We conducted a randomized controlled trial at 3 urban academic EDs. Inclusion criteria included signs of upper GI bleeding and a Glasgow Blatchford score <6. Patients were randomly assigned to 1 of the following 2 treatment arms: (1) an experimental arm that included VCE risk stratification and brief ED observation versus (2) a standard care arm that included admission for inpatient EGD. The primary outcome was hospital admission. Patients were followed for 7 and 30 days to assess for rebleeding events and revisits to the hospital. Results: The trial was terminated early as a result of low accrual. The trial was also terminated early because of a need to repurpose all staff to respond to the coronavirus disease 2019 pandemic. A total of 24 patients were enrolled in the study. In the experimental group, 2/11 (18.2%) patients were admitted to the hospital, and in the standard of care group, 10/13 (76.9%) patients were admitted to the hospital (P = 0.012). There was no difference in safety on day 7 and day 30 after the index ED visit. Conclusions: VCE is a potential strategy to decrease admissions for upper GI bleeding, though further study with a larger cohort is required before this approach can be recommended.
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    Sensitization of Vascular Endothelial Cells to Ionizing Radiation Promotes the Development of Delayed Intestinal Injury in Mice.
    (Radiation research, 2019-09) Lee, Chang-Lung; Daniel, Andrea R; Holbrook, Matt; Brownstein, Jeremy; Silva Campos, Lorraine Da; Hasapis, Stephanie; Ma, Yan; Borst, Luke B; Badea, Cristian T; Kirsch, David G
    Exposure of the gastrointestinal (GI) tract to ionizing radiation can cause acute and delayed injury. However, critical cellular targets that regulate the development of radiation-induced GI injury remain incompletely understood. Here, we investigated the role of vascular endothelial cells in controlling acute and delayed GI injury after total-abdominal irradiation (TAI). To address this, we used genetically engineered mice in which endothelial cells are sensitized to radiation due to the deletion of the tumor suppressor p53. Remarkably, we found that VE-cadherin-Cre; p53FL/FL mice, in which both alleles of p53 are deleted in endothelial cells, were not sensitized to the acute GI radiation syndrome, but these mice were highly susceptible to delayed radiation enteropathy. Histological examination indicated that VE-cadherin-Cre; p53FL/FL mice that developed delayed radiation enteropathy had severe vascular injury in the small intestine, which was manifested by hemorrhage, loss of microvessels and tissue hypoxia. In addition, using dual-energy CT imaging, we showed that VE-cadherin-Cre; p53FL/FL mice had a significant increase in vascular permeability of the small intestine in vivo 28 days after TAI. Together, these findings demonstrate that while sensitization of endothelial cells to radiation does not exacerbate the acute GI radiation syndrome, it is sufficient to promote the development of late radiation enteropathy.
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    Video capsule endoscopy for upper gastrointestinal hemorrhage in the emergency department: A systematic review and meta-analysis.
    (The American journal of emergency medicine, 2020-06) Shah, Nidhi; Chen, Chen; Montano, Nataly; Cave, David; Siegel, Rebecca; Gentile, Nina T; Limkakeng, Alexander T; Kumar, Anita B; Ma, Yan; Meltzer, Andrew C
    OBJECTIVE:The assessment of the severity of upper gastrointestinal hemorrhage in emergency department (ED) patients is difficult to assess with commonly available diagnostic tools. Small studies have shown that video capsule endoscopy (VCE) is a promising risk-stratification method and may be better than current clinical decision rules such as the Rockall score and the Glasgow Blatchford score. This review aims to assess the accuracy of VCE to detect active upper gastrointestinal hemorrhage compared to a reference standard. METHODS:The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology was used to perform a review of studies that have measured the diagnostic accuracy of VCE. Studies were included if they measured ED use of VCE for upper GI hemorrhage as compared to a reference standard of an esophagogastroduodenoscopy (EGD). A meta-analysis was performed on select patients using a fixed effects and random-effects model to determine the primary outcome of diagnostic test accuracy. RESULTS:40 studies were screened for eligibility and five studies representing 193 patients met the inclusion and exclusion criteria. All patients received both a VCE and an EGD. The sensitivity and specificity of VCE were 0.724 and 0.748, respectively. The diagnostic odds ratio was 6.29 (95% CI: 3.23-12.25) and the summary receiver operating characteristic curve was 0.782. CONCLUSIONS:VCE demonstrated high accuracy for detecting upper GI hemorrhage in this meta-analysis of existing studies. In light of the potential advantages of VCE in the ED, further research is warranted to further establish its role.