Browsing by Author "Yu, Xin"
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Item Open Access Arthritis and Physical Activity among Adults in the United States: Cross-sectional Analyses of the National Health and Nutrition Examination Survey(2023) Yu, XinArthritis is a chronic condition affecting millions of older adults worldwide and a leading cause of pain and disability. Physical activity is effective and recommended in managing arthritis and promoting overall health in older adults. However, many older adults with arthritis struggle with participation consistent in physical exercises and activity as a result of pain, stiffness, and fatigue. A cross-sectional study design is applied to derive the findings in this study using the National Health and Nutrition Examination Survey (NHANES). We found that 9467(27%) participants reported as Arthritis from 2007 to 2018. Compared with non- arthritis subjects, Arthritis participants tended to be older (62.2 ± 13.8 vs. 45.3 ± 17.0, p<.001), female (59.5% vs. 48.5%, p<.001), lower level of education (3.2 ± 1.3 vs. 3.5 ± 1.3, p<.001). The multivariable logistic regression showed that Osteoarthritis was only negatively correlated with vigorous work activity (OR: 0.75, 95%CI: 0.59-0.95, p=.018). Participants with Osteoarthritis or degenerative were more likely to perform moderate work activity (OR:1.17, 95%CI:1.07-1.28, p<.001) and instead perform less walking or bicycle (OR:0.79, 95%CI: 0.71-0.88, p<.001), and moderate recreational activities (OR:0.84, 95%CI:0.77-0.92, p<.001). Patients with other types of Arthritis were more willing to engage in recreational activities than work activity. Further, we also included the population ≥65 years of age or older with Arthritis causing physical movement difficulties, to find out about the health status of these people and whether they are physically active or how often they are physically active. Compared to arthritis patients (≥65 years older) with non-functional limitations, arthritis patients with functional limitations tended to be female (63% vs. 53%), divorced (48% vs. 39%). In addition, minutes of sedentary activity were associated with having a higher functional limitations risk among arthritis patients with 65 years or older (OR, 1.59 for >480 mins, OR, 1.32 for (360~480) mins compared with ≤240 mins, Fig.2-3). Compared with arthritis patients doing less than 30 minutes of moderate recreational activities on a regular day, those doing above 180 minutes had a higher risk of functional limitations. The findings of this study will provide important insight for developing interventions to foster physical activity among older adults with arthritis and consequently improve their health and well-being.
Item Open Access Development of Novel Antibody-Based Immunotherapies Targeting Human Chondroitin Sulfate Proteoglycan 4(2018) Yu, XinChondroitin sulfate proteoglycan 4 (CSPG4) is a promising target for cancer immunotherapy due to its high level of expression in a number of malignant tumors, and its essential role in tumor growth and progression. Clinical application of CSPG4-targeting immunotherapies is hampered by the lack of fully human CSPG4 antibodies or antibody fragments. In addition, the efficacy of cytotoxic monotherapies, such as the CSPG4-targeting immunotoxins (ITs), is limited by hyperactive anti-apoptotic pathways prevalent in tumor cells. Therefore, there is a need to discover novel, fully human antibodies for CSPG4-targeting immunotherapies and to develop new strategies that sensitize resistant CSPG4-expressing tumor cells to IT therapies.
To discover fully human antibodies that can be developed into potential CSPG4-targeting therapeutics, my first aim is to develop novel human single-chain variable fragments (scFvs) with high binding affinity and specificity to the CSPG4 antigen. Affinity maturation was performed on a novel, fully human anti-CSPG4 scFv using the random mutagenesis approach. A yeast display library was constructed for the mutant clones, and screened using a modified whole-cell panning method followed by fluorescence-activated cell sorting (FACS). After six rounds of panning and sorting, the top seven mutant scFvs were isolated and their binding affinities were characterized by flow cytometry and surface plasmon resonance. These mutant clones were highly specific to the CSPG4 antigen, and displayed nanomolar to picomolar binding affinities. While each of them harbored only two to six amino acid substitutions, they represented approximately 270-3000-fold improvement in affinity compared to the parental clone. These affinity-matured scFvs can be potentially developed into diagnostic or therapeutic agents for evaluation and treatment of CSPG4-expressing tumors.
To facilitate the screening of scFv libraries targeting CSPG4, my second aim is to develop a cell-based fluorescent assay for high-throughput analysis of antibody affinity (KD) in the nanomolar range. In this method, fluorescently labelled antibodies were added to antigen-positive and antigen-negative cell lines fixed on 96-well plates. The fluorescent signals from nonspecific binding to negative control cell lines is subtracted from the specific binding to the antigen-positive cell lines. The results confirmed that the KD values obtained using this method were comparable with values obtained by the conventional flow cytometry and radioactive (I125) scatchard assays. This demonstrates that the cell-based fluorescent method allows for accurate and efficient identification of therapeutically relevant leads.
Finally, to improve the efficacy of ITs targeting CSPG4, especially in the IT-resistant tumor cells, my third aim is to evaluate a multi-pathway therapy that combines anti-CSPG4 ITs and small molecule Bcl-2 inhibitors. To enhance sensitivity of cancer cells to ITs, we combined ITs (9.2.27-PE38KDEL or Mel-14-PE38KDEL) targeting CSPG4 with a Bcl-2 inhibitor (ABT-737, ABT-263, or ABT-199) against patient-derived glioblastoma xenografts, melanoma cell lines, and breast cancer cell lines. Results from the in vitro cytotoxicity assays demonstrated that the addition of the ABT compounds, specifically ABT-737, sensitized all three tumors to the IT treatment, and in some cases improved the IC50 values of 9.2.27-PE38KDEL by over 1000-fold. Mechanistic studies using 9.2.27-PE38KDEL and ABT-737 revealed that the rate of IT internalization and the efficiency of cleaved exotoxin accumulation in the cytosol correlated with the enhanced sensitivity of the tumor cells to the combination treatment. Furthermore, the synergistic effect of 9.2.27-PE38KDEL and ABT-737 combination therapy was confirmed in an orthotopic GBM xenograft model and a model of melanoma metastasized to the brain. For the first time, our study compares the efficacy of ABT-737 and 9.2.27-PE38KDEL combination therapy in GBM and a different brain metastases model, providing insights into overcoming IT resistance in brain tumors.
In conclusion, I discovered novel human scFvs with high binding affinities to CSPG4, developed a cell-based fluorescent method for accurate and efficient affinity analysis of antibodies, and investigated combination immunotherapies that utilized Bcl-2 inhibitors to sensitize tumor cells to treatment by CSPG4-targeting ITs. The results from these studies helped to facilitate the development of novel antibody-based immunotherapies and combination immunotherapies for CSPG4-expressing tumors.
Item Open Access Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.(Journal for immunotherapy of cancer, 2019-05-29) Chandramohan, Vidyalakshmi; Bao, Xuhui; Yu, Xin; Parker, Scott; McDowall, Charlotte; Yu, Yen-Rei; Healy, Patrick; Desjardins, Annick; Gunn, Michael D; Gromeier, Matthias; Nair, Smita K; Pastan, Ira H; Bigner, Darell DBackground
D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma.Methods
To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test.Results
D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge.Conclusions
These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.Item Open Access Strategic Planning For U.S. Industrial Water Use: Visualizing Texas, North Carolina, and Indiana Historical Trends and Projections(2018-04-27) Hill, Nicola; Yu, Xin; Paranjape, OshinChemical, oil & gas, and textile manufacturing industries are the major divers of United States industrial water use, shaping both the economy and water trends in the regions they inhabit. Texas (TX), North Carolina (NC), and Indiana (IN) are dominant examples of states influenced by the fluctuation of these industries and have therefore been selected as study states. This study analyzes historical, spatial-temporal trends in water use and makes projections for next decade using robust datasets of monthly facility-level water use data. The datasets indicate that spatially, water use and locations of facilities have remained centralized near the coast of TX, while facilities have shifted towards small clusters throughout NC and IN. NC and IN monthly water use follow a seasonal pattern with consistent major users. Additionally, TX industrial water use is estimated to decrease in next decade while the other two states remain stable. The study highlights the need for incorporating industrial water demand into a holistic water plan such as the Integrated Water Resources Management (IWRM) framework (Savenjie and Vander Zaag, 2000). Within the IWRM management strategy, this work has contributed to future local and state level planning by 1) creating a platform for state benchmarking and comparison through the interactive R Shiny Web application , 2) creating much needed projections for three states, and 3) providing a detailed documentation of how to derive the projections. Moving forward, consistent and robust local and state level reporting and recording practices from each state is essential to ensure for the ability to meet future demand.Item Open Access Synergistic antitumor effects of 9.2.27-PE38KDEL and ABT-737 in primary and metastatic brain tumors.(PloS one, 2019-01-09) Yu, Xin; Dobrikov, Mikhail; Keir, Stephen T; Gromeier, Matthias; Pastan, Ira H; Reisfeld, Ralph; Bigner, Darell D; Chandramohan, VidyalakshmiStandard treatment, unfortunately, yields a poor prognosis for patients with primary or metastatic cancers in the central nervous system, indicating a necessity for novel therapeutic agents. Immunotoxins (ITs) are a class of promising therapeutic candidates produced by fusing antibody fragments with toxin moieties. In this study, we investigated if inherent resistance to IT cytotoxicity can be overcome by rational combination with pro-apoptotic enhancers. Therefore, we combined ITs (9.2.27-PE38KDEL or Mel-14-PE38KDEL) targeting chondroitin sulfate proteoglycan 4 (CSPG4) with a panel of Bcl-2 family inhibitors (ABT-737, ABT-263, ABT-199 [Venetoclax], A-1155463, and S63845) against patient-derived glioblastoma, melanoma, and breast cancer cells/cell lines. In vitro cytotoxicity assays demonstrated that the addition of the ABT compounds, specifically ABT-737, sensitized the different tumors to IT treatment, and improved the IC50 values of 9.2.27-PE38KDEL up to >1,000-fold. Mechanistic studies using 9.2.27-PE38KDEL and ABT-737 revealed that increased levels of intracellular IT, processed (active) exotoxin, and PARP cleavage correlated with the enhanced sensitivity to the combination treatment. Furthermore, we confirmed the synergistic effect of 9.2.27-PE38KDEL and ABT-737 combination therapy in orthotopic GBM xenograft and cerebral melanoma metastasis models in nude mice. Our study defines strategies for overcoming IT resistance and enhancing specific antitumor cytotoxicity in primary and metastatic brain tumors.