15 research outputs found
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The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target
Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.</p
Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic oncology database
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The relative contributions of antigen versus interleukin-7 and interleukin-15 during the transition of effector CD8+ T cells from cytotoxic T lymphocytes to memory cells
During an immune response it is difficult to study the kinetics and requirements for memory CD8+ T cell generation because memory cells are best detected after the contraction phase and antigen clearance. To overcome these limitations, we modeled the CTL to memory transition in vitro and following adoptive transfer. In vitro generated CTL cultured for 2 days with IL-2, in the absence of antigen, resulted in the expansion of CTL, whereas culture in IL-7 or IL-15 promoted the development and expansion of central memory-like cells. Memory cell conversion occurred at a low antigen dose that selectively induced a recall response, but not at a higher dose that activated naive cells. Upon adoptive transfer to antigen-free hosts, a small population of in vitro generated CTL engrafted, proliferated extensively, and rapidly acquired properties of memory cells by 3 days post-transfer. In tumor-bearing hosts, CTL converted to memory cells during an anti-tumor response. Since IL-7 and IL-15 have been implicated in the development and homeostasis of memory cells, we generated IL-7Ralpha-deficient mice. Similar to naive OT-I cells, IL-7Ralpha-deficient OT-I cells differentiated into CTL when primed with antigen and IL-2, and upon further culture with IL-15 developed into memory-like cells. The few engrafting IL-7Ralpha-deficient OT-I cells converted to memory-like cells in both normal and IL-15-deficient hosts. In this study we demonstrated the rapid generation of memory cells without the complete removal of antigen. Moreover, there is a permissive dose of antigen for memory cell development. In our system, this permissive dose was correlated to a level of antigen that selectively induced a recall response, but was not sufficient to activate naive cells. The expression of IL-7Ralpha was not required for the conversion from CTL to memory cells. Furthermore, IL-7 and IL-15 function non-redundantly in the maintenance memory CD8 + T cells
Modeling the CD8+ T effector to memory transition in adoptive T-cell antitumor immunotherapy
Adoptive T-cell therapy with CD8(+) CTLs is often characterized by poor persistence of the transferred T cells and limited effector responses. Improved persistence and therapeutic efficacy have been noted when antigen-activated CD8(+) T cells express properties of memory cells. The current study was undertaken to more precisely characterize the development of memory-like CD8(+) T cells from short-term CTLs in vitro and upon transfer in vivo, including their antitumor activity. Ovalbumin (OVA)-specific OT-I CTLs acquired phenotypic and functional properties of memory cells 2 to 3 days later either by lowering the concentration of antigen to a level that does not support primary responses and providing a survival signal through transgenic Bcl-2 in vitro or simply by transferring early day 3 CTLs to antigen-free lymphoid-replete mice. In lymphoid-replete mice, established OVA-expressing E.G7 tumor was rejected by short-term CTLs that simultaneously acquired memory-like properties in secondary lymphoid tissues, where tumor antigen level remained low. Collectively, these data indicate that CTLs readily converted to memory-like cells upon lowering antigen to a concentration that selectively supports memory responses and suggest that such conversion predicts successful adoptive immunotherapy
Evaluating the Representation of Community Colleges in Biology Education Research Publications following a Call to Action
Interest in biology education research (BER) has been growing over the last two decades, yet few BER publications focus on community colleges, which serve a large percentage of the undergraduate student population and a majority of those students who identify with historically underserved groups. In this paper, we define community college biology education research (CC BER) as publications with a community college faculty member as an author, publications with a community college study context or a focus on community college biology teaching and learning, and publications that use community college students as a source of data. We conducted a literature review to quantify how CC BER has progressed since initial calls for broadening participation by recording the number of CC BER publications in seven prominent journals between 2016 and 2020. Our formal analysis of peer-reviewed BER literature indicates that there has been a statistically significant increase in CC BER publications from 3.2% to 5.9% of total BER publications since the last analysis in 2017. We conclude with a discussion of strategies for further broadening of participation in CC BER.publishedVersio
Combined MET Inhibition and Topoisomerase I Inhibition Block Cell Growth of Small Cell Lung Cancer
The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target
<div><p>Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability <i>in vitro</i>, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.</p></div
Bone Marrow Mesenchymal Stem Cells Loaded With an Oncolytic Adenovirus Suppress the Anti-adenoviral Immune Response in the Cotton Rat Model
Kaplan-Meier analysis of patient survival.
<p>The ordinate axis in each graph represents the fraction of living patients. <i>A</i>. Survival stratified by EphB4 expression. ACIS scores above and below 500 were chosen for stratification based on the median score of the overall cohort. Arrows represent median survival (50% living patients) in months. <i>B</i>. Survival stratified by race.</p
Tumor remission in mouse lung xenografts in response to EphB4 inhibition alone and in combination.
<p><i>A</i>. A549 cells were injected into flanks of nude mice, allowed to establish primary tumors, and treated with PBS (control), paclitaxel, soluble EphB4 (sEphB4-HSA), or paclitaxel plus soluble EphB4. Error bars indicate standard deviation among six mice per group. <i>B–C</i>. H1993 or H446 cells were injected into flanks of nude mice, allowed to establish primary tumors, and treated with PBS (control) or soluble EphB4 (sEphB4-HSA). Error bars indicate SEM among six mice per group. *, p<0.05; **, p<0.01; ****, p<0.0001.</p