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Dr. Kristina  Young   image

Dr. Kristina Young

4117 N Roxboro St
Durham NC 27704
919 848-8111
Medical School: Other - Unknown
Accepts Medicare: No
Participates In eRX: No
Participates In PQRS: No
Participates In EHR: No
License #: C004482
NPI: 1417083692
Taxonomy Codes:
2084P0800X

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Publications

Tumor immune remodeling by TGFβ inhibition improves the efficacy of radiation therapy. - Oncoimmunology
The tumor immune environment has been linked to prognosis in patients with a range of malignancies. Recently, we demonstrated in pre-clinical models that modifying the tumor immune environment using a small-molecule inhibitor of TGFb significantly improved outcome to subsequent radiation therapy. These data suggest that this and other immunotherapies may be used to remodel the tumor before conventional cancer therapies to improve outcomes.
Tumor immune remodeling by TGFβ inhibition improves the efficacy of radiation therapy. - Oncoimmunology
The tumor immune environment has been linked to prognosis in patients with a range of malignancies. Recently, we demonstrated in pre-clinical models that modifying the tumor immune environment using a small-molecule inhibitor of TGFb significantly improved outcome to subsequent radiation therapy. These data suggest that this and other immunotherapies may be used to remodel the tumor before conventional cancer therapies to improve outcomes.
TGFβ inhibition prior to hypofractionated radiation enhances efficacy in preclinical models. - Cancer immunology research
The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy. We demonstrate that inhibition of TGFβ using the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial-mesenchymal transition, or changes in vascular function in the tumor; rather, this effect was dependent on adaptive immunity and resulted in long-term protective immunity in cured mice. These data demonstrate that immunotherapy is an option to improve the immune status of patients with poor tumor infiltrates and that pretreatment improves the efficacy of radiotherapy.©2014 American Association for Cancer Research.
Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice. - Radiation research
An accumulating body of evidence demonstrates that radiation therapy can generate adaptive immune responses that contribute to tumor control. However, in the absence of additional immune therapy, the adaptive immune response is insufficient to prevent tumor recurrence or affect distant disease. It has been shown in multiple models that tumor-infiltrating myeloid cells exhibit alternative activation phenotypes and are able to suppress adaptive immune responses, and recent data suggests that the myeloid response in tumors treated with cytotoxic therapy limits tumor control. We hypothesized that tumor myeloid cells inhibit the adaptive immune response after radiation therapy through expression of the enzyme arginase I. Using a myeloid cell-specific deletion of arginase I in mice, we demonstrate an improved tumor control after radiation therapy. However, tumors still recurred despite the conditional knockdown of arginase I. Since multiple alternative factors may combine to inhibit adaptive immunity, we propose that targeting macrophage differentiation may be a more effective strategy than targeting individual suppressive pathways.
The impact of the myeloid response to radiation therapy. - Clinical & developmental immunology
Radiation therapy is showing potential as a partner for immunotherapies in preclinical cancer models and early clinical studies. As has been discussed elsewhere, radiation provides debulking, antigen and adjuvant release, and inflammatory targeting of effector cells to the treatment site, thereby assisting multiple critical checkpoints in antitumor adaptive immunity. Adaptive immunity is terminated by inflammatory resolution, an active process which ensures that inflammatory damage is repaired and tissue function is restored. We discuss how radiation therapy similarly triggers inflammation followed by repair, the consequences to adaptive immune responses in the treatment site, and how the myeloid response to radiation may impact immunotherapies designed to improve control of residual cancer cells.
Interleukin-4 deficiency induces mild preeclampsia in mice. - Journal of hypertension
Inflammation is necessary for successful pregnancy; however, excessive inflammation plays a central role in the development of the pregnancy-specific hypertensive disorder preeclampsia. Numerous anti-inflammatory cytokines are decreased in women with preeclampsia but the role of individual cytokines in blood pressure regulation during pregnancy is unknown. Therefore, we examined whether the lack of the potent anti-inflammatory cytokine interleukin-4 (IL-4) would be sufficient to elicit a preeclampsia-like syndrome in mice, and when coupled with immune system activation that these symptoms would be further augmented.Measures of splenic immune cells, placental inflammation, blood pressure, endothelial function, and urinary protein excretion were performed in pregnant IL-4-deficient mice as well as in pregnant IL-4-deficient mice treated with the Toll-like receptor 3 agonist polyinosinic:polycytidylic (poly I:C).Pregnant IL-4-deficient mice exhibited altered splenic immune cell subsets, increased levels of pro-inflammatory cytokines, placental inflammation, mild hypertension, endothelial dysfunction, and proteinuria compared to pregnant control mice. Compared to pregnant control mice treated with poly I:C which exhibit preeclampsia-like symptoms, poly I:C-treated pregnant IL-4-deficient mice exhibited a further increase in pro-inflammatory cytokine levels, which was associated with augmented SBP and endothelial dysfunction.Collectively, these data show that the absence of IL-4 is sufficient to induce mild preeclampsia-like symptoms in mice due to excessive inflammation. Thus, the anti-inflammatory effects of IL-4 are important in preventing hypertension during pregnancy.
Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. - Cardiovascular research
Elevated levels of pro-inflammatory cytokine interleukin-17A (IL-17) are associated with hypertensive autoimmune diseases; however, the connection between IL-17 and hypertension is unknown. We hypothesized that IL-17 increases blood pressure by decreasing endothelial nitric oxide production.Acute treatment of endothelial cells with IL-17 caused a significant increase in phosphorylation of the inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495). Of the kinases known to phosphorylate eNOS Thr495, only inhibition of Rho-kinase prevented the IL-17-induced increase. IL-17 caused a threefold increase in the Rho-kinase activator RhoA, and this was prevented by an IL-17 neutralizing antibody. In isolated mouse aortas, IL-17 significantly increased eNOS Thr495 phosphorylation, induced RhoA expression, and decreased NO-dependent relaxation responses, all of which were prevented by either an IL-17 neutralizing antibody or inhibition of Rho-kinase. In mice, IL-17 treatment for 1 week significantly increased systolic blood pressure and this was associated with decreased aortic NO-dependent relaxation responses, increased eNOS Thr495 phosphorylation, and increased RhoA expression. Inhibition of Rho-kinase prevented the hypertension caused by IL-17.These data demonstrate that IL-17 activates RhoA/Rho-kinase leading to endothelial dysfunction and hypertension. Inhibitors of IL-17 or Rho-kinase may prove useful as anti-hypertensive drugs in IL-17-associated autoimmune diseases.
Placental Toll-like receptor 3 and Toll-like receptor 7/8 activation contributes to preeclampsia in humans and mice. - PloS one
Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome characterized by excessive maternal immune system activation, inflammation, and endothelial dysfunction. Toll-like receptor (TLR) 3 activation by double-stranded RNA (dsRNA) and TLR7/8 activation by single-stranded RNA (ssRNA) expressed by viruses and/or released from necrotic cells initiates a pro-inflammatory immune response; however it is unknown whether viral/endogenous RNA is a key initiating signal that contributes to the development of PE. We hypothesized that TLR3/7/8 activation will be evident in placentas of women with PE, and sufficient to induce PE-like symptoms in mice. Placental immunoreactivity and mRNA levels of TLR3, TLR7, and TLR8 were increased significantly in women with PE compared to normotensive women. Treatment of human trophoblasts with the TLR3 agonist polyinosine-polycytidylic acid (poly I:C), the TLR7-specific agonist imiquimod (R-837), or the TLR7/8 agonist CLO97 significantly increased TLR3/7/8 levels. Treatment of mice with poly I:C, R-837, or CLO97 caused pregnancy-dependent hypertension, endothelial dysfunction, splenomegaly, and placental inflammation. These data demonstrate that RNA-mediated activation of TLR3 and TLR7/8 plays a key role in the development of PE.
Endothelial cell transforming growth factor-β receptor activation causes tacrolimus-induced renal arteriolar hyalinosis. - Kidney international
Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus; however, the pathophysiologic mechanisms remain unknown. In addition to increasing transforming growth factor (TGF)-β levels, tacrolimus inhibits calcineurin by binding to FK506-binding protein 12 (FKBP12). FKBP12 alone also inhibits TGF-β receptor activation. Here we tested whether tacrolimus binding to FKBP12 removes an inhibition of the TGF-β receptor, allowing ligand binding, ultimately leading to receptor activation and arteriolar hyalinosis. We found that specific deletion of FKBP12 from endothelial cells was sufficient to activate endothelial TGF-β receptors and induce renal arteriolar hyalinosis in these knockout mice, similar to that induced by tacrolimus. Tacrolimus-treated and knockout mice exhibited significantly increased levels of aortic TGF-β receptor activation as evidenced by SMAD2/3 phosphorylation, along with increased collagen and fibronectin expression compared to controls. Treatment of isolated mouse aortas with tacrolimus increased TGF-β receptor activation and collagen and fibronectin expression. These effects were independent of calcineurin, absent in endothelial denuded aortic rings, and could be prevented by the small molecule TGF-β receptor inhibitor SB-505124. Thus, endothelial cell TGF-β receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis.
Pin1 deficiency causes endothelial dysfunction and hypertension. - Hypertension
Pin1 is a peptidyl prolyl cis-trans isomerase that only binds to and isomerizes phosphorylated serine/threonine-proline motifs, inducing conformational changes that alter target protein function and phosphorylation. We have shown previously that deficiency of another peptidyl prolyl isomerase, FK506 binding protein 12/12.6, alters endothelial NO synthase phosphorylation and causes endothelial dysfunction and hypertension. Endothelial NO synthase contains the Pin1 binding sequence at (p)serine 116-proline 117 and phosphorylation of endothelial NO synthase serine 116 inhibits NO production; however, whether Pin1 deficiency alters vascular function and blood pressure is unknown. We hypothesized that Pin1 isomerizes p-endothelial NO synthase serine 116, which enables dephosphorylation and stimulates NO production. Immunoprecipitation of endothelial NO synthase and probing for Pin1 in rat aortic endothelial cells confirmed the interaction between the two. Pin1 knockdown via small interfering RNA or inhibition by juglone increased endothelial NO synthase serine 116 phosphorylation and prevented vascular endothelial growth factor-induced serine 116 dephosphorylation in endothelial cells. Acute treatment of isolated mouse aortas with juglone increased endothelial NO synthase serine 116 phosphorylation and decreased NO production and relaxation responses. Mice treated with juglone for 2 weeks, as well as Pin1 knockout mice, exhibited increased aortic endothelial NO synthase serine 116 phosphorylation, endothelial dysfunction, and hypertension. These data demonstrate that Pin1 binds endothelial NO synthase and enables dephosphorylation of serine 116, which increases NO production and endothelium-dependent dilation, leading to blood pressure maintenance.

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4117 N Roxboro St Durham, NC 27704
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