Publications by authors named "Xiaokui Mo"

148 Publications

Dopamine prevents ultraviolet B-induced development and progression of premalignant cutaneous lesions through its D2 receptors.

Cancer Prev Res (Phila) 2021 Apr 12. Epub 2021 Apr 12.

Pathology and Medical Oncology and Cancer Center, The Ohio State University

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited vascular-endothelial growth factor-A (VEGF)-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0052DOI Listing
April 2021

Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury.

Cell Rep 2021 Jan;34(4):108667

Department of Neuroscience, Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

After spinal cord injury (SCI), normally innocuous visceral or somatic stimuli can trigger uncontrolled reflex activation of sympathetic circuitry, causing pathological dysautonomia. We show that remarkable structural remodeling and plasticity occur within spinal autonomic circuitry, creating abnormal sympathetic reflexes that promote dysautonomia. However, when mice are treated early after SCI with human-equivalent doses of the US Food and Drug Administration (FDA)-approved drug gabapentin (GBP), it is possible to block multi-segmental excitatory synaptogenesis and abolish sprouting of autonomic neurons that innervate immune organs and sensory afferents that trigger pain and autonomic dysreflexia (AD). This "prophylactic GBP" regimen decreases the frequency and severity of AD and protects against SCI-induced immune suppression. These benefits persist even 1 month after stopping treatment. GBP could be repurposed to prevent dysautonomia in at-risk individuals with high-level SCI.
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http://dx.doi.org/10.1016/j.celrep.2020.108667DOI Listing
January 2021

An unexpected paradox: wall shear stress in the aorta is less in patients with severe atherosclerosis regardless of obesity.

Cardiovasc Pathol 2021 Mar-Apr;51:107313. Epub 2020 Nov 23.

Department of Pathology, The Ohio State University, Columbus, OH, USA. Electronic address:

Background: Obesity is a widespread condition that is more prevalent in Western countries compared to others. Aortic atherosclerosis (AA) is a condition that frequently has been associated with obesity. An obesity paradox, where morbidly obese decedents had either no or minimal AA compared to nonobese decedents, recently has been described by some of us. The explanation for this almost counterintuitive paradox has yet to be determined, but a number of hypotheses were advanced, including hemodynamic factors producing aortic wall shear stress (WSS). The purpose of the present study was to determine if there was a relationship between AA and WSS, as determined by postmortem measurement of aortic wall diameters.

Methods: Circumferences of the aorta at the levels of the ascending, thoracic and abdominal aorta were measured in 274 consecutive autopsies over 2-year period of time. AA was assessed using a previously described grading scale as either mild or severe. Circumferences were mathematically converted to diameters and WSS was calculated using the Hagen-Poiseuille formula. Two different methods to estimate cardiac output were used, both based on literature methods, one of which was body mass index (BMI) dependent, and the other BMI independent. Univariate and multivariable analyses of the relationship between WSS, age, BMI, gender, race and severity of AA were performed.

Results: Of the 274 decedents, 140 had mild and 134 had moderate to severe AA. BMI <35 was associated with moderate to severe AA. WSS was inversely correlated with AA in all these segments of the aorta in each BMI subgroup with the exception of the ascending aorta for decedents with BMI ≤35 kg/m. Contrary to what we had hypothesized, WSS was not a determinant of the obesity paradox. However, among all the variables analyzed, a history of hypertension, diabetes mellitus and age were significant factors for developing AA (relative risk [RR] 0.35, P = .039; RR 1.51, P = .0006, RR 1.19, P = .0001, respectively).

Conclusions: Our data demonstrate that WSS was unexpectedly lower in decedents with moderate and severe AA as compared to those with mild AA. This observation, which requires further investigations, was seen in all BMI ranges and was confirmed by 2 methods to calculate WSS.
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http://dx.doi.org/10.1016/j.carpath.2020.107313DOI Listing
November 2020

Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice.

Arthritis Res Ther 2020 11 23;22(1):273. Epub 2020 Nov 23.

Department of Pathology, Ohio State University, Hamilton Hall (H166), 1645 Neil Avenue, Columbus, OH, 43210, USA.

Background: Although vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2-3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated.

Methods: CIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo.

Results: Significant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice.

Conclusion: CI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.
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http://dx.doi.org/10.1186/s13075-020-02370-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682078PMC
November 2020

Vitamin A and D Absorption in Adults with Metabolic Syndrome versus Healthy Controls: A Pilot Study Utilizing Targeted and Untargeted LC-MS Lipidomics.

Mol Nutr Food Res 2021 01 7;65(2):e2000413. Epub 2020 Dec 7.

Human Nutrition Program, The Ohio State University, Columbus, OH, 43210, USA.

Scope: Persons with metabolic syndrome (MetS) absorb less vitamin E than healthy controls. It is hypothesized that absorption of fat-soluble vitamins (FSV) A and D would also decrease with MetS status and that trends would be reflected in lipidomic responses between groups.

Methods And Results: Following soymilk consumption (501 IU vitamin A, 119 IU vitamin D ), the triglyceride-rich lipoprotein fractions (TRL) from MetS and healthy subjects (n = 10 age- and gender-matched subjects/group) are assessed using LC-MS/MS. Absorption is calculated using area under the time-concentration curves (AUC) from samples collected at 0, 3, and 6 h post-ingestion. MetS subjects have ≈6.4-fold higher median vitamin A AUC (retinyl palmitate) versus healthy controls (P = 0.07). Vitamin D AUC is unaffected by MetS status (P = 0.48). Untargeted LC-MS lipidomics reveals six phospholipids and one cholesterol ester with concentrations correlating (r = 0.53-0.68; P < 0.001) with vitamin A concentration.

Conclusions: The vitamin A-phospholipid association suggests increased hydrolysis by PLB, PLRP2, and/or PLA IB may be involved in the trend in higher vitamin A bioavailability in MetS subjects. Previously observed differences in circulating levels of these vitamins are likely not due to absorption. Alternate strategies should be investigated to improve FSV status in MetS.
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http://dx.doi.org/10.1002/mnfr.202000413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902427PMC
January 2021

Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia.

Clin Cancer Res 2020 Dec 21;26(23):6187-6195. Epub 2020 Sep 21.

Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Infectious complications constitute a leading cause of morbidity and mortality in chronic lymphocytic leukemia (CLL). Patients respond poorly to vaccines, particularly pneumococcal polysaccharide and influenza vaccines. In addition, patients with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated clinical activity in CLL, can potentially restore immune system dysfunction associated with CLL while improving disease outcomes.

Patients And Methods: Phase II study randomized 49 patients with genetically high-risk CLL or small lymphocytic lymphoma [SLL; defined as unmutated Ig heavy chain variable region, deletion(17p) or (11q), and/or complex abnormal karyotype], to receive lenalidomide either concurrent (arm A) or sequential to (arm B) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) administered 2 months apart, in patients not meeting International Workshop on Chronic Lymphocytic Leukemia treatment criteria.

Results: Four serotypes (3, 4, 5, 6B) achieved the additional seroprotection definition of a fourfold increase in arm A, and six serotypes (3, 4, 5, 6B, 19A, 19F) in arm B. All patients achieved the defined concentration of 0.35 μg/mL for at least one serotype tested. No significant difference was observed with the addition of lenalidomide. At median time on treatment of 3.6 years, median progression-free survival (PFS) was 5.8 years [95% confidence interval (CI), 3.1-not reached]. PFS at 1, 2, and 3 years was 85% (95% CI, 72-93), 79% (95% CI, 64-88), and 72% (95% CI, 57-83), respectively.

Conclusions: Lenalidomide is efficacious with manageable toxicities as an early intervention strategy in patients with high-risk CLL, but did not enhance humoral response to PCV13 vaccine.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1280DOI Listing
December 2020

Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.

J Immunol 2020 10 16;205(8):2301-2311. Epub 2020 Sep 16.

In Vivo Multifunctional Magnetic Resonance Center, West Virginia University, Morgantown, WV 26506;

Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription factors HIF-1α and HIF-2α, regulates TEM function in the hypoxic tumor microenvironment. We orthotopically implanted PyMT breast tumor cells into the mammary fat pads of syngeneic LysMcre, HIF-1α /LysMcre, or HIF-2α /LysMcre mice and evaluated the tumor TEM population. There was no difference in the percentage of tumor macrophages among the mouse groups. In contrast, HIF-1α /LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2α /LysMcre mice. Proangiogenic TEMs in macrophage HIF-2α-deficient tumors presented significantly more CD31 microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of proangiogenic TEMs in macrophage HIF-1α-deficient tumors presented significantly less microvessel density but tumor vessels that were more functional as lectin injection revealed more perfusion, and functional electron paramagnetic resonance analysis revealed more oxygen in those tumors. Macrophage HIF-1α-deficient tumors also responded significantly to chemotherapy. These data introduce a previously undescribed and counterintuitive prohypoxia role for proangiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2α.
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http://dx.doi.org/10.4049/jimmunol.2000185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596922PMC
October 2020

Spinal cord injury causes chronic bone marrow failure.

Nat Commun 2020 07 24;11(1):3702. Epub 2020 Jul 24.

Department of Neuroscience, The Ohio State University, Columbus, OH, USA.

Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.
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http://dx.doi.org/10.1038/s41467-020-17564-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382469PMC
July 2020

Two-miRNA-based finger-stick assay for estimation of absorbed ionizing radiation dose.

Sci Transl Med 2020 07;12(552)

The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.

Nuclear radiation and radioactive fallouts resulting from a nuclear weapon detonation or reactor accidents could result in injuries affecting multiple sensitive organs, defined as acute radiation syndrome (ARS). Rapid and early estimation of injuries to sensitive organs using markers of radiation response is critical for identifying individuals who could potentially exhibit ARS; however, there are currently no biodosimetry assays approved for human use. We developed a sensitive microRNA (miRNA)-based blood test for radiation dose reconstruction with ±0.5 Gy resolution at critical dose range. Radiation dose-dependent changes in in blood were internally normalized by a miRNA, , that was nonresponsive to radiation. was not highly expressed in blood cells but was abundant in circulation and was released primarily from the lung. Our assay showed the capability for dose estimation within hours to 1 week after exposure using a drop of blood from mice. We tested this biodosimetry assay for estimation of absorbed ionizing radiation dose in mice of varying ages and after exposure to both improvised nuclear device (IND)-spectrum neutrons and gamma rays. Leukemia specimens from patients exposed to fractionated radiation showed depletion of in blood. We bridged the exposure of these patients to fractionated radiation by comparing responses after fractionated versus single acute exposure in mice. Although validation in nonhuman primates is needed, this proof-of-concept study suggests the potential utility of this assay in radiation disaster management and clinical applications.
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http://dx.doi.org/10.1126/scitranslmed.aaw5831DOI Listing
July 2020

Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

Cell Metab 2020 Aug 18;32(2):229-242.e8. Epub 2020 Jun 18.

Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. We show in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.
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http://dx.doi.org/10.1016/j.cmet.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415721PMC
August 2020

In Vivo Aortic Magnetic Resonance Elastography in Abdominal Aortic Aneurysm: A Validation in an Animal Model.

Invest Radiol 2020 07;55(7):463-472

Departments of Biomedical Informatics and Center for Biostatistics.

Objectives: Using maximum diameter of an abdominal aortic aneurysm (AAA) alone for management can lead to delayed interventions or unnecessary urgent repairs. Abdominal aortic aneurysm stiffness plays an important role in its expansion and rupture. In vivo aortic magnetic resonance elastography (MRE) was developed to spatially measure AAA stiffness in previous pilot studies and has not been thoroughly validated and evaluated for its potential clinical value. This study aims to evaluate noninvasive in vivo aortic MRE-derived stiffness in an AAA porcine model and investigate the relationships between MRE-derived AAA stiffness and (1) histopathology, (2) uniaxial tensile test, and (3) burst testing for assessing MRE's potential in evaluating AAA rupture risk.

Materials And Methods: Abdominal aortic aneurysm was induced in 31 Yorkshire pigs (n = 226 stiffness measurements). Animals were randomly divided into 3 cohorts: 2-week, 4-week, and 4-week-burst. Aortic MRE was sequentially performed. Histopathologic analyses were performed to quantify elastin, collagen, and mineral densities. Uniaxial tensile test and burst testing were conducted to measure peak stress and burst pressure for assessing the ultimate wall strength.

Results: Magnetic resonance elastography-derived AAA stiffness was significantly higher than the normal aorta. Significant reduction in elastin and collagen densities as well as increased mineralization was observed in AAAs. Uniaxial tensile test and burst testing revealed reduced ultimate wall strength. Magnetic resonance elastography-derived aortic stiffness correlated to elastin density (ρ = -0.68; P < 0.0001; n = 60) and mineralization (ρ = 0.59; P < 0.0001; n = 60). Inverse correlations were observed between aortic stiffness and peak stress (ρ = -0.32; P = 0.0495; n = 38) as well as burst pressure (ρ = -0.55; P = 0.0116; n = 20).

Conclusions: Noninvasive in vivo aortic MRE successfully detected aortic wall stiffening, confirming the extracellular matrix remodeling observed in the histopathologic analyses. These mural changes diminished wall strength. Inverse correlation between MRE-derived aortic stiffness and aortic wall strength suggests that MRE-derived stiffness can be a potential biomarker for clinically assessing AAA wall status and rupture potential.
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http://dx.doi.org/10.1097/RLI.0000000000000660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295098PMC
July 2020

Stimulation of retrotrapezoid nucleus Phox2b-expressing neurons rescues breathing dysfunction in an experimental Parkinson's disease rat model.

Brain Pathol 2020 09 2;30(5):926-944. Epub 2020 Jul 2.

Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo (USP), São Paulo, Brazil.

Emerging evidence from multiple studies indicates that Parkinson's disease (PD) patients suffer from a spectrum of autonomic and respiratory motor deficiencies in addition to the classical motor symptoms attributed to substantia nigra degeneration of dopaminergic neurons. Animal models of PD show a decrease in the resting respiratory rate as well as a decrease in the number of Phox2b-expressing retrotrapezoid nucleus (RTN) neurons. The aim of this study was to determine the extent to which substantia nigra pars compact (SNc) degeneration induced RTN biomolecular changes and to identify the extent to which RTN pharmacological or optogenetic stimulations rescue respiratory function following PD-induction. SNc degeneration was achieved in adult male Wistar rats by bilateral striatal 6-hydroxydopamine injection. For proteomic analysis, laser capture microdissection and pressure catapulting were used to isolate the RTN for subsequent comparative proteomic analysis and Ingenuity Pathway Analysis (IPA). The respiratory parameters were evaluated by whole-body plethysmography and electromyographic analysis of respiratory muscles. The results confirmed reduction in the number of dopaminergic neurons of SNc and respiratory rate in the PD-animals. Our proteomic data suggested extensive RTN remodeling, and that pharmacological or optogenetic stimulations of the diseased RTN neurons promoted rescued the respiratory deficiency. Our data indicate that despite neuroanatomical and biomolecular RTN pathologies, that RTN-directed interventions can rescue respiratory control dysfunction.
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http://dx.doi.org/10.1111/bpa.12868DOI Listing
September 2020

Fc-engineered anti-CD33 monoclonal antibody potentiates cytotoxicity of membrane-bound interleukin-21 expanded natural killer cells in acute myeloid leukemia.

Cytotherapy 2020 07 15;22(7):369-376. Epub 2020 Apr 15.

Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA. Electronic address:

Background: Qualitative and quantitative defects in natural killer (NK) cells have been noted in patients with acute myeloid leukemia (AML), providing rationale for infusion of donor-derived NK cells. We previously showed that decitabine enhances expression of NKG2D ligands in AML with additive cytotoxicity when NK cells and Fc (fragment crystallizable region)-engineered CD33 monoclonal antibody (CD33mAb) was used. We conducted a phase 1 study evaluating decitabine and haploidentical NK cells in relapsed AML. Using patient samples from this study, we evaluated whether ex vivo donor-derived expanded NK cells with or without CD33mAb was effective in decitabine-treated AML.

Methods: Bone marrow aspirates were collected from patients at pre- and post-NK cell infusion. NK cells from healthy donors were expanded for 14 days using irradiated K562 feeder cells displaying membrane-bound IL-21 (mbIL-21). Patient samples were used to test in vitro activity of mbIL-21 NK cells ± CD33m Ab-dependent cellular cytotoxicity (ADCC) and AML patient derived xenograft (PDX) mice were developed to test in vivo activity.

Results: Upon incubation with primary AML blasts, mbIL-21 NK cells showed variable donor-dependent intra-cellular interferon-γ production, which increased with CD33mAb-coated AML. ADCC assays revealed mbIL-21 NK cells effectively lysed primary AML blasts with higher activity on CD33mAb-coated AML. Importantly, CD33mAb-dependent enhanced cytotoxicity by mbIL-21 NK cells was maintained in AML cells from patients even 24 days post-decitabine treatment. In vivo infusion of mbIL-21 NK cells in AML PDX mice, treated with CD33mAb, reduced the tumor burden.

Discussion: These data show the therapeutic utility of mbIL-21 NK cells that can be further potentiated by addition of CD33mAb in AML.
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http://dx.doi.org/10.1016/j.jcyt.2020.02.001DOI Listing
July 2020

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.

Aging (Albany NY) 2020 02 2;12(3):2101-2122. Epub 2020 Feb 2.

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.
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http://dx.doi.org/10.18632/aging.102724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041757PMC
February 2020

MicroRNA-mRNA Interactions at Low Levels of Compressive Solid Stress Implicate mir-548 in Increased Glioblastoma Cell Motility.

Sci Rep 2020 01 15;10(1):311. Epub 2020 Jan 15.

Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.

Glioblastoma (GBM) is an astrocytic brain tumor with median survival times of <15 months, primarily as a result of high infiltrative potential and development of resistance to therapy (i.e., surgical resection, chemoradiotherapy). A prominent feature of the GBM microenvironment is compressive solid stress (CSS) caused by uninhibited tumor growth within the confined skull. Here, we utilized a mechanical compression model to apply CSS (<115 Pa) to well-characterized LN229 and U251 GBM cell lines and measured their motility, morphology, and transcriptomic response. Whereas both cell lines displayed a peak in migration at 23 Pa, cells displayed differential response to CSS with either minimal (i.e., U251) or large changes in motility (i.e., LN229). Increased migration of LN229 cells was also correlated to increased cell elongation. These changes were tied to epigenetic signaling associated with increased migration and decreases in proliferation predicted via Ingenuity® Pathway Analysis (IPA), characteristics associated with tumor aggressiveness. miRNA-mRNA interaction analysis revealed strong influence of the miR548 family (i.e., mir-548aj, mir-548az, mir-548t) on differential signaling induced by CSS, suggesting potential targets for pharmaceutical intervention that may improve patient outcomes.
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http://dx.doi.org/10.1038/s41598-019-56983-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962377PMC
January 2020

Magnetic resonance elastography-derived stiffness of the kidneys and its correlation with water perfusion.

NMR Biomed 2020 04 30;33(4):e4237. Epub 2019 Dec 30.

Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio.

Stiffness plays an important role in diagnosing renal fibrosis. However, kidney stiffness is altered by perfusion changes in many kidney diseases. Therefore, the aim of the current study is to determine the correlation of kidney stiffness with water intake. We hypothesize that kidney stiffness will increase with 1 L of water intake due to increased water perfusion to the kidneys. Additionally, stiffness of the kidneys will correlate with apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values before and after water intake. A 3 T MRI scanner was used to perform magnetic resonance elastography and diffusion tensor imaging of the kidneys on 24 healthy subjects (age range: 22-66 years) before and after water intake of 1 L. A 3D T1-weighted bladder scan was also performed to measure bladder volume before and after water intake. A paired t-test was performed to evaluate the effect of water intake on the stiffness of kidneys, in addition to bladder volume. A Spearman correlation test was performed to determine the association between stiffness, bladder volume, ADC and FA values of both kidneys before and after water intake. The results show a significant increase in stiffness in different regions of the kidney (ie, percentage increase ranged from 3.6% to 7.5%) and bladder volume after water intake (all P < 0.05). A moderate significant negative correlation was observed between change in kidney stiffness and bladder volume (concordance correlation coefficient = -0.468, P < 0.05). No significant correlation was observed between stiffness and ADC or FA values before and after water intake in both kidneys (P > 0.05). Water intake caused a significant increase in the stiffness of the kidneys. The negative correlation between the change in kidney stiffness and bladder volume, before and after water intake, indicates higher perfusion pressure in the kidneys, leading to increased stiffness.
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http://dx.doi.org/10.1002/nbm.4237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060814PMC
April 2020

Constitutive AKT Activity Predisposes Lung Fibrosis by Regulating Macrophage, Myofibroblast and Fibrocyte Recruitment and Changes in Autophagy.

Adv Biosci Biotechnol 2019 Oct 30;10(10):346-373. Epub 2019 Oct 30.

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

The etiology and pathogenesis of pulmonary fibrosis is poorly understood. We and others reported that M-CSF/CSF-1, M-CSF-R and downstream AKT activation plays an important role in lung fibrosis in mice models and in IPF patients. To understand potential molecular pathways used by M-CSF-R activation to direct lung fibrosis, we used a novel transgenic mouse model that expresses a constitutively-active form of AKT, myristoylated AKT (Myr-Akt), driven by the (M-CSF-R) promoter. We were particularly interested in the basal immune state of the lungs of these Myr-Akt mice to assess M-CSF-R-related priming for lung fibrosis. In support of a priming effect, macrophages isolated from the lungs of unchallenged Myr-Akt mice displayed an M2-tropism, enhanced co-expression of M-CSF-R and -SMA, reduced autophagy reflected by reduced expression of the key autophagy genes -1, MAP1-3(3), and MAP1-3(3), and increased 62/1 expression compared with littermate WT mice. Furthermore, Myr-Akt mice had more basal circulating fibrocytes than WT mice. Lastly, upon bleomycin challenge, Myr-Akt mice showed enhanced collagen deposition, increased F4/80+ and CD45+ cells, reduced autophagy genes -1, 3, and 3 expression, and a shorter life-span than WT littermates. These data provide support that M-CSF-R/AKT activation may have a priming effect which can predispose lung tissue to pulmonary fibrosis.
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http://dx.doi.org/10.4236/abb.2019.1010027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866236PMC
October 2019

CD31 Acts as a Checkpoint Molecule and Is Modulated by FcγR-Mediated Signaling in Monocytes.

J Immunol 2019 12 15;203(12):3216-3224. Epub 2019 Nov 15.

Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210;

Monocytes and macrophages express FcγR that engage IgG immune complexes such as Ab-opsonized pathogens or cancer cells to destroy them by various mechanisms, including phagocytosis. FcγR-mediated phagocytosis is regulated by the concerted actions of activating FcγR and inhibitory receptors, such as FcγRIIb and SIRPα. In this study, we report that another ITIM-containing receptor, PECAM1/CD31, regulates FcγR function and is itself regulated by FcγR activation. First, quantitative RT-PCR and flow cytometry analyses revealed that human monocyte FcγR activation leads to a significant downregulation of CD31 expression, both at the message level and at surface expression, mainly mediated through FcγRIIa. Interestingly, the kinetics of downregulation between the two varied, with surface expression reducing earlier than the message. Experiments to analyze the mechanism behind this discrepancy revealed that the loss of surface expression was because of internalization, which depended predominantly on the PI3 kinase pathway and was independent of FcγR internalization. Finally, functional analyses showed that the downregulation of CD31 expression in monocytes by small interfering RNA enhanced FcγR-mediated phagocytic ability but have little effect on cytokine production. Together, these results suggest that CD31 acts as a checkpoint receptor that could be targeted to enhance FcγR functions in Ab-mediated therapies.
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http://dx.doi.org/10.4049/jimmunol.1900059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904527PMC
December 2019

Environmental enrichment improves metabolic and behavioral health in the BTBR mouse model of autism.

Psychoneuroendocrinology 2020 01 15;111:104476. Epub 2019 Oct 15.

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Electronic address:

BTBR T + Itpr3tf/J (BTBR) mice are an Autism Spectrum Disorder (ASD)-like model that exhibit behavioral and physiological deficits similar to those observed in patients with ASD. While behavioral therapy is a first line of treatment in ASD patients, comparable non-pharmacological treatments are less explored in murine models. Here, we administer a bio-behavioral intervention for BTBR mice by way of environmental enrichment (EE) - an experimental housing paradigm previously shown to improve systemic metabolism, learning/memory, anxious behavior, neurogenesis, locomotion, and immunocompetence in C57BL/6 mice. Juvenile BTBR mice were randomized to standard or EE housing and were subjected to metabolic and behavioral assessments up to 17 weeks. Following EE exposure, we report an EE-induced metabolic and behavioral phenotype. Male BTBR mice responded metabolically to EE, displaying reduced adiposity, increased lean mass, improved glycemic control, and decreased circulating leptin. The gene expressions of brain-derived neurotrophic factor (Bdnf) and its receptor (Ntrk2/TrkB) were upregulated in several brain areas in EE-BTBR males. EE-BTBR females showed modest reduction of adiposity and no changes in glycemic control, circulating leptin, or Bdnf/Ntrk2 gene expression. With regard to behavior, EE resulted in decreased anxiety, and increased social affiliation. Together, these results suggest that EE improves metabolic and behavioral health in BTBR mice.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914218PMC
January 2020

Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention.

Metabolites 2019 Jul 11;9(7). Epub 2019 Jul 11.

Department of Pathology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

Oral cancer is a public health problem with an incidence of almost 50,000 and a mortality of 10,000 each year in the USA alone. Black raspberries (BRBs) have been shown to inhibit oral carcinogenesis in several preclinical models, but our understanding of how BRB phytochemicals affect the metabolic pathways during oral carcinogenesis remains incomplete. We used a well-established rat oral cancer model to determine potential metabolic pathways impacted by BRBs during oral carcinogenesis. F344 rats were exposed to the oral carcinogen 4-nitroquinoline-1-oxide in drinking water for 14 weeks, then regular drinking water for six weeks. Carcinogen exposed rats were fed a 5% or 10% BRB supplemented diet or control diet for six weeks after carcinogen exposure. RNA-Seq transcriptome analysis on rat tongue, and mass spectrometry and NMR metabolomics analysis on rat urine were performed. We tentatively identified 57 differentially or uniquely expressed metabolites and over 662 modulated genes in rats being fed with BRB. Glycolysis and AMPK pathways were modulated during BRB-mediated oral cancer chemoprevention. Glycolytic enzymes , , , , , and as well as the PKA-AMPK pathway genes , , , , and were downregulated by BRBs during oral cancer chemoprevention. Furthermore, the glycolysis metabolite glucose-6-phosphate decreased in BRB-administered rats. Our data reveal the novel metabolic pathways modulated by BRB phytochemicals that can be targeted during the chemoprevention of oral cancer.
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http://dx.doi.org/10.3390/metabo9070140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680978PMC
July 2019

Magnetic Resonance Elastography of kidneys: SE-EPI MRE reproducibility and its comparison to GRE MRE.

NMR Biomed 2019 11 22;32(11):e4141. Epub 2019 Jul 22.

Department of Biomedical Engineering, The Ohio State University, Columbus, OH.

The purpose of this study is 1) to demonstrate reproducibility of spin echo-echo planar imaging (SE-EPI) magnetic resonance elastography (MRE) to estimate kidney stiffness; and 2) to compare SE-EPI MRE and gradient recalled echo (GRE) MRE-derived stiffness estimations in various anatomical regions of the kidney. Kidney MRE was performed on 33 healthy subjects (8 for SE-EPI MRE reproducibility and 25 for comparison with GRE MRE; age range: 22-66 years) in a 3 T MRI scanner. To demonstrate SE-EPI MRE reproducibility, subjects were scanned for the first scan and then asked to leave the scan room and repositioned again for the second (repeat) scan. Similar set-up was used for GRE MRE as well. The displacement data was then processed to obtain overall stiffness estimates of the kidney. Concordance correlation analyses were performed to determine SE-EPI MRE reproducibility and agreement between GRE MRE and SE-EPI MRE derived stiffness. A high concordance correlation (ρ  = 0.95; p-value<0.0001) was obtained for SE-EPI MRE reproducibility. Good concordance correlation was observed (ρ  = 0.84; p < 0.0001 for both kidneys, ρ  = 0.91; p < 0.0001 for right kidney and ρ  = 0.78; p < 0.0001 for left kidney) between GRE MRE and SE-EPI MRE derived stiffness measurements. Paired t-test results showed that stiffness value of medulla was significantly (p < 0.0001) greater than cortex using SE-EPI MRE as well as GRE MRE. SE-EPI MRE was reproducible and good agreement was observed in MRE-derived stiffness measurements obtained using SE-EPI and GRE sequences. Therefore, SE-EPI can be used for kidney MRE applications.
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http://dx.doi.org/10.1002/nbm.4141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817380PMC
November 2019

Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer.

Lung Cancer 2019 08 17;134:167-173. Epub 2019 Jun 17.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

Materials And Methods: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis.

Results: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).

Conclusion: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194132PMC
August 2019

Pre-treatment serum bicarbonate predicts for primary tumor control after stereotactic body radiation therapy in patients with localized non-small cell lung cancer.

Radiother Oncol 2019 11 5;140:26-33. Epub 2019 Jun 5.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA. Electronic address:

Background: Tumor aggressiveness and hypoxia are linked to acidosis in the tumor microenvironment (TME). We hypothesized that low pre-treatment serum bicarbonate, potentially correlating with an acidic and hypoxic TME, predicts for poor outcomes after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC).

Methods: We included patients with localized NSCLC treated to a biologically effective dose (BED) ≥ 100 Gy, with available pre-treatment bicarbonate values within 3 months of treatment. We used receiver operating characteristic analysis to determine the bicarbonate concentration optimally predicting for primary tumor recurrence, and evaluated its association with recurrence and survival. We validated our findings in an independent cohort of patients from three collaborating institutions.

Results: A total of 110 patients and 114 tumors were included in the training cohort, with median follow-up of 15.0 months. Bicarbonate < 26 mEq/L was associated with primary tumor recurrence on univariate (HR = 5.92; 95% CI 1.69-24.88; p = 0.005) and multivariate analysis (HR = 5.48; 95% CI 1.37-25.19; p = 0.020). The validation cohort consisted of 195 patients and 208 tumors with median follow-up of 27.5 months. In the validation cohort, bicarbonate < 26 mEq/L was again associated with primary tumor recurrence on univariate (HR = 3.38; 95% CI 1.27-9.37; p = 0.015) and multivariate analysis (HR = 3.33; 1.18-10.07; p = 0.023).

Conclusions: Pre-treatment bicarbonate predicts for primary tumor control in NSCLC treated with SBRT and may be useful for risk stratification. These findings should be confirmed prospectively.
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http://dx.doi.org/10.1016/j.radonc.2019.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080525PMC
November 2019

ROR1-targeted delivery of miR-29b induces cell cycle arrest and therapeutic benefit in vivo in a CLL mouse model.

Blood 2019 08 31;134(5):432-444. Epub 2019 May 31.

Division of Hematology, Department of Internal Medicine, College of Medicine.

Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-29b to ROR1 CLL cells leading to downregulation of DNMT1 and DNMT3A, modulation of global DNA methylation, decreased SP1, and increased p21 expression in cell lines and primary CLL cells in vitro. Furthermore, using an Eμ-TCL1 mouse model expressing human ROR1, we report the therapeutic benefit of enhanced survival via cellular reprograming by downregulation of DNMT1 and DNMT3A in vivo. Gene expression profiling of engrafted murine leukemia identified reprogramming of cell cycle regulators with decreased SP1 and increased p21 expression after targeted miR-29b treatment. This finding was confirmed by protein modulation, leading to cell cycle arrest and survival benefit in vivo. Importantly, SP1 knockdown results in p21-dependent compensation of the miR-29b effect on cell cycle arrest. These studies form a basis for leukemic cell-targeted delivery of miR-29b as a promising therapeutic approach for CLL and other ROR1 B-cell malignancies.
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http://dx.doi.org/10.1182/blood.2018882290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676131PMC
August 2019

A Phase I/II Trial of Cetuximab in Combination with Interleukin-12 Administered to Patients with Unresectable Primary or Recurrent Head and Neck Squamous Cell Carcinoma.

Clin Cancer Res 2019 08 29;25(16):4955-4965. Epub 2019 May 29.

Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio.

Purpose: mAbs including cetuximab can induce antibody-dependent cellular cytotoxicity (ADCC) and cytokine production mediated via innate immune cells with the ability to recognize mAb-coated tumors. Preclinical modeling has shown that costimulation of natural killer (NK) cells via the Fc receptor and the IL12 receptor promotes NK-cell-mediated ADCC and production of cytokines.

Patients And Methods: This phase I/II trial evaluated the combination of cetuximab with IL12 for the treatment of EGFR-expressing head and neck cancer. Treatment consisted of cetuximab 500 mg/m i.v. every 2 weeks with either 0.2 mcg/kg or 0.3 mcg/kg IL12 s.c. on days 2 and 5 of the 2-week cycle, beginning with cycle 2. Correlative studies from blood draws obtained prior to treatment and during therapy included measurement of ADCC, serum cytokine, and chemokine analysis, determination of NK cell FcγRIIIa polymorphisms, and an analysis of myeloid-derived suppressor cell (MDSC) frequency in peripheral blood.

Results: The combination of cetuximab and IL12 was well tolerated. No clinical responses were observed, however, 48% of patients exhibited prolonged progression-free survival (PFS; average of 6.5 months). Compared with patients that did not exhibit clinical benefit, patients with PFS >100 days exhibited increased ADCC as therapy continued compared with baseline, greater production of IFNγ, IP-10, and TNFα at the beginning of cycle 8 compared with baseline values and had a predominance of monocytic MDSCs versus granulocytic MDSCs prior to therapy.

Conclusions: Further investigation of IL12 as an immunomodulatory agent in combination with cetuximab in head and neck squamous cell carcinoma is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697573PMC
August 2019

Long-term environmental enrichment affects microglial morphology in middle age mice.

Aging (Albany NY) 2019 04;11(8):2388-2402

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Aging is associated with increased central nervous system inflammation, in large part due to dysfunctional microglia. Environmental enrichment (EE) provides a model for studying the dynamics of lifestyle factors in the development of age-related neuroinflammation and microglial dysfunction. EE results in improvements in learning and memory, metabolism, and mental health in a variety of animal models. We recently reported that implementing EE in middle age promotes healthy aging. In the present study, we investigated whether EE influences microglial morphology, and whether EE is associated with changes in expression of microglial and neuroinflammatory markers. Inflammatory cytokines and MHC-II were reduced following 12-month EE in 10-month-old mice. Long-term EE for 7.5 months resulted in broad increases in Iba1 expression in hippocampus, hypothalamus, and amygdala detected by immunohistochemistry. Quantification of microglial morphology reveal both hypertrophy and ramification in these three brain regions, without increases in microglial cell density. These data indicate that long-term EE implemented in middle age results in a microglial state distinct from that of normal aging in standard laboratory housing, in specific brain regions, associated with reduced neuroinflammatory markers and improvement of systemic metabolism.
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http://dx.doi.org/10.18632/aging.101923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519992PMC
April 2019

Pre-treatment neutrophil-lymphocyte ratio is associated with overall mortality in localized non-small cell lung cancer treated with stereotactic body radiotherapy.

Radiother Oncol 2019 05 15;134:151-157. Epub 2019 Feb 15.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA. Electronic address:

Background: Neutrophil-lymphocyte ratio (NLR) has been associated with mortality in several disease sites. We hypothesized that NLR is associated with inferior outcomes in localized non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT).

Methods: We evaluated the association of pre-treatment NLR, obtained within 6 months of starting SBRT, with overall survival, as well as primary tumor, regional, and distant recurrence. Multivariate Cox regression was then used to assess pre-treatment NLR as a predictor of mortality. We validated our findings in an independent cohort of patients treated at two other institutions. In a secondary analysis, we also evaluated the association of post-treatment NLR with mortality in the training cohort.

Results: A total of 156 patients and 166 tumors were included in the training cohort with a median follow-up of 13.4 months. After dichotomization by median, NLR > 3.6 was associated with mortality on univariate (p = 0.010) and multivariate analysis (p = 0.023). In the validation cohort, NLR > 3.6 was similarly associated with mortality on univariate (p = 0.031) and multivariate (p = 0.007) analysis. In a secondary analysis in the training cohort, we found post-treatment NLR was significantly increased compared to pre-treatment NLR (p < 0.001) and associated with mortality on univariate analysis (p = 0.005) and multivariate analysis (p = 0.010).

Conclusions: Pre-treatment NLR > 3.6 is associated with mortality in patients treated with SBRT. This finding was validated in an independent cohort of patients treated at two other institutions. Additionally, post-treatment NLR was significantly increased from pre-treatment and associated with overall survival.
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http://dx.doi.org/10.1016/j.radonc.2019.01.032DOI Listing
May 2019