CHARACTERIZATION OF AGE-ASSOCIATED COPD PROGRESSION IN THE COPD GENE COHORT

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating lung disease affecting primarily older adults. Incidence, morbidity and mortality from COPD are increasing worldwide. The purpose of this study was to determine the associations between age at baseline and markers of disease progression in COPD patients using data generated by the Genetic Epidemiology of COPD (COPD Gene) study. Participants with COPD were stratified by age (younger: age \u3c65 years, elderly: age ≥ 65 years) and disease characteristics (lung function, exercise tolerance, exacerbation history, and comorbidity burden) at baseline and five-year follow up were compared between groups. Associations between age group and changes in these measures were also assessed. Disease characteristics differed significantly between elderly and younger COPD patients at both study visits. Elderly COPD patients had worse lung function and more comorbidities than younger COPD patients, while younger COPD patients reported more dyspnea and more frequent and severe exacerbations than elderly COPD patients. Following covariate adjustment, elderly participants were less likely than younger participants to develop new frequent exacerbations over the study period (relative risk ratio (95% confidence interval): 0.42 (0.20, 0.87)). There were no other significant associations between age group and markers of disease progression. These results suggest that although elderly COPD patients exhibit evidence of more severe lung function impairment than younger COPD patients, the rate of disease progression is similar between elderly and younger patients. However, further exploration is needed to understand the possible contribution of survivorship bias to this finding. Nevertheless, this study supports the importance of early detection and early intervention to slow disease progression and maximize both life expectancy and quality of life for COPD patients

Intranasal Delivery of Human Umbilical Cord Stromal Cell Conditioned Media Improves Alveolar Growth and Vascular Remodeling In Experimental Bronchopulmonary Dysplasia

Introduction: Bronchopulmonary dysplasia (BPD) is a lung disease with high morbidity and mortality in premature neonates exposed to mechanical ventilation and oxygen support. Preclinical studies demonstrate mesenchymal stromal cell (MSC) conditioned media (CdM) improves histologic changes in BPD via the release of paracrine factors. Current modes of administration include intratracheal or intraperitoneal routes with CdM cultured in ambient air. Objectives: The objective of this study was twofold: (i) assess the efficacy of intranasal delivery of CdM, and (ii) determine whether hypoxic preconditioning stimulates the therapeutic potential of CdM. Methods: Newborn rat pups were randomly assigned to four groups: (1) room air treated with αMEM vehicle (RA+Veh), (2) four days of hyperoxia (BPD+Veh), (3) BPD treated with CdM from normoxic MSCs (BPD+CdM), and (4) BPD treated with CdM from hypoxic preconditioned (1% O2) MSCs (BPD+hypoCdM). Twenty μL of human mesenchymal stromal cell CdM or hypoxic CdM (hypoCdM) was administered intranasally to rat pups on days 4, 10, and 20. Mean linear intercept, medial wall thickness, and vascular density were used to assess alveolarization, pulmonary remodeling, and vascular growth, respectively. Gene expression of cytokines and growth factors in animal lungs and CdM were measured. Results and Discussion: Intranasal CdM, but not hypoxic CdM, improved lung alveolarization. Both CdM and hypoCdM improved pulmonary vascular remodeling; however, only hypoCdM restored vascular density. CdM upregulated the expression of genes involved in wound healing and inflammation. Conclusion: Intranasal delivery of CdM/hypoCdM restored lung development in a BPD rat model. Mechanisms by which umbilical cord-derived stem cell CdM provides pulmonary benefit points toward wound repair and immunomodulation. Future directions include: (i) optimizing the timing, volume, frequency, and concentration of the CdM and (ii) improving the preconditioning approach for MSCs to enhance the therapeutic efficacy. Acknowledgements: Data were generated in the Flow Cytometry Shared Resource Facility, which is supported by UTHSCSA, NIH-NCI P30 CA054174-20 (Cancer Therapy and Research Center at UTHSCSA) and UL1 TR001129 (Clinical and Translational Science Award). Our gratitude extends to the Pathology Core at UTHSCSA

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Data from: Independent origins of resistance or susceptibility of parasitic wasps to a defensive symbiont

Insect microbe associations are diverse, widespread, and influential. Among the fitness effects of microbes on their hosts, defense against natural enemies is increasingly recognized as ubiquitous, particularly among those associations involving heritable, yet facultative, bacteria. Protective mutualisms generate complex ecological and co-evolutionary dynamics that are only beginning to be elucidated. These depend in part on the degree to which symbiont-mediated protection exhibits specificity to one or more members of the natural enemy community. Recent findings in a well-studied defensive mutualism system (i.e., aphids, bacteria, parasitoid wasps) reveal repeated instances of evolution of susceptibility or resistance to defensive bacteria by parasitoids. The present study searched for similar patterns in an emerging model system for defensive mutualisms: the interaction of Drosophila, bacteria in the genus Spiroplasma, and wasps that parasitize larval stages of Drosophila. Previous work indicated that three divergent species of parasitic wasps are strongly inhibited by the presence of Spiroplasma in three divergent species of Drosophila, including D. melanogaster. The results of this study uncovered two additional wasp species that are susceptible to Spiroplasma and two that are unaffected by Spiroplasma, implying at least two instances of loss or gain of susceptibility to Spiroplasma among larval parasitoids of Drosophila

wasp_protection_round_2_simplified070715

This file provides the raw data counts for each replicate (vial)

Association of novel markers of liver disease with neonatal liver disease in premature baboons, Papio sp.

Parenteral Nutrition (PN) Associated Liver Disease (PNALD) affects up to 60% of neonates; however, techniques for diagnosing and monitoring disease progression remain limited. The neonatal baboon model may provide a unique opportunity to identify serologic markers associated with this disease. The purpose of this study was to investigate if Hyaluronic Acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP1), Amino-terminal Propeptide of Type-III Collagen (PIIINP) and Enhanced Liver Fibrosis (ELF) score associate with histological liver disease in neonatal baboons exposed to PN. Preterm baboons delivered via c-section at 67% gestation received PN for 14 days with or without Intralipid (PRT+IL, PRT-IL, respectively) or were sacrificed after birth (PRTCTR). Term baboons were sacrificed after birth (TERMCTR) or survived 14 days (TERM+14d). Serum HA, TIMP1, and PIIINP concentrations were measured by ELISA. A blinded pathologist assigned liver histological scores following necropsy. HA increased 9.1-fold, TIMP1 increased 2.2-fold, and ELF score increased 1.4-fold in PRT-IL compared to PRTCTR. ALT, AST, and GGT were within normal limits and did not vary between groups. A trend towards increased fibrosis was found in PRT-IL baboons. Microvesicular hepatocyte steatosis and Kupffer cell hypertrophy were elevated in PRT-IL vs PRTCTR. HA and TIMP1 were significantly elevated in preterm baboons with early histological findings of liver disease evidenced by hepatic steatosis, Kupffer cell hypertrophy and a trend towards fibrosis whereas traditional markers of liver disease remained normal. These novel markers could potentially be utilized for monitoring early hepatic injury in neonates

Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: A systematic review and meta-analysis of preclinical studies

<div><p>Introduction</p><p>Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating neurologic condition with high mortality rates and long-term complications for surviving infants. Mesenchymal stem/stromal cells (MSCs) have emerged as novel therapeutic agents with promising results in experimental studies of HIE. The purpose of this study is to (a) methodically review the current preclinical literature describing MSC therapy in animal models of HIE, (b) quantify the effect size in regards to functional neurologic outcome, and (c) identify research gaps/limitations that should be addressed prior to future preclinical and clinical studies.</p><p>Methods</p><p>Adhering to the Systematic Review Protocol for Animal Intervention Studies, a systematic search of English articles was performed. Eligible studies were identified and data regarding study characteristics and outcome measures was extracted. After quality assessment, meta-analysis and meta-regression were performed to generate random effect size using standardized mean difference (SMD). Funnel plots and Egger’s tests were utilized to evaluate for the presence of publication bias.</p><p>Results</p><p>A total of 19 studies met inclusion in the current systematic review. Meta-analysis revealed that MSCs have a significant positive effect on neurobehavioral outcome following HIE injury. Sensorimotor function was improved by 2.25 SMD (95% CI; 2.04–2.46) in cylinder rearing and 2.97 SMD (95% CI; 2.56–3.38) in rotarod. Likewise, cognitive function was improved by 2.76 SMD (95% CI; 2.53–2.98) on the water maze and 2.97 SMD (95% CI; 2.58–3.35) in object recognition. Stratification demonstrated an increased effect size depending on various study characteristics.</p><p>Conclusions</p><p>Overall, these results suggest a promising role for MSCs in preclinical studies of HIE. MSC treatment demonstrates improved functional outcomes that are encouraging for future translational studies. While risk of bias and heterogeneity limited the strength of our meta-analysis, our results are consistent with those seen in this field of research.</p></div

Flow diagram demonstrating study selection process.

<p>Flow diagram demonstrating study selection process.</p

Stratification of estimated effect size for cognitive function.

<p>Stratification of estimated effect size for cognitive function.</p

Summary of study characteristics.

<p>Summary of study characteristics.</p