In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke Ernesto Caballero-Garrido, Juan Carlos Pena-Philippides, Tamar Lordkipanidze, Denis Bragin, Yirong Yang, Erik Barry Erhardt, and Tamara Roitbak. The Journal of Neuroscience, 35(36), pdf, 12446-12464 Online: September 9, 2015 http://www.jneurosci.org/content/35/36/12446.short?sid=d532fe0d-f727-4729-8f7c-ab2cf8a1e7f7 DOI: 10.1523/JNEUROSCI.1641-15.2015 Abstract A multifunctional microRNA, miR-155, has been recently recognized as an important modulator of numerous biological processes. In our previous in vitro studies, miR-155 was identified as a potential regulator of the endothelial morphogenesis. The present study demonstrates that in vivo inhibition of miR-155 supports cerebral vasculature after experimental stroke. Intravenous injections of a specific miR-155 inhibitor were initiated at 48 h after mouse distal middle cerebral artery occlusion (dMCAO). Microvasculature in peri-infarct area, infarct size, and animal functional recovery were assessed at 1, 2, and 3 weeks after dMCAO. Using in vivo two-photon microscopy, we detected improved blood flow and microvascular integrity in the peri-infarct area of miR-155 inhibitor-injected mice. Electron microscopy revealed that, in contrast to the control group, these animals demonstrated well preserved capillary tight junctions (TJs). Western blot analysis data indicate that improved TJ integrity in the inhibitor-injected animals could be associated with stabilization of the TJ protein ZO-1 and mediated by the miR-155 target protein Rheb. MRI analysis showed significant (34%) reduction of infarct size in miR-155 inhibitor-injected animals at 21 d after dMCAO. Reduced brain injury was confirmed by electron microscopy demonstrating decreased neuronal damage in the peri-infarct area of stroke. Preservation of brain tissue was reflected in efficient functional recovery of inhibitor-injected animals. Based on our findings, we propose that in vivo miR-155 inhibition after ischemia supports brain microvasculature, reduces brain tissue damage, and improves the animal functional recovery. SIGNIFICANCE STATEMENT In the present study, we investigated an effect of the in vivo inhibition of a microRNA, miR-155, on brain recovery after experimental cerebral ischemia. To our knowledge, this is the first report describing the efficiency of intravenous anti-miRNA injections in a mouse model of ischemic stroke. The role of miRNAs in poststroke revascularization has been unexplored and in vivo regulation of miRNAs during the subacute phase of stroke has not yet been proposed. Our investigation introduces a new and unexplored approach to cerebral regeneration: regulation of poststroke angiogenesis and recovery through direct modulation of specific miRNA activity. We expect that our findings will lead to the development of novel strategies for regulating neurorestorative processes in the postischemic brain.
... more

Nasal vaccination of young rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis and enteric red mouth disease Salinas, I, EB Erhardt, and S LaPatra. Developmental & Comparative Immunology, 53(1), pdf, pp. 105–111 Online: June 23, 2015 http://www.sciencedirect.com/science/article/pii/S0145305X1500124X DOI: 10.1016/j.dci.2015.05.015 Abstract Determining the earliest age at which farmed fish can be successfully vaccinated is a very important question for fish farmers. Nasal vaccines are novel mucosal vaccines that prevent aquatic infectious diseases of finfish. The present study investigates the ontogeny of the olfactory organ of rainbow trout by histology and aims to establish the earliest age for vaccination against infectious hematopoietic necrosis (IHN) and enteric red mouth (ERM) disease using the nasal route. Rainbow trout (Oncorhynchus mykiss) were vaccinated intranasally (I.N) at three different ages: 1050° days (DD) (group A); 450 DD (group B); and 360 DD (group C), or 70, 30 and 24 days post-hatch (dph), respectively. The mean weights of groups A, B and C were 4.69 g, 2.9 g and 2.37 g, respectively. Fish received either a live attenuated IHN virus vaccine, ERM formalin killed bacterin or saline (mock vaccinated). Fish were challenged to the corresponding live pathogen 28 days post-vaccination. IHN vaccine delivery at 360 DD resulted in 40% mortality likely due to residual virulence of the vaccine. No mortality was observed in the ERM nasal delivery groups. Following challenge, very high protection rates against IHN virus were recorded in all three age groups with survivals of 95%, 100% and 97.5% in groups A, B and C, respectively. Survival against ERM was 82.5%, 87.5% and 77.5% in groups A, B and C, respectively. Survival rates did not differ among ages for either vaccine. Our results indicate the feasibility and effectiveness of nasal vaccination as early as 360 DD and vaccination-related mortalities when a live attenuated viral vaccine was used in the youngest fish.
... more

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children’s Oncology Group study Linabery, AM, EB Erhardt, MM Richardson, RF Ambinder, DL Friedman, SL Glaser, A Monnereau, LG Spector, JA Ross, and S Grufferman International Journal of Cancer 137(9), pdf, pp. 2163–2174 Online: May 19, 2015 http://onlinelibrary.wiley.com.libproxy.unm.edu/doi/10.1002/ijc.29589/full DOI: 10.1002/ijc.29589 Abstract Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0–14 years at Children’s Oncology Group institutions in 1989–2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein–Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case–control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06–1.36), particularly early-onset cancers (HR = 1.30, 95% CI: 1.06–1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16–1.65), with a suggested association for LN in first-degree relatives (HR = 3.61, 95% CI: 0.87–15.01). There were no discernable patterns for EBV+ versus EBV– HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family-based studies to garner information about genetic susceptibility to HL.
... more

Family history of cancer and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group and the Utah Population Database Lupo, PJ, HE Danysh, SE Plon, K Curtin, D Malkin, S Hettmer, DS Hawkins, SX Skapek, LG Spector, K Papworth, B Melin, EB Erhardt, S Grufferman, and JD Schiffman Cancer Medicine 2015, 4(5), pdf, 781–790 Online: March 23, 2015 http://onlinelibrary.wiley.com/doi/10.1002/cam4.448/full DOI: 10.1002/cam4.448 Abstract Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case–control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children’s Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (ORs) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (ORs = 1.39, 95% CI: 0.97–1.98). Notably, this association was stronger among those with embryonal RMS (ORs = 2.44, 95% CI: 1.54–3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (<30 years) was associated with a greater risk of RMS (ORs = 2.37, 95% CI: 1.34–4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at <30 years of age.
... more