23 research outputs found
Fenofibrate reduces the severity of neuroretinopathy in a type 2 model of diabetes without inducing peroxisome proliferator-activated receptor alpha-dependent retinal gene expression
Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model
B7 Costimulation Molecules Encoded by Replication-Defective, vhs-Deficient HSV-1 Improve Vaccine-Induced Protection against Corneal Disease
Herpes simplex virus 1 (HSV-1) causes herpes stromal keratitis (HSK), a sight-threatening disease of the cornea for which no vaccine exists. A replication-defective, HSV-1 prototype vaccine bearing deletions in the genes encoding ICP8 and the virion host shutoff (vhs) protein reduces HSV-1 replication and disease in a mouse model of HSK. Here we demonstrate that combining deletion of ICP8 and vhs with virus-based expression of B7 costimulation molecules created a vaccine strain that enhanced T cell responses to HSV-1 compared with the ICP8−vhs− parental strain, and reduced the incidence of keratitis and acute infection of the nervous system after corneal challenge. Post-challenge T cell infiltration of the trigeminal ganglia and antigen-specific recall responses in local lymph nodes correlated with protection. Thus, B7 costimulation molecules expressed from the genome of a replication-defective, ICP8−vhs− virus enhance vaccine efficacy by further reducing HSK
Epstein-Barr Virus LMP2A Reduces Hyperactivation Induced by LMP1 to Restore Normal B Cell Phenotype in Transgenic Mice
Epstein-Barr virus (EBV) latently infects most of the human population and is strongly associated with lymphoproliferative disorders. EBV encodes several latency proteins affecting B cell proliferation and survival, including latent membrane protein 2A (LMP2A) and the EBV oncoprotein LMP1. LMP1 and LMP2A signaling mimics CD40 and BCR signaling, respectively, and has been proposed to alter B cell functions including the ability of latently-infected B cells to access and transit the germinal center. In addition, several studies suggested a role for LMP2A modulation of LMP1 signaling in cell lines by alteration of TRAFs, signaling molecules used by LMP1. In this study, we investigated whether LMP1 and LMP2A co-expression in a transgenic mouse model alters B cell maturation and the response to antigen, and whether LMP2A modulates LMP1 function. Naïve LMP1/2A mice had similar lymphocyte populations and antibody production by flow cytometry and ELISA compared to controls. In the response to antigen, LMP2A expression in LMP1/2A animals rescued the impairment in germinal center generation promoted by LMP1. LMP1/2A animals produced high-affinity, class-switched antibody and plasma cells at levels similar to controls. In vitro, LMP1 upregulated activation markers and promoted B cell hyperproliferation, and co-expression of LMP2A restored a wild-type phenotype. By RT-PCR and immunoblot, LMP1 B cells demonstrated TRAF2 levels four-fold higher than non-transgenic controls, and co-expression of LMP2A restored TRAF2 levels to wild-type levels. No difference in TRAF3 levels was detected. While modulation of other TRAF family members remains to be assessed, normalization of the LMP1-induced B cell phenotype through LMP2A modulation of TRAF2 may be a pathway by which LMP2A controls B cell function. These findings identify an advance in the understanding of how Epstein-Barr virus can access the germinal center in vivo, a site critical for both the genesis of immunological memory and of virus-associated tumors
Bioidentical hormone therapy: Nova Scotia pharmacists´ knowledge and beliefs
Objectives: To investigate Nova Scotia (NS)
pharmacists´ knowledge and beliefs regarding the
use of bioidentical hormones (BHs) for the
management of menopause related symptoms.
Methods: Using Dillman´s tailored design
methodology, an invitation to complete the webbased
questionnaire was emailed to pharmacists in
NS as part of the Dalhousie College of Pharmacy
Continuing Pharmacy Education Department´s
(CPE) weekly email update. Data was analyzed
using descriptive statistics.
Results: Of approximately 1300 e-mails sent, 113
pharmacists completed the questionnaire (response
rate 8.7%). The majority of respondents (94%) knew
that BHs were not free from adverse drug reactions.
More than 50% were aware that conjugated equine
estrogens and medroxyprogesterone acetate were
not examples of BHs. For seven of eleven
knowledge questions, 33-45% indicated that they
did not know the answer. When asked about their
beliefs regarding BHs, many believed that BHs were
similar in efficacy (49%) or more effective (21%)
than conventional hormone therapy (CHT) for
vasomotor symptoms. Most respondents also
believed that both BHs and CHT had similar safety
profiles. Additionally, responding pharmacists
indicated that more education would be helpful,
especially in the area of safety and efficacy of BHTs
compared to CHT.
Conclusion: NS pharmacists knew BHs were not
free of adverse effects, however knowledge was
lacking in other areas. This may reflect the level of
coverage of this topic in pharmacy school
curriculums and in the pharmacy literature. Results
indicate a need for additional education of NS
pharmacists with respect to BHs, which could be
accomplished through modification of
undergraduate pharmacy programs and
supplementary CPE.Objetivos: Investigar los conocimientos y
creencias de los farmacéuticos de Nueva Escocia
(NS) sobre el uso de hormonas bioidénticas (BH)
para el manejo de los sÃntomas relacionados con la
menopausia.
Métodos: Utilizando el diseño metodológico de
Dillman, se envió por email a los farmacéuticos de
NS una invitación a completar un cuestionario
online como parte de las actualizaciones semanales
del Departamento de Formación Continua de la
Facultad de Farmacia de la Universidad de
Dalhousie. Los datos se analizaron con estadÃstica
descriptiva.
Resultados: De los aproximadamente 1300 emails
enviados, 113 farmacéuticos completaron el
cuestionario (tasa de respuesta 8,7%). La mayorÃa
de los respondientes (94%) sabÃan que las BH no
estaban libres de reacciones adversas. Más del 50%
conocÃan que los estrógenos conjugados equinos y
la medroxiprogesterona acetato no eran ejemplos de
BH. Para 7 de las 11 preguntas, del 33-45% indicó
que no conocÃa la respuesta. Cuando se les
preguntó sobre sus creencias sobre las BH, muchos
creÃan que las BH eran similares en eficacia (49%)
o más eficaces (21%) que la terapia hormonal
convencional (CHT) para los sÃntomas
vasomotores. La mayorÃa de los respondientes
también creÃan que las BH y las CHT tenÃan
perfiles de seguridad similares. Además, los
farmacéuticos respondientes indicaron que serÃa útil
más educación, especialmente en el área de
seguridad y eficacia de las BH comparadas con las
CHT.
Conclusión: Los farmacéuticos de NS sabÃan que
las BH no estaban libres de efectos adversos, sin
embargo carecÃan de conocimientos en otras áreas.
Esto puede reflejar la cobertura de este asunto en
los currÃculos de las facultades de farmacia y en la
literatura farmacéutica. Los resultados indican una
necesidad de educación adicional de los
farmacéuticos de NS en relación a las BH, lo que
podrÃa conseguirse mediante la modificación de los
programas de pregrado y la formación continua
suplementaria
B7 Costimulation Molecules Expressed from the Herpes Simplex Virus 2 Genome Rescue Immune Induction in B7-Deficient Miceâ–¿
The interaction between B7 costimulation molecules on antigen-presenting cells and CD28 on antigen-responsive T cells is essential for T-cell activation and maturation of immune responses to herpes simplex virus (HSV) infection. Vaccine-induced immune responses also depend upon adequate upregulation of B7 costimulation molecules, but this signal may be limiting for replication-defective virus vaccines. We investigated whether expression of B7 costimulation molecules by a prototypical replication-defective antiviral vaccine could enhance immune responses to the vaccine and whether B7-1 and B7-2 would be similarly effective. We altered an ICP8− replication-defective strain of HSV type 2 (HSV-2), 5BlacZ, to encode either murine B7-1 or B7-2. B7 molecule expression was detected on the surface of cells infected in vitro and at the RNA level in tissue of immunized mice. Immunization of B7-1/B7-2 knockout mice with B7-encoding virus modestly expanded the number of gamma interferon-producing T cells and significantly augmented class-switched HSV-specific antibody responses compared with the parental virus. Mice immunized with either B7-expressing virus showed less replication of challenge virus in the genital mucosa than mice immunized with 5BlacZ, markedly fewer signs of genital and neurological disease, and little weight loss. Virtually all mice immunized with B7-encoding virus survived challenge with a large dose of HSV-2, whereas most 5BlacZ-immunized mice succumbed to infection. These results indicate that protective immune responses can be enhanced by the inclusion of host B7 costimulation molecules in a prototypical replication-defective HSV vaccine against HSV-2 genital infection and that B7-1 and B7-2 induce immune responses with similar capacities to fight HSV-2 infection
Vemurafenib in metastatic melanoma patients with brain metastases: An open-label, single-arm, phase 2, multicentre study
Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM.Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions >= 0.5 cm to assess response.Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.518.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression.Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity