Therapeutic effects of cell therapy with neonatal human dermal fibroblasts and rabbit dermal fibroblasts on disc degeneration and inflammation

BACKGROUND CONTEXT

Increasing evidence suggests transplanting viable cells into the degenerating intervertebral disc (IVD) may be effective in treating disc degeneration and back pain. Clinical studies utilizing autologous or allogeneic mesenchymal stem cells to treat patients with back pain have reported some encouraging results. Animal studies have shown that cells injected into the disc can survive for months and have regenerative effects. Studies to determine the advantages and disadvantages of cell types and sources for therapy are needed.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in children 6–59 months of age: A phase 3, randomized,noninferiority study

Background

In the Southern Hemisphere 2010 influenza season, Seqirus’ split-virion, trivalent inactivated influenza vaccine was associated with increased reports of fevers and febrile reactions in young children. A staged clinical development program of a quadrivalent vaccine (Seqirus IIV4 [S-IIV4]; Afluria® Quadrivalent/Afluria Quad?/Afluria Tetra?), wherein each vaccine strain is split using a higher detergent concentration to reduce lipid content (considered the cause of the increased fevers and febrile reactions), is now complete.

The STING activator c-di-AMP exerts superior adjuvant properties than the formulation poly(I:C)/CpG after subcutaneous vaccination with soluble protein antigen or DEC-205-mediated antigen targeting to dendritic cells

Vaccination is the most efficient strategy to protect from infectious diseases and the induction of a protective immune response not only depends on the nature of the antigen, but is also influenced by the vaccination strategy and the co-administration of adjuvants. Therefore, the precise monitoring of adjuvant candidates and their immune modulatory properties is a crucial step in vaccine development. Here, one central aspect is the induction of appropriate humoral and cellular effector mechanisms.In our study we performed a direct comparison of two promising candidates in adjuvant development, the STING activator bis-(3,5)-cyclic dimeric adenosine monophosphate (c-di-AMP) and the Toll-like receptor ligand formulation poly(I:C)/CpG. These were evaluated in C57BL/6 mice using the model antigen ovalbumin (OVA) in subcutaneous vaccination with soluble protein as well as in a dendritic cell (DC) targeting approach (αDEC-OVA). Strikingly, c-di-AMP as compared to poly(I:C)/CpG resulted in significantly higher antigen-specific IgG antibody levels when used in immunization with soluble OVA as well as in antigen targeting to DC. In vaccination with soluble OVA, c-di-AMP induced a significantly stronger CTL, Th1 and IFNγ-producing CD8⁺ memory T cell response than poly(I:C)/CpG. The response was CTL and Th1 cell dominated, a profile shared by both adjuvants. In the context of targeting OVA to DC, c-di-AMP induced significantly increased Th1 and Th2 cell responses as compared to poly(I:C)/CpG. Interestingly, the Th1 response dominated the overall T cell response only when c-di-AMP was used, indicating a distinct modulatory property of c-di-AMP when the DC targeting immunization approach was exploited.Taken together, we describe superior properties of c-di-AMP as compared to poly(I:C)/CpG in subcutaneous vaccination with soluble antigen as well as antigen targeting to DC. This indicates exceptionally effective adjuvant properties for c-di-AMP and provides compelling evidence of its potential for further adjuvant development, especially also when using DC targeting approaches.     

Influence of posture on blink reflex prepulse inhibition induced by somatosensory inputs from upper and lower limbs

BackgroundPrepulse inhibition (PPI) is a neurophysiological phenomenon whereby a weak stimulus modulates the reflex response to a subsequent strong stimulus. Its physiological purpose is to avoid interruption of sensory processing by subsequent disturbing stimuli at the subcortical level, thereby preventing undesired motor reactions. An important hub in the PPI circuit is the pedunculopontine nucleus, which is also involved in the control of posture and sleep/wakefulness.ObjectiveTo study the effect of posture (supine versus standing) on PPI, induced by somatosensory prepulses to either upper or lower limb. PPI was measured as the percentage inhibition of the blink reflex response to electrical supraorbital nerve (SON) stimulation.MethodsSixteen healthy volunteers underwent bilateral blink reflex recordings following SON stimulation either alone (baseline) or preceded by an electrical prepulse to the median nerve (MN) or sural nerve (SN), both in supine and standing. Stimulus intensity was 8 times sensory threshold for SON, and 2 times sensory threshold for MN and SN, respectively. Eight stimuli were applied in each condition.ResultsBaseline blink reflex parameters did not differ significantly between the two postures. Prepulse stimulation to MN and SN caused significant inhibition of R2. In supine but not in standing, R2 was significantly more inhibited by MN than by SN prepulses. In standing, SN stimulation caused significantly more inhibition of R2 than in supine, while the inhibition caused by MN prepulses did not differ significantly between postures.SignificancePPI induced by lower limb afferent input may contribute to postural control while standing.     

Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice

1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice.

2. In rats, ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 100?mg/kg ABT inhibited the oral absorption of NVS-CRF38, T_max was 4?hours for ABT-treated mice compared to 0.5?hours in the control group.

3. A marked inhibition of hepatic P450 activity was observed in mice fed with ABT containing food pellets for 1?month. P450 activity, as measured by the oral clearance of antipyrine, was inhibited on day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control).

4. T_max values for antipyrine were comparable between ABT-treated mice and the control group, alleviating concerns about impaired gastric function.

5. Inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of P450 activity in mice. This model has the potential to enable pharmacological proof-of-concept studies for research compounds which are extensively metabolised by P450 enzymes.     

Essential oils of Origanum compactum increase membrane permeability,disturb cell membrane integrity,and suppress quorum-sensing phenotype in bacteria

The aim of this study was to investigate antibacterial activity of Origanum compactum essential oils collected at three phenological stages on Escherichia coli and Bacillus subtilis. The antibacterial activity was evaluated using the agar-well diffusion assay. The MIC and MBC values were determined using the micro-dilution assay. The investigation of the antibacterial action was carried out by the evaluation of the effect of O. compactum essential oils on the antibacterial kinetic growth, the integrity of cell membrane and permeability of the cell membrane. The anti-quorum sensing activity was tested by the inhibition of the biofilm formation. The findings of this study showed that O. compactum essential oil has potent antibacterial activities against E. coli and B. subtilis. The lowest inhibition value against B. subtilis was obtained with O. compactum essential oil at the post-flowering stage (MIC = MBC = 0.0312% (v/v)). The antibacterial mechanisms of O. compactum essential oils are related to the disturbing of the cell membrane integrity and the increasing of the membrane permeability, which leads to the leakage of genetic materials (DNA and RNA). Moreover, O. compactum essential oils inhibited the formation of the biofilms, a phenotype that has been known to be quorum sensing regulated.     

(-)-Epigallocatechin-3-gallate,reduces corneal damage secondary from experimental grade II alkali burns in mice

Background

Since recent reports have shown that (-)-Epigallocatechin-3-gallate (EGCG) could be used for treating proliferative and inflammatory disorders, we explored its use for the management of corneal chemical burns.

Impact of Addition of Metformin to Abiraterone in Metastatic Castration-Resistant Prostate Cancer Patients With Disease Progressing While Receiving Abiraterone Treatment (MetAb-Pro): Phase 2 Pilot Study

Background

There is evidence linking metformin to improved prostate cancer–related outcomes.

Protection of White Leghorn chickens by recombinant fowlpox vector vaccine with an updated H5 insert against Mexican H5N2 avian influenza viruses

Despite decades of vaccination, surveillance, and biosecurity measures, H5N2 low pathogenicity avian influenza (LPAI) virus infections continue in Mexico and neighboring countries. One explanation for tenacity of H5N2 LPAI in Mexico is the antigenic divergence of circulating field viruses compared to licensed vaccines due to antigenic drift. Our phylogenetic analysis indicates that the H5N2 LPAI viruses circulating in Mexico and neighboring countries since 1994 have undergone antigenic drift away from vaccine seed strains. Here we evaluated the efficacy of a new recombinant fowlpox virus vector containing an updated H5 insert (rFPV-H5/2016), more relevant to the current strains circulating in Mexico. We tested the vaccine efficacy against a closely related subcluster 4 Mexican H5N2 LPAI (2010 H5/LP) virus and the historic H5N2 HPAI (1995 H5/HP) virus in White Leghorn chickens. The rFPV-H5/2016 vaccine provided hemagglutinin inhibition (HI) titers pre-challenge against viral antigens from both challenge viruses in almost 100% of the immunized birds, with no differences in number of birds seroconverting or HI titers among all tested doses (1.5, 2.0, and 3.1 log₁₀ mean tissue culture infectious doses/bird). The vaccine conferred 100% clinical protection and a significant decrease in oral and cloacal virus shedding from 1995 H5/HP virus challenged birds when compared to the sham controls at all tested doses. Virus shedding titers from vaccinated 2010 H5/LP virus challenged birds significantly decreased compared to sham birds especially at earlier time points. Our results confirm the efficacy of the new rFPV-H5/2016 against antigenic drift of LPAI virus in Mexico and suggest that this vaccine would be a good candidate, likely as a primer in a prime-boost vaccination program.     

Comparison of immunogenicity between candidate influenza A(H3N2) virus vaccine strains in Japan: A randomized controlled trial using a monovalent vaccine of A/Saitama/103/2014 (CEXP-002) and A/Hong Kong/4801/2014 (X-263)

BackgroundFor the 2017–18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain.MethodsA randomized controlled trial of 100 healthy adults aged 20–64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017).ResultsFor the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p < 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p < 0.01) and SPP (28% vs. 6%, p < 0.01) were significantly higher in the Hong Kong vaccine recipients.ConclusionThe Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population.Clinical trial registration: UMIN000029293.