19 research outputs found
In Silico Modeling of the Immune System: Cellular and Molecular Scale Approaches
The revolutions in biotechnology and information technology have produced clinical data, which complement biological data. These data enable detailed descriptions of various healthy and diseased states and responses to therapies. For the investigation of the physiology and pathology of the immune responses, computer and mathematical models have been used in the last decades, enabling the representation of biological processes. In this modeling effort, a major issue is represented by the communication between models that work at cellular and molecular level, that is, multiscale representation. Here we sketch some attempts to model immune system dynamics at both levels
MHV-68 producing mIFNâŁ1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68
Corrigendum Corrigendum to "MHV-68 producing mIFNâŁ1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68" [Vaccine 29 (2011) In this study, we focused on the effects of interferon-⣠(IFN-âŁ) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-âŁ1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFNâŁ1). Although the MHV-68mIFNâŁ1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFNâŁ1 attenuation did not result in a reduced level of longterm spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFNâŁ1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFNâŁ1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFNâŁ1 to produce IFN-⣠at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones
Involvement of the Heme-Oxygenase Pathway in the Antiallodynic and Antihyperalgesic Activity of Harpagophytum procumbens in Rats
Harpagophytum procumbens (H. procumbens), also known as Devilâs Claw, has been used to treat a wide range of pathological conditions, including pain, arthritis and inflammation. Inflammatory mediators, released at the site of injury, can sensitize nociceptive terminals and are responsible for allodynia and hyperalgesia. Carbon monoxide (CO), produced in a reaction catalyzed by the enzyme heme oxygenase (HO), may play a role in nociceptive processing and has also been recognized to act as a neurotransmitter or neuromodulator in the nervous system. This study was designed to investigate whether the HO/CO pathway is involved in the analgesic response of H. procumbens in carrageenan-induced hyperalgesia in rats. Mechanical allodynia and thermal hyperalgesia were evaluated by using von Frey filaments and the plantar test, respectively. The results of our experiments showed that pretreatment with the HO inhibitor ZnPP IX significantly decreased the antihyperalgesic effect produced by H. procumbens (800 mg/kg, i.p.) in carrageenan-injected rats. Consistently, the pretreatment with hemin, a HO-1 substrate, or CORM-3, a CO releasing molecule, before a low dose of H. procumbens (300 mg/kg, i.p.) induced a clear antiallodynic response in carrageenan injected rats. These results suggest the involvement of HO-1/CO system in the antiallodynic and antihyperalgesic effect of H. procumbens in carrageenan-induced inflammatory pain
A new delivery system of Clobetasol-17-propionate (lipid loaded microspheres 0.025%) compared with a conventional formulation (lipophilic ointment in a hydrophilic phase 0.025%) in topical treatment of atrophic-erosive oral lichen planus. A Phase IV, randomized, observer-blinded, parallel group clinical trial,
Background Topical application of clobetasol-17-propionate has been diffusely reported as an
efďŹcacious therapy in atrophic â erosive oral lichen planus (OLP), without exposing the patient to
systemic side-effects. However, prolonged contact and respective topical effects on the oral mucosa
should be avoided.
Objectives The aim of the present study was to evaluate efďŹcacy and compliance of new lipid
microspheres loaded with 0Ă025% of clobetasol propionate (formulation A) compared with a
commonly used formulation (a sort of dispersion of a lipophilic ointment in a hydrophilic phase)
with the same amount of drug (formulation B) in the topical treatment of OLP.
Patients and methods Fifty patients with symptomatic OLP were enrolled in a controlled single-
blind phase IV clinical trial. After a dropout of ďŹve patients, a total of 45 patients [12 males and
33 females; mean age 61Ă1 years (Âą 12Ă3 SD; range 25â82)] were treated (17 with formulation A
and 28 with formulation B, matched for gender and age; P > 0Ă2) with the same dosage regimen.
At times T0, T1 and T2 we evaluated the following parameters: (i) pain score (by linear visual
analogue scale; 0â100); (ii) clinical score; (iii) clinical resolution; and (iv) patient compliance.
Statistical analysis was calculated using S-Plus 4.0 and SPSS 9.0 (Studentâs t-test, v
2
, Kolmogorovâ
Smirnow, Friedman, StudentâNewmanâKeuls, MannâWhitney U-test and Spearman tests).
Results Both formulations were found to be similar for parameters ii, iii and iv, although with a
better general trend for formulation A; a signiďŹcant difference was registered for formulation A in
terms of a reduction in painful symptoms (parameter i) at time T2 (P Âź 0Ă02).
Conclusions Our results suggest that the new topical drug delivery system (formulation A) may
enhance, at least in terms of symptom remission and compliance, the effectiveness of clobetasol
propionate at a dose of 0Ă025% in OLP therapy
Chimeric Antigen Receptor Immunotherapy for Solid Tumors: Choosing the Right Ingredients for the Perfect Recipe
Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development
Discovery Of New Sigma-2 Receptor Agonist Endowed With Antiproliferative Activity
Sigma receptors (ĎR) have proved to be an attractive pharmacological target for the treatment of several pathologies. In particular, Ď1 ligands have been considered to play an important role in the treatment of various neurological disorders, including depression, schizophrenia, neuropathic pain, Alzheimer's and Parkinsonâs disease. Moreover, it has been found that ĎR are involved in the modulation of cellular proliferation and cell death and Ď1 antagonists and Ď2 agonists may represent useful tools as anticancer and tumor imaging agents.
Recently, we reported that a properly substituted 1,3-dioxolane moiety could be employed as suitable scaffold for developing ligands for both Ď1R and Ď2R.1 In this work we explore a new set of structural related analogues obtained by combining different substituted spiro-heterocyclic rings with appropriate ĎR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified BS148 (1-(1,4-ditiaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperidne) as the most interesting compound of the series, displaying good affinity and selectivity for Ď2R .The ability of BS148 to modulate the analgesic effect of the agonist morphine was evaluated in-vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on receptor-mediated analgesia, suggesting an agonistic behavior at Ď1R. Moreover, BS148 demonstrated to affect the growth (MTT test) of SK-MEL-28 and SK-MEL-2 melanoma cell lines in comparison to siramesine, suggesting an agonistic behavior at Ď2R.
The present work represents a new starting point for the design of potential therapeutically useful agents