In vitro analysis of cidofovir and genetically engineered TK expression as potential approaches for the intervention of ColoAd1-based treatment of cancer.

We have generated a novel oncolytic Adenovirus (Ad), ColoAd1, with significantly increased potency ( approximately 100-fold) relative to its parent viruses, Ad11p and Ad3, or to the clinically tested oncolytic Ad, ONYX-015. Although this agent has a significant increase in its therapeutic window relative to ONYX-015 or its parent viruses, its ability to intervene and control virotherapy in treated patient is an important safety consideration for a novel biological therapy, such as ColoAd1. As there are no approved treatments for Ad infections, we sought to define whether antivirals being used to experimentally treat Ad infections (cidofovir (CDV), ribavirin) had any activity against ColoAd1. In addition, we incorporated a well-described pro-drug converting enzyme, the herpes simplex virus-thymidine kinase (HSV-TK) gene, into the viral genome to test whether the expression of this enzyme directly from the virus could be exploited as a safety valve for arresting the viral infection in the presence of the pro-drug, ganciclovir. Both the antiviral drug, CDV, and the incorporation of the pro-drug-converting TK enzyme were validated as effective approaches to controlling ColoAd1 infection, and this represents an important advancement in the development of ColoAd1 as an anticancer treatment.

The effect of hypoxia on the uptake, replication and lytic potential of group B adenovirus type 3 (Ad3) and type 11p (Ad11p).

Replicating, tumor selective viruses are being tested as potential treatments for human cancers. Hypoxia is a pathophysiological cancer condition that alters the lytic potential of the replication-competent adenovirus serotype 5 (Ad5) virus by a mechanism independent of receptor levels or internalization rates. We extend these initial studies to examine the potential effects of hypoxia on the group B adenoviruses (Ads), adenovirus type 3 (Ad3) (group B1) and adenovirus type 11p (Ad11p) (group B2). Receptor expression (CD46) is not altered by hypoxia. However, the lytic potential is compromised in a cell-dependent fashion. Consequently, our study suggests that group B replicating Ad-based treatments, like the group C Ad-5-based viruses, will need to be modified in order to effectively treat hypoxic components of human tumors.

Gene delivery from the E3 region of replicating human adenovirus: evaluation of the 6.7 K/gp19 K region.

The use of genetically engineered, replication-selective viruses to treat cancer is being realized with viruses such as ONYX-015, a human adenovirus that selectively destroys p53 mutant cancer cells. To enhance further the clinical efficacy of ONYX-015 and viruses like it, we have developed a novel gene delivery system for replicating adenoviruses. This system has two unique features. First, it uses the endogenous adenoviral gene expression machinery (promoter, splicing, polyadenylation) to drive transgene expression. Second, a single region or gene in the multi-gene E3 transcription unit is selectively substituted for by the therapeutic transgene(s). Analyzing various transgene substitutions for the 6.7 K/gp19 K region of E3, we demonstrate the following: (1) transgene expression in this system is predictable and mimics the substituted endogenous gene expression pattern, (2) expression of surrounding E3 genes can be retained, (3) the insertion site choice can effect both the transgene expression level and the viral life cycle, and, (4) expression levels from this system are superior to those generated from a replication-defective virus using the HCMV enhancer-promoter and this is dependent on viral DNA replication. This unique methodology has broad application to the rapidly evolving field of replicating virus-based therapies.

[Spa treatment in pediatric pneumo-allergology and ENT]. / Cures thermales en pneumo-allergologie et en ORL pédiatriques.

Each year in France, 42,000 children receive spa therapy, which is covered by the national health care insurance system. In over three cases out of four, the treatment is ordered by the child's physician for respiratory tract disease which fails to respond adequately to conventional therapy. Asthma, recurrent bronchitis, and spasmodic cough are the main indications in pneumo-allergology; seromucous otitis media, naso-sinusitis and refractory pharyngitis are the most common pediatric ENT diseases treated in spa centers. The two main types of mineral water used are sulfur-rich waters in patients with prominent infection and chloride and bicarbonate-rich waters when allergy is the main problem. Experimental studies point to the fact that these waters have immunomodulating effects. However, other therapeutic interventions in spa centers, including rehabilitation and health education, also play a role. Evaluations of spa therapy for respiratory tract diseases carried out by government agencies have demonstrated decreases in school absenteeism and above all in the use of drugs in treated patients. The future of pediatric spa therapy will likely depend on the development of preventive interventions in spa centers.

[Health education for about 100 children (aged 6 to 14) in heat therapy at La Bourboule, compared to controls]. / Education pour la santé d'une centaine d'enfants (de six à quatorze ans) en cure thermale a La Bourboule, comparés à des témoins.

99 children, aged 6 to 14, received health education and were compared to 93 controls, living in another "children house" at the same resort. The two groups were similar, and completely separated. All children had respiratory and cutaneous infections or allergies, none of them being disabled. The health education consisted in five sessions held over three weeks. Topics were the excesses of what people put into their glasses, ash-trays, plates and medicine chests. The teaching method was mainly based on creative games. Evaluations were presented as games, with colored blocks. The answers given to ten questions, before the educational sessions, were similar in both groups. The final answers did not show any progress in the control group, whereas the rate of correct answers increased by 30% in the educated group. Differences were highly significant, in all age groups. Progresses concerned especially the excesses of sugar, tobacco and meat. The educational needs seemed different according to age, with the main excesses being sugar and other food in children under ten, and tobacco and alcoholic drinks in older children. Spa resorts, and La Bourboule in particular, are suitable for brief controlled health education actions.