Multivariate analysis of the immune response to different rabies vaccines.

In a previous study, we proposed as an alternative to the use of animals in infectious challenge studies, a new approach describing the vaccine-induced immune response through the multivariate analysis of a defined set of immune parameters characterizing the B and T immune responses. This multivariate analysis, i.e. immune fingerprint, was evaluated first to assess the impact of minor changes in well characterized vaccines. The approach showed promising results in the assessment of the compatibility between two licensed vaccines. In the present study, the immune fingerprint was used to compare adjuvants with the various immunological parameters of the immune fingerprint as well as to assess the ability of this approach to discriminate different Rabies vaccine formulations in dogs. RABISIN® was the reference vaccine, adjuvanted with aluminum hydroxide. An exploratory factor analysis was used to analyse the covariance structure of the immunological data. Significant differences were observed between groups. RABISIN and a linear polyacrylate (SPA09) adjuvanted vaccine performed better than chitosan adjuvanted ones, both for humoral and cell immune responses. This study showed that the immune fingerprint approach can be used to screen vaccine formulations. It provides additional information compared to classical vaccination and infectious challenge efficacy study.

[Effect of tinzaparin on survival in non-small-cell lung cancer after surgery. TILT: tinzaparin in lung tumours]. / Effet de la tinzaparine sur la mortalité du cancer bronchique non à petites cellules opéré.

BACKGROUND: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings. METHODS: Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group. EXPECTED RESULTS: A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.

The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate.

Toll-like receptors (TLRs) constitute a family of nonpolymorphic receptors that are devoted to pathogen recognition. In this work, we have explored the impact of TLR ligands (TLR-L) on human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We show that HSCs and HPCs have a comparable pattern of expression of TLR transcripts characterized by the predominance of TLR1, -2, -3, -4 and -6. In long-term cultures of HSCs, HPCs and stromal cells, most TLR-L profoundly inhibited B-cell development while preserving or enhancing the production of myeloid cells. In short-term cultures, the TLR1/2 ligand PAM(3)CSK(4) induced a large proportion of HPCs to express markers of the myelomonocytic lineage. PAM(3)CSK(4) induced only marginal expression of myeloid lineage markers on HSCs but promoted their myeloid commitment as revealed by their acquisition of the phenotype of multi- and bipotential myeloid progenitors and by upregulation of the transcription factors PU.1, C/EBPalpha and GATA-1. Our results suggest that TLR agonists can bias the lineage commitment of human HSCs and shift the differentiation of lineage-committed progenitors to favor myelopoiesis at the expense of lymphoid B-cell development.

[Alveolo-interstitial pneumonia due to Temozolamide]. / Pneumonie alvéolo-interstitielle au témozolomide.

INTRODUCTION: Temozolomide is an alkylating agent approved for treatment of glioblastoma in association with radiotherapy. CASE REPORT: We report the case of a 56 year old woman presenting with alveolo-interstitial pneumonia after treatment with Temozolomide. Initially she received induction treatment with Temozolomide and concomitant radiotherapy for bifocal high grade glioblastoma. A month later she received, as scheduled, the first course of Temozolomide maintenance chemotherapy. Grade II dyspnoea developed a few days later. High resolution computed tomography showed alveolo-interstitial opacities with basal predominance, associated with alveolar nodules. Broncho-alveolar lavage showed a lymphocytosis. No bacteria were isolated from microbiological samples. A final diagnosis of drug-induced pneumonia was based on the time sequence and absence of other causes. CONCLUSION: There is little literature concerning the pulmonary toxicity of Temozolomide. However, our case report of drug-induced pneumonia and similar observations in the databases of regional pharmacovigilance centres suggest that this side effect should be included in the summary of product characteristics.

Downregulation and nuclear relocation of MLP during the progression of right ventricular hypertrophy induced by chronic pressure overload.

The cardiac LIM domain protein MLP plays a crucial role in the architecture and mechanical function of cardiac myocytes. Mice lacking the MLP gene develop cardiac hypertrophy, dilated cardiopathy and heart failure. We investigated whether downregulation of MLP is induced by pressure overload and contributes to the physiopathology of cardiac hypertrophy and failure. We studied this mechanism in rat right ventricles submitted to pulmonary arterial hypertension, because it is known that this ventricle is very vulnerable to the deleterious effects of pressure overload. During the progression of cardiac hypertrophy to failure over a 31 days period there was a dramatic decrease by 50% of the MLP transcripts level. Consistently, immunohistochemistry detected very weak protein signals in the cytoplasms of cardiomyocytes at the failing stage, but myocytes nuclei were heavily labeled. The nuclear relocation was confirmed by the immunodetection of MLP on the nuclear and cytosolic fractions. This nuclear localization is the hallmark of a retro-differentiated phenotype, since it has been observed only in differentiating myoblasts. These changes were associated with ultrastructural disorganization of the myofibrils similar to that observed in MLP -/- mice. Therefore, MLP dowregulation occurring during gene reprogramming may critically contribute to mechanical failure of the myocardium.