[Tumour assessment criteria for immune checkpoint inhibitors]. / Critères d'évaluation de la réponse tumorale aux inhibiteurs des points de contrôle immunitaire.

The development of immune checkpoint inhibitors in thoracic oncology has led to a reconsideration of the rules for radiological tumor assessment. The RECIST criteria are widely used for the assessment of conventional treatments but are not suitable for anti-tumoral immunotherapy. The mechanism of action of this new class of drugs may induce specific patterns of response, which are not fully assessed by the RECIST criteria. Several new criteria have been proposed to better detect these patterns of response. The changes usually include confirmation of progression, new ways of assessing new lesions, and a larger role for clinical assessment. Nevertheless, harmonization and validation of these criteria remains indispensable. In this review, we will detail the different criteria that are currently available, and discuss their strengths and weaknesses.

[Anti-tumor immunotherapy in malignant pleural mesothelioma]. / Immunothérapie anti-tumorale dans le mésothéliome pleural malin.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a quite rare cancer, but with increasing incidence, that is usually induced by previous asbestos exposure. Its prognosis is poor and there is no validated curative therapy to date. Surgery of MPM, done only by few expert teams within a multimodal treatment is of limited and still disputed value. The standard treatment of MPM, relying on first-line chemotherapy by combined cisplatin-pemetrexed is often poorly effective, even if combination with bevacizumab anti-VEGF antibodies has slightly improved the results. Moreover, no second line treatment is recommended in case of failure of this chemotherapy. Therefore, the search of new therapies or strategies is crucial and the recruitment of patients in clinical trials is highly encouraged. BACKGROUND: Among the treatments under investigation, various anti-tumour immunotherapies, in particular immune checkpoints inhibitors (ICI), currently exhibit the most promising preliminary results. First data from the phase II, randomized "IFCT MAPS-2", recently presented during the 2017 ASCO meeting, confirmed the value of ICI in MPM patients in cases of chemotherapy failure. OUTLOOK AND CONCLUSIONS: However, several exciting immunotherapies other than ICI are presently being evaluated in MPM and are reported in this article. Moreover, many questions still need to be answered about immunotherapy: what is its potential value as first line treatment? How to target the best candidates for these treatments? Which combinations between immunotherapy and standard chemotherapy, targeted therapies, surgery or radiotherapy? Finally, it is now essential that every clinician has sufficient knowledge about the possible toxicities of immunotherapy.

Solution structure of the N-terminal domain of the human TFIIH MAT1 subunit: new insights into the RING finger family.

The human MAT1 protein belongs to the cyclin-dependent kinase-activating kinase complex, which is functionally associated to the transcription/DNA repair factor TFIIH. The N-terminal region of MAT1 consists of a C3HC4 RING finger, which contributes to optimal TFIIH transcriptional activities. We report here the solution structure of the human MAT1 RING finger domain (Met(1)-Asp(65)) as determined by (1)H NMR spectroscopy. The MAT1 RING finger domain presents the expected betaalphabetabeta topology with two interleaved zinc-binding sites conserved among the RING family. However, the presence of an additional helical segment in the N-terminal part of the domain and a conserved hydrophobic central beta strand are the defining features of this new structure and more generally of the MAT1 RING finger subfamily. Comparison of electrostatic surfaces of RING finger structures shows that the RING finger domain of MAT1 presents a remarkable positively charged surface. The functional implications of these MAT1 RING finger features are discussed.

[On the inhibitory effect of chloramphenicol on mitochondrial protein synthesis as a possible cause of its selective toxic side effects (author's transl)]. / Uber die Hemmwirkung von Chloramphenicol auf die Proteinsynthese von Mitochondrien als Ursache der selektiven toxischen Nebenwirkung

The inhibition of protein synthesis by tetracycline and chloramphenicol in mitochondria isolated from rat liver or rabbit bone marrow was investigated in vitro. It could be demonstrated that there is but little difference between the inhibitory effect of both substances in regard to mitochondria protein synthesis. Therefore, a selective interference of chloramphenicol with bone marrow mitochondria cannot be concluded. In in vitro tests the concentrations required for inhibiting the mitochondria protein synthesis are comparable to those found in blood levels measured under usual therapeutic conditions. It can be assumed that in the living organism the mitochondria are protected against tetracycline or chloramphenicol interference. This hypothesis is supported by the fact that due to the increase in the substrate concentration (phenylalanine), the expected inhibition of mitochondrial protein synthesis does not occur. There may be an inhibition of influx of the antibiotic by competition with substrate for transport through mitochondrial membrane. The reason for myelotoxicity of chloramphenicol is not an increased sensitivity of mitochondrial ribosomes located in the bone marrow to chloramphenicol. But the existence of special conditions for chloramphenicol influx into mitochondria of bone marrow must be concluded.