SOD2 genetic polymorphism (rs4880) has no impact on 6‐month response to antidepressant treatment and inflammatory biomarkers in depressed patients

Two thirds of patients suffering from a major depressive episode (MDE) do not reach a complete response with antidepressant drugs. This lack of response is due to several factors, including genetic determinants. Since major depressive disorder is associated with inflammatory and oxidative stress abnormalities, the metabolism of superoxide anions might be involved in non‐response to antidepressant drugs. Superoxide anions are metabolized by manganese‐dependent superoxide dismutase (SOD2) in the mitochondria. A functional genetic polymorphism (SOD2, rs4880), responsible of a 40% reduction in enzyme activity, is associated with anti‐inflammatory response of rosuvastatin. We investigated the association of ala‐allele of SOD2 rs4880 and both antidepressant efficacy and inflammatory parameters in patients treated for a MDE with antidepressant drugs. The Hamilton Depression Rating Scale (HDRS) score and levels of plasma CRP and inflammatory cytokines were assessed at baseline, one month (M1), 3 months (M3) and 6 months (M6) after antidepressant treatment. They were compared according to SOD2 genetic polymorphism. Of the 484 patients studied, 361 (74.6%) carried the ala‐allele (Ala group), 123 (25.4%) of them had Val/Val genotype (Val/Val group). No significant difference was observed between the Ala and Val/Val groups neither for baseline clinical characteristics, nor for HDRS scores, response/remission rates, plasma CRP and cytokine levels throughout the study. The rs4880 SOD2 genetic polymorphism was not associated with the clinical response and cytokines levels after antidepressant treatment. These data suggest that SOD2 is not a major genetic determinant of antidepressant response. Other genes of the oxidative stress pathways should be explored in further studies.     

Simultaneously modulated accelerated radiation therapy reduces severe oesophageal toxicity in concomitant chemoradiotherapy of locally advanced non-small-cell lung cancer

Objective:

The aim of this study was to evaluate the potential of simultaneously modulated accelerated radiation therapy (SMART) to reduce the incidence of severe acute oesophagitis in the treatment of unresectable locally advanced non-small-cell lung cancer (LANSCLC).

Methods:

21 patients were treated with SMART and concomitant platinum-based chemotherapy. The prescribed doses were limited to 54 Gy at 1.8 Gy per day to the zones of presumed microscopic extent while simultaneously maintaining doses of 66 Gy at 2.2 Gy per day to the macroscopic disease. The whole treatment was delivered over 30 fractions and 6 weeks. Dosimetric parameters of SMART and the standard technique of irradiation [intensity-modulated radiation therapy (IMRT)] were compared. Acute toxicity was prospectively recorded.

Results:

The highest grade of oesophagitis was 62% (13 patients) grade 1, 33% (7 patients) grade 2 and 5% (1 patient) grade 3. Three (14%) patients experienced acute grade 2 pneumonitis. There was no grade 4 oesophageal or pulmonary toxicity. Doses to the organs at risk were significantly reduced in SMART compared with IMRT [oesophagus: V_50Gy, 28.5 Gy vs 39.9 Gy (p = 0.003); V_60Gy, 7.1 Gy vs 30.7 Gy (p = 0.003); lung: V_20Gy, 27.4 Gy vs 30.1 Gy (p = 0,002); heart: V_40Gy, 7.3 Gy vs 10.7 Gy (p = 0.006); spine: D_max, 42.4 Gy vs 46.4 Gy (p = 0.003)]. With a median follow-up of 18 months (6–33 months), the 1-year local control rate was 70% and the disease-free survival rate was 47%.

Conclusion:

SMART reduces the incidence of severe oesophagitis and improves the whole dosimetric predictors of toxicity for the lung, heart and spine.

Advances in knowledge:

Our study shows that SMART optimizes the therapeutic ratio in the treatment of LANSCLC, opening a window for dose intensification.     

Isolation of a proline-rich mycobacterial protein eliciting delayed-type hypersensitivity reactions only in guinea pigs immunized with living mycobacteria.

Effective protection against a virulent challenge with Mycobacterium tuberculosis is induced only by a previous immunization with living attenuated mycobacteria, usually bacillus Calmette-Guérin (BCG). Living and killed bacteria share a number of common antigens. To identify and to purify molecules that are dominant antigens during immunization with living bacteria, a two-step selection procedure was used. Quantitative delayed-type hypersensitivity (DTH) reactions elicited in guinea pigs immunized either with living or with killed BCG were used to select or counterselect antigens present in BCG culture filtrates. Each major fraction eluted from a series of HPLC columns (gel filtration, DEAE, reverse-phase chromatography) was assayed and titrated on guinea pigs of each group. A protein with an unusual amino acid composition (40% proline, 12% threonine) was purified and N-terminally sequenced. To our knowledge, the sequence Thr-Pro-Pro-Xaa-Glu-Xaa-Pro-Pro-Pro-Pro-Gln-Xaa-Val-Xaa-Leu has not been previously reported. The protein was 100-fold more potent on guinea pigs immunized with living bacteria than on guinea pigs immunized with dead bacteria to elicit a DTH reaction.