Interleukin-7-engineered mesenchymal cells: in vitro effects on naive T-cell population.

T-cell homeostasis is regulated by several molecules; among these, interleukin (IL)-7 plays an essential role in the survival and homeostatic proliferation of peripheral naive T cells. In a previous study, we investigated whether human mesenchymal stromal cells (MSCs) could be engineered with the IL-7 gene to produce functional level of this cytokine. In the present study, we analyzed the impact of different quantities of IL-7 produced by MSCs on the survival and proliferation of a negative immunoselected naive (CD3(+)/CD45RA(+)) T-cell population. Co-cultivation of peripheral naive T cells with MSCs producing low (16 pg/mL) or high (1000 pg/mL) IL-7 levels or in the presence of exogenous IL-7 (0.01 ng/mL and 100 ng/mL) maintained the CD3(+)/CD45RA(+) naive T-cell phenotype. Chemokine receptor CCR7(+) expression was also maintained among this T-cell population. Naive T-cell molecular characteristics were maintained as assessed by the Vbeta spectratyping complexity score, which showed the maintenance of a broad T-cell repertoire. No Th1 or Th2 differentiation was observed, as assessed by interferon-gamma or IL-4 accumulation. In contrast, only MSCs producing high amounts of IL-7 caused increased activation (CD25 31.2% +/- 12% vs 10% +/- 3.5%; P < .05), proliferation (CD71 17.8+/-7% vs 9.3%+/-3, P < .05), apoptosis (assessed by annexin V: 18.6% +/- 5% vs 14.9% +/- 2.6%; P > .05), and the phase S cell cycle (15% vs 6.9%, P > .05). Exogenous IL-7 exhibited no significant effect. In conclusion, we demonstrated that IL-7 produced by MSCs has a dose-independent effect on naive T-cell survival while exerting a dose-dependent effect on activation/proliferation. Due to the continuous production of IL-7 by engineered cells, our system is more efficacious than exogenous IL-7.     

Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer

Objective

The phosphatidylinositol-3 kinase/serine–threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study.

Methods

This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40 mg for 5 consecutive days followed by a 2 day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting.

Results

31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5 months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6 months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status.

Conclusion

Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.     

The soluble receptor ST2 is positively associated with occupational exposure to radiation

Purpose Radiation exposure, besides the risk of cancer, may also increase the risk of non-cancer diseases, including cardiovascular disease (CVD). This study investigates whether the soluble form of the ST2 receptor (sST2), an emerging prognostic marker in patients with CVD, can be used to monitor the CVD risk in individuals occupationally exposed to radiation.

Materials and methods sST2 in blood plasma from 69 individuals, 45 workers from the nuclear industry and 24 controls, was analyzed using enzyme-linked assay (ELISA). Total antioxidant status (TAS) of blood plasma and levels of reactive oxygen species (ROS) in lymphocytes were determined by colorimetric and fluorescence assays.

Results The data suggest a 5-fold increase in the number of subjects with sST2 levels above the clinical threshold and a 10-fold increase in the number of subjects with TAS levels outside the reference range in the exposed group when compared to the group of non-exposed individuals. The strongest up-regulation of TAS was measured in the group of younger workers with cumulative doses not exceeding 50 mSv.

Conclusion The present study may represent an initial step towards the establishment of sST2 as a biomarker for CVD risk estimation in the context of radiation exposure.     

Corpus callosum area in patients with bipolar disorder with and without psychotic features: an international multicentre study

Background

Previous studies have reported MRI abnormalities of the corpus callosum (CC) in patients with bipolar disorder (BD), although only a few studies have directly compared callosal areas in psychotic versus nonpsychotic patients with this disorder. We sought to compare regional callosal areas in a large international multicentre sample of patients with BD and healthy controls.

Methods

We analyzed anatomic T₁ MRI data of patients with BD-I and healthy controls recruited from 4 sites (France, Germany, Ireland and the United States). We obtained the mid-sagittal areas of 7 CC subregions using an automatic CC delineation. Differences in regional callosal areas between patients and controls were compared using linear mixed models (adjusting for age, sex, handedness, brain volume, history of alcohol abuse/dependence, lithium or antipsychotic medication status, symptomatic status and site) and multiple comparisons correction. We also compared regional areas of the CC between patients with BD with and without a history of psychotic features.

Results

We included 172 patients and 146 controls in our study. Patients with BD had smaller adjusted mid-sagittal CC areas than controls along the posterior body, the isthmus and the splenium of the CC. Patients with a positive history of psychotic features had greater adjusted area of the rostral CC region than those without a history of psychotic features.

Limitations

We found small to medium effect sizes, and there was no calibration technique among the sites.

Conclusion

Our results suggest that BD with psychosis is associated with a different pattern of interhemispheric connectivity than BD without psychosis and could be considered a relevant neuroimaging subtype of BD.     

Visuospatial deficits in posterior cortical atrophy: structural and functional correlates

Objective To determine the neural substrates of biased spatial orienting in posterior cortical atrophy (PCA) by using a combined structural and functional neuroimaging approach. Background Patients with spatial neglect typically bisect horizontal long lines towards their brain lesions but the precise neural substrates of this spatial bias remain controversial and poorly explored in neurodegenerative disorders such as PCA. Methods 15 patients with PCA underwent brain MRI and single photon emission computed tomography (SPECT) and were required to bisect five 20 cm long lines, each centred on an A4 horizontal sheet. Direct correlations between average deviations on the bisection task and both (1) the degree of grey matter density, as estimated by voxel based morphometry and (2) regional cerebral blood flow, as assessed by SPECT, were performed. Results Seven patients (47%) had pathological bias on the bisection task, deviating consistently towards the non-neglected side for each of the five lines. Rightward bias (sign of left-sided neglect) was more frequent and severe than leftward bias (sign of right-sided neglect). Correlation analyses showed that rightward deviations correlated with atrophy and hypoperfusion exclusively in the right hemisphere, involving a large scale fronto-parietal network; cortical atrophy was prominent in the parieto-temporal cortex but extended to the frontal region; hypoperfusion was substantial both in the middle frontal gyrus and in the postcentral region. No correlations emerged from leftward deviations. Conclusion The results indicate that rightward bias (sign of left-sided neglect) in PCA depends on dysfunction of a large fronto-parietal network in the right hemisphere, related to both cortical atrophy and decreased cerebral perfusion.     

Emotional hyperreactivity as a core dimension of manic and mixed states

Despite its obvious importance in mood disorders, characterization of emotional reactivity has been neglected in bipolar disorders. Concerning manic states and the current classification, the main criterion is the presence of an elevated or expansive mood. In contrast to this characteristic and often prolonged mood state, emotional reactivity refers to a brief evoked response to salient emotional stimuli. The goal of this study was to assess the intensity of emotional responses triggered by viewing slides in bipolar patients with manic or mixed states. Our hypothesis was that all emotional responses are exacerbated, whatever the valence of the stimuli. We compared 33 patients with manic or mixed states with 33 matched euthymic patients and 33 healthy control subjects. Arousal and attribution of valence were assessed while subjects viewed slides taken from the International Affective Picture System (positive, neutral and negative slides). Patients with manic or mixed states reported a higher arousal when viewing all types of slides in comparison with the other groups. Concerning attribution of valence, patients with manic or mixed states assessed neutral slides as more pleasant. When bipolar patients with manic and mixed states are placed in front of positive, neutral and negative slides, the slides trigger a higher intensity of emotions, whatever the valence of the emotional stimuli. These results strengthen the importance of emotional hyperreactivity as a core dimension in manic and mixed states in bipolar disorder.     

Monte Carlo based geometrical model for efficiency calculation of an n-type HPGe detector

A procedure to optimize the geometrical model of an n-type detector is described. Sixteen lines from seven point sources (²⁴¹Am, ¹³³Ba, ²²Na, ⁶⁰Co, ⁵⁷Co, ¹³⁷Cs and ¹⁵²Eu) placed at three different source-to-detector distances (10, 20 and 30 cm) were used to calibrate a low-background gamma spectrometer between 26 and 1408 keV. Direct Monte Carlo techniques using the MCNPX 2.6 and GEANT 4 9.2 codes, and a semi-empirical procedure were performed to obtain theoretical efficiency curves. Since discrepancies were found between experimental and calculated data using the manufacturer parameters of the detector, a detail study of the crystal dimensions and the geometrical configuration is carried out. The relative deviation with experimental data decreases from a mean value of 18–4%, after the parameters were optimized.     

Vitamin D status and risk of infections after liver transplantation in the Swiss Transplant Cohort Study

Increasing evidence indicates a role of vitamin D in the immune system affecting response to infections. We aimed to characterize the role of vitamin D status, i.e. deficiency [25‐OH vitamin D (25‐OHD) <50 nmol/l] and no deficiency (25‐OHD ≥50 nmol/l) in incident infections after liver transplantation. In 135 liver transplant recipients, blood samples drawn at time of liver transplantation and 6 months afterwards were used to determine 25‐OHD levels. Incident infections episodes were prospectively collected within the Swiss Transplant Cohort Study database. Poisson regression was applied to address associations between vitamin D status and incident infections. Vitamin D deficiency was common at time of transplantation and 6 months afterwards without a significant change in median 25‐OHD levels. In univariable analyses, vitamin D deficiency was a risk factor for incident infections in the first 6 months post‐transplant incidence rate ratio (IRR 1.52, 95% CI 1.08–2.15, P = 0.018) and for bacterial infections occurring after 6 up to 30 months post‐transplant (IRR 2.29, 95% CI 1.06–4.94, P = 0.034). These associations were not detectable in multivariable analysis with adjustment for multiple confounders. Efforts to optimize vitamin D supplementation in liver transplant recipients are needed. Our data question the role of vitamin D deficiency in incident infections.