Polymorphisms of Homologous Recombination Genes and Clinical Outcomes of Non-Small Cell Lung Cancer Patients Treated with Definitive Radiotherapy

The repair of DNA double-strand breaks (DSBs) is the major mechanism to maintain genomic stability in response to irradiation. We hypothesized that genetic polymorphisms in DSB repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC) patients treated with definitive radio(chemo)therapy. We genotyped six potentially functional single nucleotide polymorphisms (SNPs) (i.e., RAD51 −135G>C/rs1801320 and −172G>T/rs1801321, XRCC2 4234G>C/rs3218384 and R188H/rs3218536 G>A, XRCC3 T241M/rs861539 and NBN E185Q/rs1805794) and estimated their associations with overall survival (OS) and radiation pneumonitis (RP) in 228 NSCLC patients. We found a predictive role of RAD51 −135G>C SNP in RP development (adjusted hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.31–0.86, P = 0.010 for CG/CC vs. GG). We also found that RAD51 −135G>C and XRCC2 R188H SNPs were independent prognostic factors for overall survival (adjusted HR = 1.70, 95% CI, 1.14–2.62, P = 0.009 for CG/CC vs. GG; and adjusted HR = 1.70; 95% CI, 1.02–2.85, P = 0.043 for AG vs. GG, respectively) and that the SNP-survival association was most pronounced in the presence of RP. Our study suggests that HR genetic polymorphisms, particularly RAD51 −135G>C, may influence overall survival and radiation pneumonitis in NSCLC patients treated with definitive radio(chemo)therapy. Large studies are needed to confirm our findings

Hair follicle renewal: organization of stem cells in the matrix and the role of stereotyped lineages and behaviors

International audienceHair follicles (HFs) are renewed via multipotent stem cells located in a reservoir (the bulge); however, little is known about how they generate multi-tissue HFs from a proliferative zone (the matrix). To address this issue, we temporally induced clonal labeling during HF growth. Challenging the prevailing hypothesis, we found that the matrix contains restricted self-renewing stem cells for each inner structure. These cells are located around the dermal papilla forming a germinative layer. They occupy different proximodistal sectors and produce differentiated cells along the matrix radial axis via stereotyped lineages and cell behavior. By contrast, the outer layer of HFs displays a mode of growth involving apoptosis that coordinates the development of outer and inner structures. HF morphology is therefore determined by the organization of cell fates along the proximodistal axis and by cell behavior along the radial (lateral) axis in the matrix. Thus, our studies suggest that fate and behavior are organized by two systems (uncoupled), and this uncoupling may represent a fundamental way to simplify morphogenesis

Hair follicle renewal: authentic morphogenesis that depends on a complex progression of stem cell lineages

International audienceThe hair follicle (HF) grows during the anagen phase from precursors in the matrix that give rise to each differentiated HF layer. Little is known about the lineal relationship between these layer-restricted precursors and HF stem cells. To understand how the HF stem cells regenerate the typical anagen organization, we conducted in vivo clonal analysis of key stages of the HF cycle in mice. Unexpectedly, we found that the pool of HF stem cells contains precursors with both multipotent and restricted contributions. This implies that the lineal relationships between HF stem cells (persisting during telogen) and layer-restricted precursors (in the germinative layer), responsible for HF elongation during anagen, are not stereotyped. Formation of the matrix at each cycle is accompanied by the transient expansion of an intermediary pool of precursors at the origin of the germinative layer and by the progressive restriction of cell dispersion. The regionalization of clonal patterns within the outer HF structure (the outer root sheath) suggests that the position of the precursors might be a crucial factor in determining their fate. The presence of HF stem cells with multipotent contribution and the progressive segregation of HF lineages upon anagen activation indicate that each HF renewal cycle constitutes an authentic morphogenetic process. A comprehensive model was constructed based on the different clonal patterns observed. In this model, the positions of the precursors relative to the dermal papilla together with the progressive restriction of cell dispersion are part of the mechanism that restricts their contribution to the different HF lineages

The cap size and shape of Arabidopsis thaliana primary roots condition responses to an increase in medium strength.

International audienceDuring root progression in soil, root cap cells are the first to encounter obstacles, and are known to sense environmental cues, making the root cap a relevant candidate for a mechanosensing site. A two-layered medium system was adopted to study root responses to variations in growth medium strength and the importance of the root cap in the establishment of these responses. Root growth and trajectory of primary roots of Arabidopsis thaliana seedlings were investigated using in vivo image analysis. After contact with the harder layer, the root either penetrated it or underwent rapid curvature, enabling reorientation of growth. We initially hypothesized that the root cap structure impacted apex penetration and reorientation, with pointed caps facilitating and domed caps impeding root penetration. This hypothesis was investigated by analysing the responses of Arabidopsis mutants with altered root caps. The primary root of fez-2 mutant lines, which has fewer root cap cell layers and a more pointed root cap than wild-type roots, showed impaired penetration ability. Conversely, smb-3 roots, which display a rectangular-shaped cap, showed enhanced penetration abilities. Our results, which contradict our original hypothesis, uncover a role for resistance to root buckling in determining penetration abilities

Addition of Bevacizumab to First-Line Palliative Chemotherapy in Patients with Metastatic Small Bowel Adenocarcinoma:A Population-Based Study

Background Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce. Objective The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA. Patients and methods Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated. Results In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3 months, compared to 9.1 months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5 months with and 6.4 months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59). Conclusions Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit OR benefiting from anti-VEGF therapy in metastatic SBA

Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern

BACKGROUND: The mouse cerebellum (Cb) has a remarkably complex foliated three-dimensional (3D) structure, but a stereotypical cytoarchitecture and local circuitry. Little is known of the cellular behaviors and genes that function during development to determine the foliation pattern. In the anteroposterior axis the mammalian cerebellum is divided by lobules with distinct sizes, and the foliation pattern differs along the mediolateral axis defining a medial vermis and two lateral hemispheres. In the vermis, lobules are further grouped into four anteroposterior zones (anterior, central, posterior and nodular zones) based on genetic criteria, and each has distinct lobules. Since each cerebellar afferent group projects to particular lobules and zones, it is critical to understand how the 3D structure of the Cb is acquired. During cerebellar development, the production of granule cells (gcs), the most numerous cell type in the brain, is required for foliation. We hypothesized that the timing of gc accumulation is different in the four vermal zones during development and contributes to the distinct lobule morphologies. METHODS AND RESULTS: In order to test this idea, we used genetic inducible fate mapping to quantify accumulation of gcs in each lobule during the first two postnatal weeks in mice. The timing of gc production was found to be particular to each lobule, and delayed in the central zone lobules relative to the other zones. Quantification of gc proliferation and differentiation at three time-points in lobules representing different zones, revealed the delay involves a later onset of maximum differentiation and prolonged proliferation of gc progenitors in the central zone. Similar experiments in Engrailed mutants (En1(−/+);En2(−/−)), which have a smaller Cb and altered foliation pattern preferentially outside the central zone, showed that gc production, proliferation and differentiation are altered such that the differences between zones are attenuated compared to wild-type mice. CONCLUSIONS: Our results reveal that gc production is differentially regulated in each zone of the cerebellar vermis, and our mutant analysis indicates that the dynamics of gc production plays a role in determining the 3D structure of the Cb. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13064-016-0072-z) contains supplementary material, which is available to authorized users

Lalinet status - Station expansion and lidar ratio systematic measurements

LALINET is expanding regionally to guarantee spatial coverage over South and Central Americas. One of the network goals is to obtain a set of regional representative aerosol optical properties such as particle backscatter, extinction and lidar ratio. Given the North-South extension and influence of distinct airmass circulation patterns it is paramount to distinguish these optical parameters in order to gain better perfomance in radiation transfer models. A set of lidar ratio data is presented. © The Authors, published by EDP Sciences, 2018