BackgroundThere are well-known differences in gender outcome in non-small cell lung cancer (NSCLC) and other cancers. In this work, we evaluated several randomised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy.MethodsWe performed a series of meta-analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival (PFS) in phase III randomised clinical trials comparing EGFR inhibitors versus chemotherapy (OPTIMAL, LUX-lung 3, LUX-lung 6, EURTAC, ENSURE and WTJOG); ALK inhibitors versus chemotherapy (ASCEND 4, ASCEND 5, PROFILE 1014 and NCT009323893) and anti-PD1 checkpoint inhibitors versus chemotherapy (CheckMate 017, CheckMate 026, CheckMate 057, KEYNOTE 010 and KEYNOTE 024).ResultsFemale patients with NSCLC have a reduced risk of death compared with men (HR=0.73; 95% CI 0.67 to 0.79; p<0.00001). Women had a better benefit from EGFR inhibitors than men (HR=0.34; 95% CI 0.28 to 0.40; p<0.00001 vs HR=0.44; 95% CI 0.34 to 0.56; p<0.00001, respectively). The benefit from ALK inhibitors was similar for both genders (HR=0.51; 95% CI 0.42 to 0.61; p<0.00001 vs HR=0.48; 95% CI 0.39 to 0.59; p<0.00001, for women and men, respectively). Anti-PD1 inhibitors significantly improved the PFS in male patients when compared with chemotherapy (HR=0.76; 95% CI 0.68 to 0.86; p<0.00001); in contrast, women showed no benefit in 5/5 randomised trials (HR=1.03; 95% CI 0.89 to 1.20; p=0.69).ConclusionsIn this exploratory study, some targeted treatments were influenced by gender. Despite differences in outcomes that could be attributed to different histology, EGFR and smoking status, gender should be evaluated more deeply as prognostic variable in patients with NSCLC.

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DDIT4 gene encodes a protein whose main action is to inhibit mTOR under stress conditions whilst several in vitro studies indicate that its expression favors cancer progression. We have previously described that DDIT4 expression is an independent prognostic factor for tripe negative breast cancer resistant to neoadjuvant chemotherapy. We herein report that high DDIT4 expression is related to the outcome (recurrence-free survival, time to progression and overall survival) in several cancer types. We performed in silico analysis in online platforms, in pooled datasets from KM Plotter and meta-analysis of individual datasets from SurvExpress. High levels of DDIT4 were significantly associated with a worse prognosis in acute myeloid leukemia, breast cancer, glioblastoma multiforme, colon, skin and lung cancer. Conversely, a high DDIT4 expression was associated with an improved prognostic in gastric cancer. DDIT4 was not associated with the outcome of ovarian cancers. Analysis with data from the Cell Miner Tool in 60 cancer cell lines indicated that although rapamycin activity was correlated with levels of MTOR, it is not influenced by DDIT4 expression. In summary, DDIT4 might serve as a novel prognostic biomarker in several malignancies. DDIT4 activity could be responsible for resistance to mTOR inhibitors and is a potential candidate for the development of targeted therapy.DDIT4 gene (for DNA-damage-inducible transcript 4), also known as REDD1 or RTP801, encodes a protein product that is induced by a variety of stress conditions and whose major function is to inhibit mTORC1 by stabilizing the TSC1-TSC2 inhibitory complex [1][2][3] .Despite inhibition of mTOR pathway is a current strategy in the treatment of cancer, paradoxically, several in vitro and in vivo studies indicate that DDIT4 have a protective role against apoptosis, where a knockdown of this gene lead to increased levels of dexamethasone-induced cell death in murine lymphocytes without effect in glucocorticoid-induced cell death in primary thymocytes 4,5 .A recent study by Celik et al., reported that DDIT4 may be used as a surrogate pharmacodynamic marker of ezrin inhibitors compound activity 6 . Only two previous reports describe the prognostic value of DDIT4. Jia et al. 7 , evaluated DDIT4 protein expression (assessed by immunohistochemistry) in 100 primary ovarian tumors describing that a high DDIT4 expression is related to a shorter disease-free survival (P = 0.020) and overall survival (P = 0.023) 7 . In the other hand, our group screened 449 genes related with triple negative breast cancer aggressiveness and found that a high DDIT4 expression was an independent factor associated with a shorter

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited options of targeted therapy. Recent findings suggest that the clinical course of TNBC may be modified by the presence of tumor-infiltrating lymphocytes (TILs) and chemokine’s expression, such as CCL5. Diverse studies have shown that CCL5 suppresses anti-tumor immunity and it has been related to poor outcome in different types of cancer while in other studies, this gene has been related with a better outcome. We sought to determine the association of CCL5 with the recruitment of TILs and other immune cells. With this aim we evaluated a retrospective cohort of 72 TNBC patients as well as publicly available datasets. TILs were correlated with residual tumor size after neoadjuvant chemotherapy (NAC) and CCL5 expression. In univariate analysis, TILs and CCL5 were both associated to the distant recurrence free survival; however, in a multivariate analysis, TILs was the only significant marker (HR = 0.336; 95%IC: 0.150–0.753; P = 0.008). CIBERSORT analysis suggested that a high CCL5 expression was associated with recruitment of CD8 T cells, CD4 activated T cells, NK activated cells and macrophages M1. The CD8A gene (encoding for CD8) was associated with an improved outcome in several public breast cancer datasets.

Spain launched its own strategy on bioeconomy in January 2016 aiming at boosting a bioeconomy based on the sustainable and efficient production and use of biological resources. It highlights global societal challenges related with agricultural and biotechnological sciences in Spain and the great dynamism of the private sectors involved, particularly the agri-food, biotech and biomass sectors. The targeted sectors are food, agriculture and forestry, conditioned by water availability. It also includes the production of those industrial bioproducts and bioenergy obtained from the use and valorisation of wastes and residues and other non-conventional sources of biomass, in a circular economy. The strategy also puts a focus on rural and coastal development through several uses and services linked to ecosystems. The capacity to generate know-how in this area and the promotion of public and private collaboration are important pillars in order to enhance existing value chains and to create new ones. The strategy is led by R&I and Agriculture, Food and Environment policy managers and largely supported at regional level too. The strategic objective is the maintenance of the bioeconomy as an essential part of Spanish economy to contribute to the economic growth by creating new jobs and fostering investments.