Resistance to Pembrolizumab and Axitinib in Renal Cell Carcinoma: Clinical and Genomic Evaluation

Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of renal cell carcinoma (RCC). In spite of recent advances in the treatment armamentarium and outcomes with the combined use of immune checkpoint and angiogenesis inhibitors, prediction of responses and selection of patients remain a challenge. This is a case of ccRCC with recurrence to the liver 1 year following right radical nephrectomy, who rapidly progressed on frontline therapy with axitinib/pembrolizumab. The clinical course and targeted tumor sequencing findings are discussed. In addition to established clinical prognostication in RCC, several surrogate markers of efficacy or/and resistance have been proposed for immunotherapy or/and anti-angiogenic therapy. Since the majority of patients will still progress after these combinations, it is becoming increasingly important to develop robust predictive biomarkers to guide patient selection and sequencing of targeted therapies

Effect of PEG-induced drought stress on germination of ten chickpea (Cicer arietinum L.) genotypes

Chickpea (Cicer arietinum L.) is one of the most important legume crops worldwide, with its importance mainly relying on its high protein content. Chickpea productivity is strictly threatened by abiotic stresses, of which drought exerts the most crucial role in terms of growth inhibition and yield losses encountered. Given that germination is a critical stage that is negatively affected by drought, the aim of this study was to estimate the genotypic variability among ten chickpea genotypes and to determine the seed germination and seedling growth ability under drought stress conditions. Seeds were subjected to water stress by polyethylene glycol (PEG-6000) at five stress levels (0, 5, 10, 20, 30 and 50% PEG). Germination percentage, seed water content, seed water absorbance, root and shoot development and seedling vigour index were evaluated. The analyses revealed significant genetic variability in relation to genotypic performance under drought stress. Drought significantly affected germination as well as all other associated traits, with the effects of stress being analogous to the stress level applied. Findings point to the fact that seedling vigour index is a suitable selection criterion for drought tolerance as it allowed the classification of genotypes as tolerant, moderately tolerant, moderately susceptible and susceptible. Taken together, the commercial varieties ‘Thiva’, ‘Keryneia’ and ‘Gavdos’ as well as the landrace ‘Lemnos’ showed an increased drought tolerance at high stress level, indicating their possible exploitation as valuable genetic material for breeding programs or for commercial use

Contribution of arbuscular mycorrhizal fungi to nitrogen and phosphorus uptake efficiency and productivity of faba bean crop on contrasting cropping systems

The present study was focused on evaluating the effect of AMF (Arbuscular Mycorrhizal Fungi) inoculation on nitrogen and phosphorus uptake efficiency and productivity of faba bean (Vicia faba L.) crop, under different fertilization levels on organic or conventional cropping systems. The 2-year field experiment was conducted in central Greece and laid out in a split-plot design, with three replications, two main plots (AMF inoculation treatments) and five sub-plots (fertilization treatments). The results demonstrated that plants of AMF inoculated plots exhibited greater plant height, leaf area index (LAI), leading to higher biomass, and consequently higher final seed yields. Regarding the quality parameters, including nutrients (nitrogen and phosphorus) uptake and their utilization indices, similar results to those of the productivity results were found with the AMF inoculated plants presented the higher values. Finally, all the parameters of the root system, including AMF root colonization and weighted mycorrhizal dependency (WMD), were negatively affected by fertilization level, particularly in an inorganic form. As a conclusion, the current study confirmed that replacement of inorganic inputs by organic in combination with AMF inoculation, should be seriously considered as a sustainable practice of faba bean crop cultivation under Mediterranean conditions

Current Options for Second-Line Systemic Therapy in Metastatic Renal Cell Carcinoma

Standard systemic therapy of advanced renal cell carcinoma (RCC) involves targeting angiogenesis, mainly through tyrosine kinase inhibitors (TKI) against the vascular endothelial growth factor receptor (VEGFR) pathway and targeting the immune checkpoints, namely, programmed death-1 (PD-1) or its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). With current strategies of combining these two approaches in the front-line setting, less is known about optimal selection of therapy upon development of resistance in the second and later lines of treatment for progressive disease. This review discusses currently available therapeutic options in patients who have progressive RCC after prior treatment with double immune check-point inhibitors (ICIs) or ICI-TKI combinations

The organic seed regulations framework in Europe – current status and recommendations for future development

Organic agriculture regulations, in particular European regulation EC 889/2008, prescribe the use of organically produced seed. For many cultivated plants, however, organic seed is often not available. This is mainly because investment in organic plant breeding and seed production has been low in the past. To bridge the gap between organic seed supply and demand, national and European regulations define certain circumstances under which organic producers are permitted to use non-organically produced seed. While the organic sector currently depends on these concessions, they also threaten to impede a further increase in the demand for organic seed, thereby potentially restraining present and future investment in organic seed production and plant breeding. We review the current status of the organic seed regulations framework by analysing key issues such as the role of the national derogation regimes, the role of expert groups, databases and seed prices. Key points are that (a) the situation of the organic seed sector has improved over the last few years; however, (b) reporting on organic seed to the EU by different countries needs to be harmonised; (c) the success of the organic seed sector depends critically on the implementation and improvement of national expert groups; and (d) to protect genetic diversity, the use of local varieties and landraces should not be impeded by organic seed regulations

Inverse baseline expression pattern of the NEP/neuropeptides and NFκB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Castration-resistance in prostate cancer (PC) is a critical event hallmarking a switch to a more aggressive phenotype. Neuroendocrine differentiation and upregulation of NFκB transcriptional activity are two mechanisms that have been independently linked to this process.</p> <p>Methods</p> <p>We investigated these two pathways together using <it>in vitro </it>models of androgen-dependent (AD) and androgen-independent (AI) PC. We measured cellular levels, activity and surface expression of Neutral Endopeptidase (NEP), levels of secreted Endothelin-1 (ET-1), levels, sub-cellular localisation and DNA binding ability of NFκB, and proteasomal activity in human native PC cell lines (LnCaP and PC-3) modelling AD and AI states.</p> <p>Results</p> <p>At baseline, AD cells were found to have high NEP expression and activity and low secreted ET-1. In contrast, they exhibited a low-level activation of the NFκB pathway associated with comparatively low 20S proteasome activity. The AI cells showed the exact mirror image, namely increased proteasomal activity resulting in a canonical pathway-mediated NFκB activation, and minimal NEP activity with increased levels of secreted ET-1.</p> <p>Conclusions</p> <p>Our results seem to support evidence for divergent patterns of expression of the NFκB/proteasome pathway with relation to components of the NEP/neuropeptide axis in PC cells of different level of androgen dependence. NEP and ET-1 are inversely and directly related to an activated state of the NFκB/proteasome pathway, respectively. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice.</p