Evaluation of grain yield performance and its stability in various spring barley accessions under condition of different agroclimatic zones of Ukraine

Two extremely urgent problems of biological and agronomic research nowadays are ensuring an optimal balance between usage of natural resources to meet rapidly growing needs for food production and preservation of biodiversity. It is also important to extend the genetic diversity of the main crop varieties in agroecosystems. At the same time, modern varieties should be characterized by a combination of high yield and preserving yield stability under variable conditions. Solving the outlined tasks requires comprehensive research and involvement in breeding process of the genetical diversity concentrated in genebanks of the world. Barley (Hordeum vulgare L.) is one of the most important crops that satisfy the various needs of humanity. In respect to this, in 2020–2022, a multi-environment trial was conducted in three agroclimatic zones of Ukraine (Forest-Steppe, Polissia, and Northern Steppe). We studied 44 spring barley collection accessions of different ecological and geographical origin, different subspecies and groups of botanical varieties which were obtained from the National Center for Plant Genetic Resources of Ukraine. Statistical indices (Hom, Sc) and graphical models (GGE biplot, AMMI) were used to interpret the yield performance and its stability. Both individual ecological sites in different years and combinations of different sites and years of trials were characterized for productivity, discriminating power and representativeness. The environments differed quite strongly among themselves in terms of these indicators. It was established that most of the genotypes were characterized by higher adaptability to individual environmental conditions (stability in different years), compared to adaptability for all agroclimatic zones (wide adaptation). A strong cross-over genotype by environment interaction was found for most studied accessions. Nevertheless, both genotypes with very high stability in only one agroclimatic zone (Amil (UKR), Gateway (CAN)) and genotypes with a combination of high adaptability to one or two ecological niches and relatively higher wide adaptability (Stymul (UKR), Ly-1064 (UKR), Rannij (KAZ), Shedevr (UKR), and Arthur (CZE)) were identified. There were also the accessions which did not show maximum performance in the individual sites, but had relatively higher wide adaptability (Ly-1059 (UKR), Ly-1120 (UKR), Diantus (UKR), and Danielle (CZE)). In general, the naked barley genotypes were inferior to the covered ones in terms of yield potential and wide adaptability, but at the same time, some of them (CDC ExPlus (CAN), CDC Gainer (CAN), and Roseland (CAN)), accordingly to the statistical indicators, had increased stability in certain ecological sites. Among naked barley accessions relatively better wide adaptability according to the graphical analysis was found in the accession CDC McGwire (CAN), and by the statistical parameters CDC ExPlus (CAN) was better than standard. The peculiarities of yield manifestation and its variability in different spring barley genotypes in the multi-environment trial revealed in this study will contribute to the complementation and deepening of existing data in terms of the genotype by environment interaction. Our results can be used in further studies for developing spring barley variety models both with specific and wide adaptation under conditions of different agroclimatic zones of Ukraine. The disitnguished accessions of different origin and botanical affiliation are recommended for creating a new breeding material with the aim of simultaneously increasing yield potential and stability, as well as widening the genetic basis of spring barley varieties

Src Is a Potential Therapeutic Target in Endocrine-Resistant Breast Cancer Exhibiting Low Estrogen Receptor-Mediated Transactivation.

Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection for clinical trials testing dasatinib utility in ER+ breast cancer

Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease.

Background Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit.Methods In order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations.Results Similar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome.Conclusions Our study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Elacestrant demonstrates strong anti-estrogenic activity in PDX models of estrogen-receptor positive endocrine-resistant and fulvestrant-resistant breast cancer.

The selective oestrogen receptor (ER) degrader (SERD), fulvestrant, is limited in its use for the treatment of breast cancer (BC) by its poor oral bioavailability. Comparison of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, demonstrates both drugs impact tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations but that elacestrant is active after acquired resistance to fulvestrant. In cell line models of endocrine sensitive and resistant breast cancer both drugs impact the ER-cistrome, ER-interactome and transcription of oestrogen-regulated genes similarly, confirming the anti-oestrogenic activity of elacestrant. The addition of elacestrant to CDK4/6 inhibitors enhances the antiproliferative effect compared to monotherapy. Furthermore, elacestrant inhibits the growth of palbociclib-resistant cells. Lastly, resistance to elacestrant involves Type-I and Type-II receptor tyrosine kinases which are amenable to therapeutic targeting. Our data support the wider clinical testing of elacestrant

Dysfunctional keratinocytes increase dermal inflammation in systemic sclerosis. Results from tissue-engineered scleroderma epidermis

In systemic sclerosis (SSc) evidence suggests abnormal keratinocyte-fibroblast interactions. We investigated the potential epidermal dysfunction in SSc and its effects on dermal homeostasis