Metabolic reprogramming of oestrogen receptor positive breast cancer in endocrine therapy resistance

The majority of breast tumours express oestrogen receptor (ER) and are dependent on oestrogen (E2) for their growth and survival. Endocrine therapy is the standard of care for this breast cancer subset and acts by targeting ER pathway in different ways: selective ER modulators compete with E2 to bind ER (e.g. tamoxifen), selective ER downregulators promote ER degradation (e.g. fulvestrant) and aromatase inhibitors (AI) block E2 biosynthesis. Despite the efficacy of these endocrine agents, a large proportion of women relapse with endocrine-resistant disease. In this study, we investigated the link between altered breast cancer metabolism and endocrine therapy resistance. We found that AI-resistance cells can adapt to metabolic stress and switch ad hoc between OXPHOS and glycolysis. In particular, we identified the miR-155/hexokinase-2 (HK2) axis as an important regulator of this tumour plasticity. In addition to central carbon metabolism, we found a deregulated node between miR-23b-3p and the amino acid transporter SLC6A14 in endocrine therapy resistant cells, which leads to an impairment of amino acids metabolism in the resistant cells with subsequent activation of autophagy. Furthermore, the miRNA characterised have prognostic (miR-155 and miR-23b-3p) and predictive (miR155) value in ER positive breast cancer. These results suggest that high metabolic plasticity is involved in acquiring adaptive features that allow breast cancer cell survival even in the presence of endocrine therapy

Competencies based innovative learning solutions for co-development of climate services in West Africa

Abstract. In developing countries, and particularly in West Africa, the role of Climate Services (CS) for sustainable development is growing thanks to wide spreading collaboration among European institutions, including National Meteorological and Hydrological Services (NMHS) research centers, universities, and homologue local institutions. Operationally, the implementation of CSs in developing countries is mainly pivoted on NMHS, which, according to the World Meteorological Organization (WMO), are dramatically affected by unmet learning demand. The global scale of learning needs for co-development of CSs calls for innovative solutions and a range of flexible modalities to reach learners in a variety of ways, and for sharing resources and successful strategies within the global education and training community. In order to harmonize expected learning outcomes, WMO defined a competency framework (CF) for CSs to be used in the implementation of training initiatives and knowledge sharing tools. This paper presents the strategic and methodological approach adopted in the implementation of the TOPaCS, a new knowledge-based distance learning initiative, aiming to provide a flexible learning environment within the CSs CF of WMO ensuring coherence with other WMO education initiatives (Global Campus, other RTCs, etc.). The methodological approach adopted is based on the competency-based approach to training, where competencies are composed by elements of knowledge and skill. TOPaCS integrates the WMO CF for CSs into a taxonomy co-designed with stakeholders at different levels, and allows the definition of learning paths, which are a further interactive opportunity for co-development of CSs within the TOPaCS learning ecosystem. Indeed, the approach aims also to guide further instructional strategies and assessments and becomes a starting point to build a common language enabling a better cooperation and exchange between the different CSs training initiatives

Exploring the Gut Microbiome Alteration of the European Hare (Lepus europaeus) after Short-Term Diet Modifications

This study aimed to characterise the gut microbiome composition of European hares (Lepus europaeus) and its potential changes after a short-term diet modification. The high sensitivity of European hare to habitat changes makes this species a good model to analyse possible alterations in gut microbiome after the introduction of additional nourishment into the diet. In total, 20 pairs were chosen for the experiments; 10 pairs formed the control group and were fed with standard fodder. The other 10 pairs represented the experimental group, whose diet was integrated with apples and carrots. The DNA from fresh faecal pellets collected after 4 days from the start of the experiment was extracted and the V3-V4 hypervariable regions were amplified and sequenced using the Illumina MiSeq® platform. The obtained amplicon sequence variants were classified into 735 bacterial genera belonging to 285 families and 36 phyla. The control and the experimental groups appeared to have a homogenous dispersion for the two taxonomic levels analysed with the most abundant phyla represented by Bacteroidetes and Firmicutes. No difference between control and experimental samples was detected, suggesting that the short-term variation in food availability did not alter the hares’ gut microbiome. Further research is needed to estimate significant time threshold

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2− and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2− breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance

Mutational analysis of ribosomal proteins in a cohort of pediatric patients with T-cell acute lymphoblastic leukemia reveals Q123R, a novel mutation in RPL10

T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL involving the malignant expansion of T-cell progenitors. It is driven by a number of different possible genetic lesions, including mutations in genes encoding for ribosomal proteins (RPs). These are structural constituents of ribosomes, ubiquitous effectors of protein synthesis. Albeit the R98S mutation in RPL10, recurring with a higher frequency among RP mutations, has been extensively studied, less is known about the contribution of mutations occurring in other RPs. Alterations affecting translational machinery may not be well tolerated by cells, and there may be a selective pressure that determines the emergence of mutations with a compensatory effect. To explore this hypothesis, we sequenced the exomes of a cohort of 37 pediatric patients affected by T-ALL, and analyzed them to explore the co-occurrence of mutations in genes involved in ribosome biogenesis (including RPs) and translational control, and in known T-ALL driver genes. We found that some of the mutations in these sub-classes of genes tend to cluster together in different patients, indicating that their co-occurrence may confer some kind of advantage to leukemia cells. In addition, our sequencing highlighted the presence of a novel mutation in RPL10, namely the Q123R, which we found associated with a defect in protein synthesis. Our findings indicate that genetic alterations involving ribosome biogenesis and translational control should be carefully considered in the context of precision medicine in T-ALL

Results of the Scandinavian Sarcoma Group XIV protocol for classical osteosarcoma: 63 patients with a minimum follow-up of 4 years

Background and purpose The Scandinavian Sarcoma Group (SSG) XIV protocol is based on experience from previous SSG trials and other osteosarcoma intergroup trials, and has been considered the best standard of care for patients with extremity localized, non-metastatic osteosarcoma. We analyzed the outcome in 63 consecutive patients. Patients and methods From 2001 through 2005, 63 patients recruited from centers in Sweden, Norway, and Finland were included. They received preoperative chemotherapy consisting of 2 cycles of paired methotrexate (12 g/m(2)), cisplatin (90 mg/m(2)), and doxorubicin (75 mg/m(2)). 3 cycles were administered post-operatively, and poor histological responders were given 3 additional cycles of ifosfamide (10-12 g/m(2)) as a salvage strategy. Results With a median follow-up of 77 months for survivors, the estimated metastasis-free and sarcoma-related survival at 5 years was 70% and 76%, respectively. 53 patients were treated with limb salvage surgery or rotationplasty and 2 patients experienced a local recurrence. 3 toxic deaths were recorded, all related to acute toxicity from chemotherapy. The 5-year metastasis-free survival of poor histological responders receiving add-on treatment with ifosfamide was 47%, as compared to 89% for good histological responders. Interpretation Outcome from the SSG XIV protocol compares favorably with the results of previous SSG trials and other published osteosarcoma trials. However, salvage therapy given to poor responders did not improve outcome to a similar degree as for good responders. In a multi-institutional setting, more than four-fifths of the patients were operated with limb salvage surgery or rotationplasty, with few local recurrences

Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial.

BACKGROUND Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. METHODS We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively. RESULTS The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms (p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms (p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug. CONCLUSION The study results do not support the use of ConA to prevent COVID-19 progression. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov, identifier NCT04414631

Vaccine effectiveness against COVID-19 hospitalisation in adults (≥ 20 years) during Alpha- and Delta-dominant circulation: I-MOVE-COVID-19 and VEBIS SARI VE networks, Europe, 2021

Members of the I-MOVE-COVID-19 and VEBIS hospital study teams (in addition to the named authors): Svjetlana Karabuva, Petra Tomaš Petrić, Marija Marković, Sandra Ljubičić, Bojana Mahmutović, Irena Tabain, Petra Smoljo, Iva Pem Novosel, Tanya Melillo, John Paul Cauchi, Benédicte Lissoir, Xavier Holemans, Marc Hainaut, Nicolas Dauby, Benedicte Delaere, Marc Bourgeois, Evelyn Petit, Marijke Reynders, Door Jouck, Koen Magerman, Marieke Bleyen, Melissa Vermeulen, Sébastien Fierens, François Dufrasne, Siel Daelemans, Ala’a Al Kerwi, Francoise Berthet, Guy Fagherazzi, Myriam Alexandre, Charlene Bennett, Jim Christle, Jeff Connell, Peter Doran, Laura Feeney, Binita Maharjan, Sinead McDermott, Rosa McNamara, Nadra Nurdin, Salif Mamadou Cissé, Anne-Sophie L'Honneur, Xavier Duval, Yolande Costa, Fidouh Nadhira, Florence Galtier, Laura Crantelle, Vincent Foulongne, Phillipe Vanhems, Sélilah Amour, Bruno Lina, Fabrice Lainé, Laetitia Gallais, Gisèle Lagathu, Anna Maisa, Yacine Saidi, Christine Durier, Rebecca Bauer, Ana Paula Rodrigues, Adriana Silva, Raquel Guiomar, Margarida Tavares, Débora Pereira, Maria José Manata, Heidi Gruner, André Almeida, Paula Pinto, Cristina Bárbara, Itziar Casado, Ana Miqueleiz, Ana Navascués, Camino Trobajo-Sanmartín, Miguel Fernández-Huerta, María Eugenia Portillo, Carmen Ezpeleta, Nerea Egüés, Manuel García Cenoz, Eva Ardanaz, Marcela Guevara, Conchi Moreno-Iribas, Hana Orlíková, Carmen Mihaela Dorobat, Carmen Manciuc, Simin Aysel Florescu, Alexandru Marin, Sorin Dinu, Catalina Pascu, Alina Ivanciuc, Iulia Bistriceanu, Mihaela Oprea, Maria Elena Mihai, Silke Buda, Ute Preuss, Marianne Wedde, Auksė Mickienė, Giedrė Gefenaitė, Alain Moren, Anthony NardoneIntroduction: Two large multicentre European hospital networks have estimated vaccine effectiveness (VE) against COVID-19 since 2021. Aim: We aimed to measure VE against PCR-confirmed SARS-CoV-2 in hospitalised severe acute respiratory illness (SARI) patients ≥ 20 years, combining data from these networks during Alpha (March–June)- and Delta (June–December)-dominant periods, 2021. Methods: Forty-six participating hospitals across 14 countries follow a similar generic protocol using the test-negative case–control design. We defined complete primary series vaccination (PSV) as two doses of a two-dose or one of a single-dose vaccine ≥ 14 days before onset. Results: We included 1,087 cases (538 controls) and 1,669 cases (1,442 controls) in the Alpha- and Delta-dominant periods, respectively. During the Alpha period, VE against hospitalisation with SARS-CoV2 for complete Comirnaty PSV was 85% (95% CI: 69–92) overall and 75% (95% CI: 42–90) in those aged ≥ 80 years. During the Delta period, among SARI patients ≥ 20 years with symptom onset ≥ 150 days from last PSV dose, VE for complete Comirnaty PSV was 54% (95% CI: 18–74). Among those receiving Comirnaty PSV and mRNA booster (any product) ≥ 150 days after last PSV dose, VE was 91% (95% CI: 57–98). In time-since-vaccination analysis, complete all-product PSV VE was > 90% in those with their last dose < 90 days before onset; ≥ 70% in those 90–179 days before onset. Conclusions: Our results from this EU multi-country hospital setting showed that VE for complete PSV alone was higher in the Alpha- than the Delta-dominant period, and addition of a first booster dose during the latter period increased VE to over 90%.Key public health message: - What did you want to address in this study? To understand how well the COVID-19 vaccine was performing in Europe against hospitalisation during SARS-CoV-2 Alpha and Delta variant periods, we present vaccine effectiveness results from a multi-country study of complete and booster dose COVID-19 vaccination among adults (aged 20 years and over). - What have we learnt from this study? Between March and June 2021 (Alpha period), vaccine effectiveness against hospitalisation with laboratory-confirmed SARS-CoV-2 was 43% for partial vaccination and 86% for complete vaccination. For June to December 2021 (Delta period), vaccine effectiveness for complete vaccination was lower (52%) but with addition of an mRNA booster dose, effectiveness reached 91%, and remained > 90% up to 119 days after the booster dose. - What are the implications of your findings for public health? In Europe in 2021, COVID-19 vaccine effectiveness results for the Alpha period indicated an excellent benefit for preventing hospitalisation after complete vaccination. During Delta variant circulation, however, a booster dose was required to achieve this level of effectiveness, and this was maintained for up to 4 months post booster.info:eu-repo/semantics/publishedVersio