Advanced-Metastatic Non-Small-Cell Lung Cancer EGFR-mutated in Italy: patient management costs and potential productivity losses:

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are established therapies for previously untreated advanced/metastatic non-small cell lung cancer (NSCLC) EGFR-mutated patients. Osimertinib, a third-generation TKI, has recently received the same first-line indication. This study aims at investigating management costs and potential productivity losses in Italy in this patient setting, given all the available therapeutic options. Two analyses were performed. The first evaluates first-line yearly management costs and potential productivity losses per patient, for each first-line treatment. The second, performed nationally and regionally, models all lines of treatments and costs over a five-year period, through different market-share scenarios – considering osimertinib adoption as new therapy in 60% of patients as the most probable one – and line-switch/mortality probabilities. Using this model, patients' total months of treatment and development/progression of brain metastases were also analyzed. The first analysis shows that first-line management costs and potential productivity losses are minimized by osimertinib (first-line yearly expenditure of €25.942, 8%-12% less than TKIs). The second analysis, based on a five-year horizon and on all therapy lines, shows that total management costs and potential productivity losses decrease by increasing the adoption of osimertinib as a first-line therapy (€7.4m cumulative lower cost with osimertinib at 60% compared to 0%). Considering the average month of therapy, where results are not affected by the length of the therapy, with osimertinib at 60% on naïve patients, monthly management costs and productivity losses are 10% lower than in the non-osimertinib scenario. In advanced, metastatic EGFR-mutated NSCLC, the use of osimertinib as the first-line treatment could reduce patient management costs and potential productivity losses

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Solid tumors often grow in a micro-environment characterized by <\u20092% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1\u3b1 (HIF-1\u3b1), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1\u3b1 and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future

Hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells

Estudo de caso: o uso do protocolo AWIN de avaliação de bem-estar para monitorar um grupo de jumentos abandonados

O objetivo deste estudo foi formular um diagnóstico das condições de vida de jumentos abandonados mantidos em uma área restrita de uma propriedade através da avaliação de seu nível de bem-estar, utilizando o protocolo AWIN como ferramenta metodológica. Estes animais seriam destinados ao abate, porém, depois da suspensão temporária da atividade, foram abandonados pelos proprietários. O protocolo de avaliação de bem-estar foi associado às condições ambientais e sanitárias gerais. Informações sobre os índices de mortalidade também foram coletadas. De acordo com os resultados da avaliação de bem-estar, as condições de vida destes animais estavam aceitáveis em algumas áreas, embora não houvesse sombreamento e abrigo suficientes, um período de restrição alimentar de 3 meses e um índice de mortalidade acima de 70%. Estes resultados demonstram que protocolos de avaliação de bem-estar devem ser adaptados a situações de crise, e bancos de dados para indicadores de bem-estar em condições diversas devem ser criados.The objective of this study was to reach a diagnosis of the living conditions of abandoned donkeys kept in a restricted farm area through the assessment of their welfare level utilizing the AWIN protocol as a methodological tool. These animals were supposed to be sent to slaughter, but after the activity was temporarily banned, they were abandoned by traders. The protocol of welfare assessment was associated with general environmental and sanitary conditions. Information regarding the mortality rates was also gathered. According to the welfare assessment results, the living conditions of these animals were acceptable in some areas, despite the insufficient shade and shelter, a 3-month food restriction period, and a mortality rate of over 70%. These results demonstrate that welfare assessment protocols must be adapted to crises and databases for welfare indicators in diverse conditions must be created

Accessing dementia care in Brazil: an analysis of case vignettes

Background and Objectives Despite the rapid increase in the number of people living with dementia in Brazil, dementia care is limited. This study describes how people living with dementia and their carers access care, treatment, and support, and identifies what characteristics are likely to enable or prevent access. Research Design and Methods We created 10 vignettes to illustrate fictitious but realistic scenarios involving people living with dementia in Brazil. The vignettes explore a combination of socioeconomic and demographic variables. They were completed using an in-depth desk review of the dementia care landscape in Brazil; a Strengths, Opportunities, Weaknesses, and Threats (SWOT) analysis of the desk review; and expert knowledge. The analysis focused on identifying common sources of service provision, barriers of access to care and support, and specific issues experienced by some population groups. Findings Access to a dementia diagnosis, care, and support for people living with dementia in Brazil is limited. Demographic and socio-economic circumstances play a role in determining the type of services to which a person might have access. Poor knowledge about dementia, lack of capacity in the health system, and lack of formal long-term care support are among the identified barriers to accessing timely diagnosis, care, and support in the country. Discussion and Implications Understanding the barriers and facilitators of access to diagnosis, treatment, and support for people with dementia and families with different demographic and socioeconomic characteristics is crucial for designing dementia policies that are context-specific and responsive to the care needs of different socioeconomic groups in Brazil

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAFV600 mutant melanoma. Reportedly, TERTprom, and BRAFV600 mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2-3.2; p = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1-3.3, p = 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade

Application of latent class analysis in assessing the awareness, attitude, practice and satisfaction of paediatricians on sleep disorder management in children in Italy.

AIM: To identify subgroups regarding paediatricians' awareness, attitude, practice and satisfaction about management of Sleep-Disordered Breathing (SDB) in Italy using Latent Class Analysis (LCA). METHODS: A cross-sectional study was conducted on a large sample of Italian paediatricians. Using a self-administered questionnaire, the study collected information on 420 Paediatric Hospital Paediatricians (PHPs) and 594 Family Care Paediatricians (FCPs). LCA was used to discover underlying response patterns, thus allowing identification of respondent groups with similar awareness, attitude, practice and satisfaction. A logistic regression model was used to investigate which independent variables influenced latent class membership. Analyses were performed using R 3.5.2 software. A p-value<0.05 was considered statistically significant. RESULTS: Two classes were identified: Class 1 (n = 368, 36.29%) "Untrained and poorly satisfied" and Class 2 (n = 646, 63.71%) "Trained and satisfied." Involving paediatric pneumologists or otorhinolaryngologists in clinical practice was associated with an increased probability of Class 2 membership (OR = 5.88, 95%CI [2.94-13.19]; OR = 15.95, 95% CI [10.92-23.81] respectively). Examining more than 20 children with SDB during the last month decreased the probability of Class 2 membership (OR = 0.29, 95% CI [0.14-0.61]). FCPs showed a higher probability of Class 2 membership than PHPs (OR = 4.64, 95% CI [3.31-6.55]). CONCLUSIONS: These findings suggest that the LCA approach can provide important information on how education and training could be tailored for different subgroups of paediatricians. In Italy standardized educational interventions improving paediatricians' screening of SDB are needed in order to guarantee efficient management of children with SDB and reduce the burden of disease

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor V\u3b39V\u3b42 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of V\u3b39V\u3b42 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and V\u3b39V\u3b42 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor \u3b1 (LXR\u3b1); Ras/ERK1/2/HIF-1\u3b1 axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and V\u3b39V\u3b42 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas

"Integrating China in the International Consortium for Personalized Medicine": The Coordination and Support Action to Foster Collaboration in Personalized Medicine Development between Europe and China

"Integrating China in the International Consortium for Personalized Medicine" (IC2PerMed) is a coordination and support action funded within the Horizon 2020 work program. Following the guidance of the International Consortium for Personalized Medicine (ICPerMed), the project's overarching aim is to align the European Union and China's research agendas in the field of personalized medicine (PM) to enable a swift development of PM approaches in the EU with strong leverage upon EU-Chinese collaboration. Living in the CO­VID-19 era, we are witnessing how the challenges imposed by the pandemic all around the globe have been acting as a catalyst for collaborations and knowledge sharing among national health systems worldwide. Given the strong interest on behalf of both Europe and China in the advancement of PM approaches, now more than ever, a cross-border collaboration between the 2 powers can accelerate the effective translation of such innovation to healthcare systems, advance research, and ensure that such change follows the directions toward the path of sustainability. IC2PerMed developments will be led by European and Chinese experts equally assembled into 3 Working Groups: (1) people and organization, (2) innovation and market, and (3) research and clinical studies in PM. This complex and dynamic network of actions thrives on dialog, cooperation, and alignment of research at national and global levels; work in the direction taken by IC2PerMed shall pave the way toward the realization of PM's full potential, prevent it from becoming a burden for healthcare systems, and, rather, prove that it provides an essential and irreplaceable contribution to their effectiveness, efficiency, and sustainability

Integrated analytical approach in veal calvesadministered the anabolic androgenic steroidsboldenone and boldione: urine and plasma kineticprofile and changes in plasma protein expression

Surveillance of illegal use of steroids hormones in cattle breeding is a key issue to preserve human health. To this purpose, an integrated approach has been developed for the analysis of plasma and urine from calves treated orally with a single dose of a combination of the androgenic steroids boldenone and boldione. A quantitative estimation of steroid hormones was obtained by LC-APCI-QMS/ MS analysis of plasma and urine samples obtained at various times up to 36 and 24 h after treatment, respectively. These experiments demonstrated that boldione was never found, while boldenone a- and b-epimers were detected in plasma and urine only within 2 and 24 h after drug administration, respectively. Parallel proteomic analysis of plasma samples was obtained by combined 2-DE,MALDI-TOF-MS and mLC-ESI-IT-MS/MS procedures. A specific protein, poorly represented in normal plasmasamples collected before treatment,was found upregulated even 36 h after hormone treatment.Extensivemassmapping experiments proved this component as an N-terminal truncated form of apolipoprotein A1 (ApoA1), a protein involved in cholesterol transport. The expression profile of ApoA1 analysed byWestern blot analysis confirmed a significant and time dependent increase of thisApoA1 fragment. Then, provided that further experiments performed with a growth-promoting schedule will confirm these preliminary findings, truncated ApoA1 may be proposed as a candidate biomarker for steroid boldenone and possibly other anabolic androgens misuse in cattle veal calves, when no traces of hormones are detectable in plasma or urine