Eficacia y seguridad de la combinación del sorafenib y la pravastatina como nueva terapia para el tratamiento del carcinoma hepatocelular avanzado: ensayo clínico fase II multicéntrico aleatorizado.

186 p.El carcinoma hepatocelular (CHC) es un cáncer altamente letal con una tasa de supervivencia a 5 años de aproximadamente 5%. Estudios previos han investigado la relación existente entre las estatinas y su potencial antitumoral. Además de su efecto sobre la biosíntesis del colesterol, las estatinas también tienen propiedades antineoplásicas a través de efectos anti-proliferativos, pro-apoptóticos, anti-angiogénicos, inmuno-moduladores y anti-infecciosos.Planteamos la hipótesis de que la pravastatina en combinación con sorafenib podría aumentar la supervivencia y el periodo libre de progresión en pacientes con CHC avanzado, siendo además un tratamiento seguro y bien tolerado.Se realizó un ensayo clínico fase II aleatorizado doble ciego mediante el cual se seleccionaron pacientes con CHC avanzado, que tras aleatorización recibieron placebo+sorafenib o pravastatina+sorafenib.La pravastatina asociada a sorafenib prolongó significativamente el tiempo hasta progresión, y no mejoró la supervivencia global respecto al tratamiento estándar. Factores etiológicos, estadio Child-Pugh, invasión vascular y trombosis venosa portal fueron confirmados como marcadores pronóstico basales. La toxicidad dermatológica se confirmó como marcador pronóstico de respuesta al tratamiento. La terapia combinada fue un tratamiento seguro y bien tolerado.Conclusión: el tratamiento combinado pravastatina+sorafenib es seguro y podría aportar cierto beneficio terapéutico a los pacientes.BioDonostia Osakidetz

Eficacia y seguridad de la combinación del sorafenib y la pravastatina como nueva terapia para el tratamiento del carcinoma hepatocelular avanzado: ensayo clínico fase II multicéntrico aleatorizado.

186 p.El carcinoma hepatocelular (CHC) es un cáncer altamente letal con una tasa de supervivencia a 5 años de aproximadamente 5%. Estudios previos han investigado la relación existente entre las estatinas y su potencial antitumoral. Además de su efecto sobre la biosíntesis del colesterol, las estatinas también tienen propiedades antineoplásicas a través de efectos anti-proliferativos, pro-apoptóticos, anti-angiogénicos, inmuno-moduladores y anti-infecciosos.Planteamos la hipótesis de que la pravastatina en combinación con sorafenib podría aumentar la supervivencia y el periodo libre de progresión en pacientes con CHC avanzado, siendo además un tratamiento seguro y bien tolerado.Se realizó un ensayo clínico fase II aleatorizado doble ciego mediante el cual se seleccionaron pacientes con CHC avanzado, que tras aleatorización recibieron placebo+sorafenib o pravastatina+sorafenib.La pravastatina asociada a sorafenib prolongó significativamente el tiempo hasta progresión, y no mejoró la supervivencia global respecto al tratamiento estándar. Factores etiológicos, estadio Child-Pugh, invasión vascular y trombosis venosa portal fueron confirmados como marcadores pronóstico basales. La toxicidad dermatológica se confirmó como marcador pronóstico de respuesta al tratamiento. La terapia combinada fue un tratamiento seguro y bien tolerado.Conclusión: el tratamiento combinado pravastatina+sorafenib es seguro y podría aportar cierto beneficio terapéutico a los pacientes.BioDonostia Osakidetz

TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms

[EN] Objective Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis. Design TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2-/- mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted. Results TREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2-/- mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2-/- animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2-/- livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion. Conclusion TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.Spanish Ministry of Economy and Competitiveness and ’Instituto de Salud Carlos III’ grants (MJP (PI14/00399, PI17/00022 and Ramon y Cajal Programme RYC-2015–17755); JMB (PI12/00380, PI15/01132, PI18/01075, Miguel Servet Programme CON14/00129 and CPII19/00008) cofinanced by ’Fondo Europeo de Desarrollo Regional’ (FEDER); CIBERehd: MJP, JMB and LB), Spain; IKERBASQUE, Basque foundation for Science (MJP and JMB), Spain; ’Diputación Foral de Gipuzkoa’ (MJP: DFG18/114, DFG19/081; JMB: DFG15/010, DFG16/004); BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/ BD to JMB); Department of Health of the Basque Country (MJP: 2015111100 and 2019111024; JMB: 2017111010), Euskadi RIS3 (JMB: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010) Department of Industry of the Basque Country (JMB: Elkartek: KK-2020/00008) and AECC Scientific Foundation (JMB). AE-B was funded by the University of the Basque Country (UPV/EHU) (PIF2014/11) and by the short-term training fellowship Andrew K Burroughs (European Association for the Study of the Liver, EASL). IL and AA-L were funded by the Department of Education, Language Policy and Culture of the Basque Government (PRE_2016_1_0152 and PRE_2018_1_0184). OS and SK were funded by the Austrian Science Fund (FWF25801-B22, FWF-P35168 to OS and L-Mac: F 6104-B21 to SK). FO and DAM were funded by a UK Medical Research Council programme Grant MR/R023026/1. DAM was also funded by the CRUK programme grant C18342/A23390, CRUK/AECC/AIRC Accelerator Award A26813 and the MRC MICA programme grant MR/R023026/1. JBA is supported by the Danish Medical Research Council, Danish Cancer Society, Nordisk Foundation, and APM Foundation. CJO’R and PM-G are supported by Marie Sklodowska-Curie Programme and EASL Sheila Sherlock postdoctoral fellowships

Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens. Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed. Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG (p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG (p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported. Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose.This work is partially funded by Institute of Health Carlos III (Instituto de Salud Carlos III − ISCIII −), (grants PI19CIII/00004 −JA- and PI21CIII/00025 −MPO, JG-), and COVID-19 FUND (grants COV20/00679 −MPO- and COV20/00072 −JA-) and CIBERINFEC, co-financed by the European Regional Development Fund (FEDER) “A way to make Europe”. Instituto de Salud Carlos III is a Spanish public body assigned to the Ministry of Science and Innovation that manages and promotes public clinical research related to public health. The authors thank Esther Prieto, MD (cited with consent) for editorial assistance and writing support (funded by the Research Foundation of HCSC).S

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers.This research was funded by Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129; M.J. Perugorria: PI14/00399, PI17/00022; J.J.G. Marin: FIS PI16/00598 and PI19/00819; P.M. Rodrigues: Sara Borrell CD19/00254] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); CIBERehd (ISCIII): J.M. Banales, M.J. Perugorria, L. Bujanda and J.J.G. Marin; Spanish Ministry of Economy and Competitiveness (M.J. Perugorria: Ramon y Cajal Programme RYC-2015-17755); AMMF (J.M. Banales and P.M. Rodrigues 2019/202); PSC Partners US (J.M. Banales); PSC Supports UK (J.M. Banales: 06119JB); Horizon 2020 (J.M. Banales: H2020 ESCALON project: H2020-SC1-BHC-2018-2020); IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; “Junta de Castilla y Leon” (J.J.G. Marin: SA06P17); “Diputación Foral Gipuzkoa” (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (L. Bujanda: 2013111173; J.M. Banales: 2017111010) and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, 2018222029; 2019222054). La Caixa Scientific Foundation (J.M. Banales: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin). “Centro Internacional sobre el Envejecimiento”, Spain (R.I.R. Macias: OLD-HEPAMARKER, 0348-CIE-6-E). A. Lapitz and A Santos-Laso were funded by the Basque Government (PRE_2018_2_0195 and PRE_2015_1_0126, respectively). J.B. Andersen is supported by the Danish Medical Research Council, Danish Cancer Society, Novo Nordisk Foundation, and A.P. Møller Foundation. C.J. O’Rourke is supported by Marie Skłodowska -Curie Program

In COVID-19 Health Messaging, Loss Framing Increases Anxiety with Little-to-No Concomitant Benefits: Experimental Evidence from 84 Countries.

The COVID-19 pandemic (and its aftermath) highlights a critical need to communicate health information effectively to the global public. Given that subtle differences in information framing can have meaningful effects on behavior, behavioral science research highlights a pressing question: Is it more effective to frame COVID-19 health messages in terms of potential losses (e.g., "If you do not practice these steps, you can endanger yourself and others") or potential gains (e.g., "If you practice these steps, you can protect yourself and others")? Collecting data in 48 languages from 15,929 participants in 84 countries, we experimentally tested the effects of message framing on COVID-19-related judgments, intentions, and feelings. Loss- (vs. gain-) framed messages increased self-reported anxiety among participants cross-nationally with little-to-no impact on policy attitudes, behavioral intentions, or information seeking relevant to pandemic risks. These results were consistent across 84 countries, three variations of the message framing wording, and 560 data processing and analytic choices. Thus, results provide an empirical answer to a global communication question and highlight the emotional toll of loss-framed messages. Critically, this work demonstrates the importance of considering unintended affective consequences when evaluating nudge-style interventions

In COVID-19 health messaging, loss framing increases anxiety with little-to-no concomitant benefits: Experimental evidence from 84 countries

The COVID-19 pandemic (and its aftermath) highlights a critical need to communicate health information effectively to the global public. Given that subtle differences in information framing can have meaningful effects on behavior, behavioral science research highlights a pressing question: Is it more effective to frame COVID-19 health messages in terms of potential losses (e.g., "If you do not practice these steps, you can endanger yourself and others") or potential gains (e.g., "If you practice these steps, you can protect yourself and others")? Collecting data in 48 languages from 15,929 participants in 84 countries, we experimentally tested the effects of message framing on COVID-19-related judgments, intentions, and feelings. Loss- (vs. gain-) framed messages increased self-reported anxiety among participants cross-nationally with little-to-no impact on policy attitudes, behavioral intentions, or information seeking relevant to pandemic risks. These results were consistent across 84 countries, three variations of the message framing wording, and 560 data processing and analytic choices. Thus, results provide an empirical answer to a global communication question and highlight the emotional toll of loss-framed messages. Critically, this work demonstrates the importance of considering unintended affective consequences when evaluating nudge-style interventions

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges