Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.This work was supported by grants from the European Research Council (ERC-GA 695566, THERACAN); the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033) (grant RTC2017-6576-1), cofunded by ERDF “A way of making Europe”; the Autonomous Community of Madrid (B2017/BMD-3884 iLung-CM), cofunded by FSE and ERDF “A way of making Europe”; the CRIS Cancer Foundation, the Scientific Foundation of the Spanish Association Against Cancer (GC166173694BARB); an ERA PerMed grant, funded by the Instituto de Salud Carlos III (AC20/00114), the Scientific Foundation of the Spanish Association Against Cancer (PERME20707BARB) and the European Union’s Horizon 2020 program (779282) to MB; and the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (grant RTI2018-094664-B-I00), cofunded by ERDF “A way of making Europe” to MM and MB. Additional funding included grants from the Spanish National Research and Development Plan, Instituto de Salud Carlos III, ERDF “A way of making Europe” (PI20/01837 and DTS19/00111); the Scientific Foundation of the Spanish Association Against Cancer (LABAE20049RODR) to SRP; the Instituto de Salud Carlos III (PI19/00514), cofunded by ERDF “A way of making Europe” to CG; the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (grant PID2020-116705RB-I00); and the Scientific Foundation of the Spanish Association Against Cancer (LABAE211678DROS) to MD. MB is a recipient of an endowed chair from the AXA Research Fund. M Salmón was supported by a predoctoral contract “Severo Ochoa” (BES-2016-079096) from the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación. OB is a recipient of a fellowship from the Formación de Personal Investigador (FPI) program of the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación. FFG was supported by a Formación de Profesorado Universitario (FPU) fellowship from the Ministerio de Universidades

Importancia de la ciclooxygenasa-2 en el control de la función renal / Francisca Rodríguez Mulero ; Directores: F. Javier Salazar Aparicio, María Teresa Llinás Más.

Tesis - Universidad de Murcia.MEDICINA ESPINARDO. DEPOSITO. MU-Tesis 581.Consulte la tesis en: BCA. GENERAL. ARCHIVO UNIVERSITARIO. T.M.-1794

Innovación Educativa en la Asignatura de Fisiología en la Diplomatura y 1º del Grado de Enfermería. Póster

En el primer curso de la Diplomatura de Enfermería hay alrededor de 300 alumnos matriculados cada año y con ciertas peculiaridades, como son: una edad y una formación básica muy variable y, además, un alto porcentaje de ellos compaginan estos estudios con su trabajo. Por tanto, en este proyecto nos propusimos mejorar la adaptación de la asignatura Estructura y Función II (Fisiología), que es de carácter troncal y se imparte en el primer curso, a la metodología del ECTS. Para ello, se introdujeron nuevas metodologías de enseñanza – aprendizaje, como es el trabajo en grupo, el portafolios del alumno y el autoaprendizaje, teniendo como pilar base la plataforma de enseñanza virtual SUMA. A cada una de las metodologías se las dotó de las herramientas apropiadas de evaluación. Las principales conclusiones fueron: 1) Las nuevas metodologías de enseñanza demandan un mayor esfuerzo por parte del alumno y del profesor; 2) Se requiere de una coordinación muy estrecha entre todos los profesores para asegurar el éxito de su aplicación; 3) El mayor grado de esfuerzo se ha visto recompensado por una mejoría en las calificaciones del alumnado; 4) En general, los alumnos rechazan de inicio las nuevas metodologías porque tienen que invertir más tiempo en la materia; y 5) Las nuevas metodologías no parecen influir positiva o negativamente en poblaciones concretas de alumnos.Campus Mare Nostrum, Universidad Politécnica de Cartagena, Universidad de Murcia, Región de Murci

Intratumoral expression using a NFkB-based promoter enhances IL12 antitumor efficacy

Interleukin 12 is a promising anti-cancer agent; however, IL12 systemic administration is hampered by side-effects. Although intratumoral administration of IL12 is giving promising results in clinical trials, only a small percentage of patients show a complete therapeutic response. This outcome could be improved by controlling the IL12 expression window. In this work we have tested the efficacy of a self-processing P2A and codon optimized murine IL12 (mIL12Pop) using inflammation-regulated lentivectors in a syngeneic tumor model. Our results show that implantation of cells expressing mIL12Pop employing either the strong constitutive SFFV promoter or a NFkB-based promoter reduced tumor growth, caused CD8+ T cell activation and increased IFNγ production. Importantly, the use of NFkBp-mIL12Pop increased the number of CD8+ TILs and improved the remission rate without increasing IL12-serum concentration. Further experiments suggest that there is a threshold intratumoral IL12 concentration that must be reached to trigger an efficient antitumor response and a limit that once surpassed causes detrimental systemic side effects. Altogether, these results demonstrate that using NFKBp-mIL12Pop significantly increases the overall survival of the mice. In summary, this new inflammation-regulated expression system might be useful for the development of new IL12 delivery systems with improved anti-tumor activity and limited toxicity.AR is supported by the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2012-32166) and the Comunidad Autonoma de Madrid, Spain (S2010/BMD-2312). FM is supported by the Comunidad Autonoma de Madrid, Spain (S2017/BMD-3867) and co-financed by European Structural and Investment Funds. AA and JMZ are supported by the Instituto de Salud Carlos III, Spain (PI15/01491 and PI16/00895, respectively). H.A. holds a research fellowship from Spanish Ministry of Education, Culture and Sports (MECD).Peer reviewe

Role of Activator Protein-1 Complex on the Phenotype of Human Osteosarcomas Generated from Mesenchymal Stem Cells

Osteosarcoma (OS) is a highly aggressive bone tumor that usually arises intramedullary at the extremities of long bones. Due to the fact that the peak of incidence is in the growth spurt of adolescence, the specific anatomical location, and the heterogeneity of cells, it is believed that osteosarcomagenesis is a process associated with bone development. Different studies in murine models showed that the tumor-initiating cell in OS could be an uncommitted mesenchymal stem cell (MSC) developing in a specific bone microenvironment. However, only a few studies have reported transgene-induced human MSCs transformation and mostly obtained undifferentiated sarcomas. In our study, we demonstrate that activator protein 1 family members induce osteosarcomagenesis in immortalized hMSC. c-JUN or c-JUN/c-FOS overexpression act as tumorigenic factors generating OS with fibroblastic or pleomorphic osteoblastic phenotypes, respectively. Stem Cells 2018;36:1487-1500.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS: PI11/00377 [to J.G.-C.]; and RTICC: RD12/0036/0027 [to J.G.-C.], RD12/0036/0020 [to S.N.]; Consorcio CIBERONC CB16/12/00390 [to R.R.] and CB16/12/00484 [to S.N.]; Miguel Servet II Program CPII16/00049 [to R.R.]; and Sara Borrell CD16/13/00103 [to S.T.M.] and CD11/00132 [to A.A.]); The Juan de la Cierva program JCI2010-06123 [to A.A]); the Agencia Estatal de Investigación (AEI) (MINECO/Fondo Europeo de Desarrollo Regional [FEDER]: SAF2016-75286-R [to R.R.]); and the Madrid Regional Government (CellCAM; P2010/BMD-2420 [to J.G.-C.]) in Spain.S

Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1

International audienceChronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the emergence of HSPC, it was intrinsically required for their myeloid differentiation. In addition, Gata1 transcript and protein amounts increased in inflammasome-deficient larvae, enforcing erythropoiesis and inhibiting myelopoiesis. This mechanism is evolutionarily conserved, since pharmacological inhibition of the inflammasome altered erythroid differentiation of human erythroleukemic K562 cells. In addition, caspase-1 inhibition rapidly upregulated GATA1 protein in mouse HSPC promoting their erythroid differentiation. Importantly, pharmacological inhibition of the inflammasome rescued zebrafish disease models of neutrophilic inflammation and anemia. These results indicate that the inflammasome plays a major role in the pathogenesis of neutrophilia and anemia of chronic diseases and reveal druggable targets for therapeutic interventions

Switching TNF antagonists in patients with chronic arthritis: An observational study of 488 patients over a four-year period

The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34-0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97-2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13-4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications. © 2006 Gomez-Reino and Loreto Carmona; licensee BioMed Central Ltd