ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational ...studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation.
The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted.
ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months.
ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.
Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is ...expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confi rm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specifi c AC inhibitors could act by counteracting critical growth properties of these highly aggressive tumor cells.
Background & Aims: Nonalcoholic steatohepatitis (NASH), a leading cause of cirrhosis, strongly associates with the metabolic syndrome, an insulin-resistant proinflammatory state that disrupts energy ...balance and promotes progressive liver degeneration. We aimed to define the role of Smoothened (Smo), an obligatory component of the Hedgehog signaling pathway, in controlling hepatocyte metabolic homeostasis and, thereby, susceptibility to NASH. Methods: We conditionally deleted Smo in hepatocytes of healthy chow-fed mice and performed metabolic phenotyping, coupled with single-cell RNA sequencing (RNA-seq), to characterize the role of hepatocyte Smo in regulating basal hepatic and systemic metabolic homeostasis. Liver RNA-seq datasets from 2 large human cohorts were also analyzed to define the relationship between Smo and NASH susceptibility in people. Results: Hepatocyte Smo deletion inhibited the Hedgehog pathway and promoted fatty liver, hyperinsulinemia, and insulin resistance. We identified a plausible mechanism whereby inactivation of Smo stimulated the mTORC1-SREBP1c signaling axis, which promoted lipogenesis while inhibiting the hepatic insulin cascade. Transcriptomics of bulk and single Smo-deficient hepatocytes supported suppression of insulin signaling and also revealed molecular abnormalities associated with oxidative stress and mitochondrial dysfunction. Analysis of human bulk RNA-seq data revealed that Smo expression was (1) highest in healthy livers, (2) lower in livers with NASH than in those with simple steatosis, (3) negatively correlated with markers of insulin resistance and liver injury, and (4) declined progressively as fibrosis severity worsened. Conclusions: The Hedgehog pathway controls insulin sensitivity and energy homeostasis in adult livers. Loss of hepatocyte Hedgehog activity induces hepatic and systemic metabolic stress and enhances susceptibility to NASH by promoting hepatic lipoxicity and insulin resistance.
Nonalcoholic steatohepatitis (NASH), a leading cause of cirrhosis, strongly associates with the metabolic syndrome, an insulin-resistant proinflammatory state that disrupts energy balance and ...promotes progressive liver degeneration. We aimed to define the role of Smoothened (Smo), an obligatory component of the Hedgehog signaling pathway, in controlling hepatocyte metabolic homeostasis and, thereby, susceptibility to NASH.
We conditionally deleted Smo in hepatocytes of healthy chow-fed mice and performed metabolic phenotyping, coupled with single-cell RNA sequencing (RNA-seq), to characterize the role of hepatocyte Smo in regulating basal hepatic and systemic metabolic homeostasis. Liver RNA-seq datasets from 2 large human cohorts were also analyzed to define the relationship between Smo and NASH susceptibility in people.
Hepatocyte Smo deletion inhibited the Hedgehog pathway and promoted fatty liver, hyperinsulinemia, and insulin resistance. We identified a plausible mechanism whereby inactivation of Smo stimulated the mTORC1-SREBP1c signaling axis, which promoted lipogenesis while inhibiting the hepatic insulin cascade. Transcriptomics of bulk and single Smo-deficient hepatocytes supported suppression of insulin signaling and also revealed molecular abnormalities associated with oxidative stress and mitochondrial dysfunction. Analysis of human bulk RNA-seq data revealed that Smo expression was (1) highest in healthy livers, (2) lower in livers with NASH than in those with simple steatosis, (3) negatively correlated with markers of insulin resistance and liver injury, and (4) declined progressively as fibrosis severity worsened.
The Hedgehog pathway controls insulin sensitivity and energy homeostasis in adult livers. Loss of hepatocyte Hedgehog activity induces hepatic and systemic metabolic stress and enhances susceptibility to NASH by promoting hepatic lipoxicity and insulin resistance.
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Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. ...Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.
To asses if telemedicine with telemonitoring is a clinically useful and safe tool for monitoring patients with COVID-19.
A prospective observational study of patients with COVID-19 diagnosed via a ...positive PCR test who were considered high-risk and who were monitored with telemedicine and telemonitoring in the Lugo Healthcare Area between March 17th and April 17th, 2020, was conducted. Two groups of patients were included: those in outpatient monitoring from the beginning and those in outpatient monitoring following hospital discharge. Every patient completed a clinical questionnaire with his or her temperature once per day and oxygen saturation levels three times per day. Proactive monitoring was done by getting in touch with every patient at least once a day.
A total of 313 patients (52.4% female) with a mean age of 60.9 (SD 15.9) years were included. Two patients refused to participate in the program. Finally, 224 were monitored from the beginning and 89 patients were monitored after discharged. In the first group, 38 (16.90%) were referred to the Emergency department on 43 occasions; 18 (8.03%) were hospitalized, and two died. There were no deaths or lifethreatening at home. Including the patients monitored after hospitalization, monitoring was performed in 304 cases. One patient was readmited (0.32%) and another left the program (0.32%). The mean time of monitoring was 11.64 (SD 3.58) days and 224 (73.68%) patients were discharged during the 30 days the study lasted.
Our data suggest that telemedicine with at-home telemonitoring, when used proactively, allows for clinically useful and safe monitoring of high-risk patients with COVID-19.
Evaluar si la telemedicina con telemonitorización es una herramienta clínicamente útil y segura para el seguimiento de pacientes con COVID-19.
Estudio observacional prospectivo de los pacientes con diagnóstico de COVID-19 por PCR positiva y considerados de alto riesgo que se siguieron con telemedicina y telemonitorización en el Área Sanitaria de Lugo entre el 17 de marzo y el 17 de abril del 2020. Se incluyeron 2 grupos de pacientes: seguimiento ambulatorio desde el inicio y tras el alta hospitalaria. Cada paciente remitió un cuestionario clínico al día con su temperatura y saturación de oxígeno 3 veces al día. El seguimiento fue proactivo, contactando con todos los pacientes al menos una vez al día.
Se incluyó a 313 pacientes (52,4% mujeres) con edad media 60,9 (DE 15,9) años. Otros 2 pacientes rehusaron entrar en el programa. Desde el inicio, se siguió ambulatoriamente a 224 pacientes y a 89 pacientes tras su alta hospitalaria. Entre los primeros, 38 (16,90%) se remitieron a Urgencias en 43 ocasiones con 18 (8,03%) ingresos y 2 fallecidos. En los domicilios no hubo fallecimientos ni urgencias vitales. Incluyendo a los pacientes tras hospitalización, el seguimiento se realizó en 304 casos. Un paciente reingresó (0,32%) y otro abandonó (0,32%). El tiempo medio de seguimiento fue 11,64 (DE 3,58) días y en los 30 días del estudio 224 (73,68%) pacientes fueron dados de alta.
Nuestros datos sugieren que la telemedicina con telemonitorización domiciliaria, utilizada de forma proactiva, permite un seguimiento clínicamente útil y seguro en pacientes con COVID-19 de alto riesgo.
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