Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma.

Background: Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory.

Methods: We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma.

The Relationship between Serum TWEAK Levels and Carotid Intima-media Thickness in Patients with Fabry Disease.

Fabry disease (FD) is associated with inflammation, proteinuria, and chronic kidney disease. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) plays an important role in inflammation in diabetic nephropathy and lupus nephritis. Since there is a close relationship linking serum TWEAK (sTWEAK), inflammation, and carotid intima-media thickness (CIMT) in various kidney diseases, we aimed to determine the relationship between sTWEAK levels and CIMT in subjects with and without proteinuria in a cross-sectional study involving 15 FD patients (seven females, eight males) and seven healthy controls (four females, three males).

Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma.

Background: As the variable clinical outcome of patients with hepatoblastoma (HB) cannot be explained by genetics alone, the identification of drugs with the potential to effectively reverse epigenetic alterations is a promising approach to overcome poor therapy response. The gene ubiquitin like with PHD and ring finger domains 1 (UHRF1) represents an encouraging epigenetic target due to its regulatory function in both DNA methylation and histone modifications and its clinical relevance in HB.

Methods: Patient-derived xenograft in vitro and in vivo models were used to study drug response.

Establishing a three-dimensional scaffold model of hepatoblastoma.

Emerging technologies such as three-dimensional (3D) cell culture and the generation of biological matrices offer exciting new possibilities in disease modelling and tumour therapy. The paucity of laboratory models for hepatoblastoma (HB), the most prevalent malignant liver tumour in children, has hampered the identification of new treatment options for HB patients. We aimed to establish a reliable 3D testing platform using liver-derived scaffolds and HB cell lines that reflect the heterogeneous biology of the disease so as to allow reproducible preclinical research and drug testing.

Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response.

Background And Aims: Hepatoblastoma (HB) is the predominant form of pediatric liver cancer, though it remains exceptionally rare. While treatment outcomes for children with HB have improved, patients with advanced tumors face limited therapeutic choices. Additionally, survivors often suffer from long-term adverse effects due to treatment, including ototoxicity, cardiotoxicity, delayed growth, and secondary tumors.

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma.

Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner.

Reliability and Validity of a New Computer-Based Triage Decision Support Tool: ANKUTRIAGE.

Objective: Triage is a tool used to determine patients' severity of illness or injury within minutes of arrival. This study aims to assess the reliability and validity of a new computer-based triage decision support tool, ANKUTRIAGE, prospectively.

Methods: ANKUTRIAGE, a 5-level triage tool was established considering 2 major factors, patient's vital signs and characteristics of the admission complaint.

Privacy-preserving -NN interpolation over two encrypted databases.

Cloud computing enables users to outsource their databases and the computing functionalities to a cloud service provider to avoid the cost of maintaining a private storage and computational requirements. It also provides universal access to data, applications, and services without location dependency. While cloud computing provides many benefits, it possesses a number of security and privacy concerns.

Evaluation of the Validity and Reliability of ANKUTRIAGE, a New Decision Support System in Pediatric Emergency Triage.

Background: The intensity of emergency services is an increasing health problem all over the world, necessitating an effective triage system. The aim of this study was to evaluate the validity and reliability of the "ANKUTRIAGE" in children.

Methods: This prospective, longitudinal study was carried out at a pediatric emergency department.

The Neurokinin-1 Receptor Is a Target in Pediatric Rhabdoid Tumors.

Rhabdoid tumors (RT) are among the most aggressive tumors in early childhood. Overall survival remains poor, and treatment only effectively occurs at the cost of high toxicity and late adverse effects. It has been reported that the neurokinin-1 receptor/ substance P complex plays an important role in cancer and proved to be a promising target.

Restless Leg Syndrome and Sleep Disorders in Patients with Rheumatoid Arthritis and Its Relation with Anemia Parameters.

Objectives: We aimed to investigate the prevalence of restless legs syndrome (RLS) and sleep disorders in patients with rheumatoid arthritis (RA), and the association of iron deficiency with them.

Materials And Methods: The study included 72 patients with RA (59 females, 13 males), and 50 healthy control subjects (57 females, 15 males). Assessments were made using the International RLS Rating Scale, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Fatigue Severity Scale (FSS), Beck anxiety and depression index and the SF-36 quality of life scores.

MicroRNA-497/195 is tumor suppressive and cooperates with CDKN2A/B in pediatric acute lymphoblastic leukemia.

We previously identified an association of rapid engraftment of patient-derived leukemia cells transplanted into NOD/SCID mice with early relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In a search for the cellular and molecular profiles associated with this phenotype, we investigated the expression of microRNAs (miRNAs) in different engraftment phenotypes and patient outcomes. We found high expression of miR-497 and miR-195 (hereafter miR-497/195) in patient-derived xenograft samples with slow engraftment derived from patients with favorable outcome.

Bag-1 stimulates Bad phosphorylation through activation of Akt and Raf kinases to mediate cell survival in breast cancer.

Background: Bag-1 (Bcl-2-associated athanogene) is a multifunctional anti-apoptotic protein frequently overexpressed in cancer. Bag-1 interacts with a variety of cellular targets including Hsp70/Hsc70 chaperones, Bcl-2, nuclear hormone receptors, Akt and Raf kinases. In this study, we investigated in detail the effects of Bag-1 on major cell survival pathways associated with breast cancer.

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions.

Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling.

Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients.

Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia.

Alterations of the tumor suppressor gene are found in different cancers, in particular in carcinomas of adults. In pediatric acute lymphoblastic leukemia (ALL), mutations are infrequent but enriched at relapse. As in most cancers, mainly DNA-binding domain missense mutations are found, resulting in accumulation of mutant p53, poor therapy response, and inferior outcome.

Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia.

The FOXO1 transcription factor plays an essential role in the regulation of proliferation and survival programs at early stages of B-cell differentiation. Here, we show that tightly regulated FOXO1 activity is essential for maintenance of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Genetic and pharmacological inactivation of FOXO1 in BCP-ALL cell lines produced a strong antileukemic effect associated with CCND3 downregulation.

Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor.

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms.

Bag-1 promotes cell survival through c-Myc-mediated ODC upregulation that is not preferred under apoptotic stimuli in MCF-7 cells.

Bag-1, Bcl-2 associated athanogene-1, is a multifunctional protein that can regulate a wide variety of cellular processes: proliferation, cell survival, transcription, apoptosis and motility. Bag-1 interacts with various targets in the modulation of these pathways; yet molecular details of Bag-1's involvement in each cellular event are still unclear. We first showed that forced Bag-1 expression promotes cell survival and prevents drug-induced apoptosis in MCF-7 breast cancer cells.