DSpace Collection:https://hdl.handle.net/10171/194332024-03-29T11:01:53Z2024-03-29T11:01:53ZOncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine gliomahttps://hdl.handle.net/10171/686882024-02-05T06:06:00Z2022-01-01T00:00:00ZTitle: Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma
Abstract: Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking.
Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses.
Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire.
Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).2022-01-01T00:00:00ZSignature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancerhttps://hdl.handle.net/10171/680952023-12-25T06:04:33Z2023-01-01T00:00:00ZTitle: Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
Abstract: Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.2023-01-01T00:00:00ZAn engineered periosteum for efficient delivery of rhBMP-2 and mesenchymal progenitor cells during bone regenerationhttps://hdl.handle.net/10171/678572024-01-24T09:36:39Z2023-01-01T00:00:00ZTitle: An engineered periosteum for efficient delivery of rhBMP-2 and mesenchymal progenitor cells during bone regeneration
Abstract: During bone regeneration, the periosteum acts as a carrier for key regenerative cues, delivering osteochondroprogenitor cells and crucial growth factors to the injured bone. We developed a biocompatible, 3D polycaprolactone (PCL) melt electro-written membrane to act as a mimetic periosteum. Poly (ethyl acrylate) coating of the PCL membrane allowed functionalization, mediated by fibronectin and low dose recombinant human BMP-2 (rhBMP-2) (10-25 mu g/ml), resulting in efficient, sustained osteoinduction in vitro. In vivo, rhBMP-2 functionalized mimetic periosteum demonstrated regenerative potential in the treatment of rat critical-size femoral defects with highly efficient healing and functional recovery (80%-93%). Mimetic periosteum has also proven to be efficient for cell delivery, as observed through the migration of transplanted periosteum-derived mesenchymal cells to the bone defect and their survival. Ultimately, mimetic periosteum demonstrated its ability to deliver key stem cells and morphogens to an injured site, exposing a therapeutic and translational potential in vivo when combined with unprecedentedly low rhBMP-2 doses.2023-01-01T00:00:00ZSex-specific associations between gut prevotellaceae and host genetics on adiposityhttps://hdl.handle.net/10171/678502023-11-20T06:05:04Z2020-01-01T00:00:00ZTitle: Sex-specific associations between gut prevotellaceae and host genetics on adiposity
Abstract: The gut microbiome has been recognized as a tool for understanding adiposity
accumulation and for providing personalized nutrition advice for the management of obesity
and accompanying metabolic complications. The genetic background is also involved in human
energy homeostasis. In order to increase the value of nutrigenetic dietary advice, the interplay
between genetics and microbiota must be investigated. The purpose of the present study was to
evaluate interactive associations between gut microbiota composition and 95 obesity-related single
nucleotide polymorphisms (SNPs) searched in the literature. Oral mucosa and fecal samples from 360
normal weight, overweight and obese subjects were collected. Next generation genotyping of these
95 SNPs and fecal 16S rRNA sequencing were performed. A genetic risk score (GRS) was constructed
with 10 SNPs statistically or marginally associated with body mass index (BMI). Several microbiome
statistical analyses at family taxonomic level were applied (LEfSe, Canonical Correspondence Analysis,
MetagenomeSeq and Random Forest), and Prevotellaceae family was found in all of them as one
of the most important bacterial families associated with BMI and GRS. Thus, in this family it was
further analyzed the interactive association between BMI and GRS with linear regression models.
Interestingly, women with higher abundance of Prevotellaceae and higher GRS were more obese,
compared to women with higher GRS and lower abundance of Prevotellaceae. These findings suggest
relevant interrelationships between Prevotellaceae and the genetic background that may determine
interindividual BMI differences in women, which opens the way to new precision nutrition-based
treatments for obesity2020-01-01T00:00:00Z