The selective delivery of therapeutic and imaging agents to tumoral cells has been postulated as one of the most important challenges in the nanomedicine field. Meta‐iodobenzilguanidine (MIBG) is ...widely used for the diagnosis of neuroblastoma (NB) due to its strong affinity for the norepinephrine transporter (NET), usually overexpressed on the membrane of malignant cells. Herein, a family of novel Y‐shaped scaffolds has been synthesized, which have structural analogues of MIBG covalently attached at each end of the Y‐structure. The cellular uptake capacity of these double‐targeting ligands has been evaluated in vitro and in vivo, yielding one specific Y‐shaped structure that is able to be engulfed by the malignant cells, and accumulates in the tumoral tissue, at significantly higher levels than the structure containing only one single targeting agent. This Y‐shaped ligand can provide a powerful tool for the current treatment and diagnosis of this disease.
Double trouble: Novel Y‐shaped scaffolds have been synthesized, with meta‐iodobenzilguanidine analogues covalently attached at each end of the Y‐structure, to deliver diagnostic and therapeutic agents to neuroblastoma cells. These double‐targeting agents have a strong affinity for the norepinephrine transporter, usually overexpressed on the neuroblastoma cell membrane, and accumulate in cells at a higher level than single‐targeting agents.
T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that comprises the accumulation of malignant T-cells. Despite current therapies, failure to conventional treatments ...and relapse are frequent in children with T-ALL. It is known that the chemokine CXCL12 modulates leukemia survival and dissemination; however, our understanding of molecular mechanisms used by T-ALL cells to infiltrate and respond to leukemia cells-microenvironment interactions is still vague. In the present study, we showed that CXCL12 promoted H3K9 methylation in cell lines and primary T-ALL cells within minutes. We thus identified that CXCL12-mediated H3K9 methylation affected the global chromatin configuration and the nuclear mechanics of T-ALL cells. Importantly, we characterized changes in the genomic profile of T-ALL cells associated with rapid CXCL12 stimulation. We showed that blocking CXCR4 and protein kinase C (PKC) impaired the H3K9 methylation induced by CXCL12 in T-ALL cells. Finally, blocking H3K9 methyltransferases reduced the efficiency of T-ALL cells to deform their nuclei, migrate across confined spaces, and home to spleen and bone marrow in vivo models. Together, our data show novel functions for CXL12 as a master regulator of nuclear deformability and epigenetic changes in T-ALL cells, and its potential as a promising pharmacological target against T-ALL dissemination.
Aim
The immune status of children recovering from SARS‐CoV‐2 infection is not completely understood. We describe IgG antispike persistence in children infected during the first two pandemic waves. In ...addition, we compared with healthy controls their leukocyte populations and CD64 expression.
Methods
Cross‐sectional study. Carried out from October 2021 to February 2022 in nonreinfected and nonvaccinated children with SARS‐CoV‐2 in 2020. The presence of antispike IgG was studied using chemiluminescent immunoassay. Leukocyte populations were analysed using flow cytometry and marked for CD45, CD4, CD8 and CD64. Statistical minor than 0.05 was considered significant.
Results
One hundred and eighty‐three control and 77 patients were included. IgG antispike determinations were performed after a median of 501 days (262–464); 52 of 77 children were positive. Cases showed significantly higher percentages of monocytes, lymphocytes, CD8+ and CD4+. In addition, CD64 expression was higher in monocytes and neutrophils. The presence of IgG antispike was accompanied by a higher percentage of CD64+ neutrophils.
Conclusion
In our series, the SARS‐CoV‐2 IgG antispike protein was usually positive beyond 1 year after infection. Furthermore, leukocyte populations from cases differ from controls, with higher CD64 expression on neutrophils and monocytes. Prospective clinical observations are required to confirm the implications of these findings.
We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous ...mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5–1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2–5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.
Ramírez and colleagues report here the first clinical trial of oncolytic virotherapy systemically delivered in autologous mesenchymal cells in pediatric and adult patients with advanced tumors. The results show that the infusion of repeated doses is a safe strategy and warrants further evaluation in a phase 2 setting.
Key points
Although they are unable to utilize muscle glycogen, McArdle mice adapt favourably to an individualized moderate‐intensity endurance exercise training regime. Yet, they fail to reach the ...performance capacity of healthy mice with normal glycogen availability.
There is a remarkable difference in the protein networks involved in muscle tissue adaptations to endurance exercise training in mice with and without glycogen availability.
Indeed, endurance exercise training promoted the expression of only three proteins common to both McArdle and wild‐type mice: LIMCH1, PARP1 and TIGD4.
In turn, trained McArdle mice presented strong expression of mitogen‐activated protein kinase 12 (MAPK12).
McArdle's disease is an inborn disorder of skeletal muscle glycogen metabolism that results in blockade of glycogen breakdown due to mutations in the myophosphorylase gene. We recently developed a mouse model carrying the homozygous p.R50X common human mutation (McArdle mouse), facilitating the study of how glycogen availability affects muscle molecular adaptations to endurance exercise training. Using quantitative differential analysis by liquid chromatography with tandem mass spectrometry, we analysed the quadriceps muscle proteome of 16‐week‐old McArdle (n = 5) and wild‐type (WT) (n = 4) mice previously subjected to 8 weeks’ moderate‐intensity treadmill training or to an equivalent control (no training) period. Protein networks enriched within the differentially expressed proteins with training in WT and McArdle mice were assessed by hypergeometric enrichment analysis. Whereas endurance exercise training improved the estimated maximal aerobic capacity of both WT and McArdle mice as compared with controls, it was ∼50% lower than normal in McArdle mice before and after training. We found a remarkable difference in the protein networks involved in muscle tissue adaptations induced by endurance exercise training with and without glycogen availability, and training induced the expression of only three proteins common to McArdle and WT mice: LIM and calponin homology domains‐containing protein 1 (LIMCH1), poly (ADP‐ribose) polymerase 1 (PARP1 – although the training effect was more marked in McArdle mice), and tigger transposable element derived 4 (TIGD4). Trained McArdle mice presented strong expression of mitogen‐activated protein kinase 12 (MAPK12). Through an in‐depth proteomic analysis, we provide mechanistic insight into how glycogen availability affects muscle protein signalling adaptations to endurance exercise training.
Key points
Although they are unable to utilize muscle glycogen, McArdle mice adapt favourably to an individualized moderate‐intensity endurance exercise training regime. Yet, they fail to reach the performance capacity of healthy mice with normal glycogen availability.
There is a remarkable difference in the protein networks involved in muscle tissue adaptations to endurance exercise training in mice with and without glycogen availability.
Indeed, endurance exercise training promoted the expression of only three proteins common to both McArdle and wild‐type mice: LIMCH1, PARP1 and TIGD4.
In turn, trained McArdle mice presented strong expression of mitogen‐activated protein kinase 12 (MAPK12).
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. Nuclear deformability plays a critical ...role in cancer cell invasion through confined spaces; however, the direct impact of epigenetic changes on the nuclear deformability of leukemic cells remains unclear. Here, we characterized how 3D collagen matrix conditions induced H3K4 methylation in ALL cell lines and clinical samples. We used specific shRNA and chemical inhibitors to target WDR5 (a core subunit involved in H3K4 methylation) and determined that targeting WDR5 reduced the H3K4 methylation induced by the 3D environment and the invasiveness of ALL cells in vitro and in vivo. Intriguingly, targeting WDR5 did not reduce the adhesion or the chemotactic response of leukemia cells, suggesting a different mechanism by which H3K4 methylation might govern ALL cell invasiveness. Finally, we conducted biochemical, and biophysical experiments to determine that 3D environments promoted the alteration of the chromatin, the morphology, and the mechanical behavior of the nucleus in ALL cells. Collectively, our data suggest that 3D environments control an upregulation of H3K4 methylation in ALL cells, and targeting WDR5 might serve as a promising therapeutic target against ALL invasiveness in vivo.
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•ALL cells respond to 3D matrix conditions by altering H3K4 methylation.•WDR5 mediates the H3K4 methylation induced by 3D environments in ALL cells.•Targeting H3K4 methylation blocks ALL cell invasiveness and infiltration.•3D environments and H3K4 methylation controls the nuclear deformability of ALL cells.
Highlights • First-in-humans, first-in-children use of MSCs as carriers for oncolytic virotherapy. • This strategy allows administering very high amount of oncolytic virus with minimum toxicities. • ...Pre-therapy T cell status and T effector responses were important aspects associated to the outcome. • The presence of MSCs in the medicine product may prevent antioncovirus immune responses.
Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen ...receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the "NEXT Generation CART MAD Consortium" (NEXT CART) in Madrid's Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully.
Little is known about the effect of oncolytic adenovirotherapy on pediatric tumors. Here we present the clinical case of a refractory neuroblastoma that responded positively to
(ICOVIR-5 oncolytic ...adenovirus delivered by autologous mesenchymal stem cells) for several months. We analyzed samples during tumor evolution in order to identify molecular and mutational features that could explain the interactions between treatment and tumor and how the balance between both of them evolved. We identified a higher adaptive immune infiltration during stabilized disease compared to progression, and also a higher mutational rate and T-cell receptor (TCR) diversity during disease progression. Our results indicate an initial active role of the immune system controlling tumor growth during
therapy. The tumor eventually escaped from the control exerted by virotherapy through acquisition of resistance by the tumor microenvironment that exhausted the initial T cell response.
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