Hintonbloch7924

One of the challenges in translational medicine is to select first-in-human doses of investigational drugs based on findings in preclinical studies. Despite substantial progress in the optimization of recombinant adeno-associated virus (AAV) vectors of in vivo gene therapy for treating various diseases, there remain significant limitations to the use of preclinical data to guide dose selection in clinical trials. Here we introduce a novel concept of gene efficiency factor (GEF) to describe the efficiency of the gene transfer system and describe and apply the concept of GEF in AAV-mediated in vivo gene transfer systems. We explore the utility of allometric scaling to translate GEF across species using AAV-mediated in vivo factor IX (FIX) gene therapy for hemophilia B and to demonstrate the use of GEF in predicting efficacious AAV vector doses in humans. We show for the first time that an allometric relationship exists for GEF of AAV-mediated in vivo gene therapy. Furthermore, we demonstrate the feasibility of using the allometric relationship of GEF to select efficacious first-in-human doses of virus-mediated in vivo gene therapy. Based on our findings, allometry of GEF can be used to translate biological efficiency from animal studies to clinical studies and provide a rational basis of setting first-in-human doses for new virus-mediated in vivo gene therapy products.

We aimed to better characterize the magnetic resonance imaging (MRI) findings of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE), a rare clinicopathological entity associated with pharmacoresistance recently described in patients with frontal lobe epilepsy.

We studied 12 patients who underwent epilepsy surgery and whose surgical specimens showed histopathological findings of MOGHE, characterized by preserved cortical lamination, blurred gray-white matter interface due to increased number of oligodendrocytes, and heterotopic neurons in the white matter. buy Vismodegib The age at MRI evaluation ranged from 11 to 58years, except for one 4.5-year-old patient.

Following a detailed MRI analysis using an in-house protocol, we found abnormalities in all cases. The lesion was circumscribed in the frontal lobe in six (50%) and in the temporal lobe in three (25%) patients. In the remaining three patients (25%), the lesion was multilobar (frontotemporal and temporoparieto-occipital). Cortical tse this is a rare condition, multicenter studies are necessary to characterize MOGHE further.

MRI findings associated with MOGHE are similar to those described in FCD Type IIa. Although more frequent in the frontal lobe, MOGHE also occurred in the temporal lobe or involved multiple lobes. Multilobar or extensive MOGHE MRI lesions are associated with less favorable surgical outcomes. Because this is a rare condition, multicenter studies are necessary to characterize MOGHE further.

Drowning is responsible for an estimated 320,000 deaths a year, and over 90% of drowning mortality occurs in low- to middle-income countries (LMICs), with peak drowning rates among children aged 1 to 4 years. In this age group, mortality due to drowning is particularly common in rural settings and about 75% of drowning accidents happen in natural bodies of water close to the home. Providing adequate child supervision can protectchildren from drowning, and organized formal day care programs could offer a way to achieve this.

Primary objective • To assess the effects of day care programs for children under 6 years of age on drowning-related mortality or morbidity, or on total drowning accidents (fatal and non-fatal), in LMICs, compared to no day care programs or other drowning prevention interventions Secondary objectives • To assess the effects of day care programs in LMICs for children under 6 years of age on unsafe water exposure • To assess safety within these programs (e.g. transmission of infection wirowning mortality risk in regions with a high burden of drowning compared to no intervention.

This review provides evidence suggesting that a day care program with additional out-of-day care components such as community-based education, parent education, and playpens provided to parents likely reduces the drowning mortality risk in regions with a high burden of drowning compared to no intervention.As part of the adaptive immune system, T cells are vital for the eradication of infected and malignantly transformed cells. To perform their protective function, T cells produce effector molecules that are either directly cytotoxic, such as granzymes, perforin, interferon-γ and tumour necrosis factor α, or attract and stimulate (immune) cells, such as interleukin-2. As these molecules can also induce immunopathology, tight control of their production is required. Indeed, inflammatory cytokine production is regulated on multiple levels. Firstly, locus accessibility and transcription factor availability and activity determine the amount of mRNA produced. Secondly, post-transcriptional mechanisms, influencing mRNA splicing/codon usage, stability, decay, localization and translation rate subsequently determine the amount of protein that is produced. In the immune suppressive environments of tumours, T cells gradually lose the capacity to produce effector molecules, resulting in tumour immune escape. Recently, the role of post-transcriptional regulation in fine-tuning T-cell effector function has become more appreciated. Furthermore, several groups have shown that exhausted or dysfunctional T cells from cancer patients or murine models possess mRNA for inflammatory mediators, but fail to produce effector molecules, hinting that post-transcriptional events also play a role in hampering tumour-infiltrating lymphocyte effector function. Here, the post-transcriptional regulatory events governing T-cell cytokine production are reviewed, with a specific focus on the importance of post-transcriptional regulation in anti-tumour responses. Furthermore, potential approaches to circumvent tumour-mediated dampening of T-cell effector function through the (dis)engagement of post-transcriptional events are explored, such as CRISPR/Cas9-mediated genome editing or chimeric antigen receptors.