Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying ...molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.
Glioblastoma, the most frequent and aggressive primary malignant tumor, often presents with alterations in the telomerase reverse transcriptase promoter. Telomerase is responsible for the maintenance ...of telomere length to avoid cell death. Telomere lengthening is required for cancer cell survival and has led to the investigation of telomerase activity as a potential mechanism that enables cancer growth. The aim of this systematic review is to provide an overview of the available data concerning
alterations and glioblastoma in terms of incidence, physiopathological understanding, and potential therapeutic implications.
Ultra-high-resolution imaging mass spectrometry using matrix-assisted laser desorption ionization (MALDI) MS coupled to a Fourier transform ion cyclotron resonance (FTICR) mass analyzer is a powerful ...technique for the visualization of small molecule distribution within biological tissues. The FTICR MS provides ultra-high resolving power and mass accuracy that allows large molecular coverage and molecular formula assignments, both essential for untargeted metabolomics analysis. These performances require fine optimizations of the MALDI FTICR parameters. In this context, this study proposes a new strategy, using experimental design, for the optimization of ion transmission voltages and MALDI parameters, for tissue untargeted metabolomics analysis, in both positive and negative ionization modes. These experiments were conducted by assessing the effects of nine factors for ion transmission voltages and four factors for MALDI on the number of peaks, the weighted resolution, and the mean error within
m/z
150–1000 mass range. For this purpose, fractional factorial designs were used with multiple linear regression (MLR) to evaluate factor effects and to optimize parameter values. The optimized values of ion transmission voltages (RF amplitude TOF, RF amplitude octopole, frequency transfer optic, RF frequency octopole, deflector plate, funnel 1, skimmer, funnel RF amplitude, time-of-flight, capillary exit), MALDI parameters (laser fluence, number of laser shots), and detection parameters (data size, number of scans) led to an increase of 32% and 18% of the number of peaks, an increase of 8% and 39% of the resolution, and a decrease of 56% and 34% of the mean error in positive and negative ionization modes, respectively.
Graphical abstract
Purpose
Spinal meningiomas are slow-growing intradural-extramedullary tumors. They are usually associated with good outcomes. However, there are few descriptions of factors predictive of impaired ...evolution. Our objective was to identify predictive factors of post-operative deterioration as well as outcomes at follow-up.
Methods
Between 2009 and 2016, 87 patients had surgery for spinal meningioma in our referral center. Clinical presentation, management and outcomes were reported during the post-operative period and at 3-month follow-up. Evaluation was based on post-operative neurological deterioration defined as an increase of at least one point in the McCormick score compared to the status at admission.
Results
During the study period, post-operative deterioration occurred in 17 patients (19.5%). Risk factors associated with this deterioration were the absence of pre-operative neurological signs (Relative Risk; RR = 2.38, p = 0.04), an anterior location of the meningioma and a grade 2 meningioma on WHO classification score (RR = 6, p ≤ 0.01). At 3-month follow-up, in patients who initially presented with a motor deficit, partial recovery was found in 75%, stability in 20% and a deterioration of their clinical status in 5%. After a mean follow-up of 92.4 ± 51.9 months, the recurrence rate was 8%.
Conclusions
Spinal meningiomas are usually benign tumors whose treatment is based on complete surgical resection. Progress in surgical techniques has resulted in lower morbidity rates and improvement in post-operative recovery. In this study, we observed several factors associated with clinical deterioration. Before surgery, patients should be fully informed of these predictive factors of post-operative deterioration and their association with surgical morbidity.
Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving ...early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.
Lung adenocarcinoma (LUAD) is the major subtype of non-small cell lung cancer, accounting for approximately 60% of cases. Molecular analysis of LUADs showed that the
gene is mutated in up to 30% of ...cases; such cases were previously considered "undruggable". The KRAS G12C mutation has become a hot topic of research after initial, promising, phase I and II trials with targeted inhibitors. We analyzed the morphological and genomic landscape of 202 KRAS G12C mutated LUADs using next-generation sequencing, and identified a specific subtype of patients that could show an improved response to KRAS G12C inhibitors. The main histological subtype was acinar in 29.7% of cases. Tumor-infiltrating lymphocytes (TILs) were highly or moderately abundant in more than 60% of cases. The immunohistochemical profile showed TTF1 positivity in 78.7% of cases and PD-L1 positivity in 44.1% of cases. The molecular profile showed an association between
and
mutations in 25.2% of cases. This subgroup was associated with a statistically significant lower TTF1 (
= 0.0092) and PD-L1 (
< 0.0001) positivity. This type of combined morphological and molecular analysis can improve our understanding of tumor biology, and help us to identify specific patient subgroups that can achieve the best treatment response.
In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous ...cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.
•Ethanol impairs activity of endothelial proteases in pial microvessels.•Alcohol-induced effect on MMP-9 is tPA and endothelial NMDAR-dependent.•In utero alcohol exposure induces overexpression of NMDAR subunits.•In utero alcohol exposure induces a mispositioning of vessel-associated migrating interneurons.•Alcohol-induced interneuron mispositioning occurs in mouse and human cortex.
The clinical implications of plasmatic cell-free and tumor DNA (cfDNA and ctDNA) are challenging in glioblastoma. This prospective study included 52 consecutive newly diagnosed glioblastoma (n = 49) ...or gliosarcoma (n = 3) patients treated with concomitant temozolomide and radiotherapy (RT-TMZ), followed by a TMZ maintenance phase. Plasma samples were collected at baseline, before RT-TMZ (pre-RT-TMZ) and at the end of adjuvant TMZ, or at the time of progression in cases of progressive disease (PD). The cfDNA concentration was measured with a fluorometric method, and ctDNA was detected using targeted droplet digital PCR. The main objectives were to analyze the associations between cfDNA and ctDNA measurements during the course of treatment with PD and survival. There was a significant decrease in median cfDNA concentration from baseline to pre-RT-TMZ-19.4 versus 9.7 ng/mL (p < 0.0001)-in the entire cohort. In patients with PD, a significant increase in cfDNA concentration from pre-RT-TMZ to time of PD was observed, from 9.7 versus 13.1 ng/mL (p = 0.037), respectively, while no difference was observed for nonprogressive patients. Neither the cfDNA concentration at baseline nor its kinetics correlated with survival. ctDNA was detected in 2 patients (3.8%) and only in gliosarcoma subtypes.Trial registration ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1 .
•First study to assess the prognostic impact of cfDNA size in glioblastoma.•Short-length circulating DNA (slDNA) fragments (i.e. lower than 250 base pairs) better reflect tumor evolution.•Early ...decrease of slDNA concentration is associated with improved survival.
Liquid biopsy application is still challenging in glioblastoma patients and the usefulness of short-length DNA (slDNA) fragments is not established. The aim was to investigate slDNA concentration as a prognostic marker in unresected glioblastoma patients.
Patients with unresected glioblastoma and treated by radiochemotherapy (RT/TMZ) were included. Plasmas were prospectively collected at three times: before (pre-) RT, after (post-) RT and at the time of progression. Primary objective was to investigate the impact on survival of slDNA concentration slDNA variation during RT/TMZ. Secondary objectives were to explore the association between tumor volume, corticosteroid exposition and slDNA; and the impact of slDNA detection at pre-RT on survival.
Thirty-six patients were analyzed: 11 patients (30.6 %) experienced slDNA decrease during RT/TMZ, 22 patients (61.1 %) experienced increase and 3 patients (8.3 %) had stability. Decrease of slDNA during RT/TMZ was associated with better outcome compared to increase or stability: median OS, since end of RT, of 13.2 months 11.4 - NA vs 10.1 months 7.8 - 12.6 and 6.8 months 4.5 - NA, p = 0.015, respectively. slDNA detection at pre-RT time was associated with improved OS: 11.7 months in the slDNA(+) group versus 8.8 months in the slDNA(-) group, p = 0.004. slDNA was not associated with corticosteroids exposition or tumor volume. No influence on survival was observed for both whole cfDNA concentration or slDNA peak size.
slDNA decrease during radiochemotherapy phase is a favorable prognostic marker on OS for unresected glioblastoma patients. Larger and independent cohorts are now required.
ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1
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