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ObjectivesTo perform head-to-head comparisons of the feasibility and diagnostic performance of transient elastography (TE), point shear-wave elastography (pSWE), and magnetic resonance elastography (MRE).MethodsThis prospective, cross-sectional, dual-center imaging study included 100 patients with known or suspected chronic liver disease caused by hepatitis B or C virus, nonalcoholic fatty liver disease, or autoimmune hepatitis identified between 2014 and 2018. Liver stiffness measured with the three elastographic techniques was obtained within 6 weeks of a liver biopsy. Confounding effects of inflammation and steatosis on association between fibrosis and liver stiffness were assessed. Obuchowski scores and AUCs for staging fibrosis were evaluated and the latter were compared using the DeLong method.ResultsTE, pSWE, and MRE were technically feasible and reliable in 92%, 79%, and 91% subjects, respectively. At univariate analysis, liver stiffness measured by all techniques increased with fibrosis stages and inflammation and decreased with steatosis. For classification of dichotomized fibrosis stages, the AUCs were significantly higher for distinguishing stages F0 vs. ≥ F1 with MRE than with TE (0.88 vs. 0.71; p < 0.05) or pSWE (0.88 vs. 0.73; p < 0.05), and for distinguishing stages ≤ F1 vs. ≥ F2 with MRE than with TE (0.85 vs. 0.75; p < 0.05). TE, pSWE, and MRE Obuchowski scores for staging fibrosis stages were respectively 0.89 (95% CI 0.85–0.93), 0.90 (95% CI 0.85–0.94), and 0.94 (95% CI 0.91–0.96).ConclusionMRE provided a higher diagnostic performance than TE and pSWE for staging early stages of liver fibrosis.Trial registrationNCT02044523Key Points• The technical failure rate was similar between MRE and US-based elastography techniques.• Liver stiffness measured by MRE and US-based elastography techniques increased with fibrosis stages and inflammation and decreased with steatosis.• MRE provided a diagnostic accuracy higher than US-based elastography techniques for staging of early stages of histology-determined liver fibrosis.

Background Aquaculture production is expected to double by 2030, and demands for aquafeeds and raw materials are expected to increase accordingly. Sustainable growth of aquaculture will require the development of highly nutritive and functional raw materials to efficiently replace fish meal. Enzymatic hydrolysis of marine and aquaculture raw materials could bring new functionalities to finished products. The aim of this study was to determine the zootechnical and transcriptomic performances of protein hydrolysates of different origins (tilapia, shrimp, and a combination of the two) in European seabass ( Dicentrarchux labrax ) fed a low fish meal diet (5%), for 65 days. Results Results were compared to a positive control fed with 20% of fish meal. Growth performances, anterior intestine histological organization and transcriptomic responses were monitored and analyzed. Dietary inclusion of protein hydrolysates in the low fish meal diet restored similar growth performances to those of the positive control. Inclusion of dietary shrimp hydrolysate resulted in larger villi and more goblet cells, even better than the positive control. Transcriptomic analysis of the anterior intestine showed that dietary hydrolysate inclusion restored a pattern of intestinal gene expression very close to the pattern of the positive control. However, as compared to the low fish meal diet and depending on their origin, the different hydrolysates did not modulate metabolic pathways in the same way. Dietary shrimp hydrolysate inclusion modulated more metabolic pathways related to immunity, while nutritional metabolism was more impacted by dietary tilapia hydrolysate. Interestingly, the combination of the two hydrolysates enhanced the benefits of hydrolysate inclusion in diets: more genes and metabolic pathways were regulated by the combined hydrolysates than by each hydrolysate tested independently. Conclusions Protein hydrolysates manufactured from aquaculture by-products are promising candidates to help replace fish meal in aquaculture feeds without disrupting animal metabolism and performances.

Malignant glioma including glioblastoma (GBM) is the most common group of primary brain tumors. Despite standard optimized treatment consisting of extensive resection followed by radiotherapy/concomitant and adjuvant therapy, GBM remains one of the most aggressive human cancers. GBM is a typical example of intra-heterogeneity modeled by different micro-environmental situations, one of the main causes of resistance to conventional treatments. The resistance to treatment is associated with angiogenesis, hypoxic and necrotic tumor areas while heterogeneity would accumulate during glioma cell invasion, supporting recurrence. These complex mechanisms require a focus on potential new molecular actors to consider new treatment options for gliomas. Among emerging and underexplored targets, transient receptor potential (TRP) channels belonging to a superfamily of non-selective cation channels which play critical roles in the responses to a number of external stimuli from the external environment were found to be related to cancer development, including glioma. Here, we discuss the potential as biological markers of diagnosis and prognosis of TRPC6, TRPM8, TRPV4, or TRPV1/V2 being associated with glioma patient overall survival. TRPs-inducing common or distinct mechanisms associated with their Ca 2+ -channel permeability and/or kinase function were detailed as involving miRNA or secondary effector signaling cascades in turn controlling proliferation, cell cycle, apoptotic pathways, DNA repair, resistance to treatment as well as migration/invasion. These recent observations of the key role played by TRPs such as TRPC6 in GBM growth and invasiveness, TRPV2 in proliferation and glioma-stem cell differentiation and TRPM2 as channel carriers of cytotoxic chemotherapy within glioma cells, should offer new directions for innovation in treatment strategies of high-grade glioma as GBM to overcome high resistance and recurrence.

Subarachnoid hemorrhage (SAH) can be associated with neurological deficits and has profound consequences for mortality and morbidity. Cerebral vasospasm (CVS) and delayed cerebral ischemia affect neurological outcomes in SAH patients, but their mechanisms are not fully understood, and effective treatments are limited. Here, we report that urotensin II receptor UT plays a pivotal role in both early events and delayed mechanisms following SAH in male mice. Few days post-SAH, UT expression is triggered by blood or hemoglobin in the leptomeningeal compartment. UT contributes to perimeningeal glia limitans astrocyte reactivity, microvascular alterations and neuroinflammation independent of CNS-associated macrophages (CAMs). Later, CAM-dependent vascular inflammation and subsequent CVS develop, leading to cognitive dysfunction. In an SAH model using humanized UT h+ / h+ male mice, we show that post-SAH CVS and behavioral deficits, mediated by UT through Gq/PLC/Ca 2+ signaling, are prevented by UT antagonists. These results highlight the potential of targeting UT pathways to reduce early meningeal response and delayed cerebral ischemia in SAH patients. “In subarachnoid hemorrhage (SAH), therapies are limited and clinical outcomes remain disappointing. The authors show a contribution of the urotensin II system in microvascular changes, vasospasm, neuroinflammation and cognitive deficits post-SAH, primarily through meningeal cells and border-associated macrophages

Background The discovery of the importance of the immune system and its role in oncogenesis led to the development of immunotherapy, a treatment that represents a major advance in oncology management. Due to the recent nature of immunotherapy, little is known about its side effects and their impact on quality of life. To date, there is no published study that accurately assesses the impact of immunotherapy on cognition, mood and/or fatigue in patients treated for cancer, despite potential neurological toxicities. The purpose of this study is to prospectively assess the incidence of cognitive impairment and cognitive complaints among cancer patients naïve for immunotherapy without concomitant anti-cancer treatment. Methods The Cog-Immuno trial is a multicentre longitudinal study addressing patients with cancer candidate to receive immunotherapy alone ( n  = 100). Immunotherapy treatment will include either anti-PD1/PDL1 or anti-CTLA4 monotherapy or combination therapy. Cognitive and quality of life assessment, electrocardiogram (ECG) and biological tests will be performed at baseline, thereafter 3, and 6 months after immunotherapy initiation. The primary endpoint is the proportion of patients treated by immunotherapy who will experience a decline in cognitive performances or in Montreal Cognitive Assessment (MoCA) score within 3 months after inclusion. Secondary endpoints concern: anxiety, depression, fatigue, clinical characteristics, biological data and neurophysiological measures (heart rate variability and hemispheric lateralization). A pre-clinical study will be conducted in cancer bearing mice receiving checkpoint inhibitors (ICI) with the evaluation of cognitive functions and emotional reactivity, collection of blood samples and investigation of neurobiological mechanisms from brain slices. Discussion Assessing and understanding the incidence and the severity of cognitive impairment and its impact on quality of life in cancer patients treated by immunotherapy is a major issue. The results of this study will provide information on the impact of these treatments on cognitive functions in order to help the physicians in the choice of the treatment. Trial registration NCT03599830, registered July 26, 2018. Protocol version Version 5.1 dated from 2020/10/02.

Several studies have shown that Parkinson’s disease causative gene products, including α-synuclein (α-syn), display tight links with the tumor suppressor p53. The purpose of this study is to determine the implication of α-syn in glioblastoma development and elucidate how it elicits a tumor suppressor function. We show that the expression of α-syn, a TP53 transcriptional target and a key molecular player in Parkinson’s disease, is detected in 1p/19q-codeleted and isocitrate dehydrogenase (IDH)-mutant oligodendroglioma and in IDH-wild-type glioblastoma, while reduced in glioblastoma biopsies, corroborating the link of α-syn expression with a better prognosis among all glioma patients. Accordingly, protein expression is drastically reduced in oligodendrogliomas and glioblastoma biopsies. This could be accounted for by a reduction of p53 transcriptional activity in these samples. Interestingly, genetic manipulation of p53 in glioblastoma cells and in mouse brain shows that p53 up-regulates α-synuclein, a phenotype fully abolished by the prominent p53 hot spot mutation R175H. Downstream to its p53-linked control, α-syn lowers cyclin D1 protein and mRNA levels and reduces glioblastoma cells proliferation in a cyclin D1-dependent-manner. Further, in temozolomide (TMZ)-resistant U87 cells, α-syn reduces O 6 -methylguanine-DNA methyltransferase (MGMT) expression and rescues drug sensitivity by a mechanism implying its transcriptional activation by X-box binding protein 1 (XBP1), an effector of the UPR response. Furthermore, α-syn lowers MGMT and cyclin D1 (CCDN1) expressions and reduces tumor development in allografted mice. Overall, our data reveals a new role of α-syn as an oligodendroglioma biomarker and as a glioblastoma tumor suppressor capable of either potentiate TMZ effect or avoid TMZ-associated resistance.

PurposeTo evaluate the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS) v2017 major features, the impact of ancillary features, and categories on contrast-enhanced computed tomography (CECT) for the diagnosis of hepatocellular carcinoma (HCC).Materials and methodsThis retrospective study included 59 patients (104 observations including 72 HCCs) with clinical suspicion of HCC undergoing CECT between 2013 and 2016. Two radiologists independently assessed major and ancillary imaging features for each liver observation and assigned a LI-RADS category based on major features only and in combination with ancillary features. The composite reference standard included pathology or imaging. Per-lesion estimates of diagnostic performance of major features, ancillary features, and LI-RADS categories were assessed by generalized estimating equation models.ResultsMajor features (arterial phase hyperenhancement, washout, capsule, and threshold growth) respectively had a sensitivity of 86.1%, 81.6%, 20.7%, and 26.1% and specificity of 39.3%, 67.9%, 89.9%, and 85.0% for HCC. Ancillary features (ultrasound visibility as discrete nodule, subthreshold growth, and fat in mass more than adjacent liver) respectively had a sensitivity of 42.6%, 50.8%, and 15.1% and a specificity of 79.2%, 66.9%, and 96.4% for HCC. Ancillary features modified the final category in 4 of 104 observations. For HCC diagnosis, categories LR-3, LR-4, LR-5, and LR-TIV (tumor in vein) had a sensitivity of 5.3%, 29.0%, 53.7%, and 10.7%; and a specificity of 49.1%, 84.4%, 97.3%, and 96.4%, respectively.ConclusionOn CT, LR-5 category has near-perfect specificity for the diagnosis of HCC and ancillary features modifies the final category in few observations.

Background Radiotherapy as a complement or an alternative to neurosurgery has a central role in the treatment of skull base grade I-II meningiomas. Radiotherapy techniques have improved considerably over the last two decades, becoming more effective and sparing more and more the healthy tissue surrounding the tumour. Currently, hypo-fractionated stereotactic radiotherapy (SRT) for small tumours and normo-fractionated intensity-modulated radiotherapy (IMRT) or proton-therapy (PT) for larger tumours are the most widely used techniques. It is expected a decrease of the risk of cognitive impairment with these modern techniques. However prospective data about cognitive long-term consequences of partial brain irradiation with SRT, PT, or IMRT remain very scarce to date. Methods CANCER COG is one of the first multicentric study in the world to prospectively assess the cognitive performances of patients following different modalities of cerebral radiotherapy (stereotactic radiotherapy, proton therapy, intensity modulated radiotherapy) for the treatment of grade I-II skull base meningioma, up to at least 10 years after the end of radiotherapy. This longitudinal study includes the follow-up of 3 cohorts, including: patients treated with PRT, IMRT, and SRT. An additionally control group will be formed. The primary objective is to report long-term cognitive deterioration in each cohort until 10 years after the end of irradiation. The rate of clinical symptomatology improvement over time after irradiation, the evolution of health-related quality-of-life, anxiety/depression, fatigue, over time after irradiation, the tumoral local control after irradiation, the progression-free survival (PFS), the professional reintegration for working-age patients will also be assessed. CANCER COG aims to help clinicians to choose the best irradiation techniques with the best benefit/risk ratio. Inclusions started on september 2023. Trial registration The study was registered on clinicaltrials.gov with the following number: NCT 06036706.

Purpose Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however, that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas. Methods To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth. Results We show that contrary to PAK1 and PAK2 , high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma sub-groups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice. Conclusions Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.

Autophagy is a highly conserved self-degradative process that plays a key role in diverse cellular processes such as stress response or differentiation. A growing body of work highlights the direct involvement of autophagy in cell migration and cancer metastasis. Specifically, autophagy has been shown to be involved in modulating cell adhesion dynamics as well as epithelial-to-mesenchymal transition. After providing a general overview of the mechanisms controlling autophagosome biogenesis and cell migration, we discuss how chemotactic G protein-coupled receptors, through the repression of autophagy, may orchestrate membrane trafficking and compartmentation of specific proteins at the cell front in order to support the critical steps of directional migration.