Early use of teduglutide in paediatric patients with intestinal failure is associated with a greater response rate: a multicenter study.

Teduglutide is a glucagon-like-peptide-2 analogue that reduces the need for parenteral support in patients with short bowel syndrome (SBS). Nevertheless, data about long-term therapy with teduglutide in children are still scarce. Our objective was to describe the real-life experience with teduglutide in children with SBS over the last 5 years in Spain. This was a national multicentre and prospective study of paediatric patients with intestinal failure (IF) treated with teduglutide for at least 3 months. The data included demographic characteristics, medical background, anthropometric data, laboratory assessments, adverse events, and parenteral nutrition (PN) requirements. Treatment response was defined as a > 20% reduction in the PN requirement. The data were collected from the Research Electronic Data Capture (REDCap) database. Thirty-one patients from seven centres were included; the median age at the beginning of the treatment was 2.3 (interquartile range (IQR) 1.4-4.4) years; and 65% of the patients were males. The most frequent cause of IF was SBS (94%). The most common cause of SBS was necrotizing enterocolitis (35%). The median residual bowel length was 29 (IQR 12-40) cm. The median duration of teduglutide therapy was 19 (IQR 12-36) months, with 23 patients (74%) treated for > 1 year and 9 treated for > 3 years. The response to treatment was analysed in 30 patients. Twenty-four patients (80%) had a reduction in their weekly PN energy > 20% and 23 patients (77%) had a reduction in their weekly PN volume > 20%. Among the responders, 9 patients (29%) were weaned off PN, with a median treatment duration of 6 (IQR 4.5-22) months. The only statistically significant finding demonstrated an association between a > 20% reduction in the weekly PN volume and a younger age at the start of treatment (p = 0.028).   Conclusions: Teduglutide seems to be an effective and safe treatment for paediatric patients with IF. Some patients require a prolonged duration of treatment to achieve enteral autonomy. Starting treatment with teduglutide at a young age is associated with a higher response rate. What is Known: •  Glucagon-like peptide-2 (GLP-2) plays a crucial role in the regulation of intestinal adaptation in short bowel syndrome (SBS). Teduglutide is a GLP-2 analog that reduces the need for parenteral support in patients with SBS. • Data about long-term therapy with teduglutide in children in real life are still scarce. What is New: • Most pediatric patients with SBS respond in a satisfactory manner to teduglutide treatment. The occurrence of long-term adverse effects is exceptional. • Starting treatment with the drug at a young age is associated with a greater response rate.

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example.

OBJECTIVE: To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. DATA SOURCES: Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. DATA SUMMARY: Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. CONCLUSION: Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.

Barbed versus conventional suture in elective posterior spine surgery.

PURPOSE: Barbed sutures are tissue control devices that can reduce operating room time and costs. We analyzed the utility of barbed sutures in posterior spinal surgery in order to prove non-inferiority to conventional methods for wound closure. METHODS: A cohort of patients undergoing elective posterior spinal surgery in which barbed (prospective) versus conventional sutures (retrospective) were used was analyzed. The primary endpoint was the occurrence of wound healing complications or the need for surgical revision. Secondary endpoints included postoperative stay, readmission rate, and duration and cost of wound closure. RESULT: A total of 483 patients participated in the study, 183 in the Barbed group and 300 in the Conventional group. Wound dehiscence or seroma occurred in 3.8% and 2.7% of the Barbed and Conventional groups, respectively (p = 0.6588). Both superficial (1.6% versus 4.0%, P = 0.2378) and deep infections (2.7% versus 4.7%, p = 0.4124) occurred similarly in both groups. Overall, the rate of re-intervention due to wound healing problems was also similar (4.9% versus 5.3%, p = 0.9906), as well as, total median hospital stay, postoperative stay and 30-day re-admission rates. The average duration of wound closure (1.66 versus 4.16 min per level operated, p < 0.0001) strongly favored the Barbed group. The mean cost of wound closure per patient was higher in the Barbed group (43.23 € versus 22.67 €, p < 0.0001). CONCLUSIONS: In elective posterior spinal procedures, the use of barbed sutures significantly reduced the duration of wound closure. The wound healing process was not hindered and the added cost related to the suture material was small.

Synthesis and Characterisation of Core-Shell Microparticles Formed by Ni-Mn-Co Oxides.

In this work, core and core-shell microparticles formed by Ni-Mn-Co oxides with controlled composition were fabricated by an oxalate-assisted co-precipitation route, and their properties were analysed by diverse microscopy and spectroscopy techniques. The microparticles exhibit dimensions within the 2-6 µm range and mainly consist of NiO and NiMn2O4, the latter being promoted as the temperature of the treatment increases, especially in the shell region of the microparticles. Aspects such as the shell dimensions, the vibrational modes of the spinel compounds primarily observed in the shell region, the oxidation states of the cations at the surface of the microparticles, and the achievement of a Ni-rich 811 core and a Mn-rich 631 shell were thoroughly evaluated and discussed in this work.

Endocannabinoid signalling in stem cells and cerebral organoids drives differentiation to deep layer projection neurons via CB1 receptors.

The endocannabinoid (eCB) system, via the cannabinoid CB1 receptor, regulates neurodevelopment by controlling neural progenitor proliferation and neurogenesis. CB1 receptor signalling in vivo drives corticofugal deep layer projection neuron development through the regulation of BCL11B and SATB2 transcription factors. Here, we investigated the role of eCB signalling in mouse pluripotent embryonic stem cell-derived neuronal differentiation. Characterization of the eCB system revealed increased expression of eCB-metabolizing enzymes, eCB ligands and CB1 receptors during neuronal differentiation. CB1 receptor knockdown inhibited neuronal differentiation of deep layer neurons and increased upper layer neuron generation, and this phenotype was rescued by CB1 re-expression. Pharmacological regulation with CB1 receptor agonists or elevation of eCB tone with a monoacylglycerol lipase inhibitor promoted neuronal differentiation of deep layer neurons at the expense of upper layer neurons. Patch-clamp analyses revealed that enhancing cannabinoid signalling facilitated neuronal differentiation and functionality. Noteworthy, incubation with CB1 receptor agonists during human iPSC-derived cerebral organoid formation also promoted the expansion of BCL11B+ neurons. These findings unveil a cell-autonomous role of eCB signalling that, via the CB1 receptor, promotes mouse and human deep layer cortical neuron development.

The SRSF4-GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy.

[Figure: see text].

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain.

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST-/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36-0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20-440) per 100,000 person-years), both probable de novo infections. CONCLUSION: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective. WHAT IS KNOWN: • The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain. • Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease. WHAT IS NEW: • A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone. • Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.

Exercise effects on functional capacity and quality of life in older patients with colorectal cancer: study protocol for the ECOOL randomized controlled trial.

BACKGROUND: Surgery and treatment for colorectal cancer (CRC) in the elderly patient increase the risk of developing post-operative complications, losing functional independence, and worsening health-related quality of life (HRQoL). There is a lack of high-quality randomized controlled trials evaluating the potential benefit of exercise as a countermeasure. The primary aim of this study is to evaluate the effectiveness of a home-based multicomponent exercise program for improving HRQoL and functional capacity in older adults undergoing CRC surgery and treatment. METHODS: This randomized, controlled, observer-blinded, single-center trial aims to randomize 250 patients (>74 years) to either an intervention or a control group (i.e., usual care). The intervention group will perform an individualized home-based multicomponent exercise program with weekly telephone supervision from diagnosis until three months post-surgery. The primary outcomes will be HRQoL (EORTC QLQ-C30; CR29; and ELD14) and functional capacity (Barthel Index and Short Physical Performance Battery), which will be assessed at diagnosis, at discharge, and one, three, and six months after surgery. Secondary outcomes will be frailty, physical fitness, physical activity, inspiratory muscle function, sarcopenia and cachexia, anxiety and depression, ambulation ability, surgical complications, and hospital length of stay, readmission and mortality. DISCUSSION: This study will examine the effects of an exercise program in older patients with CRC across a range of health-related outcomes. Expected findings are improvement in HRQoL and physical functioning. If proven effective, this simple exercise program may be applied in clinical practice to improve CRC care in older patients. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05448846.

Factors influencing the cleaning of plant samples with ultrasonic technology.

Effective cleaning of biological samples is a critical step in environmental studies. However, the literature lacks standardized cleaning procedures and protocols and there is little information about how even the most basic conditions may affect cleaning efficiency. Here, leaves of different species were first exposed to the soil naturally containing mercury particles and then washed in an ultrasound water bath under the following conditions: newly cleaned/reused beakers, water temperature, sample immersion/free-floating, sample quantity, and the number of washing cycles. Additionally, the effects of sample pubescence on cleaning efficacy were also assessed. Results indicated that the best cleaning efficacy was recorded when samples were placed in cold water under forced immersion and beakers were cleaned between washing cycles. At least two of these three conditions were needed for adequate washing. The results also indicated that, for the glabrous leaves, a cumulative leaf surface area of ≤10,000 mm2 was efficiently cleaned after 3-5 washing cycles, while as pubescence increased, 9-11 cycles were needed and often the sample quantity had to be reduced (<5,000 mm2). Our experiments reveal that cleaning can be optimized by applying easy procedures and according to individual sample typology, resulting in faster and more effective cleaning. Novelty statementThe cleaning of samples is a frequent stage in the analytical processes of phytoremediation studies. This work provides new and valuable information to optimize the cleaning of plant samples by simply applying ultrasonic technology and distilled water. In fact, we have tested the influence of some factors never taken into account previously.

Comparison of Rheological Properties of Healthy versus Dupuytren Fibroblasts When Treated with a Cell Contraction Inhibitor by Atomic Force Microscope.

Mechanical properties of healthy and Dupuytren fibroblasts were investigated by atomic force microscopy (AFM). In addition to standard force curves, rheological properties were assessed using an oscillatory testing methodology, in which the frequency was swept from 1 Hz to 1 kHz, and data were analyzed using the structural damping model. Dupuytren fibroblasts showed larger apparent Young's modulus values than healthy ones, which is in agreement with previous results. Moreover, cell mechanics were compared before and after ML-7 treatment, which is a myosin light chain kinase inhibitor (MLCK) that reduces myosin activity and hence cell contraction. We employed two different concentrations of ML-7 inhibitor and could observe distinct cell reactions. At 1 µM, healthy and scar fibroblasts did not show measurable changes in stiffness, but Dupuytren fibroblasts displayed a softening and recovery after some time. When increasing ML-7 concentration (3 µM), the majority of cells reacted, Dupuytren fibroblasts were the most susceptible, not being able to recover from the drug and dying. These results suggested that ML-7 is a potent inhibitor for MLCK and that myosin II is essential for cytoskeleton stabilization and cell survival.

CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells.

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.

A comprehensive review on carotenoids in foods and feeds: status quo, applications, patents, and research needs.

Carotenoids are isoprenoids widely distributed in foods that have been always part of the diet of humans. Unlike the other so-called food bioactives, some carotenoids can be converted into retinoids exhibiting vitamin A activity, which is essential for humans. Furthermore, they are much more versatile as they are relevant in foods not only as sources of vitamin A, but also as natural pigments, antioxidants, and health-promoting compounds. Lately, they are also attracting interest in the context of nutricosmetics, as they have been shown to provide cosmetic benefits when ingested in appropriate amounts. In this work, resulting from the collaborative work of participants of the COST Action European network to advance carotenoid research and applications in agro-food and health (EUROCAROTEN, www.eurocaroten.eu, https://www.cost.eu/actions/CA15136/#tabs|Name:overview) research on carotenoids in foods and feeds is thoroughly reviewed covering aspects such as analysis, carotenoid food sources, carotenoid databases, effect of processing and storage conditions, new trends in carotenoid extraction, daily intakes, use as human, and feed additives are addressed. Furthermore, classical and recent patents regarding the obtaining and formulation of carotenoids for several purposes are pinpointed and briefly discussed. Lastly, emerging research lines as well as research needs are highlighted.

Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder.

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction.

RATIONALE: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. OBJECTIVE: To investigate the role of SRSF3 in cardiac function. METHODS AND RESULTS: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. CONCLUSIONS: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.

Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma.

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Postsynaptic δ1 glutamate receptor assembles and maintains hippocampal synapses via Cbln2 and neurexin.

The δ1 glutamate receptor (GluD1) was cloned decades ago and is widely expressed in many regions of the brain. However, its functional roles in these brain circuits remain unclear. Here, we find that GluD1 is required for both excitatory synapse formation and maintenance in the hippocampus. The action of GluD1 is absent in the Cbln2 knockout mouse. Furthermore, the GluD1 actions require the presence of presynaptic neurexin 1ß carrying the splice site 4 insert (+S4). Together, our findings demonstrate that hippocampal synapse assembly and maintenance require a tripartite molecular complex in which the ligand Cbln2 binds with presynaptic neurexin 1ß (+S4) and postsynaptic GluD1. We provide evidence that this mechanism may apply to other forebrain synapses, where GluD1 is widely expressed.

LTP requires postsynaptic PDZ-domain interactions with glutamate receptor/auxiliary protein complexes.

Long-term potentiation (LTP) is a persistent strengthening of synaptic transmission in the brain and is arguably the most compelling cellular and molecular model for learning and memory. Previous work found that both AMPA receptors and exogenously expressed kainate receptors are equally capable of expressing LTP, despite their limited homology and their association with distinct auxiliary subunits, indicating that LTP is far more promiscuous than previously thought. What might these two subtypes of glutamate receptor have in common? Using a single-cell molecular replacement strategy, we demonstrate that the AMPA receptor auxiliary subunit TARP γ-8, via its PDZ-binding motif, is indispensable for both basal synaptic transmission and LTP. Remarkably, kainate receptors and their auxiliary subunits Neto proteins share the same requirement of PDZ-binding domains for synaptic trafficking and LTP. Together, these results suggest that a minimal postsynaptic requirement for LTP is the PDZ binding of glutamate receptors/auxiliary subunits to PSD scaffolding proteins.

Volumetric growth rate of incidental asymptomatic meningiomas: a single-center prospective cohort study.

BACKGROUND: Decision about treatment of incidentally found intracranial meningiomas is controversial and conditioned by the growth potential of these tumors. We aimed to evaluate the growth rate of a cohort of incidentally found asymptomatic meningiomas and to analyze their natural course and the need for eventual treatment. METHODS: A total of 193 patients harboring intracranial meningiomas (85 with 109 incidental and 108 with 112 symptomatic) were included between 2015 and 2019. In the prospective cohort of incidental meningiomas, we measured size at diagnosis, volumetric growth rate (by segmentation software), appearance of symptoms, and need for surgery or radiotherapy. Progression-free survival and risk factors for growth were assessed with Kaplan-Meier survival and Cox regression analyses. RESULTS: Among incidental meningiomas, 94/109 (86.2%) remained untreated during a median follow-up of 49.3 months. Tumor growth was observed in 91 (83.5%) and > 15% growth in 40 (36.7%). Neurological symptoms developed in 1 patient (1.2%). Volume increased an average of 0.51 cm3/year (95% CI, 0.20-0.82). Nine patients were operated (9.2%) and 4 underwent radiotherapy (4.7%). Treatment-related complication rates of incidental and symptomatic meningiomas were 0% and 35.4%, respectively. Persistent neurological defects occurred in 46 (40.7%) of symptomatic versus 2 (2.3%) of incidental meningiomas. Among covariates, only brain edema resulted in an increased risk of significant tumor growth in the female subgroup (Cox regression HR 2.96, 95% CI 1.02-8.61, p = 0.046). Size at diagnosis was significantly greater in the symptomatic meningioma group (37.33 cm3 versus 4.74 cm3, p < 0.001). CONCLUSIONS: Overall, 86% of incidentally found meningiomas remained untreated over the first 4 years of follow-up. The majority grew within the 20% range, yet very few developed symptoms. Treatment-related morbidity was absent in the incidental meningioma group.