It's About Time: Parent-Child Turn-Taking in Early Stuttering.

Purpose: Most common treatments for stuttering offer advice that parents modify temporal features of conversational interaction to assist children who stutter (CWS). Advice includes but is not limited to slowing of adult speech, increasing turn-taking/response-time latencies (RTLs), and reducing interruptions. We looked specifically at RTL and parental speech rate in a longitudinal data set that included baseline behaviors.

Stimulator of interferon gene facilitates recruitment of effector CD8 T cells that drive neurofibromatosis type 1 nerve tumor initiation and maintenance.

Plexiform neurofibromas (PNFs) are benign nerve tumors driven by loss of the tumor suppressor in Schwann cells. PNFs are rich in immune cells, but whether immune cells are necessary for tumorigenesis is unknown. We show that inhibition of stimulator of interferon gene (STING) reduces plasma CXCL10, tumor T cell and dendritic cell (DC) recruitment, and tumor formation.

NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14.

The blood-nerve-barrier (BNB) that regulates peripheral nerve homeostasis is formed by endoneurial capillaries and perineurial cells surrounding the Schwann cell (SC)-rich endoneurium. Barrier dysfunction is common in human tumorigenesis, including in some nerve tumors. We identify barrier disruption in human deficient neurofibromas, which were characterized by reduced perineurial cell glucose transporter 1 (GLUT1) expression and increased endoneurial fibrin(ogen) deposition.

Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors.

[This corrects the article DOI: 10.3389/fimmu.2024.

Should We Stop Using Lexical Diversity Measures in Children's Language Sample Analysis?

Purpose: Prior work has identified weaknesses in commonly used indices of lexical diversity in spoken language samples, such as type-token ratio (TTR) due to sample size and elicitation variation, we explored whether TTR and other diversity measures, such as number of different words/100 (NDW), vocabulary diversity (VocD), and the moving average TTR would be more sensitive to child age and clinical status (typically developing [TD] or developmental language disorder [DLD]) if samples were obtained from standardized prompts.

Method: We utilized archival data from the norming samples of the Test of Narrative Language and the Edmonton Narrative Norms Instrument. We examined lexical diversity and other linguistic properties of the samples, from a total of 1,048 children, ages 4-11 years; 798 of these were considered TD, whereas 250 were categorized as having a language learning disorder.

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene . Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST.

C5aR plus MEK inhibition durably targets the tumor milieu and reveals tumor cell phagocytosis.

Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages.

Schwann cells modulate nociception in neurofibromatosis 1.

Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome neurofibromatosis 1 (NF1), even when tumors are absent. Nerve Schwann cells (SCs) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in wild-type mice. In mouse models, animals showed afferent and behavioral hypersensitivity when SCs, but not neurons, lacked Nf1.

Shedding New Light: Novel Therapies for Common Disorders in Children with Neurofibromatosis Type I.

Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas.

Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFβ coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs.

Assessment and Therapy Goal Planning Using Free Computerized Language Analysis Software.

Background: We discuss a free software system (Computerized Language Analysis [CLAN]) that can enable fast, thorough, and informative language sample analysis (LSA).

Method: We describe methods for eliciting, transcribing, analyzing, and interpreting language samples. Using a hypothetical child speaker, we illustrate use KidEval to generate a diagnostic report.

Brain activity during the preparation and production of spontaneous speech in children with persistent stuttering.

Speech production forms the basis for human verbal communication. Though fluent speech production is effortless and automatic for most people, it is disrupted in speakers who stutter, who experience difficulties especially during spontaneous speech and at utterance onsets. Brain areas comprising the basal ganglia thalamocortical (BGTC) motor loop have been a focus of interest in the context of stuttering, given this circuit's critical role in initiating and sequencing connected speech.

Motor Function and Physiology in Youth With Neurofibromatosis Type 1.

Background: Neurofibromatosis type 1 (NF1) is a genetic neurocutaneous disorder commonly associated with motor and cognitive symptoms that greatly impact quality of life. Transcranial magnetic stimulation (TMS) can quantify motor cortex physiology, reflecting the basis for impaired motor function as well as, possibly, clues for mechanisms of effective treatment. We hypothesized that children with NF1 have impaired motor function and altered motor cortex physiology compared to typically developing (TD) control children and children with attention-deficit/hyperactivity disorder (ADHD).

Combining SOS1 and MEK Inhibitors in a Murine Model of Plexiform Neurofibroma Results in Tumor Shrinkage.

Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK.

Merlin tumor suppressor function is regulated by PIP2-mediated dimerization.

Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region, and a C-terminal domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity.

Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis.

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers.

The synaptic organization in the neural network suggests significant local compartmentalized computations.

Neurons are characterized by elaborate tree-like dendritic structures that support local computations by integrating multiple inputs from upstream presynaptic neurons. It is less clear whether simple neurons, consisting of a few or even a single neurite, may perform local computations as well. To address this question, we focused on the compact neural network of  animals for which the full wiring diagram is available, including the coordinates of individual synapses.

Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment.

To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor-like (SCP-like) population.

The Need for New Treatments Targeting MPNST: The Potential of Strategies Combining MEK Inhibitors with Antiangiogenic Agents.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that represent an important clinical challenge, particularly given their strong tendency to relapse and metastasize and their relatively poor response to conventional therapies. To date, targeted, noncytotoxic treatments have demonstrated limited clinical success with MPNSTs, highlighting the need to explore other key pathways to find novel, improved therapeutic approaches. Here, we review evidence supporting the crucial role of the RAS/MEK/ERK pathway and angiogenesis in MPNST pathogenesis, and we focus on the potential of therapies targeting these pathways to treat this disease.

Linguistic aspects of stuttering: research updates on the language-fluency interface.

Purpose: Although commonly defined as a speech disorder, stuttering interacts with the language production system in important ways. Our purpose is to summarize research findings on linguistic variables that influence stuttering assessment and treatment.

Method And Results: Numerous topics are summarized.

P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis.

Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs.

Adults Who Stutter Show Diminished Word Fluency, Regardless of Mode.

Purpose: Language abilities have long been thought to be weaker in adults who stutter (AWS) compared to adults who do not stutter (AWNS). However, it is unknown whether modality affects language performance by AWS in time pressure situations. This study aimed to examine lexical access and retrieval abilities of AWS in oral and typed modes.

The Index of Productive Syntax: Psychometric Properties and Suggested Modifications.

Purpose: The Index of Productive Syntax (IPSyn) is a well-known language sample analysis tool. However, its psychometric properties have not been assessed across a wide sample of typically developing preschool-age children and children with language disorders. We sought to determine the profile of IPSyn scores by age over early childhood.