Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade.

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained.

Paths to learning: How residents navigate transience in supervisory relationships in the emergency department.

Background: Strong relationships between trainees and physician supervisors can positively influence how trainees navigate workplace learning. How trainees act and learn in clinical workplaces characterized by rapidly developing and dissolving supervisory pairings is less well understood. This study uses the emergency department (ED) to examine the impact of transient supervisory relationships on how residents approach clinical learning opportunities.

Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade.

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained.

Preprocedural Oxygenation and Procedural Oxygenation During Pediatric Procedural Sedation: Patterns of Use and Association With Interventions.

Study Objective: Preprocedural oxygenation (pre-emptive oxygenation started during presedation and/or induction) and procedural oxygenation (pre-emptive oxygenation started during any phase of sedation) are easy-to-use strategies with potential to decrease adverse events. Here, we describe practice patterns of preprocedural oxygenation and procedural oxygenation. We hypothesized that patients who received preprocedural oxygenation or procedural oxygenation would have a lower risk of airway/breathing/circulation interventions during sedation compared with patients without procedural oxygenation.

Determination, categorization, and hierarchy of content for a pediatric emergency medicine curriculum designed for emergency medicine residents.

Background: Currently, the Accreditation Council of Graduate Medical Education requires time-based pediatric experiences for emergency medicine (EM) residents in both pediatric emergency medicine (PEM) and critical care settings. The American Board of Emergency Medicine has published the Model of the Clinical Practice of Emergency Medicine, which is a list of content an EM resident should learn. However, this list is large and without prioritization and therefore can be difficult to incorporate into time-limited curricula.

The multifaceted role of the CXC chemokines and receptors signaling axes in ALS pathophysiology.

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS.

In vitro exposure to PM of olfactory Ensheathing cells and SH-SY5Y cells and possible association with neurodegenerative processes.

PM exposure represents a risk factor for the public health. PM is able to cross the blood-alveolar and blood-brain barriers and reach the brain through three routes: nasal olfactory pathway, nose-brain pathway, blood-brain barrier pathway. We evaluated the effect of PM to induce cytotoxicity and reduced viability on in vitro cultures of OECs (Olfactory Ensheathing Cells) and SH-SY5Y cells.

Neuroprotective effect of the PACAP-ADNP axis on SOD1G93A mutant motor neuron death induced by trophic factors deprivation.

Amyotrophic lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the central nervous system. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately in 20% of familial ALS cases. The pathological mechanisms underlying the toxicity induced by mutated SOD1 are still unknown.

Transcriptomic Analysis in the Hippocampus and Retina of Tg2576 AD Mice Reveals Defective Mitochondrial Oxidative Phosphorylation and Recovery by Tau 12A12mAb Treatment.

Increasing evidence implicates decreased energy metabolism and mitochondrial dysfunctions among the earliest pathogenic events of Alzheimer's disease (AD). However, the molecular mechanisms underlying bioenergetic dysfunctions in AD remain, to date, largely unknown. In this work, we analyzed transcriptomic changes occurring in the hippocampus and retina of a Tg2576 AD mouse model and wild-type controls, evaluating their functional implications by gene set enrichment analysis.

The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, β, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA () and protein immunoreactivity in a subset of sporadic ALS patients.

Alternative care sites and resident exposure in pediatric emergency medicine: Who, what, and where.

Objectives: Emergency medicine (EM) physicians and pediatricians who provide acute pediatric care depend on clinical exposure during residency to learn pediatric EM. Increasing volumes of pediatric patients, especially with behavioral health complaints, have stressed pediatric emergency departments (ED) and prompted clinical operations innovations including alternative care sites outside the main ED. We investigated the impact of these recent trends and resulting alternative care sites on the exposure of residents to core pediatric conditions.

Detection of Single-Nucleotide and Copy Number Defects Underlying Hyperphenylalaninemia by Next-Generation Sequencing.

Hyperphenylalaninemia (HPA) is the most common inherited amino acid metabolism disorder characterized by serious clinical manifestations, including irreversible brain damage, intellectual deficiency and epilepsy. Due to its extensive genic and allelic heterogeneity, next-generation sequencing (NGS) technology may help to identify the molecular basis of this genetic disease. Herein, we describe the development and validation of a targeted NGS (tNGS) approach for the simultaneous detection of single-nucleotide changes and copy number variations (CNVs) in genes associated with HPA (, , , , , ) or useful for its differential diagnosis ().

CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice.

Critical Revisits Among Children After Emergency Department Discharge.

Study Objective: Identifying higher risk groups could reveal ways to prevent critical emergency department (ED) revisits. The study objectives were to determine the rate of critical ED revisits among children discharged from the ED and to identify factors associated with critical revisits.

Methods: We performed a retrospective study using the Healthcare Cost and Utilization Project State ED Databases (SEDD) and the State Inpatient Databases (SID).

The Cleavage-Specific Tau 12A12mAb Exerts an Anti-Amyloidogenic Action by Modulating the Endocytic and Bioenergetic Pathways in Alzheimer's Disease Mouse Model.

Beyond deficits in hippocampal-dependent episodic memory, Alzheimer's Disease (AD) features sensory impairment in visual cognition consistent with extensive neuropathology in the retina. 12A12 is a monoclonal cleavage specific antibody (mAb) that in vivo selectively neutralizes the AD-relevant, harmful N-terminal 20-22 kDa tau fragment(s) (i.e.

Analyses of single extracellular vesicles from non-small lung cancer cells to reveal effects of epidermal growth factor receptor inhibitor treatments.

Precision cancer medicine has changed the treatment landscape of non-small cell lung cancer (NSCLC) as illustrated by the introduction of tyrosine kinase inhibitors (TKIs) towards mutated epidermal growth factor receptor (EGFR). However, as responses to EGFR-TKIs are heterogenous among NSCLC patients, there is a need for ways to early monitor changes in treatment response in a non-invasive way e.g.

Cracking the Code of Neuronal Cell Fate.

Transcriptional regulation is fundamental to most biological processes and reverse-engineering programs can be used to decipher the underlying programs. In this review, we describe how genomics is offering a systems biology-based perspective of the intricate and temporally coordinated transcriptional programs that control neuronal apoptosis and survival. In addition to providing a new standpoint in human pathology focused on the regulatory program, cracking the code of neuronal cell fate may offer innovative therapeutic approaches focused on downstream targets and regulatory networks.

Updates in pediatric emergency medicine for 2022.

As a relatively new field, there has been a recent explosion in evidence around the management of children in the emergency department (ED). This review highlights 10 articles published in the last year providing evidence that is germane to the care of children by emergency medicine (EM) physicians. There is a focus on high prevalence conditions, such as fever and trauma, as well as interventions that can improve mortality, such as cardiopulmonary resuscitation and massive transfusion.

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem metabolic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the cells. Although biochemical enzymatic assays are considered the gold standard for diagnosis of symptomatic patients, genotyping is a requirement for inclusion in enzyme replacement programs and is a prerequisite for carrier tests in relatives and DNA-based prenatal diagnosis. The emerging next-generation sequencing (NGS) technologies are now offering a powerful diagnostic tool for genotyping LSDs patients by providing faster, cheaper, and higher-resolution testing options, and are allowing to unravel, in a single integrated workflow SNVs, small insertions and deletions (indels), as well as major structural variations (SVs) responsible for the pathology.

A Targeted Next-Generation Sequencing Panel to Genotype Gliomas.

Gliomas account for the majority of primary brain tumors. Glioblastoma is the most common and malignant type. Based on their extreme molecular heterogeneity, molecular markers can be used to classify gliomas and stratify patients into diagnostic, prognostic, and therapeutic clusters.