Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure–activity relationships.     

Effects of SARS-CoV-2 infection on neuroimaging and neurobehavior in neonates

Background We collected neonatal neurological,clinical,and imaging data to study the neurological manifestations and imaging characteristics of neonates with co...     

Unfinished Business in Classifying HPV-Positive Oropharyngeal Carcinoma: Identifying the Bad Apples in a Good Staging Barrel

This commentary highlights three important findings in the study by Vijayvargiya et al, published in this journal, involving 9554 oropharyngeal cancer patients from the SEER database. Firstly, there is improved performance in outcome prediction with TNM-8 in HPV+ OPC. However, heterogeneity exists, especially in TNM-8 stage I disease, and there is need for ongoing improvement in risk stratification. Several anatomical and non-anatomical prognostic factors have been proposed. Among them, radiologic extranodal extension has emerged as one of the promising parameters to be considered for future staging. These baseline prognostic factors should address sensitivity, specificity, and diagnostic accuracy to serve different clinical needs. Secondly, cure is possible for some patients presenting with M1 disease. Optimal management of such patients remains to be explored, and clinical trials targeting de novo M1 disease should be encouraged to optimize outcomes for this subset. Finally, methodologies to address missing tumor HPV status in historical cohorts have been discussed, including using baseline demographics and clinical characteristics, as well as statistical procedures such as multiple imputation.     

Histamine H4 receptor regulates Th2-cytokine profile through thymic stromal lymphopoietin in allergic rhinitis

European Archives of Oto-Rhino-Laryngology - Epithelial thymic stromal lymphopoietin (TSLP) promotes Th2 inflammatory responses through induction of OX40 ligand (OX40L) on dendritic cells in...     

Melatonin inhibits EMT and PD‐L1 expression through the ERK1/2/FOSL1 pathway and regulates anti‐tumor immunity in HNSCC

Melatonin is an endogenous hormone with various biological functions and possesses anti‐tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in patients with HNSCC were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among patients with HNSCC. Moreover, melatonin significantly suppressed programmed death‐ligand 1 (PD‐L1) expression and inhibited epithelial–mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and in vivo. In SCC7/C3H syngeneic mouse models, anti‐programmed death‐1 (PD‐1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti‐tumor immunity by increasing CD8⁺ T cell infiltration and decreasing the regulatory T cell (Treg) proportion in the tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD‐L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti‐PD‐1 antibody in vivo, which could provide promising strategies for HNSCC treatment.     

Network pharmacology explores the mechanisms of Eucommia ulmoides cortex against postmenopausal osteoporosis

Postmenopausal osteoporosis (PMOP) has become one of most frequent chronic disease worldwide with aging population. Eucommia ulmoides cortex (EU), a traditional Chinese medicine, has long since been used to treat PMOP. The aim of this study is to explore pharmacological mechanisms of EU against PMOP through using network pharmacology approach.The active ingredients of EU were obtained from Traditional Chinese Medicine System Pharmacology database, and target fishing was performed on these ingredients in UniProt database for identification of their relative targets. Then, we screened the targets of PMOP using GeneCards database and DisGeNET database. The overlapping genes between PMOP and EU were obtained to performed protein–protein interaction, Gene Ontology analysis, Kyoto encyclopedia of genes, and genomes analysis.Twenty-eight active ingredients were identified in EU, and corresponded to 207 targets. Also, 292 targets were closely associated with PMOP, and 50 of them matched with the targets of EU were considered as therapeutically relevant. Gene ontology enrichment analysis suggested that EU exerted anti-PMOP effects via modulating multiple biological processes including cell proliferation, angiogenesis, and inflammatory response. Kyoto encyclopedia of genes and genomes enrichment analysis revealed several pathways, such as PI3K-AKT pathway, mitogen-activated protein kinase pathway, hypoxia-inducible factors-1 pathway, tumor necrosis factor pathway, and interleukin-17 pathway that might be involved in regulating the above biological processes.Through the method of network pharmacology, we systematically investigated the mechanisms of EU against PMOP. The multi-targets and multi-pathways identified here could provide new insights for further determination of more exact mechanisms of EU.     

Novel Amdoparvovirus Infecting Farmed Raccoon Dogs and Arctic Foxes

A new amdoparvovirus, named raccoon dog and fox amdoparvovirus (RFAV), was identified in farmed sick raccoon dogs and arctic foxes. Phylogenetic analyses showed that RFAV belongs to a new species within the genus Amdoparvovirus of the family Parvoviridae. An RFAV strain was isolated in Crandell feline kidney cell culture.     

Nitric oxide-mediated bystander effect induced by heavy-ions in human salivary gland tumour cells

Purpose : To investigate the signal factor and its function in the medium-mediated bystander effect during heavy-ion irradiation of human salivary gland (HSG) neoplastic cells. Materials and methods : Unirradiated recipient HSG cells were co-cultivated with HSG donor cells irradiated with 290 MeV/u carbon beams having different LET values. Cell proliferation and micronucleus (MN) induction in recipient cells with and without treatment of a NO scavenger (PTIO) were measured and the concentration of nitrite in the co-culture medium was detected. As a direct control, the effects of a nitric oxide (NO) generator (sper/NO) on cell proliferation and MN induction were also examined. Results : Increases in cell proliferation and MN induction were found in the recipient HSG cells as a result of co-culturing and cell proliferation was obviously enhanced during a further subculture. In comparison with 13 keV/ μ m, 100 keV/ μ m carbon-ion irradiation was found to be a more efficient inducer of the medium-mediated bystander effect. The treatment of cells by PTIO resulted in elimination of such effects, which supports a role for NO in the medium-mediated bystander effect. As an oxidization product of NO, nitrite was detected in the co-culture medium, and the dose-response for its concentration was similar to that of cell proliferation and MN induction in the recipient cells. When the HSG cells were treated by sper/NO with a concentration of less than 20 μ M, cell proliferation was enhanced, whereas MN increased along with sper/NO concentration. Conclusion : NO participated in the medium-mediated bystander effects on cell proliferation and MN induction, depending on the LET of irradiation.     

Poland's syndrome complicated with breast cancer: mammographic, ultrasonographic, and computed tomographic findings

Poland's syndrome is a rare congenital anomaly characterized by unilateral chest wall hypoplasia and ipsilateral hand abnormalities. It has been reported in association with various malignancies and other developmental defects. We report here the case of a 58-year-old woman with Poland's syndrome who developed breast cancer in the ipsilateral normal breast. A review of the literature reveals that two studies of breast carcinoma associated with Poland's syndrome have been reported, but this paper is the first example of a carcinoma occurring in an otherwise normal breast associated with Poland's syndrome.