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Allosteric modulators (AMs) that bind allosteric sites can exhibit greater selectivity than the orthosteric ligands and can either enhance agonist-induced receptor activity (termed positive allosteric modulator or PAM), inhibit agonist-induced activity (negative AM or NAM), or have no effect on activity (silent AM or SAM). Until now, it is not clear what the exact effects of AMs are on the orthosteric active site or the allosteric binding pocket(s). In the present work, we collected both the three-dimensional (3D) structures of receptor-orthosteric ligand and receptor-orthosteric ligand-AM complexes of a specific target protein. Using our novel algorithm toolset, molecular complex characterizing system (MCCS), we were able to quantify the key residues in both the orthosteric and allosteric binding sites along with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or cryo-electron microscopy (cryo-EM) complexes, including 4 pairs of GPCRs, 5 pairs of ion channels, 11 pairs of enzymes, and 1 pair of transcription factors, we found that the binding of AMs had little impact on both the orthosteric and allosteric binding pockets. In return, given the accurately predicted allosteric binding pocket(s) of a drug target of medicinal interest, we can confidently conduct the virtual screening or lead optimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by heightened autophagy and systemic immune dysfunction. Modest improvements in clinical outcomes have been demonstrated in completed clinical trials targeting autophagy with combination hydroxychloroquine (HCQ) and chemotherapy. Recent mechanistic insights into the role of autophagy-dependent immune evasion have prompted the need for more precise and druggable targets of autophagy inhibition. Sequestosome-1 (SQSTM-1) is a multidomain scaffold protein with well-established roles in autophagy, tumor necrosis factor alpha (TNFα)- and NF-κB-related signaling pathways. SQSTM1 overexpression is frequently observed in PDAC, correlating with clinical stage and outcome. Given the unique molecular structure of SQSTM-1 and its diverse activity, identifying means of limiting SQSTM-1-dependent autophagy to promote an effective immune response in PDAC could be a promising treatment strategy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Designing covalent allosteric modulators brings new opportunities to the field of drug discovery towards G-protein-coupled receptors (GPCRs). Targeting an allosteric binding pocket can allow a modulator to have protein subtype selectivity and low drug resistance. Utilizing covalent warheads further enables the modulator to increase the binding potency and extend the duration of action. This review starts with GPCR allosteric modulation to discuss the structural biology of allosteric binding pockets, the different types of allosteric modulators, as well as the advantages of employing allosteric modulation. This is followed by a discussion on covalent modulators to clarify how covalent ligands can benefit the receptor modulation and to illustrate moieties that can commonly be used as covalent warheads. Finally, case studies are presented on designing class A, B, and C GPCR covalent allosteric modulators to demonstrate successful stories on combining allosteric modulation and covalent binding. Limitations and future perspectives are also covered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Infantile subglottic hemangiomas are rare congenital lesions of the larynx that are difficult to manage. Our experience with 10 cases was reviewed. All patients presented with stridor at birth, or shortly after. The minimum follow-up was 6 months, with an average of 44 months. The patients were classified and treated according to the size of the hemangioma. The treatment included expectant management, systemic steroids, CO2 laser excision, and tracheostomies. Overall, eight patients were cured, one developed subglottic stenosis, and one died due to unrelated causes. We recommend that (1) patients with small lesions (< 25% of lumen) be treated expectantly, (2) patients with moderate lesions (25-60% of lumen) be treated with systemic steroids initially, and CO2 laser excision if steroids fail, and (3) patients with large lesions (> 60% of lumen) be treated with tracheostomies initially, and staged CO2 laser excision.

Children with cystic fibrosis universally have involvement of the paranasal sinuses, and endoscopic management of this sinus disease with its attendant benefits may help them. Ten children with cystic fibrosis underwent examination and computed tomographic scans of their sinuses in 1987 and 1988. All had sinus disease demonstrated and seven went on to undergo endoscopic surgery in the same period. All children had repeated examinations and computed tomographic scans in 1990. All had recurrence or persistence of their sinus disease. However, when the patients and their parents were asked about the subjective value of the surgery all believed there were benefits. I conclude that endoscopic sinus surgery does not eradicate sinus disease in children with cystic fibrosis but that it is of value for symptomatic relief of nasal disease.

This is a case presentation of a neonate with McKusick-Kaufman Syndrome (hydrometrocolpos, polydactyly and congenital heart disease) accompanied by a complete tracheal ring in the distal trachea. This undiagnosed anomaly caused acute respiratory failure after another surgical procedure. Emergent bronchoscopy revealed the diagnosis and the ring was successfully dilated. This is the only known survivor of a complete tracheal ring associated with this syndrome.

Sixteen children with indwelling tracheostomy tubes or Montgomery T-tubes were cared for at home under the supervision of the Respiratory Home Care Program. The infants and children ranged in age from five months to 15 years and required tracheostomy for various forms of pathology. There was one unexpected death at home, but it did not appear to be caused by tracheostomy tube problems. We believe that home tracheostomy care in the pediatric patient is safe and is a great benefit to the wellbeing of the patient.

It is well documented that prolonged endotracheal intubation can lead to subglottic trauma and stenosis. Newborn infants with hyaline membrane disease often require assisted ventilation for prolonged periods of time. We examined 11 such children ranging in age from four months to 4.25 years by endoscopy. Some abnormality was found in every child, and in nine there was minor narrowing of the airway.

Children from the University of Alberta Cystic Fibrosis Clinic were evaluated for nasal polyposis and sinusitis. The results of office examination, coronal CT scanning, and functional endoscopic sinus surgery are compared. Sinonasal disease was found to be ubiquitous in children with cystic fibrosis evaluated with coronal CT scanning. Coronal CT scanning was found to be an accurate predictor of sinonasal disease, and useful for defining the complex anatomy of this region. Outpatient endoscopic sinus surgery, after pre-op assessment by a pediatric pulmonologist, was found to be a safe procedure, with lesser morbidity, than conventional sinus surgery.

Explanation of linguistic ambiguity occurring in a naturalistic context was examined for children and adolescents at various ages. Subjects ages 9 through 18 were asked to explain the meanings of 14 ambiguous advertisements taken from recent magazines, newspapers, and brochures. All of the ads were lexically ambiguous and contained a word or phrase that had both a physical and a psychological meaning (e.g., "Introducing the Upper Crusts. Two sensational new entrees from Stouffer's"). Results were that older subjects explained the meanings correctly more frequently than younger subjects, although adolescents who were 18-years-old did not perform perfectly. It was also found that the psychological meanings of the ads were more difficult to explain than the physical meanings. The results were interpreted in relation to previous developmental studies of ambiguity involving sentences, jokes, and riddles, and studies of figurative language explanation.

Treatment of angiofibromata is both controversial and challenging. The two major treatment modalities are surgery and radiation. Adjuvant treatment with chemotherapy or embolization can be used as well. The major treatment options and adjuvant therapy will be discussed and two illustrative case studies will be presented.