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Advanced-stage lesions of the hypopharynx or tongue base often involve the larynx. The difficulty of reconstructing large partial laryngopharyngeal defects can result in total laryngectomy being performed to avoid the assumed problems with aspiration. This article describes the first reported experience using the pectoralis musculocutaneous flap for primary one-stage reconstruction of laryngopharyngeal defects following resection of advanced-stage lesions, to reconstruct both the laryngeal and the pharyngeal components of the defect. In this group of 21 patients, there were 16 with hypopharyngeal and 5 with tongue base cancers. Two had received prior treatment, and all received some form of postoperative radiotherapy and/or chemotherapy. Six patients experienced complications, including two fistulae, three wound infections, two myocardial infarctions, and one colon perforation. There were no instances of stenosis of the reconstructed segment. The length of hospitalization ranged from 9 to 60 days, the average being 17 days. Forty-seven percent (21) of the patients were not tolerating an oral diet at the time of discharge. However, 15 patients (71%) ultimately were eating by mouth, with 13 (62%) achieving an oral intake of liquids and solids. This analysis supports the hypothesis that the pectoralis major musculocutaneous flap is an effective one-stage primary reconstruction technique for laryngopharyngeal defects in patients either who have received prior therapy or who will receive postoperative therapy. [ABSTRACT FROM AUTHOR]

Background: There are approximately 10,000 rare diseases that affect around 30,000,000 individuals in the U.S.A., most of which do not have an FDA-approved treatment. This fact highlights the failure of traditional research approaches to overcome the unique challenges of developing rare disease treatments. The Castleman Disease Collaborative Network was founded in 2012 to advance research and treatments for Castleman disease, a rare and deadly disease that involves the immune system attacking the body's vital organs for an unknown cause. It has spearheaded a novel strategy for advancing biomedical research, the Collaborative Network Approach. This approach consists of eight steps, one of which is to identify and prioritize high-impact research questions through crowdsourcing ideas from the entire community of stakeholders: patients, loved ones, physicians, and researchers. Rather than hoping that the right researcher will apply for the right research project at the right time, crowdsourcing high-priority research projects into a research strategy ensures that the most high-impact, patient-centered studies are prioritized. The Castleman Disease Collaborative Network launched an initiative in 2021 to systematically generate this list of community-directed studies to focus Castleman disease research efforts., Results: The Castleman Disease Collaborative Network was able to successfully create a patient-centered research agenda through engaging the entire community of stakeholders. The community contributed important questions about Castleman disease, which were prioritized and reviewed by our Scientific Advisory Board, and the result was a finalized list of studies that address these prioritized questions. We were also able to generate a best practices list which can serve as a model that can be utilized for other rare diseases., Conclusion: Creating a patient-centered research agenda through crowdsourcing research ideas from the community is one of the most important ways that the Castleman Disease Collaborative Network operationalizes its commitment to keeping patients at the center of research and we hope that by sharing these insights we can assist other rare disease organizations to pursue a patient-centric approach., (© 2023. The Author(s).)

Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure., Competing Interests: A.L. reports employment and equity ownership from BridgeBio Pharma. A.R. reports consultancy to LabCorp and Consonance Capital, board member of Safeguard Biosystems, and member of academic advisory council to AMN. S.F. reports consultancy, advisory board membership, research funding, and speakers’ honoraria from Janssen Pharmaceuticals; consultancy, advisory board membership, and speakers’ honoraria from EUSA Pharma; advisory board membership in Clinigen; speakers’ honoraria from Servier; and research funding from Gilead. P.L.Z. reports consultancy to Verastem, MSD, EUSA Pharma, and Sanofi; speakers’ bureau of Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, Immune Design, Celgene, Portola, Roche, EUSA Pharma, and Kyowa Kirin; advisory board membership in Verastem, Celltrion, Gilead, and Janssen-Cilag, BMS, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi. L.T. reports advisory board membership in EUSA Pharma. C.C. reports consultancy to EUSA Pharma. E.O. reports advisory board membership in and consultancy to EUSA Pharma. G.S. reports speakers’ bureau involvement with Takeda, Janssen Pharmaceuticals, Foundation Medicine, and EUSA Pharma. T.S.U. reports research support from Roche and Celgene and receives study drug for a clinical trial from Merck. F.v.R. reports a consultancy relationship with Takeda, Sanofi Genzyme, EUSA Pharma, Adicet Bio, Kite Pharma, and Karyopharm Therapeutics. D.C.F. reports research funding from Janssen Pharmaceuticals (former financial sponsor) and EUSA Pharma (current financial sponsor) for the ACCELERATE Natural History Registry, donation of study drug from Pfizer for NCT03933904, and a provisional patent application filed by the University of Pennsylvania for Methods of Treating Idiopathic Multicentric Castleman disease with JAK1/2 inhibition (62/989,437). All of the other authors report no competing interests., (© 2020 The Authors.)

The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA . Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.

Mechanisms of protein-carbohydrate recognition attract a lot of interest due to their roles in various cellular processes and metabolism disorders. We have performed a large-scale analysis of protein structures solved in complex with glucose, galactose and their substituted analogues. We found that, on average, sugar molecules establish five hydrogen bonds (HBs) in the binding site, including one to three HBs with bridging water molecules. The free energy contribution of bridging and direct HBs was estimated using the free energy perturbation (FEP+) methodology for mono- and disaccharides that bind to l-ABP, ttGBP, TrmB, hGalectin-1 and hGalectin-3. We show that removing hydroxy groups that are engaged in direct HBs with the charged groups of Asp, Arg and Glu residues, protein backbone amide or buried water dramatically decreases binding affinity. In contrast, all solvent-exposed hydroxy groups and hydroxy groups engaged in HBs with the solvent-exposed bridging water molecules contribute weakly to binding affinity and so can be replaced to optimize ligand potency. Finally, we rationalize an effect of binding site water replacement on the binding affinity to l-ABP., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.

Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and protein-protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-α-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post-processing with physics-based implicit solvent MM-GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD ≤ 2.0 Å for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach.