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Tapinarof is a stilbene drug that is used to treat psoriasis and atopic dermatitis, and is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases. It is produced by the gammaproteobacterial Photorhabdus genus, which thus represents a model to probe tapinarof structural and functional transformations. We show that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that a cupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers. One dimer has activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to a cyclopropane-bridge-containing hexacyclic framework that exhibits activity against Mycobacterium. These dimers lack efficacy in a colitis mouse model, whereas the monomer reduces disease symptoms. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.This contribution follows the recent remarkable catalysis observed by Groves et al. this website in hydrogen-abstraction reactions by a) an oxoferryl porphyrin radical-cation complex [Por⋅+ FeIV (O)Lax ] and b) a hydroxoiron porphyrazine ferric complex [PyPzFeIII (OH)Lax ], both of which involve positively charged substituents on the outer circumference of the respective macrocyclic ligands. These charge-coronated complexes are analogues of the biologically important Compound I (Cpd I) and synthetic hydroxoferric species, respectively. We demonstrate that the observed enhancement of the H-abstraction catalysis for these systems is a purely electrostatic effect, elicited by the local charges embedded on the peripheries of the respective macrocyclic ligands. Our findings provide new insights into how electrostatics can be employed to tune the catalytic activity of metalloenzymes and can thus contribute to the future design of new and highly efficient hydrogen-abstraction catalysts. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.The thioredoxin system is highly conserved system found in all living cells and comprises NADPH, thioredoxin, and thioredoxin reductase. This system plays a critical role in preserving a reduced intracellular environment, and its involvement in regulating a wide range of cellular functions makes it especially vital to cellular homeostasis. Its critical role is not limited to healthy cells, it is also involved in cancer development, and is overexpressed in many cancers. This makes the thioredoxin system a promising target for cancer drug development. As such, over the last decade, many inhibitors have been developed that target the thioredoxin system, most of which are small molecules targeting the thioredoxin reductase C-terminal redox center. A few inhibitors of thioredoxin have also been developed. We believe that more efforts should be invested in developing protein/peptide-based inhibitors against both thioredoxin reductase and/or thioredoxin. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.OBJECTIVE To investigate the relation of age at disease onset and clinical outcomes across the life-span from adolescence in multiple sclerosis (MS) patients on disease-modifying therapy (DMT). METHODS We analysed data from the Swiss association for joint tasks of health insurers database containing data from 14,718 MS patients. Patients were included in this analysis when they were on DMT for at least one year. The influence of age at disease onset on future relapses and disability worsening was explored with multivariable Cox proportional hazard regression models. RESULTS Data from 9,705 MS patients was analysed. Pediatric-onset patients (n=236) had higher relapse rates and marginally slower disability worsening rates compared with adult-onset MS patients (n=9,469). The risk for relapses was highest in childhood and decreased continuously to about 35 years of age. It remained stable for about a decade and then again continuously decreased. In contrast, disability worsening hazards remained stable from childhood to about 32 years of age and then increased sharply around the age of 45 years. CONCLUSIONS Age is an important factor affecting clinical outcomes in MS. This should be considered when designing clinical trials or choosing DMT. This article is protected by copyright. All rights reserved.BACKGROUND Oral cancer patients can benefit from dental implant placement. Traditionally, implants are placed after completing oncologic treatment (secondary implant placement). Implant placement during ablative surgery (primary placement) in oral cancer patients seems beneficial in terms of early start of oral rehabilitation and limiting additional surgical interventions. Guidelines on the ideal timing of implant placement in oral cancer patients are missing. OBJECTIVE To perform a scoping literature review on studies examining the timing of dental implant placement in oral cancer patients and propose a clinical practice recommendations guideline. METHODS A literature search for studies dealing with primary and/or secondary implant placement in MEDLINE was conducted (last search December 27, 2019). The primary outcome was 5-year implant survival. RESULTS Sixteen out of 808 studies were considered eligible. Both primary and secondary implant placement showed acceptable overall implant survival ratios with a higher pooled 5-year implant survival rate for primary implant placement 92.8% (95% CI 87.1%-98.5%) than secondary placed implants (86.4%, 95% CI 77.0%-95.8%). Primary implant placement is accompanied by earlier prosthetic rehabilitation after tumor surgery. CONCLUSION Patients with oral cancer greatly benefit from, preferably primary placed, dental implants in their prosthetic rehabilitation. The combination of tumor surgery with implant placement in native mandibular bone should be provided as standard care. © 2020 The Authors. Oral Diseases published by John Wiley & Sons Ltd.BACKGROUND Distant metastases (DMs) are the primary cause of treatment failure in patients with salivary gland carcinoma. There is no consensus on the standard treatment. METHODS Patients with DMs were identified from an institutional database of 884 patients with salivary gland cancer who underwent resection of the primary tumor between 1985 and 2015. Survival outcomes for patients with DMs were determined with the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify factors associated with DM. RESULTS Of the 884 patients identified, 137 (15%) developed DMs during follow-up. Most of the primary tumors (n = 77 [56%]) were located in a major salivary gland. At clinical presentation, 53% of the tumors were classified as T3 or T4, and 32% had clinical node metastases. The median time to DM was 20.3 months. The factors associated with shorter distant recurrence-free survival were male sex, high-risk tumor histology, and advanced pathological T and N classifications. Patients with bone metastases had a lower survival rate than patients with lung metastases.
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