SUMMARY In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur , M. pachydermatis , M. sympodialis , M. globosa , M. obtusa , M. restricta , and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis , M. japonica , M. yamatoensis , M. nana , M. caprae , M. equina , and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia -synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation-induced carcinogenesis.

Malassezia are lipid dependent basidiomycetous yeasts that inhabit the skin and mucosa of humans and other warm-blooded animals, and are a major component of the skin microbiome. They occur as skin commensals, but are also associated with various skin disorders and bloodstream infections. The genus currently comprises 17 species and has recently been assigned its own class, Malasseziomycetes. Importantly, multiple Malassezia species and/or genotypes may cause unique or similar pathologies and vary in their antifungal susceptibility. In addition to culture-based approaches, culture-independent methods have added to our understanding of Malassezia presence and abundance and their relationship to pathogenicity. Moreover, these novel approaches have suggested a much wider-spread presence, including other human body parts and even other ecosystems, but their role in these arenas requires further clarification. With recent successful transformation and genetic engineering of Malassezia, the role of specific genes in pathogenesis can now be studied. We suggest that characterizing the metabolic impact of Malassezia communities rather than species identification is key in elucidation of pathophysiological associations. Finally, the increasing availability of genome sequences may provide key information aiding faster diagnostics, and understanding of the biochemical mechanisms for Malassezia skin adaptation and the design of future drugs.

We present a new method for studying melanin in vivo based on diffuse reflectance spectroscopy of human skin. We find that the optical absorption spectrum of in vivo melanin exhibits an exponential dependence on wavelength, consistent with, but with a higher decay slope than, in vitro results. We offer theoretical justification for this exponential dependence on the basis of a recently proposed model for the structure of eumelanin protomolecules. Moreover, we report on a new method for analysis of diffuse reflectance spectra, which identifies intrinsic differences in absorption spectra between malignant melanoma and dysplastic nevi in vivo. These preliminary results are confirmed both by analysis of our own clinical data as well as by analysis of data from three independent, previously published studies. In particular, we find evidence that the histologic transition from dysplastic nevi to melanoma in situ and then to malignant melanoma is reflected in the melanin absorption spectra. Our results are very promising for the development of techniques for the noninvasive detection of melanoma and, more generally, for the study and characterization of pigmented skin lesions. It is also a promising approach for a better understanding of the biological role, structure, and function of melanin.

Background Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. MethodsWe did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FindingsBetween Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths.Interpretation Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy.Funding Regeneron Pharmaceuticals and Sanofi.

Malassezia yeasts are connected with seborrheic dermatitis (SD) whereas M. furfur pathogenicity is associated with the production of bioactive indoles. In this study, the production of indoles by M. furfur isolates from healthy and diseased skin was compared, the respective HPLC patterns were analyzed, and substances that are preferentially synthesized by strains isolated from SD lesions were isolated and characterized. Malassezin, pityriacitrin, indole-3-carbaldehyde, and indolo[3,2-b]carbazole (ICZ) were isolated by HPLC from extracts of M. furfur grown in L-tryptophan agar, and identified by nuclear magnetic resonance and mass spectroscopy. Of these, ICZ, a potent ligand of the aryl hydrocarbon receptor (AhR), is described for the first time to our knowledge as a M. furfur metabolite. HPLC-photodiode array detection analysis of strain extracts from 7 healthy subjects and 10 SD patients showed that M. furfur isolates from only SD patients consistently produce malassezin and ICZ. This discriminatory production of AhR agonists provides initial evidence for a previously unreported mechanism triggering development of SD and indicates that the variable pathogenicity patterns recorded for M. furfur-associated SD conditions may be attributed to selective production (P<0.001) of measurable bioactive indoles.

This is the first report of drug-induced BP as a group adverse event of the gliptins plus metformin combination therapy for glycaemia control in type 2 diabetes mellitus patients.

Malassezia yeasts are commensal microorganisms which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia associated diseases demonstrated 10–1000 fold higher AhR activating capacity than control skin extracts. LC/MS/MS analysis of the patients’ extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9/12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture-extracts and pure metabolites in HaCaT cells by Reverse Transcriptase Real-Time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1 and AhRR. Indirubin and FICZ activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared to the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development.

The water permeability of the stratum corneum (SC) appears to be regulated primarily by the lamellar arrangement of lipid bilayers between the corneocytes. A significant body of evidence already exists, suggesting that the specific structural organization of these intercellular lipid lamellae is responsible for the very low water permeability of the intact skin and that these lipid-rich structures may also influence the process of desquamation in the SC. In this electron microscopic study the structure of the intercellular domains at different levels within the SC of normal skin from 18 healthy subjects has been evaluated with a special fixation protocol utilizing acrolein vapour as primary fixation, followed by a modified ruthenium tetroxide (RuO4)-post-fixation technique. This procedure permitted an insight into the process of post-secretory extracellular processing of the lamellar body (LB)-derived lipids into lamellar lipid bilayers. This transformation takes place in unique saccular invaginations of the intercellular domains, which indent the underlying stratum granulosum (SG) cells. In this specialized environment LB lipids are first processed into broad sheets before they become part of the typical lamellar lipid structure of the SC. Furthermore, in the process of lipid maturation distinct differences between inner and outer parts of the SC emerge, in particular an increase in both the number of the lamellae per intercellular space, and their order of arrangement. Moreover, distinct structural relationships between desmosomes (at the SG/SC interface and lower SC) and desmosomal remnants (at the stratum disjunctum) on the one hand, and lipid layers on the other, have been demonstrated, pointing to an important functional interaction of these components in normal human skin.