EGFR Inhibition by Erlotinib Rescues Desmosome Ultrastructure and Keratin Anchorage and Protects Against Pemphigus Vulgaris IgG-Induced Acantholysis in Human Epidermis.

Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity. Especially for the acute phase, additional treatment options allowing to reduce corticosteroids would fulfill an unmet medical need. Here, we provide evidence that epidermal growth factor receptor (EGFR) inhibition by erlotinib ameliorates pemphigus vulgaris immunoglobulin G (PV-IgG) -induced acantholysis in intact human epidermis. PV-IgG caused phosphorylation of EGFR (Y845) and SRC in human epidermis. In line with that, a phosphotyrosine kinome analysis revealed a robust response associated with EGFR and SRC family kinase signaling in response to PV-IgG but not pemphigus foliaceus autoantibodies. Erlotinib inhibited PV-IgG-induced epidermal blistering and EGFR phosphorylation, loss of desmosomes as well as ultrastructural alterations of desmosome size, plaque symmetry, keratin filament insertion and restored the desmosome midline considered as hallmark of mature desmosomes. Erlotinib enhanced both single molecule DSG3 binding frequency and strength and delayed DSG3 fluorescence recovery supporting that EGFR inhibition increases DSG3 availability and cytoskeletal anchorage. Our data indicate that EGFR is a promising target for pemphigus therapy due to its link to several signaling pathways known to be involved in pemphigus pathogenesis.

Initiating Students' Reflections on Life's Passing in the Anatomy Course - an International Observation at 14 Universities.

BACKGROUND: Medical and dental students' feelings and thoughts about the topic of death and life's passing are often associated with learning in the gross anatomy course, when students begin working with a deceased body donor in order to study human anatomy. Little is known of whether the format of anatomy teaching has an impact on these experiences. An observational study was performed to capture the initiation of students' sentiments on the topic of life's passing during the anatomy course at 14 international universities, identify common themes regarding these thoughts, and to study the connection to variations in anatomy course formats and included elements. METHOD: Preclinical anatomy students reflected on one question (i.e., "How did your experience in the anatomy laboratory bring about your reflections on the meaning of life and human existence as well as the sanctity of one's passing?"). Written assignments were collected and anonymously coded. Information on anatomy courses was obtained via faculty questionnaires. RESULT: A variety of themes were identified at the different schools, correlated with different anatomy formats and elements. Results indicate that the courses that offer hands-on cadaveric dissections may play an important role in triggering these sentiments. DISCUSSION: The initiation of students' sentiments about the topic of death varies and includes several themes. There can be a connection to the way anatomy is taught, particularly if hands-on comprehensive cadaveric dissection or prosections are included. CONCLUSION: In summary, anatomy courses can initiate students' thinking about life's passing - particularly in schools that offer hands-on cadaveric dissections or prosections.

Desmosomal Hyperadhesion Is Accompanied with Enhanced Binding Strength of Desmoglein 3 Molecules.

Intercellular adhesion of keratinocytes depends critically on desmosomes that, during maturation, acquire a hyperadhesive and thus Ca2+ independent state. Here, we investigated the roles of desmoglein (Dsg) 3 and plakophilins (Pkps) in hyperadhesion. Atomic force microscopy single molecule force mappings revealed increased Dsg3 molecules but not Dsg1 molecules binding strength in murine keratinocytes. However, keratinocytes lacking Dsg3 or Pkp1 or 3 revealed reduced Ca2+ independency. In addition, Pkp1- or 3-deficient keratinocytes did not exhibit changes in Dsg3 binding on the molecular level. Further, wild-type keratinocytes showed increased levels of Dsg3 oligomers during acquisition of hyperadhesion, and Pkp1 deficiency abolished the formation of Ca2+ independent Dsg3 oligomers. In concordance, immunostaining for Dsg1 but not for Dsg3 was reduced after 24 h of Ca2+ chelation in an ex vivo human skin model, suggesting that desmosomal cadherins may have different roles during acquisition of hyperadhesion. Taken together, these data indicate that hyperadhesion may not be a state acquired by entire desmosomes but rather is paralleled by enhanced binding of specific Dsg isoforms such as Dsg3, a process for which plaque proteins including Pkp 1 and 3 are required as well.