Increased Doses of Adalimumab are Associated With Clinical Improvement of Hidradenitis Suppurativa.

BACKGROUND: TNF-inhibitor adalimumab 40 mg/week (ADA40) is the only approved treatment for hidradenitis suppurativa (HS); however, it is not uniformly effective. Despite a high prevalence of comorbid obesity in HS patients, adalimumab dosing is not weight-based, unlike other TNF-inhibitors. OBJECTIVE: To evaluate the effectiveness of adalimumab 80 mg/week (ADA80) compared with ADA40 in overweight and obese patients with moderate to severe HS. METHODS: We conducted a dual-center retrospective chart review of HS patients treated with ADA80 between August 2016 and December 2021. We collected data on demographics, comorbidities, treatments, and disease severity that are presented as descriptive statistics and compared with Wilcoxon signed-rank test. RESULTS: Eight patients with median body mass index of 36.6 (IQR 32.5–40.7) and no improvements in HS severity on ADA40 were prescribed ADA80. Patients experienced improved HS-Physician Global Assessment (ADA40: median 3.0 (3.0-3.8); ADA80: (2.0 (1.8, 2.0)) (P=0.01)), all 5 patients who had lesion counts documented achieved HS Clinical Response, and all 8 patients reported symptom improvements. CONCLUSIONS: Increased adalimumab dose may be associated with improved outcomes for overweight and obese patients with moderate to severe HS. J Drugs Dermatol. 2023;22(6) doi:10.36849/JDD.6868.

Structure of VanS from vancomycin-resistant enterococci: A sensor kinase with weak ATP binding.

The VanRS two-component system regulates the resistance phenotype of vancomycin-resistant enterococci. VanS is a sensor histidine kinase that responds to the presence of vancomycin by autophosphorylating and subsequently transferring the phosphoryl group to the response regulator, VanR. The phosphotransfer activates VanR as a transcription factor, which initiates the expression of resistance genes. Structural information about VanS proteins has remained elusive, hindering the molecular-level understanding of their function. Here, we present X-ray crystal structures for the catalytic and ATP-binding (CA) domains of two VanS proteins, derived from vancomycin-resistant enterococci types A and C. Both proteins adopt the canonical Bergerat fold that has been observed for CA domains of other prokaryotic histidine kinases. We attempted to determine structures for the nucleotide-bound forms of both proteins; however, despite repeated efforts, these forms could not be crystallized, prompting us to measure the proteins' binding affinities for ATP. Unexpectedly, both CA domains displayed low affinities for the nucleotide, with KD values in the low millimolar range. Since these KD values are comparable to intracellular ATP concentrations, this weak substrate binding could reflect a way of regulating expression of the resistance phenotype.

Characterizing the cellular architecture of dynamically remodeling vascular tissue using 3-D image analysis and virtual reconstruction.

Epithelial tubules form critical structures in lung, kidney, and vascular tissues. However, the processes that control their morphogenesis and physiological expansion and contraction are not well understood. Here we examine the dynamic remodeling of epithelial tubes in vivo using a novel model system: the extracorporeal vasculature of Botryllus schlosseri, in which the disruption of the basement membrane triggers rapid, massive vascular retraction without loss of barrier function. We developed and implemented 3-D image analysis and virtual reconstruction tools to characterize the cellular morphology of the vascular wall in unmanipulated vessels and during retraction. In both control and regressed conditions, cells within the vascular wall were planar polarized, with an integrin- and curvature-dependent axial elongation of cells and a robust circumferential alignment of actin bundles. Surprisingly, we found no measurable differences in morphology between normal and retracting vessels under extracellular matrix (ECM) disruption. However, inhibition of integrin signaling through focal adhesion kinase inhibition caused disruption of cellular actin organization. Our results demonstrate that epithelial tubes can maintain tissue organization even during extreme remodeling events, but that the robust response to mechanical signals-such as the response to loss of vascular tension after ECM disruption-requires functional force sensing machinery via integrin signaling.