Hidradenitis suppurativa: a new, principle-centered paradigm for managing a dynamic disease.

Hidradenitis suppurativa (HS) is a chronic, debilitating skin condition that disproportionately affects socioeconomically underserved patients. Currently, treatment outcomes for patients with HS remain poor, largely because of a deficiency in current guidelines on exactly how and when to employ the myriad treatment tools, resulting in heterogeneous care models and confusion. Aggressive medical therapy is often started too late, pursued for too long whilst delaying procedural intervention, or skipped over altogether for procedures.

Multiple atypical vascular lesions following breast-conserving surgery and radiation.

Atypical vascular lesions (AVLs) of the breast are purple papules or nodules that have been reported in breast cancer patients following radiation treatment, typically presenting with fewer than 5 lesions at diagnosis. We report a patient with 29 lesions within previously irradiated breast tissue. Due to the large number of lesions and concern for development of angiosarcoma, the patient's case was brought before a multidisciplinary tumor board that decided she should undergo a radical mastectomy with flap reconstruction.

Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation.

Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3.

Multiple Cathepsins Promote Pro-IL-1β Synthesis and NLRP3-Mediated IL-1β Activation.

Sterile particles induce robust inflammatory responses that underlie the pathogenesis of diseases like silicosis, gout, and atherosclerosis. A key cytokine mediating this response is IL-1β. The generation of bioactive IL-1β by sterile particles is mediated by the NOD-like receptor containing a pyrin domain 3 (NLRP3) inflammasome, although exactly how this occurs is incompletely resolved.

Inducing cells to disperse nickel nanowires via integrin-mediated responses.

We present non-cytotoxic, magnetic, Arg-Gly-Asp (RGD)-functionalized nickel nanowires (RGD-nanowires) that trigger specific cellular responses via integrin transmembrane receptors, resulting in dispersal of the nanowires. Time-lapse fluorescence and phase contrast microscopy showed that dispersal of 3 μm long nanowire increased by a factor of 1.54 with functionalization by RGD, compared to polyethylene glycol (PEG), through integrin-specific binding, internalization and proliferation in osteosarcoma cells.

Suppression of systemic autoimmunity by the innate immune adaptor STING.

Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates.

The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C.

The sterile inflammatory response to cell death and irritant crystals is medically important because it causes disease. Although these stimuli are structurally distinct, they cause inflammation through a common pathway that requires the cytokine IL-1. In vitro, the inflammasome, and in particular its generation of active caspase-1, is absolutely required to produce bioactive IL-1β.

Actin reorganization is required for the formation of polarized B cell receptor signalosomes in response to both soluble and membrane-associated antigens.

B cells encounter both soluble Ag (sAg) and membrane-associated Ag (mAg) in the secondary lymphoid tissue, yet how the physical form of Ag modulates B cell activation remains unclear. This study compares actin reorganization and its role in BCR signalosome formation in mAg- and sAg-stimulated B cells. Both mAg and sAg induce F-actin accumulation and actin polymerization at BCR microclusters and at the outer rim of BCR central clusters, but the kinetics and magnitude of F-actin accumulation in mAg-stimulated B cells are greater than those in sAg-stimulated B cells.

Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells.

Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity.

Btk regulates B cell receptor-mediated antigen processing and presentation by controlling actin cytoskeleton dynamics in B cells.

The high efficiency of Ag processing and presentation by B cells requires Ag-induced BCR signaling and actin cytoskeleton reorganization, although the underlying mechanism for such requirements remains elusive. In this study, we identify Bruton's tyrosine kinase (Btk) as a linker connecting BCR signaling to actin dynamics and the Ag transport pathway. Using xid mice and a Btk inhibitor, we show that BCR engagement increases actin polymerization and Wiskott-Aldrich syndrome protein activation in a Btk-dependent manner.