An uncommon case of a fleeting rash from Western Rajasthan.

A 35 year old farmer presented with an erythematous serpiginous rash on dorsal aspect of left foot with intense pruritus and a feeling of something moving slowly in the rash. The photo of the rash is presented below and the case is discussed further.

Combinations of Toll-like receptor 8 agonist TL8-506 activate human tumor-derived dendritic cells.

BACKGROUND: Dendritic cells (DCs) are professional antigen presenting cells that initiate immune defense to pathogens and tumor cells. Human tumors contain only few DCs that mostly display a non-activated phenotype. Hence, activation of tumor-associated DCs may improve efficacy of cancer immunotherapies. Toll-like receptor (TLR) agonists and interferons are known to promote DC maturation. However, it is unclear if DCs in human tumors respond to activation signals and which stimuli induce the optimal activation of human tumor DCs. METHODS: We first screened combinations of TLR agonists, a STING agonist and interferons (IFNs) for their ability to activate human conventional DCs (cDCs). Two combinations: TL8-506 (a TLR8 agonist)+IFN-γ and TL8-506+Poly(I:C) (a TLR3 agonist) were studied in more detail. cDC1s and cDC2s derived from cord blood stem cells, blood or patient tumor samples were stimulated with either TL8-506+IFN-γ or TL8-506+Poly(I:C). Different activation markers were analyzed by ELISA, flow cytometry, NanoString nCounter Technology or single-cell RNA-sequencing. T cell activation and migration assays were performed to assess functional consequences of cDC activation. RESULTS: We show that TL8-506 synergized with IFN-γ or Poly(I:C) to induce high expression of different chemokines and cytokines including interleukin (IL)-12p70 in human cord blood and blood cDC subsets in a combination-specific manner. Importantly, both combinations induced the activation of cDC subsets in patient tumor samples ex vivo. The expression of immunostimulatory genes important for anticancer responses including CD40, IFNB1, IFNL1, IL12A and IL12B were upregulated on stimulation. Furthermore, chemokines associated with CD8+ T cell recruitment were induced in tumor-derived cDCs in response to TL8-506 combinations. In vitro activation and migration assays confirmed that stimulated cDCs induce T cell activation and migration. CONCLUSIONS: Our data suggest that cord blood-derived and blood-derived cDCs are a good surrogate to study treatment responses in human tumor cDCs. While most cDCs in human tumors display a non-activated phenotype, TL8-506 combinations drive human tumor cDCs towards an immunostimulatory phenotype associated with Th1 responses on stimulation. Hence, TL8-506-based combinations may be promising candidates to initiate or boost antitumor responses in patients with cancer.

Myofibroblasts and their resistance to apoptosis: a possible mechanism of osteoradionecrosis.

Osteoradionecrosis (ORN) in the head and neck area is the most devastating long-term complication of radiotherapy, with slow progression and inability to heal spontaneously. ORN can lead to intolerable pain, fractures, and sequestration of devitalized bone and fistulae, making oral feeding impossible and causing facial deformation. In spite of its notorious reputation over at least 90 years, the precise pathogenesis of ORN has not been fully clarified, which has led to obstacles in the management of the disease. Several theories about its pathogenesis have been formulated, and radiation-induced fibrosis is the newest one. According to this theory, ORN is essentially a type of fibrosis induced by radiotherapy, and antifibrosis therapy has been shown to be effective in its treatment. We assumed that ORN, like fibrosis in other organs, is the result of a process of fibrogenesis in which myofibroblasts are the key effector cells. The uninterrupted accumulation of myofibroblasts and consequent persistent excess production of collagenous extracellular matrix and tensile force result in loss of normal function and ultimately radiation-induced fibrosis. During this process, myofibroblasts may be protected from apoptosis by acquiring an immune-privileged capacity, which allows continuous matrix synthesis. If this hypothesis proves to be correct, it would enable better understanding of the cellular and molecular mechanisms underlying the pathogenesis and progression of ORN, and would help improve our ability to prevent occurrence of ORN, give an earlier diagnosis, and treat it more effectively.