IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer.

Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.

Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism.

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches.

Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4.

Fibrosis of lung tissue is a frequent and serious consequence of radiotherapy of mammary carcinoma. The pathogenesis of radiation-induced pulmonary fibrosis remains unclear. Cytokines such as transforming growth factor beta (TGFbeta) and interleukin-4 (IL-4) have been reported to stimulate collagen synthesis in fibroblasts in vitro. The aim of this study was to document the presence of IL-4 during the development of post-irradiation lung fibrosis. Right lungs of male Fischer rats were irradiated with a single dose of 20 Gy and IL-4 expression in the irradiated lungs was monitored for a period of three months. IL-4 gene transcription as determined by ribonuclease protection assay (RPA) as well as IL-4 synthesis as shown by Western blotting increased in the irradiated lungs reaching a plateau concentration within 3 weeks after irradiation. Enhanced IL-4 production was still detected at day 84 after irradiation. The cellular origin of IL-4 was analyzed by in situ hybridization and two-color immunofluorescence on lung tissue sections and on cytospin preparations of leukocytes obtained from bronchoalveolar lavages. These experiments revealed a substantial IL-4 production by macrophages during development of post-irradiation lung fibrosis.

Respiratory failure produced by severe procainamide intoxication in a patient with preexisting peripheral neuropathy caused by amiodarone.

We describe a patient in whom respiratory failure, due to extreme neuromuscular weakness, was produced by procainamide intoxication superimposed on a peripheral neuropathy secondary to long-term amiodarone therapy. Respiratory failure reversed rapidly after procainamide was discontinued, and the serum level fell to a therapeutic range.

Complications of transthoracic needle biopsy decreased with isobutyl 2-cyanoacrylate: a pilot study.

To explore the possibility of performing percutaneous lung biopsy safely in patients mechanically ventilated with positive-end expiratory pressure (PEEP), transthoracic needle biopsy was performed in 16 anesthetized mongrel dogs mechanically ventilated with 10 cm H2O of PEEP. To obtain the biopsy sample, a 25-gauge "skinny needle" was passed through a 20-gauge sheath and placed up to 6.25 cm deep. After satisfactory samples were obtained, both needles were withdrawn in the control group, but in the treated group, the outer sheath was used to inject 0.5 ml of isobutyl 2-cyanoacrylate to seal the needle track. Pneumothorax was present in 7 (87.5%) of 8 dogs in the control group and in 2 (25%) of 8 dogs in the treated group (p = .0147). Lung tissue exhibited an apparent foreign-body granulomatous inflammatory reaction. This technique could extend the benefits of transthoracic needle biopsy to mechanically ventilated patients, but further studies to prove the safety of isobutyl 2-cyanoacrylate are necessary.