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FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 . Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo . A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation. Synopsis In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies. MYC is a key master regulator of proliferation activated by aberrantly activated FGFR3. FGFR3‐dependent MYC accumulation is dependent on p38, which regulates MYC mRNA levels, and AKT, which stabilizes MYC protein. FGFR3 is directly targeted by MYC. Disrupting the FGFR3/MYC loop using FGFR3, p38, AKT, or BET bromodomain inhibitors decreases cell viability and tumor growth in FGFR3‐dependent cell lines. Evidence for the relevance of the FGFR3/MYC feedback loop to human tumors is provided by the decrease in both FGFR3 and MYC levels induced by a pan‐FGFR inhibitor in a PDX model bearing an FGFR3 mutation, and by the positive correlation between MYC and FGFR3 levels in human tumors with FGFR3 mutations. Graphical Abstract In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies.

Materials in the nanometer size range may possess unique and beneficial properties, which are very useful for different medical applications including stomatology, pharmacy, and implantology tissue engineering. The application of nanotechnology to medicine, known as nanomedicine, concerns the use of precisely engineered materials at this length scale to develop novel therapeutic and diagnostic modalities. Nanomaterials have unique physicochemical properties, such as small size, large surface area to mass ratio, and high reactivity, which are different from bulk materials of the same composition. Polymeric and ceramic nanoparticles have been extensively studied as particulate carriers in the pharmaceutical and medical fields, because they show promise as drug delivery systems as a result of their controlled- and sustained-release properties, subcellular size, and biocompatibility with tissue and cells. These properties can be used to overcome some of the limitations found in traditional therapeutic and diagnostic agents. Nanotechnology is showing promising developments in many areas and may benefit our health and welfare. However, a wide range of ethical issues has been raised by this innovative science. Many authorities believe that these advancements could lead to irreversible disasters if not limited by ethical guidelines.

Background Muscle-invasive bladder cancer (MIBC) is an aggressive neoplasm with poor prognosis, lacking effective therapeutic targets. Oncogenic dependency on members of the TAM tyrosine kinase receptor family (TYRO3, AXL, MERTK) has been reported in several cancer types, but their role in bladder cancer has never been explored. Methods TAM receptor expression was evaluated in two series of human bladder tumours by gene expression (TCGA and CIT series), immunohistochemistry and western blotting analyses (CIT series). The role of the different TAM receptors was assessed by loss-of-function experiments and pharmaceutical inhibition in vitro and in vivo. Results We reported a significantly higher expression of TYRO3, but not AXL or MERTK, in both non-MIBCs and MIBCs, compared to normal urothelium. Loss-of-function experiments identified a TYRO3-dependency of bladder carcinoma-derived cells both in vitro and in a mouse xenograft model, whereas AXL and MERTK depletion had only a minor impact on cell viability. Accordingly, TYRO3-dependent bladder tumour cells were sensitive to pharmacological treatment with two pan-TAM inhibitors. Finally, growth inhibition upon TYRO3 depletion relies on cell cycle inhibition and apoptosis associated with induction of tumour-suppressive signals. Conclusions Our results provide a preclinical proof of concept for TYRO3 as a potential therapeutic target in bladder cancer.

FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3. Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo. A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.

This study analyzes an oral supplement of molecular iodine (I2), alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I2 (5 mg/day) or placebo (colored water) for 7–35 days before surgery. For the Advanced group, 30 patients received I2 or placebo, along with FEC/TE treatment. After surgery, all patients received FEC/TE + I2 for 170 days. I2 supplementation showed a significant attenuation of the side effects and an absence of tumor chemoresistance. The control, I2, FEC/TE, and FEC/TE + I2 groups exhibited response rates of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients treated with the I2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% versus 46%). I2-treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial to analyze chemotherapy + I2 treatment for advanced breast cancer.

ObjectivesSystemic autoinflammatory diseases (SAIDs) represent a set of conditions with exaggerated innate immune responses. IL-1β and IL-18 are key cytokines involved in the pathogenesis of some SAID. We aimed to assess the diagnostic value of serum levels of IL-1β, IL-18, their respective inhibitors IL-1Ra and IL-18 binding protein (IL-18BP), and IFN-γ in SAID.MethodsA cohort of patients with active SAID, including monogenic (mSAID) and genetically undiagnosed SAID (guSAID) from different European countries, with active disease at inclusion, was established. Serum levels of cytokines were measured by immunoassays.ResultsSera from 53 mSAID, 220 guSAID and 49 controls without inflammatory disease were analysed. Serum levels of total and free IL-18 were significantly increased in Still’s disease in comparison to most SAID and non-inflammatory controls. Levels of total IL-18 were also elevated in patients with familial Mediterranean fever to a comparable extent as in Still’s disease. In contrast, free IL-18 levels were selectively higher in Still’s disease. Receiver operating characteristic curve analysis showed that total IL-18 was the most sensitive and specific marker for the diagnosis of Still’s disease (area under the curve=0.91). There was a positive correlation between IL-18 and ferritin. In 10 patients with Still’s disease who had a second blood collection, we found a significant decrease in serum levels of free IL-18 after treatment.ConclusionsOur results show that IL-18 can discriminate Still’s disease from other SAID, and free IL-18 levels may be relevant to assess response to therapy in these patients.

Background FGFR3 mutations are among the most frequent genetic alterations in bladder cancer and are enriched in the luminal papillary subtype of muscle-invasive tumors (MIBC) and luminal-like classes 1 and 3 of non-MIBC. To study their oncogenic properties in vivo, we developed here a genetically engineered mouse (GEM) model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Methods Bladder tumorigenesis was monitored in FGFR3-S249C mice. FGFR3 expression was assessed by RT-qPCR in the transgenic mice urothelium and in various human epithelia. Transcriptomic data were obtained from mouse bladder tumors and cross-species comparisons were performed. Sex bias in FGFR3-mutated tumors was evaluated in our GEM model and in the TCGA and UROMOL cohorts of patients including 408 MIBC and 419 NMIBC, respectively. The association of androgen receptor (AR) activity, based on the expression of its target genes, with FGFR3 mutations was examined in these two cohorts. The binding of AR to its response element and AR phosphorylation in FGFR3-dependent cell lines were evaluated. Results FGFR3-S249C expression in the urothelium of mice induced spontaneous low-grade papillary bladder tumors resembling the human counterpart at the histological and transcriptomic levels. Mutant-FGFR3 expression levels impacted tumor formation incidence in mice and mutant-FGFR3-driven human tumors were restricted to epithelia presenting high normal expression levels of FGFR3. The known bladder cancer male gender bias, also found in our model, was even higher in human FGFR3-mutated compared to wild-type tumors and associated with a higher AR regulon activity considering gender adjustment. AR phosphorylation and regulon activity were modulated by FGFR3 in FGFR3-dependent models. Conclusions Mutant-FGFR3 is an oncogene per se, inducing bladder tumorigenesis. Patients with early-stage bladder lesions could thus potentially benefit from FGFR3 targeting. Our results also reinforce the interest in elucidating the role of AR in bladder carcinogenesis, specifically in FGFR3-mutated driven tumors. Finally, our results suggest FGFR3 expression level in the epithelium as a determinant for the FGFR3-driven tumors tissue specificity. Competing Interest Statement The authors have declared no competing interest.