We applied a set of in silico and in vitro assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquine‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID‐19. Each drug or drug combination was tested in patch clamp assays on 7 cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay ® ) using control (healthy) or high‐risk cell populations, and in human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes. In each assay, concentration‐response curves encompassing and exceeding therapeutic free plasma levels were generated. Both chloroquine and hydroxychloroquine showed blocking activity against some potassium, sodium and calcium currents. Chloroquine and hydroxychloroquine inhibited I Kr (IC 50 : 1µM and 3‐7µM, respectively) and I K1 currents (IC 50 : 5 and 44µM, respectively). When combining hydroxychloroquine with azithromycin, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC 50 >300‐1000µM). Using Virtual Assay ® , both antimalarials affected several TdP indicators, chloroquine being more potent than hydroxychloroquine. Effects were more pronounced in the high‐risk cell population. In hiPSC‐derived cardiomyocytes, all drugs showed early‐after‐depolarizations, except azithromycin. Combining chloroquine or hydroxychloroquine with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off‐label use in COVID‐19, chloroquine and hydroxychloroquine use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.
Bladder cancer is a common urinary malignancy and a prevalent cause of cancer-related death. Current therapies of early stage non-muscle-invasive bladder cancer (NMIBC) are frequently associated with undesirable toxicities and recurrence. Active antigen-specific immunotherapy may provide a valid therapeutic option for patients with NMIBC. Cancer-testis antigens (CTA) expressed in various tumour types and in a limited range of healthy tissues may represent potential targets for specific immunotherapy. MAGE-A10 is probably the most immunogenic antigen of the MAGE-A family. We evaluated the expression of MAGE-A10 in NMIBC. Seventy-nine patients undergoing surgical treatment for NMIBC were enrolled in the study. MAGE-A10 gene expression was assessed by quantitative real-time polymerase chain reaction. Immunohistochemistry was performed on paraffin-embedded sections. MAGE-A10 gene was specifically expressed in one-third of NMIBC (n 5 24: 32.43%). Gene expression was correlated with high tumour grade. MAGE-A10 protein was exclusively detectable in nuclei of tumour cells. More importantly, MAGE-A10 protein was also more frequently detectable in high-grade tumours (p 5 0.0001) and in stage T1 tumours invading subepithelial tissue or lamina propria (p 5 0.01). A strong correlation between MAGE-A10 staining score and tumour grade and stage could accordingly be observed. These data indicate that MAGE-A10 expression is a feature of aggressive NMIBC and might be used as a novel target for specific immunotherapy of these cancers. IntroductionTransitional cell bladder carcinoma is the most common malignancy of the urinary tract and a prevalent cause of cancerrelated death. 1 Transurethral resection (TUR) of bladder tumour followed by intravesical immunotherapy with attenuated bacillus Calmette-Guerin or chemotherapy are most commonly used to treat intermediate-or high-risk patients with non-muscle-invasive bladder cancer (NMIBC). 2 These treatments may be associated with related toxicities and suboptimal efficacy possibly leading to tumour progression and recurrence. 2 Active specific tumour immunotherapy generating immune responses directed against antigens predominantly expressed by cancer cells may provide a valid treatment option for patients with NMIBC, alone or in combination with current therapies.Cancer-testis antigens (CTA) are a category of tumourassociated antigens expressed in various types of cancer and in a very limited number of healthy tissues such as testicular germ cells, thymus and placenta. [3][4][5] Because of this expression pattern, they are considered as interesting targets in cancer immunotherapy. 6 To date, several CTA families have been identified including melanoma antigen (MAGE), G antigen 1, New York eosophageal squamous cell carcinoma 1 (NY-ESO-1) and synovial sarcoma. 5 The expression of different CTA in transitional-cell carcinomas has been investigated in the past, and MAGE-A1, ÀA2, ÀA3, ÀA4, ÀA8, ÀA9 and ÀA12 were shown to be expressed in bladder cancer. [7][8][9][10][11][12] MAGE-A10 represe...
These data indicate that IDO gene expression is a feature of aggressive NMIBC, suggesting a potential immunosuppressive role of IDO.
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