The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

Keywords: Adrenergic signaling in cardiomyocytes; cardiac muscle contraction; Chagas disease; diabetic cardiomyopathy; dilated cardiomyopathy; glycerolipid metabolism; glycolisis/glucogenesis; hypertrophic cardiomyopathy; purine metabolism; steroid hormone biosynthesis.

This research explores the predictive capabilities of autonomous driving systems by integrating human factor considerations within the context of safety-critical events. Recognizing the significance of human behaviors in influencing driving dynamics, the study employs advanced modeling techniques to enhance the accuracy of predictions in scenarios that demand heightened safety measures. Traditional rule-based systems and monotonic logic often fall short in addressing the complexities of safety-critical events. To overcome these limitations, the research proposes the application of non-monotonic logic, allowing for flexible and adaptive reasoning that accommodates exceptions and context-specific information.The study emphasizes the importance of incorporating individual differences among drivers, such as risk-taking tendencies, reaction times, decision-making processes, and driving styles. By considering these human factors, the research aims to develop realistic and accurate autonomous driving models that capture the nuances of real-world driving scenarios, especially in safety-critical situations. The predictive model takes into account both internal and external factors, enabling the autonomous system to anticipate and respond effectively to unforeseen events.The primary goal is to provide autonomous vehicles with the capability to make plausible inferences, handle conflicting data, and adapt their behavior in real-time during safety-critical events. The proposed model integrates personalized cognitive agents for each driver, incorporating their unique preferences, characteristics, and needs. This personalized approach aims to optimize the safety and efficiency of autonomous driving, contributing to the ongoing evolution of intelligent transportation systems.In conclusion, this research contributes to advancing the field of autonomous driving by introducing a predictive model that leverages human factor considerations to enhance safety in safety-critical events. The incorporation of non-monotonic logic and individualized cognitive agents signifies a comprehensive approach to address the challenges associated with predicting autonomous driving behavior, paving the way for safer and more reliable autonomous vehicles in dynamic and unpredictable environments.

The use of chimeric antigen receptors (CAR-T cells) for the treatment of patients with malignant haematological diseases has become a well-established application, for conditions such as refractory or relapsed B cell acute lymphoblastic leukaemia (B-ALL), B cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR-T cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR-T cells with approval by different regulatory agencies around the globe. In the USA the Food and Drug Administration (FDA) has approved 6 commercial CAR-T cells that are widely distributed worldwide. At the time of this writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR-T cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all the current areas of treatments with CAR-T cells, we offer a brief summary of some of the most relevant aspects of the use of CAR-T cells for some of these conditions.