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• CAR-T therapy offers durable remissions in refractory hematological malignancies. • Meta-analyses show significant efficacy in various hematologic cancers. • CAR T-cell therapy improves quality of life for blood cancer patients. • Encouraging results in CD22-targeting CAR T-cell therapy for B-cell malignancies. • Long-term studies reveal durable remissions but also persistent adverse effects. Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects. [ABSTRACT FROM AUTHOR]

Alpha-fetoprotein (AFP) is a glycoprotein that has many important physiological functions, including transportation, immunosuppression, and induction of apoptosis by T lymphocytes. AFP is closely related to the development of hepatocellular carcinoma and many kinds of tumors, all of which can show high concentrations, so it is used as a positive test indicator for many kinds of tumors. This paper reviews recent advances in the detection of the tumor marker AFP based on three immuno-biosensors: electrochemical (EC), photoelectrochemical (PEC), and electrochemical luminescence (ECL). The electrodes are modified by different materials or homemade composites, different signaling molecules are selected as single probes or dual probes for the detection of AFP. The detection limit was as low as 3 fg/mL, which indicated that the AFP immunosensor had achieved highly sensitive detection. In addition, we also reviewed and summarized the current development status and application prospect of AFP immunoelectrochemical sensors. There are not too many researches on immunosensors based on dual-signal ratios, and the commonly used probes are methylene blue (MB) and ferrocene (Fc). It would be more innovative to have more novel signaling molecules as probes to prepare dual-signal ratio sensors. This paper reviews recent advances in the detection of the tumor marker AFP in recent years based on three different types of electrochemical biosensors: electrochemical (EC) immunosensors, photoelectrochemical (PEC) sensors, and electrochemical luminescence (ECL) sensors. Among them, EC sensors are classified as single-probe and dual-probe. [Display omitted] • This manuscript reviews recent research on the detection of AFP. • The review describes three immunobiosensors: EC, PEC and ECL. • A comprehensive summary and comparison of three sensors for AFP detection. • This review provides guidelines for future research on immunobiosensors. [ABSTRACT FROM AUTHOR]

As transistors shrink in size, the integration density of memory circuits like Static Random Access Memory (SRAM) cells rises, making them increasingly susceptible to Single Event Effects (SEE). In the space environment, memory circuits face stability and reliability challenges due to the presence of various charged particles such as α-particles, neutrons, electrons, heavy ions, and photons. These high-energy particles create ion tracks when they strike the memory device, leading to upsets in the storage bits. Conventional 6 T SRAM cells are susceptible to these upsets. As a solution this paper proposes a new Radiation Tolerable (RT 13 T) SRAM cell that is better suited for deep-space applications compared to other memory cell. RT13T has been validated to withstand radiation hazards through Critical Charge (Q Crit) analysis, which shows that it exhibits 1.17×, 1.1×, 1.94× and 1.06× highest Q Crit than QUCCE 10 T/12 T,traditional 6 T and LIOR 13 T memory cells, respectively. As the comparison made, our Proposed RT 13 T saved by5.1 %,9.9 %, 20.1 % and 7 % of the power consumption compared to QUCCE10T/12 T/LIOR 13 T/SERSC-16 T SRAM cells at a nominal supply voltage of 0.7 V. It also exhibits shorter read delay (T RA) 10.6 %, 1.34 %, 9.6 %, 22.16 %compared to QUCCE 10 T/12 T,6T, SERSC-16Tmemory cells, respectively. In terms of stability,our proposed RT13T SRAM cell exhibits 2.32×/2.05×/2.9×/1.05×/1.01 × higher read stability as compared with QUCCE10T/12 T/6T/LIOR 13 T/SERSC-16 T memory cells during the read operation. The our proposed RT13T shows improvements in design metrics are at the expense of a longer write delay. To characterize the performances of the proposed RT13T, 16-nm CMOS predictive technology model and validated through extensive simulation with licensed PrimeSim HSPICE of Synopsys. The results of our proposed RT13T cell are compared with some other previously proposed memory cells such as 6 T, QUCCE 10 T, QUCCE 12 T, LIOR 13 T and SERSC-16 T memory cells. The obtained results are tabulated and plotted for graphical analysis. In terms of area consumption our proposed 13 T consumes 0.9×/0.6 × lesser area than QUCCE 12 T/SERSC-16 T memory cells but our proposed circuit consumes 3.1×/1.08×/1.05 × more area than QUCCE10T/conventional 6 T/LIOR 13 T because QUCCE10T and 6 T consist of less number of transistors in memory cells.The cell proposed in this paper demonstrates strong radiation-hardened capabilities and excellent overall performance, making it well-suited for aerospace electronic devices and ensuring stable operation in space radiation environments. [ABSTRACT FROM AUTHOR]

Stable fault self-healing ensures the smooth operation of intelligent industrial manufacturing processes. However, current research, while capable of inferring fault propagation paths or individually controlling manufacturing processes, still faces some challenges and limitations in addressing issues within manufacturing processes. In particular, it is easy to overlook the impact of fault variables on normal causal relationships in the manufacturing process and how to achieve adaptive fault repair from the source of faults. The biological immune system possesses sensitive nodes and a neuro-endocrine-immune network with interconnected functionalities, bearing remarkable resemblance to the sensor arrays, information networks, and intelligent controller systems in modern self-healing control systems. These problem domains have significant practical implications in industrial manufacturing processes and urgently require new methods and technologies to address them. To address the issue of root cause fault self-healing in intelligent industrial manufacturing processes, this paper proposes an innovative method that utilizes root cause inference and bio-inspired heuristic reinforcement learning models to achieve fault self-healing in industrial processes. First, innovatively introduce the Variational Autoencoder (VAE) into the Time Convolutional Network (TCN) to construct the TCN-VAE network. By performing feature reconstruction, the network's feature extraction capability is enhanced, further exploring the relationships between latent variables, and consequently building a causal graph of faults. A multi-head attention mechanism is introduced into the network, and the inference process is quantitatively evaluated, thereby improving the generalization and accuracy of root cause inference. Root cause determination rules are established to identify the fundamental reasons for fault occurrence, ensuring self-healing from the source of faults. Next, we developed for the first time a fault self-healing model based on reinforcement learning, utilizing the immune repair process of effector T cells to characterize the fault self-healing process. It effectively adapts to eliminate various levels of faults based on the state transition process of antigens in T helper cells. Additionally, stability control analysis is performed on the proposed model. The average reward function curve and Sobol sensitivity index demonstrates the model's strong robustness in practical applications. The validation results from case studies on the Tennessee Eastman (TE) and Continuous Stirred Tank Reactor (CSTR) show that the average improvement in fault repair F1 score was 0.0941 and 0.105 respectively, and the fastest improvement in fault repair response time was 0.266s and 0.258s respectively. It was confirmed that the root cause inference and fault repair results align with the actual mechanisms of the manufacturing processes. The proposed method has been verified to achieve stable and accurate root cause fault repair in real-world intelligent industrial manufacturing systems, making a significant contribution to achieving stable and accurate root cause fault repair in intelligent industrial manufacturing systems. • TCN-VAE enables feature reconstruction and latent variable exploration for root cause reasoning. • Multi-head attention enhances generality and accuracy in root cause reasoning. • Effector T-cell immune-inspired RL adapts to eliminate faults effectively. • The fault self-healing model exhibits strong reliability and robustness. • Method validated on Tennessee Eastman and continuous stirred-tank reactor datasets. [ABSTRACT FROM AUTHOR]

Adoptive T cell therapy has undergone remarkable advancements in recent decades; nevertheless, the rapid and effective ex vivo expansion of tumor-reactive T cells remains a formidable challenge, limiting their clinical application. Artificial antigen-presenting substrates represent a promising avenue for enhancing the efficiency of adoptive immunotherapy and fostering T cell expansion. These substrates offer significant potential by providing flexibility and modularity in the design of tailored stimulatory environments. Polydimethylsiloxane (PDMS) silicone elastomer stands as a widely utilized biomaterial for exploring the varying sensitivity of T cell activation to substrate properties. This paper explores the optimization of PDMS surface modification and formulation to create customized stimulatory surfaces with the goal of enhancing T cell expansion. By employing soft PDMS elastomer functionalized through silanization and activating agent, coupled with site-directed protein immobilization techniques, a novel T cell stimulatory platform is introduced, facilitating T cell activation and proliferation. Notably, our findings underscore that softer modified elastomers (Young' modulus E∼300 kPa) exhibit superior efficacy in stimulating and activating mouse CD4+ T cells compared to their stiffer counterparts (E∼3 MPa). Furthermore, softened modified PDMS substrates demonstrate enhanced capabilities in T cell expansion and Th1 differentiation, offering promising insights for the advancement of T cell-based immunotherapy. [Display omitted] • Chemically modified layers and Protein A enhance antibody density and stability. • Softer elastomers better stimulate CD4+ T cells compared to stiffer ones. • Softened PDMS substrates enhance T cell expansion and Th1 differentiation. • Study shows surface chemistry and mechanical cues influence T cell behavior. [ABSTRACT FROM AUTHOR]

Despite recent breakthroughs of immune-checkpoint inhibitors in the management of bladder cancer (BC), only 20% of patients with non-muscle invasive BC (NMIBC) completely respond, leaving room for improvement. Due to challenges in developing a preclinical model which reflects the heterogeneity and biology of bladder tumors, patient-derived xenograft (PDX) models were created. PDX models involve implanting tumor extracted from patients into immunocompromised mice, which therefore keep the morphology and genomic fidelity of their parental patient cancers. The state of immunodeficiency, however, precludes study of immunotherapy and consequently humanized mice models engrafted with a human immune system were developed, though this led to spontaneous xenogenic graft vs host disease (GVHD). As a potential solution to GVHD in humanized mouse models, this paper describes successful creation of a double-humanized mouse (DHM) by simultaneously engrafting human immune cells and human tumors from the same donor. BC tissue was processed +/- digested into single-cell suspensions (SCS, F0 tissue) and injected orthotopically or subcutaneously into flanks of NSG™ mice. Subsequent tumor growth (PDX-F1) was measured, and PDX-F1 tumors reaching >200mm3 were processed into SCS and reimplanted subcutaneously into a new NSG™ (PDX-F2). Continuous passages (PDX-Fn) were repeated.; Extra SCS-F1 and Fn was analyzed for human epithelial cell adhesion molecule (EpCAM) expression. From an individual F1, a stable cell line (PDX257S) was cultured, and also analyzed for EpCAM expression by flow cytometry. For the DHM model, autologous γδ T-cells expanded in vitro from PDX257S donors were injected with PDX257S cells (effector: target = 2:1) into the NSG™ flanks and were observed for body condition/hematuria for 45 days. Total RNA-sequencing was performed on F0, PDX-Fn and PDX257S cell line. Tumor growth curves were analyzed with 2-way analysis of variance (ANOVA). F0 tissue was obtained from 60 patients. Tumor acceptance in orthotopic injection was not observed in the first 11 suitable tumors, and this method was ceased. Subcutaneous tumor acceptance rate improved with digestion and processing of F0 rather than processing alone (11% vs 5%). EpCAM expression was 98% vs 70% in PDX257S vs its F1 tissue, and < 30% in F1 tissue from other donors that did not yield further passages. In the DHM, while tumor growth was significantly reduced compared to control group after 45 days (mean vol 200 mm3 vs 580 mm3, p=0.02) post injection, it was not completely suppressed. RNA sequencing revealed increased expression of genes including BCL2L1, KRAS, MYC, E2F1, and E2F4 in both PDX257 subcutaneous tumor and cell line compared with donor tumor tissue, and very low/no expression of CDKN2A and FHIT genes in both PDX257 cell line and donor tumor tissue. Creation of a double-humanized mouse model is feasible, and tumor growth is not completely suppressed with the addition of autologous γδ T-cells. PDX257S tumor and cell line is associated with increased EpCAM expression and on RNA sequencing, increased expression of BCL2L1, KRAS, MYC, E2F1, and E2F4. [ABSTRACT FROM AUTHOR]

Highly expressed azo-reductase (AZOR) selectively reduces Azo-DON to DON in hypoxic tumor environments, impair glutamine metabolism in cancer cells, and promote tumor cell death without affecting T cell metabolism and proliferation, thereby generating strong antitumor immune responses. CB-PLG nanoparticles (CBP) mentioned in the paper can enhance the degree of hypoxia in normoxic tumors, which is conducive to efficient reduction of Azo-DON at tumor sites. [Display omitted] • Azo-DON is a novel hypoxia-active prodrug of glutamine antagonist. • Azo-DON selectively blocks tumor glutamine metabolism after reducing to DON. • T cells continue to proliferate and remain active when Azo-DON is reduced to DON. • CBP nanoparticles increase tumor hypoxia and facilitate the reduction of Azo-DON. Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), have demonstrated remarkable anti-tumor effects by blocking tumor glutamine metabolism, but their use is frequently causing toxicity. Despite the existence of multiple glutamine antagonist prodrug designs, a tumor-selective prodrug has yet to be developed. Herein, a novel prodrug of DON, Azo-DON, has been developed, which remains stable and inactive in normal tissues with sufficient oxygen levels, while can be selectively reduced to DON by highly expressed azo-reductase in hypoxic tumor environments. This leads to blockade of glutamine metabolism in cancer cells and promotes cell death without affecting T cell proliferation. In a high-hypoxic H22 hepatoma cancer model, Azo-DON showed a 1.8-fold enhancement in glutamine blockade compared to the control group, resulting in a tumor suppression rate (TSR) of 84.2% in vivo with no significant weight loss. In a low-hypoxic CT26 colon cancer model, when combined with vascular disrupting agent nanoparticles (CBP) to induce a hypoxic environment, Azo-DON exhibited a 4.6-fold enhancement in glutamine blockade over the control group, resulted in a remarkable TSR of 96.6% in vivo. This innovative approach represents a promising strategy for the application of broad-spectrum metabolic inhibitors in the field of precision cancer treatment. [ABSTRACT FROM AUTHOR]

With the success of immunosuppressive checkpoint in tumor therapy, the corresponding adverse response and drug resistance defects have been exposed. T cells and NK cells are the body's immune system of the two substantial main forces. in recent years, study of T cell checkpoints appeared a certain block, such as PD-1 the effect not benign, on the distribution of NK cell surface excitatory and inhibitory receptors under normal conditions to maintain steady, could be targeted in the tumor treatment blockade have therapeutic effect. This paper reviews the function of NK cells and the effects of corresponding receptors in various types of tumors, providing a direction for the selection of appropriate gate control sites for future treatment. [ABSTRACT FROM AUTHOR]