Chimeric antigen receptor-based immunotherapy in breast cancer: Recent progress in China.

Breast cancer (BC) is the fourth most prevalent cancer in China. Despite conventional treatment strategies, BC patients often have poor therapeutic outcomes, leading to significant global cancer mortality rates. Chimeric antigen receptor (CAR)-based immunotherapy is a promising and innovative approach for cancer treatment that redirects immune cells to attack tumor cells expressing selected tumor antigens (TAs). T cells, natural killer (NK) cells, and macrophages, key components of the immune system, are used in CAR-based immunotherapies. Although remarkable progress has been made with CAR-T cells in hematologic malignancies, the application of CAR-based immunotherapy to BC has lagged. This is partly due to obstacles such as tumor heterogeneity, which is further associated with the TA and BC subtypes, and the immunosuppressive tumor microenvironment (TME). Several combinatorial approaches, including the use of immune checkpoint inhibitors, oncolytic viruses, and antitumor drugs, have been proposed to overcome these obstacles in BC treatment. Furthermore, several CAR-based immunotherapies for BC have been translated into clinical trials. This review provides an overview of the recent progress in CAR-based immunotherapy for BC treatment, including targeting of TAs, consideration of BC subtypes, assessment of the TME, and exploration of combinatorial therapies. The authors focused on preclinical studies and clinical trials of CAR-T cells, CAR-NK cells, and CAR-macrophages especially conducted in China, followed by an internal comparison and discussion of current limits. In conclusion, this review elucidates China's contribution to CAR-based immunotherapies for BC and provides inspiration for further research. PLAIN LANGUAGE SUMMARY: Despite conventional treatment strategies, breast cancer (BC) patients in China often have poor therapeutic outcomes. Chimeric antigen receptor (CAR)-based immunotherapy, a promising approach, can redirect immune cells to kill tumor cells expressing selected tumor antigens (TAs). However, obstacles such as TA selection, BC subtypes, and immunosuppressive tumor microenvironment still exist. Therefore, various combinatorial approaches have been proposed. This article elucidates several Chinese CAR-based preclinical and clinical studies in BC treatment with comparisons of foreign research, and CAR-immune cells are analyzed, providing inspiration for further research.

The effect of Piper laetispicum extract (EAE-P) during chronic unpredictable mild stress based on interrelationship of inflammatory cytokines, apoptosis cytokines and neurotrophin in the hippocampus.

BACKGROUD: The Piper laetispicum C.DC. (Piperaceae) is a traditionally used herb in China for invigorating circulation and reducing stasis, detumescence and analgesia, which is distributed in the southern part of China and the southeastern part of Asia. Previous studies demonstrated that the ethyl acetate extract (EAE-P) of P. laetispicum possesses a significant antidepressant-like effect at doses higher than 60 mg/kg in Kunming (KM) mice, and this effect was not due to an increase in locomotive activity. METHODS: To research this mechanism, in the present study, the chronic unpredictable mild stress (CUMS) model in Sprague-Dawley rats was used to further elucidate behavioral changes and corresponding changes in inflammatory cytokines (TNF-α, IL-6, IL-10), apoptosis cytokines (P53, Bax, Bcl2, caspase-3) and neurotrophin (BDNF) in the hippocampus of EAE-P treatment animals. RESULTS AND CONCLUSIONS: The results suggest that EAE-P is beneficial to the behavioral outcome of the CUMS model animals, and decreased amounts of inflammatory cytokine IL-6 contributed to the antidepressant-like activation of EAE-P in every dosage group (15, 30, 60 mg/kg). In the low dosage group, down-regulated apoptosis cytokine p53 is associated with EAE-P effect, but it is inflammatory cytokine TNF-α that is related to the effect of EAE-P in the high dosage group. Meanwhile, the P53-dependent antiapoptotic effect of EAE-P may not be through Bcl-2 and Bax modulation. Furthermore, EAE-P showed up-regulated expression of brain-derived neurotrophic factor (BDNF) mRNA and down-regulated apoptosis cytokine caspase-3 mRNA, which was the same change tendency as with Fluoxetine.

Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis.

Aims: In cancer biology, the aberrant overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) has been correlative with an ominous prognosis, thereby underscoring its pivotal role in fostering metastatic progression. Consequently, EIF5A2 has garnered significant attention as a compelling prognostic biomarker for various malignancies. Our research endeavors were thus aimed at elucidating the utility and significance of EIF5A2 as a robust indicator of cancer outcome prediction. Method: An exhaustive search of the PubMed, EMBASE, and Web of Science databases found relevant studies. The link between EIF5A2 and survival prognosis was examined using hazard ratios and 95% confidence intervals. Subsequently, The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases were employed to validate EIF5A2 expression across various cancer types. Results: Through pooled analysis, we found that increased EIF5A2 expression was significantly associated with decreased overall survival (OS) and disease-free survival/progression-free survival/relapse-free survival (DFS/PFS/RFS). Moreover, TCGA analysis revealed that EIF5A2 was significantly upregulated in 27 types of cancer, with overexpression being linked to shorter OS in three, worse DFS in two, and worse PFS in six types of cancer. GEPIA showed that patients with EIF5A2 overexpression had reduced OS and DFS. Conclusions: In solid tumors, EIF5A2 emerges as a reliable prognostic marker. Our meta-analysis comprehensively analyzed the prognostic value of EIF5A2 in solid tumors and assessed its efficacy as a predictive marker.

Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications.

The tumor microenvironment (TME) is a highly intricate milieu, comprising a multitude of components, including immune cells and stromal cells, that exert a profound influence on tumor initiation and progression. Within the TME, angiogenesis is predominantly orchestrated by endothelial cells (ECs), which foster the proliferation and metastasis of malignant cells. The interplay between tumor and immune cells with ECs is complex and can either bolster or hinder the immune system. Thus, a comprehensive understanding of the intricate crosstalk between ECs and immune cells is essential to advance the development of immunotherapeutic interventions. Despite recent progress, the underlying molecular mechanisms that govern the interplay between ECs and immune cells remain elusive. Nevertheless, the immunomodulatory function of ECs has emerged as a pivotal determinant of the immune response. In light of this, the study of the relationship between ECs and immune checkpoints has garnered considerable attention in the field of immunotherapy. By targeting specific molecular pathways and signaling molecules associated with ECs in the TME, novel immunotherapeutic strategies may be devised to enhance the efficacy of current treatments. In this vein, we sought to elucidate the relationship between ECs, immune cells, and immune checkpoints in the TME, with the ultimate goal of identifying novel therapeutic targets and charting new avenues for immunotherapy.

Preclinical assessment of the distribution, metabolism, and excretion of S-propargyl-cysteine, a novel H2S donor, in Sprague-Dawley rats.

AIM: To study the distribution, metabolism and excretion of S-propargyl-cysteine (SPRC), a novel hydrogen sulfide (H2S) donor, after oral administration in rats. METHODS: Adult Sprague-Dawley rats were used. The tissue distribution of [(35)S] SPRC-derived radioactivity was measured using a liquid scintillation counter. The plasma protein binding of SPRC was examined using 96-well equilibrium dialysis. The excretion of SPRC in urine, bile and feces was analyzed using the LC-MS/MS method. The major metabolites in rat biomatrices were identified using MRM information-dependent, acquisition-enhanced product ion (MRM-IDA-EPI) scans on API 4000QTrap system. RESULTS: After oral administration of [(35)S]-SPRC at a dose of 75 mg/kg, [(35)S] SPRC-derived radioactivity displayed broad biological distribution in various tissues of rats, including its target organs (heart and brain) with the highest in kidney. On the other hand, the binding of SPRC to human, rat and dog plasma protein was low. Only 2.18% ± 0.61% and 0.77% ± 0.61% of the total SPRC administered was excreted unchanged in the bile and urine. However, neither intact SPRC nor its metabolites were detected in rat feces. The major metabolic pathway in vivo (rat bile, urine, and plasma) was N-acetylation. CONCLUSION: The preliminary results suggest that SPRC possesses acceptable pharmacokinetic properties in rats.

Recent Advances in the Aging Microenvironment of Breast Cancer.

Aging is one of the risk factors for advanced breast cancer. With the increasing trend toward population aging, it is important to study the effects of aging on breast cancer in depth. Cellular senescence and changes in the aging microenvironment in vivo are the basis for body aging and death. In this review, we focus on the influence of the aging microenvironment on breast cancer. Increased breast extracellular matrix stiffness in the aging breast extracellular matrix can promote the invasion of breast cancer cells. The role of senescence-associated secretory phenotypes (SASPs) such as interleukin-6 (IL-6), IL-8, and matrix metalloproteases (MMPs), in breast cancer cell proliferation, invasion, and metastasis is worthy of exploration. Furthermore, the impact of senescent fibroblasts, adipocytes, and endothelial cells on the mammary matrix is discussed in detail. We also list potential targets for senotherapeutics and senescence-inducing agents in the aging microenvironment of breast cancer. In conclusion, this review offers an overview of the influence of the aging microenvironment on breast cancer initiation and progression, with the aim of providing some directions for future research on the aging microenvironment in breast cancer.