Chondroitin Sulfate-Modified Hydroxyapatite for Caspase-1 Activated Induced Pyroptosis through Ca Overload/ER Stress/STING/IRF3 Pathway in Colorectal Cancer.

Immune checkpoint inhibitors, are the fourth most common therapeutic tool after surgery, chemotherapy, and radiotherapy for colorectal cancer (CRC). However, only a small proportion (≈5%) of CRC patients, those with "hot" (immuno-activated) tumors, benefit from the therapy. Pyroptosis, an innovative form of programmed cell death, is a potentially effective means to mediate a "cold" to "hot" transformation of the tumor microenvironment (TME). Calcium-releasing hydroxyapatite (HAP) nanoparticles (NPs) trigger calcium overload and pyroptosis in tumor cells. However, current limitations of these nanomedicines, such as poor tumor-targeting capabilities and insufficient calcium (Ca) ion release, limit their application. In this study, chondroitin sulfate (CS) is used to target tumors via binding to CD44 receptors and kaempferol (KAE) is used as a Ca homeostasis disruptor to construct CS-HAP@KAE NPs that function as pyroptosis inducers in CRC cells. CS-HAP@KAE NPs bind to the tumor cell membrane, HAP released Ca in response to the acidic environment of the TME, and kaempferol (KAE) enhances the influx of extracellular Ca, resulting in intracellular Ca overload and pyroptosis. This is associated with excessive endoplasmic reticulum stress triggered activation of the stimulator of interferon genes/interferon regulatory factor 3 pathway, ultimately transforming the TME from "cold" to "hot".

RNA modification Regulators' Co-Expression Score (RMRCoeS) predicts biochemical recurrence and therapy response in prostate cancer: A multi-omics and experimental validation study.

BACKGROUND: Owing to the heterogeneity of prostate cancer (PCa), the clinical indicators traditionally fall short of meeting the requirements for personalized medicine. The realm of RNA modification has emerged as an increasingly relevant domain, shedding light on its pivotal role in tumor heterogeneity. However, the specific contributions of RNA modification regulators within the context of PCa remain largely unexplored. METHODS: In this study, we undertook a literature review to summarize the common 8 types of RNA modifications (ac4c, AI, APA, m1A, m5c, m6A, m7G, Ψ) encompassing a total of 84 regulators. Moreover, we integrated multi-center cohorts with Ridge regression to develop the Regulators' Co-Expression Score (RMRCoeS). Then we assessed the role of RMRCoeS in several clinical aspects such as biochemical recurrence (BCR), responses to chemotherapy, androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy in PCa. Finally, we validated the cancer-promoting performance of five hub genes through immunohistochemistry and in vitro assays. RESULTS: Within the mutation landscape of RNA modification regulators, we observed a relatively low overall mutation rate. Remarkably, RMRCoeS, comprising 81 RNA modification regulators, exhibited a notable capability for accurately predicting the prognosis and therapeutic responses in PCa patients subjected to BCR, chemotherapy, ARSI therapy, and immunotherapy. A high RMRCoeS was indicative of a poor prognosis and unfavorable therapy responses. Functional enrichment analysis unveiled that RMRCoeS may exert its influence on PCa progression through various metabolic pathways. Furthermore, a higher RMRCoeS showed a positive correlation with elevated CNV mutations. Lastly, we validated the oncogene effects of CPSF4, WBSCR22, RPUSD3, TRMT61A, and NSUN5-five hub regulators-within the context of PCa. CONCLUSION: The function of different RNA modifications is interconnected. Comprising eight distinct RNA modifications' regulators, RMRCoeS exhibits multifaceted roles in various aspects of PCa, including disease progression, prognosis, and responses to multiple therapies. Furthermore, we provide the initial validation of the oncogene effect associated with WBSCR22, RPUSD3, TRMT61A and NSUN5 in PCa. Our findings offer novel insights into the significance of RNA modifications in PCa personalized medicine.

Curcumin/L-OHP co-loaded HAP for cGAS-STING pathway activation to enhance the natural immune response in colorectal cancer.

Insufficient immune cell infiltration into the tumor microenvironment (TME) greatly compromises the clinical application of immune-checkpoint inhibitors (ICIs)-based immunotherapy. Recent findings have shown that activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can enhance natural immunity and increase lymphocyte infiltration into the TME, which presents a promising strategy for cancer immunotherapy. In this study, we constructed hydroxyapatite nanoparticles co-loaded with curcumin and L-oxaliplatin (Cur/L-OHP@HAP NPs). We analyzed the particle-size distribution, zeta potential, spectral characteristics (Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopy), and drug-release properties of the Cur/L-OHP@HAP NPs. The cellular uptake of the Cur/L-OHP@HAP NPs detected by flow cytometry and confocal laser-scanning microscopy. We comprehensively evaluated the anti-tumor properties and immune-activating effects of the NPs, both in vitro and in vivo. Physicochemical characterizations demonstrated that the Cur/L-OHP@HAP NPs were successfully synthesized and were capable of pH-dependent drug release. Notably, the Cur/L-OHP@HAP NPs efficiently entered cancer cells, after which the released L-OHP induced nuclear DNA (nDNA) damage to some extent. HAP promoted the release of intracellular Ca2+ stores in cancer cells, and curcumin inhibited Ca2+ efflux, resulting in intracellular Ca2+ overload and the release of mitochondrial DNA (mtDNA). Damage to both nDNA and mtDNA greatly stimulated the cGAS-STING pathway, thereby activating natural immunity, accompanied by immune cell recruitment to the TME. In summary, the Cur/L-OHP@HAP NPs show good prospects for improving cancer immunotherapy.

The effects of text direction of different text lengths on Chinese reading.

This study investigates the effects of text direction (horizontal and vertical) and length (long and short) on Chinese reading performance. The experiment enrolled 68 university students aged 19-29 years who were asked to read articles. We recorded reading times and measured recall after reading using a memory test and measured task load using the NASA-TLX scale. The results show that horizontal text was read faster than vertical text. When reading long texts, horizontal reading has a better memory effect than vertical reading. When reading short texts, the effect of text direction on memory was not significant. Moreover, the mental, physical, and temporal demands of horizontal text were lower than those of vertical text. These findings contribute to a better understanding of the impact of text direction, provide valuable suggestions for Chinese typography, and help readers obtain better reading outcomes.