Advancing ASD identification with neuroimaging: a novel GARL methodology integrating Deep Q-Learning and generative adversarial networks.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects an individual's behavior, speech, and social interaction. Early and accurate diagnosis of ASD is pivotal for successful intervention. The limited availability of large datasets for neuroimaging investigations, however, poses a significant challenge to the timely and precise identification of ASD. To address this problem, we propose a breakthrough approach, GARL, for ASD diagnosis using neuroimaging data. GARL innovatively integrates the power of GANs and Deep Q-Learning to augment limited datasets and enhance diagnostic precision. We utilized the Autistic Brain Imaging Data Exchange (ABIDE) I and II datasets and employed a GAN to expand these datasets, creating a more robust and diversified dataset for analysis. This approach not only captures the underlying sample distribution within ABIDE I and II but also employs deep reinforcement learning for continuous self-improvement, significantly enhancing the capability of the model to generalize and adapt. Our experimental results confirmed that GAN-based data augmentation effectively improved the performance of all prediction models on both datasets, with the combination of InfoGAN and DQN's GARL yielding the most notable improvement.

Icariside I enhances the effects of immunotherapy in gastrointestinal cancer via targeting TRPV4 and upregulating the cGAS-STING-IFN-I pathway.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.

SCD1 promotes the stemness of gastric cancer stem cells by inhibiting ferroptosis through the SQLE/cholesterol/mTOR signalling pathway.

Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.

FPR3 reprograms glycolytic metabolism and stemness in gastric cancer via calcium-NFATc1 pathway.

Aerobic glycolysis accelerates tumor proliferation and progression, and inhibitors or drugs targeting abnormal cancer metabolism have been developing. Cancer stem-like cells (CSCs) significantly contribute to tumor initiation, metastasis, therapy resistance, and recurrence. Formyl peptide receptor 3 (FPR3), a member of FPR family, involves in inflammation, tissue repair, and angiogenesis. However, studies in exploring the regulatory mechanisms of aerobic glycolysis and CSCs by FPR3 in gastric cancer (GC) remain unknown. Here, we demonstrated that overexpressed FPR3 suppressed glycolytic capacity and stemness of tumor cells, then inhibited GC cells proliferation. Mechanistically, FPR3 impeded cytoplasmic calcium ion flux and hindered nuclear factor of activated T cells 1 (NFATc1) nuclear translocation, leading to the transcriptional inactivation of NFATc1-binding neurogenic locus notch homolog protein 3 (NOTCH3) promoter, subsequently obstructing NOTCH3 expression and the AKT/mTORC1 signaling pathway, and ultimately downregulating glycolysis. Additionally, NFATc1 directly binds to the sex determining region Y-box 2 (SOX2) promoter and modifies stemness in GC. In conclusion, our work illustrated that FPR3 played a negative role in GC progression by modulating NFATc1-mediated glycolysis and stemness in a calcium-dependent manner, providing potential insights into cancer therapy.

Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFß1.

Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFß1 expression and activates the TGFß1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade.

Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses.

A novel deep domain adaptation method for automated detection of sleep apnea/hypopnea events.

Objective.Sleep apnea-hypopnea syndrome (SAHS) is a common sleep-related respiratory disorder that is generally assessed for severity using polysomnography (PSG); however, the diversity of sampling devices and patients makes this not only costly but may also degrade the performance of the algorithms.Approach.This paper proposes a novel deep domain adaptation module which uses a long short-term memory-convolutional neural network embedded with the channel attention mechanism to achieve autonomous extraction of high-quality features. Meanwhile, a domain adaptation module was built to achieve domain-invariant feature extraction for reducing the differences in data distribution caused by different devices and other factors. In addition, during the training process, the algorithm used the last second label as the label of the PSG segment, so that second-by-second evaluation of respiratory events could be achieved.Main results.The algorithm applied the two datasets provided by PhysioNet as the source and target domains. The accuracy, sensitivity and specificity of the algorithm on the source domain were 86.46%, 86.11% and 93.17%, respectively, and on the target domain were 83.63%, 82.52%, 91.62%, respectively. The proposed algorithm showed strong generalization ability and the classification results were comparable to the current advanced methods. Besides, the apnea-hypopnea index values estimated by the proposed algorithm showed a high correlation with the manual scoring values on both domains.Significance.The proposed algorithm can effectively perform SAHS detection and evaluation with certain generalization.

Tumor-Targeted Polydopamine-Based Nanoparticles for Multimodal Mapping Following Photothermal Therapy of Metastatic Lymph Nodes.

Purpose: Lymphadenectomy with lymph node (LN) mapping is essential for surgical removal of solid tumors. Existing agents do not provide accurate multimodal mapping and antitumor therapy for metastatic LNs; therefore, we fabricated a polydopamine (PDA) nanoparticle (NP)-based tumor-targeted LN mapping agent capable of multimodal mapping and guided photothermal therapy (PTT) for metastatic LNs. Materials and Methods: PDA NPs modified with polyethylene glycol (PEG) were obtained by polymerization under alkaline conditions. The PEG-PDA NPs were loaded with the circular tripeptide Arg-Gly-Asp (cRGD) to achieve tumor-targeting capacity and with the fluorescent dye IR820 and magnetic resonance imaging (MRI) contrast Gd(NH2)2 for in situ detection. The resulting cRGD-PEG-PDA@IR820/Gd(NH2)2 (cRGD-PPIG) NPs were tested for their biosafety and metastatic LN mapping ability. They were drained specifically into LNs and selectively taken up by gastric MKN45 cells via αvß3 integrin-mediated endocytosis. Results: This phenomenon enabled MR/optical/near-infrared fluorescence multimodal metastatic LN mapping, guiding the creation of accurate and highly efficient PTT for gastric cancer metastatic LNs in mice. Conclusion: In summary, we fabricated tumor-targeted cRGD-PPIG NPs with MR/optical/near-infrared fluorescence multimodal metastatic LN mapping capacity for surgery and efficient PTT guidance post-surgery.

Manganese-containing polydopamine nanoparticles as theranostic agents for magnetic resonance imaging and photothermal/chemodynamic combined ferroptosis therapy treating gastric cancer.

Gastric cancer (GC) is a serious disease with high morbidity and mortality rates worldwide. Chemotherapy plays a key role in GC treatment, while inevitable drug resistance and systematic side effects hinder its clinical application. Fenton chemistry-based chemodynamic therapy (CDT) has been used as a strategy for cancer ferroptosis, and the CDT efficiency could be enhanced by photothermal therapy (PTT). With the trend of treatment and diagnosis integration, the combination of magnetic resonance imaging (MRI) and CDT/PTT exhibits enormous progress. Herein, we constructed a platform based on PEGylated manganese-containing polydopamine (PDA) nanoparticles, named as PEG-PDA@Mn (PP@Mn) NPs. The PP@Mn NPs were stable and globular. Furthermore, they demonstrated near-infrared (NIR)-triggered PTT and Fenton-like reaction-based CDT effects and T1-weighted MRI capabilities. According to in vitro studies, the PP@Mn NPs trigger ferroptosis in cancer cells by producing abundant reactive oxygen species (ROS) via a Fenton-like reaction combined with PTT. Furthermore, in vivo studies showed that, under MRI guidance, the PP@Mn NPs combined with the PTT at the tumor region, have CDT anti-tumor effect. In conclusion, the PP@Mn NPs could provide an effective strategy for CDT/PTT synergistic ferroptosis therapy for GC.

VB12-Sericin-PBLG-IR780 Nanomicelles for Programming Cell Pyroptosis via Photothermal (PTT)/Photodynamic (PDT) Effect-Induced Mitochondrial DNA (mitoDNA) Oxidative Damage.

Pyroptosis, a kind of programmed cell death involving inflammation, might be a powerful way to fight against tumors, for example, using immunotherapy. However, how to trigger pyroptosis in cancer cells is an important issue. Photothermal (PTT)/photodynamic (PDT) therapy is a crucial strategy for inducing cancer cell pyroptosis with noninvasiveness. In this work, a sericin derivative modified with poly(γ-benzyl-l-glutamate) (PBLG) could self-assemble and was stable in an aqueous environment. Furthermore, the sericin derivative was conjugated with the tumor-targeting agent VB12 and loaded with IR780. Finally, we successfully synthesized VB12-sericin-PBLG-IR780 nanomicelles. The as-designed nanomicelles showed appropriate particle sizes, spherical morphology, improved photothermal stability, and high photothermal conversion efficiency (∼40%), which generated reactive oxygen species (ROS) simultaneously. Through enhanced cellular uptake, VB12-sericin-PBLG-IR780 could deliver more IR780 into cancer cells. With near-infrared (NIR), the VB12-sericin-PBLG-IR780 could significantly inhibit the expression of ATP synthase, called ATP5MC3, followed by mitochondrial damage. The presence of mitochondrial reactive oxygen species (mitoROS) led to oxidative damage of mitochondrial DNA (mitoDNA), which further activates NLRP3/Caspase-1/gasdermin D (GSDMD)-dependent pyroptosis and could promote dendritic cell (DC) maturation by pyroptosis. Furthermore, our data showed that VB12-sericin-PBLG-IR780 could achieve a brilliant antitumor effect and could activate DC maturation, initiate T-cell recruiting, and prime adaptive antitumor efficiency. Overall, our well-prepared nanomicelles might offer a tumor-targeted approach for programmed cell pyroptosis and inducing antitumor immunity via photothermal PTT/PDT effect-induced mitoDNA oxidative damage.

Ferroptosis: A Novel Type of Cell Death in Male Reproduction.

Ferroptosis, an iron-dependent type of regulated cell death, is triggered by the accumulation of lethal lipid peroxides. Due to its potential in exploring disease progression and highly targeted therapies, it is still a widely discussed topic nowadays. In recent studies, it was found that ferroptosis was induced when testicular tissue was exposed to some high-risk factors, such as cadmium (Cd), busulfan, and smoking accompanied by a variety of reproductive damage characteristics, including changes in the specific morphology and ferroptosis-related features. In this literature-based review, we summarize the related mechanisms of ferroptosis and elaborate upon its relationship network in the male reproductive system in terms of three significant events: the abnormal iron metabolism, dysregulation of the Cyst(e)ine/GSH/GPX4 axis, and lipid peroxidation. It is meaningful to deeply explore the relationship between ferroptosis and the male reproductive system, which may provide suggestions regarding pristine therapeutic targets and novel drugs.