Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition.

Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.

Accurate and fast implementation of soybean pod counting and localization from high-resolution image.

Introduction: Soybean pod count is one of the crucial indicators of soybean yield. Nevertheless, due to the challenges associated with counting pods, such as crowded and uneven pod distribution, existing pod counting models prioritize accuracy over efficiency, which does not meet the requirements for lightweight and real-time tasks. Methods: To address this goal, we have designed a deep convolutional network called PodNet. It employs a lightweight encoder and an efficient decoder that effectively decodes both shallow and deep information, alleviating the indirect interactions caused by information loss and degradation between non-adjacent levels. Results: We utilized a high-resolution dataset of soybean pods from field harvesting to evaluate the model's generalization ability. Through experimental comparisons between manual counting and model yield estimation, we confirmed the effectiveness of the PodNet model. The experimental results indicate that PodNet achieves an R2 of 0.95 for the prediction of soybean pod quantities compared to ground truth, with only 2.48M parameters, which is an order of magnitude lower than the current SOTA model YOLO POD, and the FPS is much higher than YOLO POD. Discussion: Compared to advanced computer vision methods, PodNet significantly enhances efficiency with almost no sacrifice in accuracy. Its lightweight architecture and high FPS make it suitable for real-time applications, providing a new solution for counting and locating dense objects.

Functional Upgrading of an Organo-Ir(III) Complex to an Organo-Ir(III) Prodrug as a DNA Damage-Responsive Autophagic Inducer for Hypoxic Lung Cancer Therapy.

The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.

Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition.

Breast cancer is the most commonly diagnosed cancer and second­leading cause of cancer deaths in women. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting breast cancer cell proliferation, invasion, angiogenesis, and metastasis, and the high expression of STAT3 is related to the occurrence and poor chemotherapy sensitivity of breast cancer. Iridium(III) complexes Ir-PTS-1- 4 containing a pterostilbene-derived ligand were synthesized to inhibit the STAT3 pathway in breast cancer. Ir-PTS-4 inhibited the proliferation of breast cancer cells by suppressing the expression of phosphorylated STAT3 and STAT3-related cyclin D1, arresting cell cycle in the S-phase, inducing DNA damage and reactive oxygen species (ROS) generation, eventually leading to autophagic cell death. The cell metastasis and invasion were also inhibited after Ir-PTS-4 treatment. Besides, Ir-PTS-4 exhibited excellent anti-proliferation activity in 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work presents the rational design of metal-based anticancer agents to block the STAT3 pathway for simultaneously inhibiting breast cancer proliferation and metastasis.

Eukaryotic Translation Initiation Factor 2 Subunit ß as a Prognostic Biomarker Associates With Immune Cell Infiltration in Breast Cancer.

INTRODUCTION: The present study aims to explore the expression level of eukaryotic translation initiation factor 2 subunit ß (EIF2S2) in breast cancer tissue, and its role both in breast cancer prognosis and in the immune microenvironment. METHODS: To assess the association between the expression levels of EIF2S2 and prognosis, the Gene Expression Profiling Interactive Analysis database was initially applied to determine differences in the gene expression of EIF2S2 in various malignant and normal tissues. Furthermore, the expression levels of EIF2S2 were determined in the clinical breast cancer tissues and corresponding para-neoplastic tissues using immunohistochemical analysis. In addition, Kaplan-Meier survival and Cox regression analyses were employed to explore the association between EIF2S2 expression levels and patient prognosis. Finally, the correlation between the expression levels of EIF2S2 and immune cell infiltration in breast cancer was analyzed using the TIMER2.0 database, and subsequently validated by immunohistochemical experiments. RESULTS: The Gene Expression Profiling Interactive Analysis database revealed the presence of higher expression levels of EIF2S2 in various different types of cancer compared with normal cells, also correlating its expression with both the age and the tumor stage of patients with breast cancer. The survival analysis results revealed that high expression levels of EIF2S2 could be a risk factor for poor prognosis in patients with breast cancer. Moreover, the EIF2S2 expression level was found to be closely associated with the infiltration levels of various immune cells, including regulatory T cells, CD4+, CD8+, and natural killer cells, in breast cancer. CONCLUSIONS: In conclusion, the present study has demonstrated that an upregulated expression level of EIF2S2 in breast cancer may be associated with poor patient prognosis, affecting immune cell infiltration in breast cancer. Taken together, the findings of the present study have shown that EIF2S2 expression may be a novel therapeutic target for breast cancer.

Coupling of Dissolved Organic Matter Molecular Fractionation with Iron and Sulfur Transformations during Sulfidation-Reoxidation Cycling.

Iron (oxyhydr)oxides and organic matter (OM) are intimately associated in natural environments, and their fate might be linked to sulfur during sulfidation-reoxidation cycling. However, the coupling of DOM molecular fractionation with Fe and S transformations following a full sulfidation-reoxidation cycle remains poorly understood. Here, we reacted Fh and Fh-OM associations with S(-II) anaerobically and then exposed the sulfidic systems to air. S(-II) preferentially reacted with Fh to form inorganic S (e.g., mackinawite, S0, and S22-) over being incorporated into OM as organic S and therefore indirectly affected OM fate by altering Fe speciation. Fh sulfidation was inhibited by associated OM, and the main secondary Fe species were mackinawite, Fe(II)-OM compounds, and lepidocrocite. Concomitantly, organic molecules high in unsaturation, aromaticity, and molecular weight were detached from solid-phase Fe species due to their lower affinities for secondary Fe species than for Fh. During the reoxidation stage, the previously formed Fe(II) species were reoxidized to Fh with a stronger aggregation, which recaptured formerly released OM with higher selectivity. Additionally, •OH was generated from Fe(II) oxygenation and degraded a portion of the DOM molecules. Overall, these results have significant implications for Fe, C, and S cycling in S-rich environments characterized by oscillating redox conditions.

WheatLFANet: in-field detection and counting of wheat heads with high-real-time global regression network.

BACKGROUND: Detection and counting of wheat heads are of crucial importance in the field of plant science, as they can be used for crop field management, yield prediction, and phenotype analysis. With the widespread application of computer vision technology in plant science, monitoring of automated high-throughput plant phenotyping platforms has become possible. Currently, many innovative methods and new technologies have been proposed that have made significant progress in the accuracy and robustness of wheat head recognition. Nevertheless, these methods are often built on high-performance computing devices and lack practicality. In resource-limited situations, these methods may not be effectively applied and deployed, thereby failing to meet the needs of practical applications. RESULTS: In our recent research on maize tassels, we proposed TasselLFANet, the most advanced neural network for detecting and counting maize tassels. Building on this work, we have now developed a high-real-time lightweight neural network called WheatLFANet for wheat head detection. WheatLFANet features a more compact encoder-decoder structure and an effective multi-dimensional information mapping fusion strategy, allowing it to run efficiently on low-end devices while maintaining high accuracy and practicality. According to the evaluation report on the global wheat head detection dataset, WheatLFANet outperforms other state-of-the-art methods with an average precision AP of 0.900 and an R2 value of 0.949 between predicted values and ground truth values. Moreover, it runs significantly faster than all other methods by an order of magnitude (TasselLFANet: FPS: 61). CONCLUSIONS: Extensive experiments have shown that WheatLFANet exhibits better generalization ability than other state-of-the-art methods, and achieved a speed increase of an order of magnitude while maintaining accuracy. The success of this study demonstrates the feasibility of achieving real-time, lightweight detection of wheat heads on low-end devices, and also indicates the usefulness of simple yet powerful neural network designs.

Effectiveness of oncology nurse navigator on the incidence of postoperative pulmonary complications in gastric cancer patients undergoing radical gastrectomy.

BACKGROUND: Management of postoperative pulmonary complications (PPCs) can be challenging in gastric cancer patients undergoing radical gastrectomy and is always associated with poor prognosis. Even though oncology nurse navigator (ONN) provide effective and critical individualized care to patients, little is known about their impact on the occurrence of PPCs in gastric cancer patients. This study aimed to determine whether ONN decreases the incidence of PPCs in gastric cancer patients. METHODS: This was a retrospective review in which data for gastric cancer patients at one centre was evaluated before and after an ONN hired. An ONN was introduced to patients at their initial visit to manage pulmonary complications throughout treatment. The research was conducted from 1 August 2020 to 31 January 2022. The study participants were divided into the non-ONN group (from 1 August 2020 to 31 January 2021) and the ONN group (from 1 August 2021 to 31 January 2022). The incidence and severity of PPCs between the groups were then compared. RESULTS: ONN significantly decreased the incidence of PPCs (15.0% vs. 9.8%) (OR = 2.532(95% CI: 1.087-3.378, P = 0.045)), but there was no significant difference in the components of PPCs including pleural effusion, atelectasis, respiratory infection, and pneumothorax. The severity of PPCs was also significantly higher in the non-ONN group (p = 0.020). No significant statistical difference was observed for the major pulmonary complications ([Formula: see text] 3) between the two groups (p = 0.286). CONCLUSIONS: Role of ONN significantly decrease the incidence of PPCs in gastric cancer patients undergoing radical gastrectomy.

TasselLFANet: a novel lightweight multi-branch feature aggregation neural network for high-throughput image-based maize tassels detection and counting.

Accurately and rapidly counting the number of maize tassels is critical for maize breeding, management, and monitoring the growth stage of maize plants. With the advent of high-throughput phenotyping platforms and the availability of large-scale datasets, there is a pressing need to automate this task for genotype and phenotype analysis. Computer vision technology has been increasingly applied in plant science, offering a promising solution for automated monitoring of a large number of plants. However, the current state-of-the-art image algorithms are hindered by hardware limitations, which compromise the balance between algorithmic capacity, running speed, and overall performance, making it difficult to apply them in real-time sensing field environments. Thus, we propose a novel lightweight neural network, named TasselLFANet, with an efficient and powerful structure for accurately and efficiently detecting and counting maize tassels in high spatiotemporal image sequences. Our proposed approach improves the feature-learning ability of TasselLFANet by adopting a cross-stage fusion strategy that balances the variability of different layers. Additionally, TasselLFANet utilizes multiple receptive fields to capture diverse feature representations, and incorporates an innovative visual channel attention module to detect and capture features more flexibly and precisely. We conducted a series of comparative experiments on a new, highly informative dataset called MrMT, which demonstrate that TasselLFANet outperforms the latest batch of lightweight networks in terms of performance, flexibility, and adaptability, achieving an F1 measure value of 94.4%, a mAP.@5 value of 96.8%, and having only 6.0M parameters. Moreover, compared with the regression-based TasselNetV3-Seg† model, our proposed model achieves superior counting performance, with a mean absolute error (MAE) of 1.80, a root mean square error (RMSE) of 2.68, and a R2 of 0.99. The proposed model meets the accuracy and speed requirements of the vision system in maize tassel detection. Furthermore, our proposed method is reliable and unaffected by geographical changes, providing essential technical support for computerized counting in the field.

A neuroprotective role of Ufmylation through Atg9 in the aging brain of Drosophila.

Ufmylation is a recently identified small ubiquitin-like modification, whose biological function and relevant cellular targets are poorly understood. Here we present evidence of a neuroprotective role for Ufmylation involving Autophagy-related gene 9 (Atg9) during Drosophila aging. The Ufm1 system ensures the health of aged neurons via Atg9 by coordinating autophagy and mTORC1, and maintaining mitochondrial homeostasis and JNK (c-Jun N-terminal kinase) activity. Neuron-specific expression of Atg9 suppresses the age-associated movement defect and lethality caused by loss of Ufmylation. Furthermore, Atg9 is identified as a conserved target of Ufm1 conjugation mediated by Ddrgk1, a critical regulator of Ufmylation. Mammalian Ddrgk1 was shown to be indispensable for the stability of endogenous Atg9A protein in mouse embryonic fibroblast (MEF) cells. Taken together, our findings might have important implications for neurodegenerative diseases in mammals.

Self-Assembly Mitochondria-Targeting Donor-Acceptor Type Theranostic Nanosphere Activates ROS Storm for Multimodal Cancer Therapy.

The rational design of cancer theranostics with natural diagnostic information and therapeutic behavior has been considered to be a big challenge, since common theranostics from photothermal and photodynamic therapy need to be activated with external stimuli of photoirradiation to enable the chemotherapeutic effects. In this contribution, we have designed and synthesized a series of simple theranostic agents, TPA-N-n (n = 4, 8, 12), which could accumulate at the tumor site over 48 h and indicate superior antiproliferative performance in vivo. TPA-N-n was constructed with electron donor triphenylamine-acceptor benzothiadiazole-mitochondria-targeting moiety pyridinium. Complex TPA-N-8 indicated the best cytotoxicity to cancerous HeLa cells, with an IC50 value of 4.3 µM, and could self-assemble to a nanosphere with a size of 161.2 nm in the DMSO/PBS solution. It is worth noting that TPA-N-8 could accumulate in the mitochondria and produce major ROS species O2•- and OH• as well as small amounts of 1O2 without photoirradiation. Oxidative DNA damage is initiated due to the imbalance of intracellular redox homeostasis from the significant ROS storm. Multimodal synergistic therapy for HeLa cells was activated, as the PINK1-mediated mitophagy from the damaged mitochondria and DNA damage responsive (DDR) induced necroptosis and autophagy. This work not only provided a successful D-A type theranostic agent with superior anticancer performance from multimodal synergistic therapy but also further demonstrated the high efficacy of a mitochondria-targeting strategy for cancer treatment.

Switching the Mode of Cell Death between Apoptosis and Autophagy by Histone Deacetylase 6 Inhibition Levels.

Inhibition of histone deacetylase (HDAC) has been demonstrated to be an effective strategy for cancer treatment. In this work, we have developed a new agent Ir-VPA, which exhibits the cell death mode switching between apoptosis and autophagy due to the distinct level of HDAC6 inhibition. Ir-VPA indicates the best anticancer activity to HeLa cells, and could be hydrolyzed due to the high expression of the esterase in HeLa cells. Ir-VPA could accumulate in nuclei, induce severe DNA damages and cell cycle arrest at G2/M phase. The anticancer mechanism of Ir-VPA to HeLa cells was dependent on the HDAC6 inhibitory performance, as the caspase dependent apoptosis at low concentration (IC50 ) and autophagy with the autophagy flux blockage at high concentration (2×IC50 ). This is resulted from the distinct inhibitory levels of HDAC6, as moderate/complete inhibition at the concentration of IC50 /2×IC50 .In the presence of autophagic inhibitor chloroquine, the apoptotic population elevated from 32.7 % to 61.7 %, indicating that Ir-VPA could activate apoptotic process through the autophagolysosome fusion inhibition. Ir-VPA also exhibits excellent antiproliferative behavior to 3D HeLa multicellular tumor spheroids (MCTSs). This work not only provided a new HDAC6 inhibitor and novel anticancer mechanism for the effective treatment of cervical cancer, but also demonstrated the strategy to conjugate the metal fragment with active organic drug to enhance the anticancer performance.

Combination of Peglated-H1/HGFK1 Nanoparticles and TAE in the Treatment of Hepatocellular Carcinoma.

Transarterial embolization (TAE) constitutes the gold standard for the treatment of hepatocellular carcinoma. The effect of combination of TAE and peglated-H1/HGFK1 nanoparticles was explored on hepatocellular carcinoma. MTT and Annexin V-FITC were used to determine the cell viability and apoptosis of HepG2, ml-1, LO2, and VX2 cells after the treatment of HGFK1. Next, the orthotopic rabbit was selected to establish the in situ models of VX2 hepatocellular carcinoma. Nanoparticles were synthesized with peglated-PH1 and used to deliver HGFK1 overexpressing plasmids. MRI was performed to monitor tumor volume after being treated with TAE. The protein expression levels of CD31, CD90, and Ki67 were determined by immunohistochemistry. H&E and TUNEL staining were used to determine the necrosis and apoptosis in vivo. HGFK1 significantly inhibited the proliferation and increased the apoptosis of HepG2 and ml-1 cells (P < 0.05). MRI on 14 days after modeling suggested that the tumor showed ring enhancement. MRI on 7 days and 14 days after interventional therapy showed that tumor volume was significantly inhibited after the treatment with TAE and HGFK1 (P < 0.05). The immunohistochemical results 7 days after interventional therapy indicated that the expressions of CD31, CD90, and Ki67 were significantly lower after treatment with TAE and HGFK1 (P < 0.05). TAE and HGFK1 all extended the survival period of rabbits (P < 0.05). PH1/HGFK1 nanoparticle is an innovative and effective embolic agent, which could limit angiogenesis post-TAE treatment. The combination of TAE with PH1/HGFK1 is a promising strategy and might alter the way that surgeons manage hepatocellular carcinoma (HCC).