APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Tumor microenviroment-responsive self-assembly of barium titanate nanoparticles with enhanced piezoelectric catalysis capabilities for efficient tumor therapy.

Catalytic therapy based on piezoelectric nanoparticles has become one of the effective strategies to eliminate tumors. However, it is still a challenge to improve the tumor delivery efficiency of piezoelectric nanoparticles, so that they can penetrate normal tissues while specifically aggregating at tumor sites and subsequently generating large amounts of reactive oxygen species (ROS) to achieve precise and efficient tumor clearance. In the present study, we successfully fabricated tumor microenvironment-responsive assembled barium titanate nanoparticles (tma-BTO NPs): in the neutral pH environment of normal tissues, tma-BTO NPs were monodisperse and possessed the ability to cross the intercellular space; whereas, the acidic environment of the tumor triggered the self-assembly of tma-BTO NPs to form submicron-scale aggregates, and deposited in the tumor microenvironment. The self-assembled tma-BTO NPs not only caused mechanical damage to tumor cells; more interestingly, they also exhibited enhanced piezoelectric catalytic efficiency and produced more ROS than monodisperse nanoparticles under ultrasonic excitation, attributed to the mutual extrusion of neighboring particles within the confined space of the assembly. tma-BTO NPs exhibited differential cytotoxicity against tumor cells and normal cells, and the stronger piezoelectric catalysis and mechanical damage induced by the assemblies resulted in significant apoptosis of mouse breast cancer cells (4T1); while there was little damage to mouse embryo osteoblast precursor cells (MC3T3-E1) under the same treatment conditions. Animal experiments confirmed that peritumoral injection of tma-BTO NPs combined with ultrasound therapy can effectively inhibit tumor progression non-invasively. The tumor microenvironment-responsive self-assembly strategy opens up new perspectives for future precise piezoelectric-catalyzed tumor therapy.

A Two-stage Diagnostic Framework for Post-ablation Treatment Response Assessment in Patients with Hepatocellular Carcinoma.

Contrast-enhanced ultrasound (CEUS) video plays an important role in post-ablation treatment response assessment in patients with hepatocellular carcinoma (HCC). However, the assessment of treatment response using CEUS video is challenging due to issues such as high inter-frame data repeatability, small ablation area and poor imaging quality of CEUS video. To address these issues, we propose a two-stage diagnostic framework for post-ablation treatment response assessment in patients with HCC using CEUS video. The first stage is a location stage, which is used to locate the ablation area. At this stage, we propose a Yolov5-SFT to improve the location results of the ablation area and a similarity comparison module (SCM) to reduce data repeatability. The second stage is an assessment stage, which is used for the evaluation of postoperative efficacy. At this stage, we design an EfficientNet-SK to improve assessment accuracy. The Experimental results on the self-collected data show that the proposed framework outperforms other selected algorithms, and can effectively assist doctors in the assessment of post-ablation treatment response.

Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion.

Immune therapies targeting the PD-1/PD-L1 pathway have been employed in the treatment of breast cancer, which requires aerobic glycolysis to sustain breast cancer cells growth. However, whether PD-L1 expression is regulated by glycolysis in breast cancer cells remains to be further elucidated. Here, we demonstrate that glycolytic enzyme hexokinase 2 (HK2) plays a crucial role in upregulating PD-L1 expression. Under high glucose conditions, HK2 acts as a protein kinase and phosphorylates IκBα at T291 in breast cancer cells, leading to the rapid degradation of IκBα and activation of NF-κB, which enters the nucleus and promotes PD-L1 expression. Immunohistochemistry staining of human breast cancer specimens and bioinformatics analyses reveals a positive correlation between HK2 and PD-L1 expression levels, which are inversely correlated with immune cell infiltration and survival time of breast cancer patients. These findings uncover the intrinsic and instrumental connection between aerobic glycolysis and PD-L1 expression-mediated tumor cell immune evasion and underscore the potential to target the protein kinase activity of HK2 for breast cancer treatment.

Mechanisms of Xuefu Zhuyu Decoction in the treatment of coronary heart disease based on integrated metabolomics and network pharmacology approach.

Coronary heart disease (CHD) has become the leading cause of mortality, morbidity, and disability worldwide. Though the therapeutic effect of Xuefu Zhuyu Decoction (XFZY) on CHD has been demonstrated in China, the active ingredients and molecular mechanisms of XFZY have not been elucidated. The purpose of the current study is to explore the molecular mechanisms of XFZY in the treatment of CHD via network pharmacology, metabolomics, and experimental validation. First, we established a CHD rat model by permanently ligating the left anterior descending coronary artery (LAD), and evaluated the therapeutic effect of XFZY by hemorheology and histopathology. Second, network pharmacology was employed to screen the active ingredients and potential targets of XFZY for the treatment of CHD. Metabolomic was applied to identify the molecules present in the serum after XFZY treatment. Third, the results of network pharmacology and metabolomics were further analyzed by Cytoscape to elucidate the core ingredients and pathways. Finally, the obtained key pathways were verified by transmission electron microscopy and immunofluorescence assay. The results showed that XFZY was effective in the treatment of CHD in the rat model, and the highest dose exerted the best effect. Network pharmacology analysis revealed 215 active ingredients and 129 key targets associated with XFZY treatment of CHD. These targets were enriched in pathways of cancer, lipid and atherosclerosis, fluid shear stress and atherosclerosis, proteoglycans in cancer, chemical carcinogenesis - receptor activation, HIF-1 signaling, et al. Serum metabolomic identified 1081 metabolites involved in the therapeutic effect of XFZY on CHD. These metabolites were enriched in taurine and hypotaurine metabolism, histidine metabolism, retrograde endocannabinoid signaling pathways, et al. Cytoscape analysis combining the data from serum metabolomic and network pharmacology revealed that energy metabolism as the core pathway for XFZY treatment of CHD. Electron microscope observation identified changes in the level of autophagy in the mitochondrial structure of cardiomyocytes. Immunofluorescence assay showed that the expression levels of autophagy-related proteins LC3-B and P62/SQSTM1 were consistent with the levels of autophagy observed in mitochondria. In conclusion, our findings suggest that the possible mechanisms of XFZY in the treatment of CHD are reducing the level of autophagy, improving energy metabolism, and maintaining mitochondrial homeostasis in cardiomyocytes. Our study also shows that the combined strategies of network pharmacology, metabolomics, and experimental validation may provide a powerful approach for TCM pharmacology study.

Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer.

Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.

Self-supervised multi-modal fusion network for multi-modal thyroid ultrasound image diagnosis.

Ultrasound is a typical non-invasive diagnostic method often used to detect thyroid cancer lesions. However, due to the limitations of the information provided by ultrasound images, shear wave elastography (SWE) and color doppler ultrasound (CDUS) are also used clinically to assist in diagnosis, which makes the diagnosis time-consuming, labor-intensive, and highly subjective process. Therefore, automatic diagnosis of benign and malignant thyroid nodules is beneficial for the clinical diagnosis of the thyroid. To this end, based on three modalities of gray-scale ultrasound images(US), SWE, and CDUS, we propose a deep learning-based multi-modal feature fusion network for the automatic diagnosis of thyroid disease based on the ultrasound images. First, three ResNet18s initialized by self-supervised learning are used as branches to extract the image information of each modality, respectively. Then, a multi-modal multi-head attention branch is used to remove the common information of three modalities, and the knowledge of each modal is combined for thyroid diagnosis. At the same time, to better integrate the features between modalities, a multi-modal feature guidance module is also proposed to guide the feature extraction of each branch and reduce the difference between each-modal feature. We verify the multi-modal thyroid ultrasound image diagnosis method on the self-collected dataset, and the results prove that this method could provide fast and accurate assistance for sonographers in diagnosing thyroid nodules.

Clinical application status and prospect of the combined anti-tumor strategy of ablation and immunotherapy.

Image-guided tumor ablation eliminates tumor cells by physical or chemical stimulation, which shows less invasive and more precise in local tumor treatment. Tumor ablation provides a treatment option for medically inoperable patients. Currently, clinical ablation techniques are widely used in clinical practice, including cryoablation, radiofrequency ablation (RFA), and microwave ablation (MWA). Previous clinical studies indicated that ablation treatment activated immune responses besides killing tumor cells directly, such as short-term anti-tumor response, immunosuppression reduction, specific and non-specific immune enhancement, and the reduction or disappearance of distant tumor foci. However, tumor ablation transiently induced immune response. The combination of ablation and immunotherapy is expected to achieve better therapeutic results in clinical application. In this paper, we provided a summary of the principle, clinical application status, and immune effects of tumor ablation technologies for tumor treatment. Moreover, we discussed the clinical application of different combination of ablation techniques with immunotherapy and proposed possible solutions for the challenges encountered by combined therapy. It is hoped to provide a new idea and reference for the clinical application of combinate treatment of tumor ablation and immunotherapy.

Shape Designed Implanted Drug Delivery System for In Situ Hepatocellular Carcinoma Therapy.

In this study, an intelligent drug delivery system (DDS) based on implanted triboelectric nanogenerator (iTENG) and red blood cell (RBC) is established for in situ hepatocellular carcinoma (HCC) therapy. Apatinib (APA), as an oral antitumor drug, which can inhibit the expression of vascular endothelial growth factor receptor-2 (VEGFR2) is loaded inside RBC, realizing the transform from oral formulation to injection preparation. Multishape designed iTENG adapted for different implant sites and environments can harvest biomechanical energy efficiently. The electric field (EF) generated by the iTENG can increase the release of APA, and the release will decrease quickly when the EF disappears, which shows that the DDS is highly controllable. The controllable DDS demonstrates an exciting killing ability of HCC cells both in vitro and in vivo with strikingly reduced APA dosage. After implantation, the self-powered DDS has a prominent therapeutic effect of HCC-bearing rabbits, which is expected to be applied in clinical medicine.

Elevated LOXL2 expression by LINC01347/miR-328-5p axis contributes to 5-FU chemotherapy resistance of colorectal cancer.

Chemotherapy resistance after curative surgery is a major contributor to the mortality of colorectal cancer (CRC). Detailed mechanism studies of specific molecular alterations are critical to improving the available therapies for long-term disease administration. We explored the functional role of LINC01347 in chemotherapy resistance of CRC. Elevated LINC01347 expression was correlated with CRC disease progression during chemotherapy treatment. However, the functional role of LINC01347 and mechanism remained undefined. In this study, we demonstrated that elevated LINC01347 expression was correlated with late clinical stage and poor prognosis in CRC tumor tissues with TCGA data. Exogenous LINC01347 expression promoted cell proliferation and 5-FU resistance of CRC cells, while LINC01347 knockdown attenuated cell growth and 5-FU resistance in vitro and in vivo. Molecular analysis indicated that LINC01347 participated in the transcriptional regulation of LOXL2 by sponging miR-328-5p. LOXL2 knockdown impaired the LINC01347 overexpression induced 5-FU resistance in CRC cells. The clinical analysis supported miR-328-5p/LOXL2 as a candidate biomarker for chemotherapy resistance of CRC patients. Our study provided a molecular basis for the development of 5-FU based chemotherapy resistance in CRC by LINC01347/miR-328/LOXL2 axis. We identified LINC01347 as a prognostic biomarker and potential therapeutic target against 5-FU based chemotherapy resistance of CRC.

LncRNA POU3F3 Contributes to Dacarbazine Resistance of Human Melanoma Through the MiR-650/MGMT Axis.

Background: Alkylating agents are critical therapeutic options for melanoma, while dacarbazine (DTIC)-based chemotherapy showed poor sensitivity in clinical trials. Long non-coding RNAs (lncRNAs) were highlighted in the progression of malignant tumors in recent years, whereas little was known about their involvement in melanoma. Methods: The functional role and molecular mechanism of lncRNA POU3F3 were evaluated on DTIC-resistant melanoma cells. Further studies analyzed its clinical role in the disease progression of melanoma. Results: We observed elevated the expression of lncRNA POU3F3 in the DTIC-resistant melanoma cells. Gain-of-function assays showed that the overexpression of lncRNA POU3F3 maintained cell survival with DTIC treatment, while the knockdown of lncRNA POU3F3 restored cell sensitivity to DTIC. A positive correlation of the expression O6-methylguanine-DNA-methyltransferase (MGMT) was observed with lncRNA POU3F3 in vitro and in vivo. Bioinformatic analyses predicted that miR-650 was involved in the lncRNA POU3F3-regulated MGMT expression. Molecular analysis indicated that lncRNA POU3F3 worked as a competitive endogenous RNA to regulate the levels of miR-650, and the lncRNA POU3F3/miR-650 axis determined the transcription of MGMT in melanoma cells to a greater extent. Further clinical studies supported that lncRNA POU3F3 was a risk factor for the disease progression of melanoma. Conclusion: LncRNA POU3F3 upregulated the expression of MGMT by sponging miR-650, which is a crucial way for DTIC resistance in melanoma. Our results indicated that lncRNA POU3F3 was a valuable biomarker for the disease progression of melanoma.

AB4 inhibits Notch signaling and promotes cancer cell apoptosis in liver cancer.

The etiology for liver cancer has been clearly defined. Unfortunately, therapeutic approaches for liver cancer are rather limited, and liver cancer is insensitive to chemotherapy and radiotherapy. Traditional Chinese medicine (TCM) has become a promising strategy for cancer treatment as TCM elicits broad spectrum anticancer activity. In the present study, we evaluated the anticancer efficacy of AB4, an extract from the medical herb Pulsatilla chinensis (Bunge) Regel, in liver cancer in vitro and in vivo. We found that AB4 readily dose­ and time­dependently inhibited liver cancer HepG2 and Huh­7 cell proliferation and colony formation. Western blot and flow cytometry analyses suggested that AB4 treatment induced liver cancer cell apoptosis. Moreover, these findings could be readily recaptured in vivo, in which the AB4 regimen resulted in tumor suppression and cancer cell apoptosis in xenograft tumor­bearing nude mice. Importantly, we noted that treatment with a Notch signaling inhibitor DAPT produced very similar anticancer efficacy in both HepG2 and Huh­7 cell lines, and administration of DAPT also efficiently suppressed HepG2 xenograft outgrowth. To this end, we anticipated that AB4 and DAPT may act on the same signaling pathway, probably through inhibition of the Notch pathway. Indeed, we found decreased expression of Notch1 protein, as well as downstream targets Hes1 and Hey1, after AB4 treatment. Immunohistochemistry analysis further confirmed the suppression of Notch signaling in HepG2 xenograft­bearing mice. Taken together, our study highlighted the anticancer efficacy of AB4 in liver cancer. We also provided preliminary data showing Notch as a therapeutic target of AB4. It would be interesting to investigate the anticancer efficacy of AB4 in other types of cancer with elevated Notch activity.

Anemoside B4 exerts anti-cancer effect by inducing apoptosis and autophagy through inhibiton of PI3K/Akt/mTOR pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and novel therapeutic approaches are urgently required. Anemoside B4 (AB4) is a compound extracted from Pulsatilla chinensis (P. chinensis). Previous studies have indicated that P. chinensis extract P. chinensis saponins has anti-cancer activity. However, the pharmacological effect of AB4 in cancer is largely unknown. In this study, we investigated the anti-cancer efficacy of AB4 in HCC. We used CCK-8 assay and colony formation assay to evaluate the cytotoxicity of AB4 and found that this agent markedly inhibited SMMC7721 cell proliferation. By using a panel of morphological and molecular experiments, we reported that AB4 induced HCC SMMC7721 cell apoptosis and autophagy. Notably, AB4 treatment acts on the Bcl-2-caspase-3 pathway and Beclin-1-LC3-p62 pathway, thereby regulates both apoptosis and autophagy. Finally, we showed that AB4-induced apoptosis and autophagy converges at the PI3K/Akt/mTOR signaling. AB4 treatment inhibits this signaling transduction pathway and leads to HCC cell death. Collectively, our study highlighted the anti-cancer efficacy of AB4 and suggested that AB4 might be a novel way to treat HCC.

[Application of lateral malleolus hook-plate in treatment of stage II supination-adduction type medial malleolus fracture].

OBJECTIVE: To investigate the application of lateral malleolus hook-plate for the treatment of stage II supination-adduction type medial malleolus fractures. METHODS: Between January 2011 and June 2013, 21 patients with stage II supination-adduction type ankle fractures were treated with lateral malleolus hook-plate, including 12 males and 9 females with an average age of 55.5 years (range, 27-65 years). The injury causes were sprain in 17 cases and traffic accident in 4 cases. The mean time between injury and admission was 12.4 hours (range, 2-72 hours). The tibial distal medial articular surface collapse was found in 7 cases by CT examination and in 3 cases by X-ray film. Of 21 cases, there were 12 cases of low transverse fractures of lateral malleolus, 7 cases of short oblique fractures of lateral malleolus, and 2 cases of ankle joint lateral collateral ligament injury without fractures of lateral malleolus. After operation, the clinical outcome was evaluated according to the talus-leg angle, the recovery of Coin-sign continuity, inside-outside and top ankle gap, talus slope, American Orthopedic Foot and Ankle Society (AOFAS) score, Olerud-Molander score, Kofoed evaluation standards, and patient satisfaction. RESULTS: Seventeen cases were followed up 18.7 months on average (range, 12-25 months). Primary healing was obtained in 16 cases except 1 case of delayed healing. Fracture healed at an average of 14.6 weeks (range, 12-16 weeks). All cases achieved anatomical reduction, the continuity of Coin-sign, and consistency of inside and outside joint gap; no talus tilt occurred. There was no complication of reduction loss, loosening or breakage of internal fixation, or osteoarthritis during follow-up. The talus-leg angle of the affected side was significantly improved to (83.4 ± 1.8)° at 1 week after operation from preoperative (74.8 ± 7.1)° (t = 5.370, P = 0.000), but no significant difference was found when compared with normal side (83.8 ± 2.3)° (t = 0.676, P = 0.509). The AOFAS score, Olerud-Molander score, and range of motion at 1 week, 3 months, and 1 year after operation were significantly improved when compared with preoperative ones (P < 0.05). According to Kofoed evaluation standard, the outcome was excellent in 15 cases and good in 2 cases; the excellent and good rate was 100%. According to patient satisfaction, the outcome was excellent in 13 cases, good in 3 cases, and poor in 1 case; the excellent and good rate was 94.1%. CONCLUSION: The use of lateral malleolus hook-plate for fixation of stage II supination-adduction type medial malleolus fracture not only can effectively maintain anatomical reduction and supporting function, but also can prevent re-collapsing of the reset joint surface. The surgical method can not increase soft tissue complication, so it is a safe and effective method.