AI-Based multimodal Multi-tasks analysis reveals tumor molecular heterogeneity, predicts preoperative lymph node metastasis and prognosis in papillary thyroid carcinoma: A retrospective study.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the predominant form of thyroid cancer globally, especially when lymph node metastasis (LNM) occurs. Molecular heterogeneity, driven by genetic alterations and tumor microenvironment components, contributes to the complexity of PTC. Understanding these complexities is essential for precise risk stratification and therapeutic decisions. METHODS: This study involved a comprehensive analysis of 521 patients with PTC from our hospital and 499 patients from The Cancer Genome Atlas (TCGA). The real-world cohort 1 comprised 256 patients with stage I-III PTC. Tissues from 252 patients were analyzed by DNA-based next-generation sequencing, and tissues from four patients were analyzed by single-cell RNA sequencing (scRNA-seq). Additionally, 586 PTC pathological sections were collected from TCGA, and 275 PTC pathological sections were collected from the real-world cohort 2. A deep learning multimodal model was developed using matched histopathology images, genomic, transcriptomic, and immune cell data to predict LNM and disease-free survival (DFS). RESULTS: This study included a total of 1,011 PTC patients, comprising 256 patients from cohort 1, 275 patients from cohort 2, and 499 patients from TCGA. In cohort 1, we categorized PTC into four molecular subtypes based on BRAF, RAS, RET, and other mutations. BRAF mutations were significantly associated with LNM and impacted DFS. ScRNA-seq identified distinct T cell subtypes and reduced B cell diversity in BRAF-mutated PTC with LNM. The study also explored cancer-associated fibroblasts and macrophages, highlighting their associations with LNM. The deep learning model was trained using 405 pathology slides and RNA sequences from 328 PTC patients and validated with 181 slides and RNA sequences from 140 PTC patients in the TCGA cohort. It achieved high accuracy, with an AUC of 0.86 in the training cohort, 0.84 in the validation cohort, and 0.83 in the real-world cohort 2. High-risk patients in the training cohort had significantly lower DFS rates (P<0.001). Model AUCs were 0.91 at 1 year, 0.93 at 3 years, and 0.87 at 5 years. In the validation cohort, high-risk patients also had lower DFS (P<0.001); the AUCs were 0.89, 0.87, and 0.80 at 1, 3, and 5 years. We utilized the GradCAM algorithm to generate heatmaps from pathology-based deep learning models, which visually highlighted high-risk tumor areas in PTC patients. This enhanced clinicians' understanding of the model's predictions and improved diagnostic accuracy, especially in cases with lymph node metastasis. CONCLUSION: The AI-based analysis uncovered vital insights into PTC molecular heterogeneity, emphasizing BRAF mutations' impact. The integrated deep learning model shows promise in predicting metastasis, offering valuable contributions to improved diagnostic and therapeutic strategies.

Exploring the impact of N4-acetylcytidine modification in RNA on non-neoplastic disease: unveiling its role in pathogenesis and therapeutic opportunities.

RNA modifications include not only methylation modifications, such as m6A, but also acetylation modifications, which constitute a complex interaction involving "writers," "readers," and "erasers" that play crucial roles in growth, genetics, and disease. N4-acetylcytidine (ac4C) is an ancient and highly conserved RNA modification that plays a profound role in the pathogenesis of a wide range of diseases. This review provides insights into the functional impact of ac4C modifications in disease and introduces new perspectives for disease treatment. These studies provide important insights into the biological functions of post-transcriptional RNA modifications and their potential roles in disease mechanisms, offering new perspectives and strategies for disease treatment.

Unraveling the unfolded protein response signature: implications for tumor immune microenvironment heterogeneity and clinical prognosis in stomach cancer.

BACKGROUND: Stomach cancer is a leading cause of cancer-related deaths globally due to its high grade and poor response to treatment. Understanding the molecular network driving the rapid progression of stomach cancer is crucial for improving patient outcomes. METHODS: This study aimed to investigate the role of unfolded protein response (UPR) related genes in stomach cancer and their potential as prognostic biomarkers. RNA expression data and clinical follow-up information were obtained from the TCGA and GEO databases. An unsupervised clustering algorithm was used to identify UPR genomic subtypes in stomach cancer. Functional enrichment analysis, immune landscape analysis, and chemotherapy benefit prediction were conducted for each subtype. A prognostic model based on UPR-related genes was developed and validated using LASSO-Cox regression, and a multivariate nomogram was created. Key gene expression analyses in pan-cancer and in vitro experiments were performed to further investigate the role of the identified genes in cancer progression. RESULTS: A total of 375 stomach cancer patients were included in this study. Analysis of 113 UPR-related genes revealed their close functional correlation and significant enrichment in protein modification, transport, and RNA degradation pathways. Unsupervised clustering identified two molecular subtypes with significant differences in prognosis and gene expression profiles. Immune landscape analysis showed that UPR may influence the composition of the tumor immune microenvironment. Chemotherapy sensitivity analysis indicated that patients in the C2 molecular subtype were more responsive to chemotherapy compared to those in the C1 molecular subtype. A prognostic signature consisting of seven UPR-related genes was constructed and validated, and an independent prognostic nomogram was developed. The gene IGFBP1, which had the highest weight coefficient in the prognostic signature, was found to promote the malignant phenotype of stomach cancer cells, suggesting its potential as a therapeutic target. CONCLUSIONS: The study developed a UPR-related gene classifier and risk signature for predicting survival in stomach cancer, identifying IGFBP1 as a key factor promoting the disease's malignancy and a potential therapeutic target. IGFBP1's role in enhancing cancer cell adaptation to endoplasmic reticulum stress suggests its importance in stomach cancer prognosis and treatment.

Unraveling the role of M1 macrophage and CXCL9 in predicting immune checkpoint inhibitor efficacy through multicohort analysis and single-cell RNA sequencing.

The exact function of M1 macrophages and CXCL9 in forecasting the effectiveness of immune checkpoint inhibitors (ICIs) is still not thoroughly investigated. We investigated the potential of M1 macrophage and C-X-C Motif Chemokine Ligand 9 (CXCL9) as predictive markers for ICI efficacy, employing a comprehensive approach integrating multicohort analysis and single-cell RNA sequencing. A significant correlation between high M1 macrophage and improved overall survival (OS) and objective response rate (ORR) was found. M1 macrophage expression was most pronounced in the immune-inflamed phenotype, aligning with increased expression of immune checkpoints. Furthermore, CXCL9 was identified as a key marker gene that positively correlated with M1 macrophage and response to ICIs, while also exhibiting associations with immune-related pathways and immune cell infiltration. Additionally, through exploring RNA epigenetic modifications, we identified Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3G (APOBEC3G) as linked to ICI response, with high expression correlating with improved OS and immune-related pathways. Moreover, a novel model based on M1 macrophage, CXCL9, and APOBEC3G-related genes was developed using multi-level attention graph neural network, which showed promising predictive ability for ORR. This study illuminates the pivotal contributions of M1 macrophages and CXCL9 in shaping an immune-active microenvironment, correlating with enhanced ICI efficacy. The combination of M1 macrophage, CXCL9, and APOBEC3G provides a novel model for predicting clinical outcomes of ICI therapy, facilitating personalized immunotherapy.

Unveiling the best predictive models for early­onset metastatic cancer: Insights and innovations (Review).

Cancer metastasis is the primary cause of cancer deaths. Metastasis involves the spread of cancer cells from the primary tumors to other body parts, commonly through lymphatic and vascular pathways. Key aspects include the high mutation rate and the capability of metastatic cells to form invasive tumors even without a large initial tumor mass. Particular emphasis is given to early metastasis, occurring in initial cancer stages and often leading to misdiagnosis, which adversely affects survival and prognosis. The present review highlighted the need for improved understanding and detection methods for early metastasis, which has not been effectively identified clinically. The present review demonstrated the clinicopathological and molecular characteristics of early­onset metastatic types of cancer, noting factors such as age, race, tumor size and location as well as the histological and pathological grade as significant predictors. In conclusion, the present review underscored the importance of early detection and management of metastatic types of cancer and called for improved predictive models, including advanced techniques such as nomograms and machine learning, so as to enhance patient outcomes, acknowledging the challenges and limitations of the current research as well as the necessity for further studies.

Synergistic role of activated CD4+ memory T cells and CXCL13 in augmenting cancer immunotherapy efficacy.

The development of immune checkpoint inhibitors (ICIs) has significantly advanced cancer treatment. However, their efficacy is not consistent across all patients, underscoring the need for personalized approaches. In this study, we examined the relationship between activated CD4+ memory T cell expression and ICI responsiveness. A notable correlation was observed between increased activated CD4+ memory T cell expression and better patient survival in various cohorts. Additionally, the chemokine CXCL13 was identified as a potential prognostic biomarker, with higher expression levels associated with improved outcomes. Further analysis highlighted CXCL13's role in influencing the Tumor Microenvironment, emphasizing its relevance in tumor immunity. Using these findings, we developed a deep learning model by the Multi-Layer Aggregation Graph Neural Network method. This model exhibited promise in predicting ICI treatment efficacy, suggesting its potential application in clinical practice.

Tumor-associated macrophages in non-small-cell lung cancer: From treatment resistance mechanisms to therapeutic targets.

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide. Different treatment approaches are typically employed based on the stage of NSCLC. Common clinical treatment methods include surgical resection, drug therapy, and radiation therapy. However, with the introduction and utilization of immune checkpoint inhibitors, cancer treatment has entered a new era, completely revolutionizing the treatment landscape for various cancers and significantly improving overall patient survival. Concurrently, treatment resistance often poses a critical challenge, with many patients experiencing disease progression following an initial response due to treatment resistance. Increasing evidence suggests that the tumor microenvironment (TME) plays a pivotal role in treatment resistance. Tumor-associated macrophages (TAMs) within the TME can promote treatment resistance in NSCLC by secreting various cytokines activating signaling pathways, and interacting with other immune cells. Therefore, this article will focus on elucidating the key mechanisms of TAMs in treatment resistance and analyze how targeting TAMs can reduce the levels of treatment resistance in NSCLC, providing a comprehensive understanding of the principles and approaches to overcome treatment resistance in NSCLC.

Associations between cardiac structure and function and depressive disorder: A centenarian study in China.

Background: Depressive disorder is a common comorbidity in patients with cardiovascular diseases and is associated with increased hospitalization and death rates. The relationships between cardiac structure and function and depressive disorder remains unclear in the older adults, especially in centenarians. Therefore, this study aimed to explore the possible associations between cardiac structure and function and depressive disorder among centenarians. Methods: In the China Hainan Centenarian Cohort Study, the 15-item Geriatric Depression Scale scores and echocardiography were used to evaluate depressive disorder and cardiac structure and function, respectively. All information, including epidemiological questionnaires, physical examinations, and blood tests, was obtained following standardized procedures. Results: A total of 682 centenarians were enrolled in the study (mean age: 102.35 ± 2.72 years). The prevalence of depressive disorder in centenarians is 26.2% (179 older adults), of whom 81.2% (554 older adults) are women. Centenarians with depressive disorder have significantly higher left ventricular ejection fraction (60.02 ± 3.10) and interventricular septum thickness (9.79 ± 1.54). Stepwise multiple linear regression analysis detected positive associations of left ventricular ejection fraction (Bets: 0.093) and interventricular septum thickness (Bets: 0.440) with Geriatric Depression Scale scores. Both left ventricular ejection fraction (odds ratio: 1.081) and interventricular septum thickness (odds ratio: 1.274) were independently associated with depressive disorder in multiple logistic regression analysis (P < 0.05, all). Conclusions: The prevalence of depressive disorder remains very high, and associations were found between left ventricular ejection fraction, interventricular septum thickness, and depressive disorder in Chinese centenarians. Future studies should focus on their temporal relationships to improve cardiac structure and function, prevent depressive disorder, and achieve healthy aging by coordinating their relationships.

The Application of Platelet-Rich Plasma for Patients Following Total Joint Replacement: A Meta-Analysis of Randomized Controlled Trials and Systematic Review.

Background: The clinical efficacy of platelet-rich plasma (PRP) in the treatment of total joint replacement (TJR) remains inconclusive. In this paper, systematic review and meta-analysis was adopted to assess the efficacy of using PRP for the treatment of TJR. Methods: A comprehensive search of Medline, Embase, and Cochrane library databases for randomized controlled trial (RCT) articles recording data of PRP for TJR was conducted from inception to February 2022. Outcomes concerned were pain, range of motion (ROM), WOMAC score, length of hospital stay (LOS), hemoglobin (Hb) drop, total blood loss, wound healing rate, and wound infection. The methodological quality of the included RCTs was evaluated by using the Cochrane Risk of Bias Tool 2.0 (RoB 2.0). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was utilized to assess the level of evidence for the outcomes. Subgroup analysis was conducted according to the type of TJR. Results: Ten RCTs were included in the meta-analysis. In the TKA subgroup, the available data demonstrated that there were significant differences in the outcomes of pain and Hb drop, while it was the opposite of ROM, WOMAC score, LOS, total blood loss, wound healing rate, and wound infection. In the THA subgroup, no significant differences could be seen between two groups in the outcomes of LOS and wound infection. However, the PRP group gained a higher wound healing rate in the THA subgroup. Conclusion: The application of PRP did not reduce blood loss but improved the wound healing rate. However, more prospective and multicenter studies are warranted to confirm these results.

The Emerging Roles of Circ-ABCB10 in Cancer.

Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) without 5' caps and 3' tails, which are formed from precursor mRNAs (pre-mRNAs) that are inversely back-spliced by exons. CircRNAs are characterized by a covalently closed circular structure and are abundantly expressed in eukaryotic cells. With the development of RNA-sequencing, it was discovered that circRNAs play important roles in the regulation of numerous human genes and are related to the occurrence, development, and prognosis of diseases. Studies in various cancers have revealed that circRNAs have both positive and negative effects on the occurrence and development of tumors. Circ-ABCB10, a circular RNA originating from exons of ABCB10 located on chromosome 1q42, has been proven to play an important role in different types of cancers. Here, we report the primary findings of recent research studies by many contributors about the roles of circ-ABCB10 in cancer and clearly formulate its influence and functions in different aspects of cancer biology, which gives us a broad picture of circ-ABCB10. Thus, this study aimed to generalize the roles of circ-ABCB10 in the diagnosis and treatment of different types of tumors and its related miRNA genes. In this way, we wish to provide a sufficient understanding and assess the future development direction of the research on circ-ABCB10.

The Roles of FHL3 in Cancer.

The four and a half LIM domain protein 3, also named the LIM-protein FHL3, belongs to the LIM-only family. Based on the special structure of LIM-only proteins, FHL3 can perform significant functions in muscle proliferation and cardiovascular diseases by regulating cell growth and signal transduction. In recent years, there has been increasing evidence of a relation between FHLs and tumor biology, since FHL3 is often overexpressed or downregulated in different cancers. On the one hand, FHL3 can function as a tumor suppressor and influence the expression of downstream genes. On the other hand, FHL3 can also play a role as an oncoprotein in some cancers to promote tumor progression via phosphorylation. Thus, FHL3 is proposed to have a dual effect on cancer progression, reflecting its complex roles in cancer. This review focuses on the roles of FHL3 in cancer progression and discusses the interaction of FHL3 with other proteins and transcription factors. Finally, the clinical significance of FHL3 for the treatment of cancers is discussed.

Association between immunoglobulin A and depression in Chinese older adults: findings from a cross-sectional study.

BACKGROUND: Depression is considered to be an immune-related disease; however, previous studies have focused on inflammatory factors, and there is no conclusive conclusion on the relationships between immunoglobulins and depression. Therefore, the objective of this cross-sectional study was to evaluate the associations between immunoglobulins and depressive symptoms in Chinese older adults. RESULTS: The China Hainan Centenarian Cohort Study (CHCCS) provides a significant population-based sample of older adults in Hainan, China. A total of 1547 older adults were included in this study. A baseline survey was conducted using a structured questionnaire. Blood samples were obtained following standard procedures. The Geriatric Depression Scale (GDS-15) was used to evaluate depressive symptoms of the participants. This sample of older adults had a median age of 94.75 (range: 80-116) years, and the proportion of women was 72.07%. The prevalence of older adults with depressive symptoms was 20.36% (315 older adults). After adjusting for all covariates, we found that immunoglobulin A levels were positively associated with depression. The adjusted reliability of the association between immunoglobulin A and depression was 0.106 (beta) and 1.083 (odds ratio) (P < 0.05 for both). CONCLUSIONS: The present study provides epidemiological evidence that depression has significant associations with immunoglobulin A levels in older adults. Further research should be conducted on the effects of regulating immunoglobulin A to improve depressive symptoms.

Nickel-Catalyzed 1,1-Dihydrophosphinylation of Nitriles with Phosphine Oxides.

Treatment of phosphine oxides with nitriles usually furnishes 1,2-dihydrophosphinylation products. Herein, we developed a nickel-catalyzed 1,1-dihydrophosphinylation of nitriles with phosphine oxides to access primary amines. This reaction proceeded smoothly under very mild conditions. A series of nitriles and phosphine oxides were compatible with this conversion, and the desired products were obtained in moderate to good yields.

Are third-generation active-targeting nanoformulations definitely the best? In vitro and in vivo comparisons of pixantrone-loaded liposomes modified with different sialic acid derivatives.

Treatment with sialic acid-octadecylamine (SA-ODA)-modified pixantrone (Pix) liposomes results in favorable antitumor effects by targeting tumor-associated macrophages (TAMs). To explore the influence of different types of SA decorations on antitumor efficiency, we synthesized a PEGylated SA derivative, SA-PEG2000-DSPE, and combined it with SA-ODA to construct three representative types of SA-modified liposomes (SA-ODA-modified Pix liposomes, SA-ODA-modified Pix liposomes with different PEG densities, and SA-PEG2000-DSPE-modified Pix liposomes, named Pix-SACL, Pix-SPL-0.2/0.5/2.0/5.0, and Pix-SAPL, respectively). All the Pix liposomes were nanoscale formulations, having diameters between 100 and 150 nm, high encapsulation efficiencies (> 90%), and slow drug release properties. The in vivo blood circulation time of the PEGylated formulations (Pix-SPL-0.2/0.5/2.0/5.0 and Pix-SAPL) showed an upward trend with increasing PEG density, but there was no significant difference between adjacent groups. All PEGylated formulations displayed increased tumor accumulation when compared with Pix-SACL, but there was no significant difference among them. However, the antitumor activity of SA-modified liposomes was not positively correlated with circulation time or tumor accumulation in S180-bearing mice. Pix-SPL-0.2 displayed the strongest antitumor effect and lowest toxicity among the formulations tested in this study. With Pix-SPL-0.2 treatment, 66.7% of the mice demonstrated tumor shedding and wound healing.

Preparation of a hydrophobically associated cationic polyacrylamide and its regulation of the sludge dewatering performance.

A hydrophobically associating cationic polyacrylamide (HACPAM) was prepared by using a micellar polymerization method with V-50 (azobisisobutyramidine hydrochloride) as the initiator and acrylamide, acryloyloxyethyl trimethylammonium chloride and butyl methacrylate as substrates under ultraviolet light irradiation. Structural analysis using Fourier transform infrared spectroscopy, proton nuclear magnetic resonance and X-ray photoelectron spectroscopy analyses showed that the substrates were successfully polymerized. HACPAM was used to condition sludge to improve its dewatering performance, and the results showed that as the amount of HACPAM increases, the sludge dewatering performance is significantly improved, and 3.532 kg/t dry solids of HACPAM is regarded as the optimal amount. Compared with the commercially available cationic polyacrylamide (CPAM), HACPAM has a stronger hydrophobic group association effect, with better promotion of the conversion of bound water in sludge flocs into free water, thereby improving the sewage dewatering performance. The 3D spatial structure of dewatered sludge cakes analyzed by computed tomography technology showed that the number of pores of the dewatered sludge cake treated by HACPAM 3 was smaller than that of the cake treated by CPAM, with a reduction in the porosity of 68.8%, resulting in a better hydrophobic effect. In addition, the mechanism of HACPAM improving the dewatering performance is discussed.

Protective Effect of Electroacupuncture at Zusanli on Myocardial Injury in Septic Rats.

The protective effect of electroacupuncture (EA) at Zusanli points (ST36) on myocardial injury in a model of sepsis was observed. Forty-eight male Sprague-Daley rats were subjected to sepsis by cecal ligation and puncture (CLP) and randomly divided into 4 groups (n=12; A: sepsis + EA; B: sepsis + sham acupuncture; C: sepsis + vagotomy; D: sepsis + vagotomy + EA). Bilateral points were stimulated (2mA, 2-100 Hz) for 1 hour. Abdominal vagotomy was performed in groups C and D. At 6h after CLP, the plasma activity of creatine kinase-MB (CK-MB) was determined. A part of cardiac muscle was harvested for evaluating levels of tumor necrosis factor (TNF-α), nitric oxide (NO), myeloperoxidase (MPO), and the rate of water content. The activities of CK-MB, TNF-α, NO, and MPO and the rate of water content in group A were significantly lower than those of the other groups 6h after CLP. EA after vagotomy showed less anti-inflammatory and protective effects. The results indicated that EA obviously reduced the increased levels of the proinflammatory factors at 6h after CLP, and vagotomy could weaken or eliminate the effects of EA. Cholinergic anti-inflammatory pathway is one of the main mechanisms of cardioprotective effect of EA.

Aspirin induces Beclin-1-dependent autophagy of human hepatocellular carcinoma cell.

Aspirin not only reduces the incidence of hepatocellular carcinoma (HCC) but also plays a synergistic role with chemotherapy for HCC treatment. However, the underlying mechanisms remain incompletely elucidated. Given that autophagy triggers cancer cell death, the present study examined the autophagic effect of aspirin on HCC cells. Results showed that aspirin increased LC3II/LC3I ratio, decreased p62 expression, and enhanced autophagic flux (autophagosome and autolysosome puncta) in Hep3B, HepG2, or SMMC-7721 cells, reflecting the autophagy of HCC cells. The autophagic effects of aspirin depended on Beclin-1 expression. Aspirin disrupted the interaction between Bcl-2 and Beclin-1. In addition to activating the AMP-activated protein kinase, c-Jun N-terminal kinase, and Glycogen synthase kinase-3 pathways, aspirin inhibited the mammalian-target-of rapamycin-S6K1/4E-BP1 signaling. Aspirin induced autophagy of HCC cell. This study contributes to understanding the chemoprotective and inhibitory effects of aspirin on HCC development.

Novel, nano-sized, liposome-encapsulated polyamidoamine dendrimer derivatives facilitate tumour targeting by overcoming the polyethylene glycol dilemma and integrin saturation obstacle.

Drug delivery systems (DDSs) commonly employ arginine-glycine-aspartic acid (RGD) peptides with polyethylene glycol (PEG)-dependent enhanced permeability and retention (EPR) effect to optimise tumour-targeting. However, the PEG dilemma and integrin saturation obstacle are major challenges. To address these issues, we constructed a novel, nano-sized DDS by encapsulating doxorubicin (DOX)-loaded folic acid derivatives of polyamidoamine dendrimer (PAMAM G5.0) in cyclic RGD-tyrosine-lysine pentapeptide (c[RGDyK])-modified liposomes (RGD-SL[FND/DOX]), prepared using thin-film hydration, film-dispersion and hydration-sonication. The liposomes were PEGylated, sterically stabilised and pH-sensitive. In vitro, RGD-SL[FND/DOX] showed pH-sensitive holistic FND/DOX release, and pH-dependent uptake and cytotoxicity in human cancer KB cells. At pH 7.4, RGD-SL[FND/DOX] demonstrated greater cellular uptake and cytotoxicity than relevant control formulations (except FND/DOX) did, although this advantage disappeared at pH 6.5. In vivo, RGD-SL[FND/DOX] inhibited S180 sarcoma xenografted tumour growth in Kunming mice more effectively than FND/DOX did. These findings demonstrate the feasibility of constructing double-stage tumour-targeting nano-sized DDSs such as RGD-SL[FND/DOX]. c[RGDyK] and the EPR effect, facilitated by the particle size (about 110 nm) and PEGylation, helped to target the DDS to the tumour tissue, while the subsequent pH-dependent release of FND/DOX and folic acid-mediated endocytosis specifically targeted the tumour cells, thereby overcoming the PEG dilemma and integrin saturation obstacle.

[Pharmacodynamics of liposomes modified with different chain length of sialic acid derivatives].

A large number of experimental and clinical data indicates that tumor-associated macrophages(TAMs) were involved in the whole process of tumor growth, invasion and metastasis. Like macrophages in other tissues, TAMs originate from blood monocytes, which are recruited to the tumor tissues by cytokines and then differentiated into TAMs. It is interesting that the monocytes overexpress siglec receptor in their surface, which has a high binding specificity to sialic acid(SA). From this point of view, we hypothesize that if SA was used as a ligand in the surfaces of drug delivery systems, SA would enhance the targeting efficiency to monocytes, and thus to achieve a higher specificity to TAMs. In our previous study, an SA derivative of SA-octadecylamine(SA-18) was synthesized and was found to enhance cytotoxicity on TAMs in vitro. The chain length is a critical factor for SA efficiency in liposomes and it has a significant influence on the TAM targeting effects of the carriers. So in this study, four kinds of different chain length of SA fatty amine derivatives were synthesized, including SA-18, SA-hexadecylamine(SA-16), SA-tetradecylamine(SA-14) and SA-dodecylamine(SA-12), and were modified on the surfaces of blank liposomes(BLK-Sn L, n = 18, 16, 14, 12) and pixantrone maleate-loaded liposomes(Pix-Sn L, n = 18, 16, 14, 12). TAM targeting effects of these SA derivatives were evaluated by acute toxicity and antitumor efficacy in vivo. The results of acute toxicity experiments showed that the toxicities of the SA derivatives deceased gradually with the reduction in the length of lipophilic chain. The in vivo antitumor efficacies of SA-modified blank liposomes showed that these blank formulations had no effect on the tumor inhibition except BLK-S14L(61.4% ± 18.8%), and BLK-S16 L even promoted the tumor growth(-31.7% ± 13.1%, the 18 th day). The in vivo antitumor efficacies of SA-modified Pix liposomes showed that the tumor inhibition effects were Pix-S18L(97.4% ± 2.1%) > Pix-S14L(73.1% ±21.1%) > Pix-S12L(53.9% ± 17.8%) > Pix-S16L(32.9%). Because of the relatively strong binding ability of SA-18, it was hard to fall off from the liposomes in the transport process, leading to a good TAM targeting ability and less toxicity to the normal tissues. Meanwhile, 50% of the mice in Pix-S18 L group showed "tumor shedding" and "wound healing" phenomena without recurrence in two months following the treatment. Therefore, SA-18 is the most potential TAM targeting material among these SA fatty amine derivatives.

Puerarin prevents cardiac hypertrophy induced by pressure overload through activation of autophagy.

This study aimed to explore the effects of puerarin on autophagy in cardiac hypertrophy. Decreased 5'-adenosine monophosphate kinase (AMPK) activity alone with inhibited autophagy could be detected in rats within 3 weeks after aortic banding (AB). Puerarin treatment for 3 weeks in AB rats significantly restored autophagy. Administration of puerarin for 6 weeks effectively restricted cardiomyocyte hypertrophy and apoptosis. In an in vitro study, similar anti-hypertrophy and anti-apoptosis effects of puerarin on isoprenaline-induced H9c2 cells were also observed. After inhibition of autophagy by pretreatment with 3-methyladenine, the protective effects of puerarin were blocked. Further in vivo study demonstrated that puerarin significantly enabled phosphorylation of 5'-AMPK to be activated, subsequently inhibiting expression of the mammalian target of rapamycin (mTOR) target proteins S6 ribosomal protein and 4E-binding protein 1. All these data indicate that puerarin exerts protective effects against cardiomyocyte hypertrophy and apoptosis, partly by restoration of autophagy through AMPK/mTOR-mediated signaling.