A Porphyrin-Based 3D Metal-Organic Framework Featuring [Cu8Cl6]10+ Cluster Secondary Building Units: Synthesis, Structure Elucidation, Anion Exchange, and Peroxidase-Like Activity.

Herein, we report a rare example of cationic three-dimensional (3D) metal-organic framework (MOF) of [Cu5Cl3(TMPP)]Cl5 ⋅ xSol (denoted as Cu-TMPP; H2TMPP=meso-tetrakis (6-methylpyridin-3-yl) porphyrin; xSol=encapsulated solvates) supported by [Cu8Cl6]10+ cluster secondary building units (SBUs) wherein the eight faces of the Cl--based octahedron are capped by eight Cu2+. Surface-area analysis indicated that Cu-TMPP features a mesoporous structure and its solvate-like Cl- counterions can be exchanged by BF4 -, PF6 -, and NO3 -. The polyvinylpyrrolidone (PVP) coated Cu-TMPP (denoted as Cu-TMPP-PVP) demonstrated good ROS generating ability, producing ⋅OH in the absence of light (peroxidase-like activity) and 1O2 on light irradiation (650 nm; 25 mW cm-2). This work highlights the potential of Cu-TMPP as a functional carrier of anionic guests such as drugs, for the combination therapy of cancer and other diseases.

Natural ursolic acid based self-therapeutic polymer as nanocarrier to deliver natural resveratrol for natural therapy of acute kidney injury.

Acute kidney injury (AKI) is a common kidney disease associated with excessive reactive oxygen species (ROS). Unfortunately, due to the low kidney targeting and undesired side effects, the existing antioxidant and anti-inflammatory drugs are unavailable for AKI management in clinic. Therefore, it's essential to develop effective nanodrugs with high renal targeting and biocompatibility for AKI treatment. Herein, we reported a novel nanodrug for AKI treatment, utilizing poly(ursolic acid) (PUA) as a bioactive nanocarrier and resveratrol (RES) as a model drug. The PUA polymer was synthesized form ursolic acid with intrinsic antioxidant and anti-inflammatory activities, and successfully encapsulated RES through a nanoprecipitation method. Subsequently, we systemically investigated the therapeutic potential of RES-loaded PUA nanoparticles (PUA NPs@RES) against AKI. In vitro results demonstrated that PUA NPs@RES effectively scavenged ROS and provided substantial protection against H2O2-induced cellular damage. In vivo studies revealed that PUA NPs significantly improved drug accumulation in the kidneys and exhibited favorable biocompatibility. Furthermore, PUA NPs alone exhibited additional anti-inflammatory and antioxidant effect, synergistically enhancing therapeutic efficacy in AKI mouse models when combined with RES. Overall, our study successfully developed an effective nanodrug using self-therapeutic nanocarriers, presenting a promising option for the treatment of AKI.

Development of poly(p-coumaric acid) as a self-anticancer nanocarrier for efficient and biosafe cancer therapy.

Using biocompatible polymers with potential therapeutic activity is an appealing strategy for the development of new functional drug carriers. In this study, we report the synthesis of therapeutic poly(p-coumaric acid) (PCA) from p-coumaric acid, a common plant phenolic acid with multiple bioactivities. The prepared PCA was formulated into nanoparticles (NPs) using the nanoprecipitation method and docetaxel (DTX) was encapsulated to form DTX-loaded PCA NPs (DTX@PCA NPs). Their potential as a nanocarrier for anticancer drug delivery was systematically evaluated. The DTX@PCA NPs not only had a small particle size and good stability, but also exhibited superior in vitro anticancer activity, anti-metastasis ability compared with free drugs, and preferable cellular uptake by tumor cells. In addition, the three-dimensional tumor spheroid assay revealed the effective tumor penetration and anticancer activity of the DTX@PCA NPs. Importantly, the DTX@PCA NPs preferentially accumulated in tumors and prolonged systemic circulation, significantly inhibiting tumor growth in vivo and simultaneously attenuating the side effects of DTX. Interestingly, the blank PCA NPs themselves also exhibited additional tumor suppression activity to some extent with high biosafety, further indicating the significant potential of PCA as a novel self-therapeutic nanocarrier for anticancer drug delivery and enhanced cancer therapy.

A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T-Cell Acute Lymphoblastic Leukemia.

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting-therapy efficacy remains unexplored. Here, an L-phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting myeloid-derived suppressor cells (MDSCs) in T-ALL murine model. Stable-isotope tracer and in vivo drug distribution experiments show that T-ALL cells and MDSCs have enhanced cellular uptake of L-phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN-Dox) specifically targets T-ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN-Dox has reduced cardiotoxicity and myeloablation side effects in treating T-ALL mice. Mechanistically, MRIAN degrades into L-phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T-ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

mRNA Network: Solution for Tracking Chemotherapy Insensitivity in Small-Cell Lung Cancer.

Background: Small-cell lung cancer (SCLC) has poor prognosis and is prone to drug resistance. It is necessary to search for possible influencing factors for SCLC chemotherapy insensitivity. Therefore, we proposed an mRNA network to track the chemotherapy insensitivity in SCLC. Methods: Six samples of patients with SCLC were recruited for RNA sequencing. TopHat2 and Cufflinks were used to make differential analysis. Functional analysis was applied as well. Finally, multidimensional validation was applied for verifying the results we obtained by experiment. Results: This study was a trial of drug resistance in 6 SCLC patients after first-line chemotherapy. The top 10 downregulated genes differentially expressed in the chemo-insensitive group were SERPING1, DRD5, PARVG, PRAME, NKX1-1, MCTP2, PID1, PLEKHA4, SPP1, and SLN. Cell-cell signaling by Wnt (p=6.98E - 21) was the most significantly enriched GO term in biological process, while systemic lupus erythematosus (p=6.97E - 10), alcoholism (p=1.01E - 09), and transcriptional misregulation in cancer (p=0.00227988) were the top three ones of KEGG pathways. In multiple public databases, we also highlighted and verified the vital role of glycolysis/gluconeogenesis pathway and corresponding genes in chemo-insensitivity in SCLC. Conclusion: Our study confirmed some SCLC chemotherapy insensitivity-related genes, biological processes, and pathways, thus constructing the chemotherapy-insensitive network for SCLC.

Collection on reports of molecules linked to epithelial-mesenchymal transition in the process of treating metastasizing cancer: a narrative review.

Epithelial-mesenchymal transition (EMT) is a morphological process in which epithelial cells transform into mesenchymal cells via a specific procedure. EMT plays an important role in the cancer invasion-metastasis cascade and the current treatment of metastatic cancer, influences the migration, polarity, and adhesion of tumor cells, promotes their migration, invasiveness, anti-apoptotic ability. It contributes to the changes of the tumor microenvironment and suppresses the sensitivity of tumor cells to chemotherapy, causing cancer metastasis and worse, hindering the control and therapy of it. This paper reviews the mechanisms, detection, and treatments of cancer metastasis that have been identified and applied to date, summarizes the EMT-related biological molecules, providing a reference for EMT-targeted research and therapy. As EMT is significant in the progress of tumor metastasis, it is meaningful for the therapy and control of metastatic cancer to understand the mechanism of EMT at the molecular level. We summarized the mechanisms, detection and therapeutic implications of EMT, listed the research progress of molecules like genes, miRNAs, signaling pathways in EMT. We also discussed the prospects of EMT-targeted treatment in cancer metastasis interventions and the challenges the treatment and researches are facing. The summary is conducive to the treatment and further research of EMT and metastatic cancer.

Nanomaterial-Facilitated Cyclin-Dependent Kinase 7 Inhibition Suppresses Gallbladder Cancer Progression via Targeting Transcriptional Addiction.

Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract cancer, and there is a lack of effective treatment. Here, we developed a nanoparticle platform (8P4 NP) that can deliver THZ1, a cyclin-dependent kinase 7 (CDK7) inhibitor, to treat GBC. Analysis of datasets demonstrated that CDK7 was positively correlated with poor prognosis. CDK7 inhibition suppressed cell proliferation, induced apoptosis, and caused cell cycle block in GBC cells. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II (RNAPII), resulting in a significant downregulation of transcriptional programs, with a preferential repression of oncogenic transcription factors. To improve the tumor targeting efficiency of THZ1, 8P4 NPs were prepared and assembled with THZ1 to form THZ1@8P4 NPs. Compared with free THZ1, THZ1@8P4 NPs showed more advantages in prolonging blood circulation, escaping from lysosomes and increasing cellular uptake. Importantly, THZ1@8P4 NPs demonstrated a more significant inhibition effect on GBC cells than free THZ1 in vitro. In addition, THZ1@8P4 NPs could efficiently deliver THZ1 to tumor sites in a patient-derived xenograft model of early recurrence, leading to tumor regression and transcriptional inhibition with minimal toxicity. In summary, we conclude that THZ1@8P4 NPs provide a potent therapeutic strategy that targets CDK7-mediated transcriptional addiction in GBC.

Assessment of the value of adjuvant radiotherapy for treatment of gastric adenocarcinoma based on pattern of post-surgical progression.

PURPOSE: To assess the value of adjuvant radiotherapy for treatment of gastric adenocarcinoma and to investigate subgroups of patients suitable for adjuvant radiotherapy. METHODS AND MATERIALS: Data from 785 patients with gastric adenocarcinoma who had undergone D1/D2 radical resection and adjuvant chemotherapy were collected, the site of first progression was determined, and the relationship between the rate of local recurrence and clinicopathologic features was analyzed. RESULTS: By the end of the follow-up period, progression was observed in 405 patients. Local recurrence was observed as the first progression in 161 cases. The local recurrence rate was significantly lower than the non-local progression rate (20.5% vs 31.5%, p=0.007). Multivariate Cox regression analysis showed a significant relationship among degree of differentiation, T stage, N stage, and rate of local recurrence. CONCLUSIONS: Not all patients with gastric carcinoma required adjuvant radiotherapy. However, patients with poorly differentiated cancer cells, advanced T stage (T3/T4), and positive lymph nodes, which included patients in the T4N1-2M0 subgroup, were recommended for adjuvant radiotherapy.

Extracapsular lymph node involvement is a robust survival predictor in esophageal cancer patients: A pooled analysis.

BACKGROUND: Although extracapsular lymph node involvement (EC-LNI) has been proposed to be incorporated into the staging system of esophageal cancer, the prognostic value of EC-LNI remains controversial with conflicting data available, especially in the era of neoadjuvant therapy. METHODS: An electronic literature search was undertaken using four public databases. Studies investigating the effects of EC-LNI on survival were included. In addition to analysis of the entire cohort, subset analyses were also performed to assess the impact of EC-LNI on patients receiving different treatment modalities. RESULTS: A total of 20 studies were included in this meta-analysis. Pooling 13 studies on overall survival (OS), we observed that presence of EC-LNI was associated with significantly worse OS (HR = 2.09, 95%CI: 1.63-2.68; p < 0.01). Nine studies describing disease-free survival (DFS) included, the pooled data revealed that presence of EC-LNI was associated with significantly worse DFS (HR = 1.89, 95%CI: 1.63-2.20; p < 0.001). Subset analyses of patients receiving neoadjuvant therapy demonstrated a survival disadvantage of EC-LNI on OS (HR = 1.928, 95%CI: 1.196-3.107; p = 0.007) and DFS (HR = 1.985, 95%CI: 1.585-2.487; p < 0.001). Similar result was also seen in patients receiving primary surgery (OS: HR = 2.219, 95%CI: 1.720-2.864; p < 0.001; DFS: HR = 1.659, 95%CI: 1.285-2.141; p < 0.001). CONCLUSION: EC-LNI is a strong prognostic predictor of inferior survival in patients with esophageal cancer irrespective of treatment modality. The currently pooled evidence indicates that EC-LNI has great potential to be incorporated into the future staging system.

Research progress on the molecular mechanisms of hepatic metastasis in lung cancer: a narrative review.

The liver is one of the most common sites of metastatic spread of lung cancer, and the process of metastasis is regulated by many factors. A number of genes, including multiple tumor suppressor 1 (mts1), p120 catenin, and CT45A1, increase the possibility of hepatic metastasis in lung cancer, whereas Tip30/CC3, CUL5, and SOCS3 expression in lung tumors inhibit tumor metastasis. microRNAs (miRNAs), such as miRNA-126, miRNA-338, and miRNA-218, can affect the metastasis of lung cancer cells to the liver. The D114-Notch signaling pathway can inhibit liver metastasis in small cell lung cancer. Serum tumor markers cytokeratin 19 fragment antigen 21-1 and neuron-specific enolase (NSE) are closely related to the risk of hepatic metastasis in lung cancer. Based on previously published literature, we found that the metastasis and invasion of lung cancer to the liver are determined by molecular factors. Therefore, the selective identification and intervention of these erroneous signals can predict early lung cancer metastasis to the liver. In this review article, we describe the mechanisms and influencing factors (genes, signal pathways, chemicals, proteins, miRNAs) of hepatic metastasis in lung cancer. We hope to provide a summary of the evidence for the mechanisms by which related genes or proteins affect the malignancy of liver metastasis from lung cancer so that doctors and researchers can improve treatment options.

Aberrant methylation modifications reflect specific drug responses in small cell lung cancer.

In the study, Methylated DNA immunoprecipitation sequencing, RNA sequencing, and whole-exome sequencing were employed to clinical small cell lung cancer (SCLC) patients. Then, we verified the therapeutic predictive effects of differentially methylated genes (DMGs) in 62 SCLC cell lines. Of 4552 DMGs between chemo-sensitive and chemo-insensitive group, coding genes constituted the largest percentage (85.08%), followed by lncRNAs (10.52%) and miRNAs (3.56%). Both two groups demonstrated two methylation peaks near transcription start site and transcription end site. Two lncRNA-miRNA-mRNA networks suggested the extensive genome connection between chemotherapy efficacy-related non-coding RNAs (ncRNAs) and mRNAs. Combing miRNAs and lncRNAs could effectively predict chemotherapy response in SCLC. In addition, we also verified the predictive values of mutated genes in SCLC cell lines. This study was the first to evaluate multiple drugs efficacy-related ncRNAs and mRNAs which were modified by methylation in SCLC. DMGs identified in our research might serve as promising therapeutic targets to reverse drugs-insensitivity by complex lncRNA-miRNA-mRNA mechanisms in SCLC.

Hemostatic nanotechnologies for external and internal hemorrhage management.

An uncontrolled hemorrhage can easily lead to death during surgery and military operations. Despite the significant advances in hemostatic research, there is still an urgent and increasing need for safer and more effective hemostatic materials. Recently, nanotechnologies have been receiving increasing interest owing to their unique advantages and have been propelling the developement of hemostatic materials. This review summarizes the fundamentals of hemostasis and emphasizes the recent developments regarding hemorrhage-related hemostatic nanotechnologies. In terms of external accessible hemorrhage management, natural and synthetic polymers and inorganic components that have been used in traditional hemostats provide novel nanoscale solutions. Regarding internal noncompressible hemorrhage management, current research endeavors are dedicated to the development of substitutes for blood components, and nanoformulated hemostatic drugs. This review also briefly discusses the main and persistent problems of hemostatic nanomaterials, including safety concerns and clinical translation challenges. This review is hoped to provide critical insight into hemostatic nanomaterial development.

Targeting Super-Enhancers via Nanoparticle-Facilitated BRD4 and CDK7 Inhibitors Synergistically Suppresses Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant cancer with complex genomic variations, and no targetable genomic lesions have been found yet. Super-enhancers (SEs) have been found to contribute to the continuous and robust oncogenic transcription. Here, histone H3 lysine 27 acetylation (H3K27ac) is profiled in PDAC cell lines to establish SE landscapes. Concurrently, it is also shown that PDAC is vulnerable to the perturbation of the SE complex using bromodomain-containing protein 4 (BRD4) inhibitor, JQ1, synergized with cyclin-dependent kinase 7 (CDK7) inhibitor, THZ1. Formulations of hydrophobic l-phenylalanine-poly (ester amide) nanoparticles (NPs) with high drug loading of JQ1 and THZ1 (J/T@8P4s) are further designed and developed. J/T@8P4s is assessed for size, encapsulation efficiency, morphology, drug release profiles, and drug uptake in vitro. Compared to conventional free drug formulation, the nanodelivery system dramatically reduces the hepatotoxicity while significantly enhancing the tumor inhibition effects and the bioavailability of incorporated JQ1 and THZ1 at equal doses in a Gemcitabine-resistant PDAC patient-derived xenograft (PDX) model. Overall, the present study demonstrates that the J/T@8P4s can be a promising therapeutic treatment against the PDAC via suppression of SE-associated oncogenic transcription, and provides a strategy utilizing NPs to assist the drug delivery targeting SEs.

Cysteine-based redox-responsive nanoparticles for small-molecule agent delivery.

As a significant part of molecular-targeted therapies, small-molecule agents (SMAs) have been increasingly used for cancer treatment. Nevertheless, most SMAs are currently administered orally due to their poor solubility, resulting in a low bioavailability and unavoidable side effects. Herein, we proposed a promising SMA delivery strategy using a biocompatible and redox-responsive nanoparticle (NP) delivery system to improve their bioavailability, alleviate side effects and enhance therapeutic performance. To demonstrate the feasibility of this strategy, a type of cysteine-based hydrophobic polymer was employed to construct a redox-sensitive nanoplatform for the delivery of various hydrophobic oral SMAs. These SMA-loaded nanoparticles (SMA-NPs) all have a small particle size and good drug-loading capacity. Particularly, lapatinib-loaded nanoparticles (LAP-NPs) with a minimal particle size (79.71 nm) and an optimal drug-loading capacity (12.5%) were utilized as a model to systemically explore the in vitro and in vivo anticancer potential of SMA-NPs. As expected, the LAP-NPs exhibited rapid redox-responsive drug release, enhanced in vitro cytotoxicity and cell apoptosis, and demonstrated notable anti-metastasis ability and desirable intracellular localization. Additionally, the in vivo results demonstrated the preferential accumulation of LAP-NPs in tumor tissues and the significant suppression of tumor growth. Therefore, the generated SMA-NP delivery system shows great SMA delivery potential for advanced molecular-targeted therapies.

Annexin A1-mediated inhibition of inflammatory cytokines may facilitate the resolution of inflammation in acute radiation-induced lung injury.

The present study evaluated the role of annexin A1 (ANXA1) in the treatment of acute radiation-induced lung injury (RILI) and investigated the mechanism of its action. The expression of ANXA1, interleukin-6 (IL-6) and myeloperoxidase (MPO) in the plasma of patients with RILI prior to and following hormonotherapy was assessed by enzyme-linked immunosorbent assay. The association of plasma ANXA1 concentration with clinical effect, and the correlation between the expression of ANXA1 and that of IL-6 and MPO were evaluated. ANXA1 was overexpressed or knocked down in a macrophage cell line, and its impact on IL-6 and MPO expression was measured. Following glucocorticoid hormonotherapy, patients with RILI exhibited a higher plasma concentration of ANXA1 compared with that prior to treatment, while IL-6 and MPO levels were lower. The concentration of ANXA1 in plasma was negatively correlated with IL-6 and MPO levels, with a correlation coefficient of -0.492 and -0.437, respectively (P<0.001). The increasing concentration of ANXA1 in plasma following treatment was associated with the clinical effect in patients with RILI (P=0.007). The expression levels of of IL-6 and MPO were inhibited both in the cytoplasm and in the culture solution, when ANXA1 expression was upregulated in a macrophage cell line. In conclusion, ANXA1 inhibited the synthesis and secretion of IL-6 and MPO inflammatory cytokines, indicating that ANXA1 may have therapeutic potential as a treatment target for RILI.

pH-Triggered Conformational Change of Antp-Based Drug Delivery Platform for Tumor Treatment with Combined Photothermal Therapy and Chemotherapy.

Poor cellular uptake and low therapeutic efficacy of small-molecule antitumor drugs limit the application of drug delivery systems (DDSs) in cancer therapy. A conformational change of the Antp mimetic peptide (AMP) in tumor microenvironments can greatly increase the cellular uptake as well as control drug release from a DDS. In this study, AMP-based nanoparticles (AMP-NPs) conjugated with tyroserleutide (YSL), an immunologically therapeutic tripeptide, are designed to encapsulate doxorubicin (Dox) and indocyanine green (ICG) to improve cellular uptake and cancer therapeutic efficacy by combining chemotherapy with photothermal therapy. In vitro studies verify that AMP-NPs can control the release of Dox and YSL at different pH values. Cell experiments show that AMP-NPs can promote the cellular uptake of Dox, and YSL can promote hepatocarcinoma cell (H22) apoptosis through downregulating Bcl-2 and cyclin D1 expression. In a mouse xenograft model using H22 cells, tumors are ablated when Dox- and ICG-loaded AMP-NPs are injected with the combination of hyperthermia effect induced by near-infrared (NIR) laser irradiation and chemotherapy from Dox and YSL. The pH-, photothermal-, and glutathione-responsive AMP-NPs with a conformational transition strategy can be utilized to synergistically enhance the cancer therapeutic efficacy with few side effects upon NIR laser irradiation.

Association of serum annexin A1 with treatment response and prognosis in patients with esophageal squamous cell carcinoma.

OBJECTIVE: Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein, is known to be regulated by microRNA-196a (miR-196a) in esophageal adenocarcinoma, and its high expression in tumor tissue is correlated with the poor prognosis of esophageal squamous cell carcinoma (ESCC). However, the role of ANXA1 in the serum of patients with ESCC remains unclear. MATERIALS AND METHODS: In this study, we used enzyme-linked immunosorbent assay to evaluate the levels of ANXA1 and real-time polymerase chain reaction to detect the expression of miR-196a in the serum of ESCC patients (healthy donors as controls) and evaluated the relationship between ANXA1 and clinical outcomes. RESULTS: The results showed that the level of serum ANXA1 in ESCC patients was significantly lower than that in controls (P = 0.001) but increased after chemoradiotherapy (P = 0.001). There was no correlation between the baseline level of serum ANXA1 and the short-term efficacy of treatment (P = 0.26) as well as the 1-year progression-free survival (PFS) (P = 0.094). However, there existed a significant correlation between the increases of serum ANXA1 expression and the 1-year PFS (P = 0.04). A higher increase (>2-fold of baseline) in the serum ANXA1 levels was correlated with a poorer PFS (hazard ratio = 3.096, 95% confidence interval 1.239-7.861). There was an inverse correlation between the expressions of miR-196a and ANXA1 in serum (Pearson's correlation of -0.54, P = 0.021). CONCLUSION: Our data revealed that the expression of serum ANXA1 in ESCC patients increases after chemoradiotherapy and the increased fold change in serum ANXA1 confers independent negative prognostic impact in ESCC. The higher the increase in serum ANXA1 levels, the poorer the outcome.