An osteosarcoma-on-a-chip model for studying osteosarcoma matrix-cell interactions and drug responses.

Marrow niches in osteosarcoma (OS) are a specialized microenvironment that is essential for the maintenance and regulation of OS cells. However, existing animal xenograft models are plagued by variability, complexity, and high cost. Herein, we used a decellularized osteosarcoma extracellular matrix (dOsEM) loaded with extracellular vesicles from human bone marrow-derived stem cells (hBMSC-EVs) and OS cells as a bioink to construct a micro-osteosarcoma (micro-OS) through 3D printing. The micro-OS was further combined with a microfluidic system to develop into an OS-on-a-chip (OOC) with a built-in recirculating perfusion system. The OOC system successfully integrated bone marrow niches, cell‒cell and cell-matrix crosstalk, and circulation, allowing a more accurate representation of OS characteristics in vivo. Moreover, the OOC system may serve as a valuable research platform for studying OS biological mechanisms compared with traditional xenograft models and is expected to enable precise and rapid evaluation and consequently more effective and comprehensive treatments for OS.

Detection of lineage-reprogramming efficiency of tumor cells in a 3D-printed liver-on-a-chip model.

Background: The liver metastasis accompanied with the loss of liver function is one of the most common complications in patients with triple-negative breast cancers (TNBC). Lineage reprogramming, as a technique direct inducing the functional cell types from one lineage to another lineage without passing through an intermediate pluripotent stage, is promising in changing cell fates and overcoming the limitations of primary cells. However, most reprogramming techniques are derived from human fibroblasts, and whether cancer cells can be reversed into hepatocytes remains elusive. Methods: Herein, we simplify preparation of reprogramming reagents by expressing six transcriptional factors (HNF4A, FOXA2, FOXA3, ATF5, PROX1, and HNF1) from two lentiviral vectors, each expressing three factors. Then the virus was transduced into MDA-MB-231 cells to generated human induced hepatocyte-like cells (hiHeps) and single-cell sequencing was used to analyze the fate for the cells after reprogramming. Furthermore, we constructed a Liver-on-a-chip (LOC) model by bioprinting the Gelatin Methacryloyl hydrogel loaded with hepatocyte extracellular vesicles (GelMA-EV) bioink onto the microfluidic chip to assess the metastasis behavior of the reprogrammed TNBC cells under the 3D liver microenvironment in vitro. Results: The combination of the genes HNF4A, FOXA2, FOXA3, ATF5, PROX1 and HNF1A could reprogram MDA-MB-231 tumor cells into human-induced hepatocytes (hiHeps), limiting metastasis of these cells. Single-cell sequencing analysis showed that the oncogenes were significantly inhibited while the liver-specific genes were activated after lineage reprogramming. Finally, the constructed LOC model showed that the hepatic phenotypes of the reprogrammed cells could be observed, and the metastasis of embedded cancer cells could be inhibited under the liver microenvironment. Conclusion: Our findings demonstrate that reprogramming could be a promising method to produce hepatocytes and treat TNBC liver metastasis. And the LOC model could intimate the 3D liver microenvironment and assess the behavior of the reprogrammed TNBC cells.

Enhancing prognostic accuracy in head and neck squamous cell carcinoma chemotherapy via a lipid metabolism-related clustered polygenic model.

OBJECTIVE: Systemic chemotherapy is the first-line therapeutic option for head and neck squamous cell carcinoma (HNSCC), but it often fails. This study aimed to develop an effective prognostic model for evaluating the therapeutic effects of systemic chemotherapy. METHODS: This study utilized CRISPR/cas9 whole gene loss-of-function library screening and data from The Cancer Genome Atlas (TCGA) HNSCC patients who have undergone systemic therapy to examine differentially expressed genes (DEGs). A lipid metabolism-related clustered polygenic model called the lipid metabolism related score (LMRS) model was established based on the identified functionally enriched DEGs. The prediction efficiency of the model for survival outcome, chemotherapy, and immunotherapy response was evaluated using HNSCC datasets, the GEO database and clinical samples. RESULTS: Screening results from the study demonstrated that genes those were differentially expressed were highly associated with lipid metabolism-related pathways, and patients receiving systemic therapy had significantly different prognoses based on lipid metabolism gene characteristics. The LMRS model, consisting of eight lipid metabolism-related genes, outperformed each lipid metabolism gene-based model in predicting outcome and drug response. Further validation of the LMRS model in HNSCCs confirmed its prognostic value. CONCLUSION: In conclusion, the LMRS polygenic prognostic model is helpful to assess outcome and drug response for HNSCCs and could assist in the timely selection of the appropriate treatment for HNSCC patients. This study provides important insights for improving systemic chemotherapy and enhancing patient outcomes.

Perspectives of lipid metabolism reprogramming in head and neck squamous cell carcinoma: An overview.

Recent studies showed that lipid metabolism reprogramming contributes to tumorigenicity and malignancy by interfering energy production, membrane formation, and signal transduction in cancers. HNSCCs are highly reliant on aerobic glycolysis and glutamine metabolism. However, the mechanisms underlying lipid metabolism reprogramming in HNSCCs remains obscure. The present review summarizes and discusses the "vital" cellular signaling roles of the lipid metabolism reprogramming in HNSCCs. We also address the differences between HNSCCs regions caused by anatomical heterogeneity. We enumerate these recent findings into our current understanding of lipid metabolism reprogramming in HNSCCs and introduce the new and exciting therapeutic implications of targeting the lipid metabolism.

Synthesis and Photothermal Effects of Intracellular Aggregating Nanodrugs Targeting Nasopharyngeal Carcinoma.

Chemotherapy for the treatment of nasopharyngeal carcinoma (NPC) is usually associated with many side effects; therefore, its treatment options have not yet been completely resolved. Improving distribution to the targeted tumor region and enhancing the cellular uptake of drugs can efficiently alleviate the above adverse medical effects. Near-infrared (NIR) laser light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) are promising strategies for cancer treatment. In the present study, we developed an efficient multifunctional nanocluster with enhanced targeting and aggregation efficiency for PTT and PDT that is composed of a biocompatible folic acid (FA), indocyanine green (ICG) and 2-cyanobenzothiazole (CBT)-functionalized peptide labeled with an aldehyde sodium alginate-modified magnetic iron oxide nanoparticle (ASA-MNP)-based nanocarrier. FA can bind to folate receptors on cancer cell membranes to enhance nanocluster uptake. CBT-modified peptide can react with glutathione (GSH), which is typically present at higher levels in cancer cells, to form intracellular aggregates and increase the local concentration of the nanodrug. In in vitro studies, these nanodrugs displayed the desired uptake capacity by NPC cells and the ability to suppress the growth of cancer cells under laser irradiation. Animal studies validated that these nanodrugs are safe and nontoxic, efficiently accumulate in NPC tumor sites following injection via the caudal vein, and shows superior inhibition of tumor growth in a tumor-bearing mouse model upon near-infrared laser irradiation. The results indicate the potential application of the multifunctional nanoparticles (NPs), which can be used as a new method for the treatment of folate receptor-positive NPC.

IAP-1 promoted cisplatin resistance in nasopharyngeal carcinoma via inhibition of caspase-3-mediated apoptosis.

Recurrent/metastatic nasopharyngeal carcinoma (NPC) is known for having a poor prognosis due to its unfavorable response to chemoradiotherapy. However, the specific processes involved remain poorly understood. This study focused on the cisplatin-resistance mechanism in NPC to help understand the occurrence of advanced NPC and aims to explore the potential therapeutic target for cisplatin-resistant NPC. Two cisplatin-resistant NPC cell lines, HNE-1/DDP and CNE-2/DDP, were established and the differentially expressed genes (DEGs) between parental and cisplatin-resistance cell lines, filtering from high-throughput sequencing results, were analyzed. Next, the effects of IAP-1 on cisplatin-resistant nasopharyngeal cancer cell proliferation, apoptosis, drug resistance and associated cell signaling were evaluated in vitro and in vitro. From our bioinformatic results, more than 15,000 differentially expressed genes (DEGs) were found between parental and resistant cell lines. Nine related DEGs were found in the classic platinum resistance pathway, three of which (ATM, IAP-1, and IAP-2) also appeared in the top five differentially expressed pathways, with elevated IAP-1 showing the highest fold change. Further studies revealed that high IAP-1 expression can lead to an increased cisplatin inhibitory concentration and apoptosis inhibition. IAP-1 silencing can induce upregulation of the caspase-3 and enhance the antiproliferation and proapoptotic effects of cisplatin. Clinical data also showed that IAP-1 overexpression was associated with a worse survival status. In summary, in vitro and in vivo experiments demonstrated that IAP-1 plays a vital role in cisplatin resistance by regulating caspase induced apoptosis and serve as a potential novel therapeutic target and a prognostic indicator for advanced NPC.

Recent Advances in Natural Products with Antiviral Activities.

Virus is a type of noncellular organism, which is simple in structure, small in size and contains only one kind of nucleic acid (RNA or DNA). It must be parasitized in living cells and proliferates by replication. Viruses can infect plants or animals, which leads to many epidemic diseases, such as the current pandemic COVID-19. Viral infectious diseases have brought serious threats to the health of people around the world. Natural products are chemical substances that are usually produced by living organisms and have biological or pharmacological activity. Many of these natural products show antiviral activity. Based on the increasing importance of antiviral research, this paper focuses on the discovery and development of antiviral natural products since 2010.

TAT peptide-modified cisplatin-loaded iron oxide nanoparticles for reversing cisplatin-resistant nasopharyngeal carcinoma.

As chemo-radiotherapy continues to increase the lifespan of patients with nasopharyngeal carcinoma (NPC), adverse reaction and drug resistance remain two major problems when using cisplatin (CDDP). In this study, we took the lead in designing a dual-mechanism anti-cancer system modified with cell-penetrating peptide on the surface of superparamagnetic iron oxide nanoparticles (SPION) to enhance CDDP delivery efficacy to NPC cells, especially CDDP resistant NPC cells. The combinatorial delivery of CDDP and iron oxide nanoparticles showed an unexpected effect on reversal of CDDP resistance due to the Fenton reaction with an average decrease in the half maximal inhibitory concentration (IC 50) of 85% and 94% in HNE-1/DDP and CNE-2/DDP resistant cells respectively compared to CDDP alone. On this basis, modification with TAT peptide (YGRKKRRQRRR) significantly improved tumor intracellular uptake, devoting to better curative effects and minimized side effects by reducing CDDP therapeutic doses. Furthermore, we specifically labelled CDDP with fluorescence for detection of intracellular nanoparticles uptake and mechanism research through drug tracing. This novel compound provides a promising therapy for reducing chemotherapy side effects and reversing CDDP-resistant nasopharyngeal carcinoma.

Multifunctional magnetic co-delivery system coated with polymer mPEG-PLL-FA for nasopharyngeal cancer targeted therapy and MR imaging.

The gene and drug co-delivery system has become one of the primary strategies to overcome cancers. Here, we designed a multifunctional magnetic co-delivery system for nasopharyngeal carcinoma-targeted therapy and MR imaging. Aldehyde sodium alginate (ASA) was used to decorate the oxide iron and load cisplain through coordinate bond to form a core complex. The polymer shell poly(l-lysine)-methoxy-polyethylene glycol-folate was used to coat the core complex through electric interaction to give this nano-medicine a target ability. And this polymer could also give the nano-medicine abilities to adhere and protect DNA, and enhance its solubleness in water. After being transfected with this nano-medicine, the plasmids which contain cancer suppressor gene TFPI2 could enter and express in HNE-1 cells. It caused a higher death and apoptosis rate, inhibited nasopharyngeal carcinoma cells' migration and cloning by the synergic effect together with cisplain. Besides, clear images of this nano-medicine could be got under T2 MR imaging. This magnetic co-delivery system demonstrates a potential as a powerful multifunctional vector for drug delivery and gene vector applications in nasopharyngeal carcinoma.

Conjugating an anticancer drug onto thiolated hyaluronic acid by acid liable hydrazone linkage for its gelation and dual stimuli-response release.

A prodrug gelation strategy was developed for the sustained and dual stimuli-response release of doxorubicin hydrochloride (DOX·HCl), a commonly used anticancer drug. For this purpose, the chemical conjugation of DOX·HCl onto thiolated hyaluronic acid (HA) was carried out by an acid liable hydrazone linkage and verified by (1)H NMR analyses. When exposed to the air, such a polysaccharide conjugate showed unique self-gelation ability in aqueous solution. The gelation time and extent depended mainly on the content of thiol groups on thiolated HA. The resultant hydrogel exhibited a dominant elastic response and a thixotropic property. In particular, it could release sustainably conjugated DOX·HCl in dual pH- and reduction-responsive modes. The cumulative drug release was found to be significantly accelerated under the conditions mimicking the intracellular environments of cancer cells. The in vitro cytotoxicity assays for the human nasopharyngeal carcinoma CNE2 cells treated with various release media confirmed the effectiveness of this conjugate hydrogel for cancer cell inhibition.

Risk factors for deep infection after total knee arthroplasty: a meta-analysis.

OBJECTIVE: Estimated the risk factors for postoperative infection after total knee arthroplasty (TKA) to prevent its occurrence. DESIGN: The meta-analysis collected twelve cohorts or case-control studies which included 548 infected persons in 57,223 general cases. Review Manager 5.0 was operated to assess the heterogeneity and to give an overall estimate of the association of factors with postoperative infection after TKA. RESULTS: The main factors distinctly associated with infection after TKA were BMI (BMI >30: OR = 2.53, 95 % CI 1.25, 5.13; BMI >40: OR = 4.00, 95 % CI 1.23, 12.98), diabetes mellitus (OR = 3.72, 95 % CI 2.30, 6.01), hypertension (OR = 2.53, 95 % CI 1.07, 5.99), steroid therapy (OR = 2.04, 95 % CI 1.11, 3.74), and rheumatoid arthritis (OR = 1.83; 95 % CI 1.42, 2.36). It had no sufficient evidences to reveal that gender could lead to infection after TKA. Osteoarthritis appeared to have a moderately protective effect. Statistical analysis revealed no correlation between urinary tract infection, fixation method, ASA, bilateral operation, age, transfusion, antibiotics, bone graft, and infection. CONCLUSION: There were positive evidences for some certain factors which could be targeted for prevention of the onset of infection, but more studies are needed to define the association of some other controversial factors in infection, like osteoarthritis, gender and so on. The quality of studies also needs to be improved.