Cellular elasticity in cancer: a review of altered biomechanical features.

A large number of studies have shown that changes in biomechanical characteristics are an important indicator of tumor transformation in normal cells. Elastic deformation is one of the more studied biomechanical features of tumor cells, which plays an important role in tumourigenesis and development. Altered cell elasticity often brings many indications. This manuscript reviews the effects of altered cellular elasticity on cell characteristics, including adhesion viscosity, migration, proliferation, and differentiation elasticity and stiffness. Also, the physical factors that may affect cell elasticity, such as temperature, cell height, cell-viscosity, and aging, are summarized. Then, the effects of cell-matrix, cytoskeleton, in vitro culture medium, and cell-substrate with different three-dimensional structures on cell elasticity during cell tumorigenesis are outlined. Importantly, we summarize the current signaling pathways that may affect cellular elasticity, as well as tests for cellular elastic deformation. Finally, we summarize current hybrid materials: polymer-polymer, protein-protein, and protein-polymer hybrids, also, nano-delivery strategies that target cellular resilience and cases that are at least in clinical phase 1 trials. Overall, the behavior of cancer cell elasticity is modulated by biological, chemical, and physical changes, which in turn have the potential to alter cellular elasticity, and this may be an encouraging prediction for the future discovery of cancer therapies.

Epigenetic editing of BRCA1 promoter increases cisplatin and olaparib sensitivity of ovarian cancer cells.

Drug resistance is the primary contributor to the high mortality rate of ovarian cancer (OC). The loss of BRCA1/2 function is linked to drug sensitivity in OC cells. The aim of this study is to enhance the drug sensitivity of OC cells by inducing BRCA1 dysfunction through promoter epigenetic editing. Epigenetic regulatory regions within the BRCA1 promoter, affecting gene expression, were initially discerned through analysis of clinical samples. Subsequently, we designed and rigorously validated epigenetic editing tools. Ultimately, we evaluated the cisplatin and olaparib sensitivity of the OC cells after editing. The BRCA1 promoter contains two CpG-rich regions, with methylation of the region covering the transcription start site (TSS) strongly correlating with transcription and influencing OC development, prognosis, and homologous recombination (HR) defects. Targeting this region in OC cells using our designed epigenetic editing tools led to substantial and persistent DNA methylation changes, accompanied by significant reductions in H3K27ac histone modifications. This resulted in a notable suppression of BRCA1 expression and a decrease in HR repair capacity. Consequently, edited OC cells exhibited heightened sensitivity to cisplatin and olaparib, leading to increased apoptosis rates. Epigenetic inactivation of the BRCA1 promoter can enhance cisplatin and olaparib sensitivity of OC cells through a reduction in HR repair capacity, indicating the potential utility of epigenetic editing technology in sensitization therapy for OC.

White light powered antimicrobial nanoagents for triple photothermal, chemodynamic and photodynamic based sterilization.

Antibacterial nanoagents have been increasingly developed due to their favorable biocompatibility, cost-effective raw materials, and alternative chemical or optical properties. Nevertheless, there is still a pressing need for antibacterial nanoagents that exhibit outstanding bacteria-binding capabilities and high antibacterial efficiency. In this study, we constructed a multifunctional cascade bioreactor (GCDCO) as a novel antibacterial agent. This involved incorporating carbon dots (CDs), cobalt sulfide quantum dots (CoSx QDs), and glucose oxidase (GOx) to enhance bacterial inhibition under sunlight irradiation. The GCDCO demonstrated highly efficient antibacterial capabilities attributed to its favorable photothermal properties, photodynamic activity, as well as the synergistic effects of hyperthermia, glucose-augmented chemodynamic action, and additional photodynamic activity. Within this cascade bioreactor, CDs played the role of a photosensitizer for photodynamic therapy (PDT), capable of generating ˙O2- even under solar light irradiation. The CoSx QDs not only functioned as a catalytic component to decompose hydrogen peroxide (H2O2) and generate hydroxyl radicals (˙OH), but they also served as heat generators to enhance the Fenton-like catalysis process. Furthermore, GOx was incorporated into this cascade bioreactor to internally supply H2O2 by consuming glucose for a Fenton-like reaction. As a result, GCDCO could generate a substantial amount of reactive oxygen species (ROS), leading to a significant synergistic effect that greatly induced bacterial death. Furthermore, the in vitro antibacterial experiment revealed that GCDCO displayed notably enhanced antibacterial activity against E. coli (99+ %) when combined with glucose under simulated sunlight, surpassing the efficacy of the individual components. This underscores its remarkable efficiency in combating bacterial growth. Taken together, our GCDCO demonstrates significant potential for use in the routine treatment of skin infections among diabetic patients.

Reduced Viral Shedding Time in High-Risk COVID-19 Patients Infected by Omicron and Treated with Paxlovid: A Real-World Study from China.

Introduction: The purpose of this study was to compare the viral shedding time in patients infected with the Omicron variant during Paxlovid therapy and conventional therapy and to analyze the effects of Paxlovid on patients infected with COVID-19. Methods: In this study, the demographic and clinical characteristics and laboratory data of 3159 patients infected with the SARS-CoV-2 Omicron variant treated at Jilin Province People's Hospital were collected and analyzed. A total of 362 patients received Paxlovid therapy, and 2797 patients received conventional therapy. After propensity score matching (PSM), 1086 patients were obtained. Results: The difference in platelet (PLT) count between the two groups was statistically significant but within the normal range (P < 0.05). CT value revealed that the nucleic acid test results became negative more quickly in the Paxlovid therapy group. Analysis of the Paxlovid therapy group showed that IgG and IgM levels were increased after Paxlovid therapy administration. Conclusion: The CT value of the Paxlovid therapy group became negative more quickly. This finding suggests that Paxlovid treatment after early diagnosis of the Omicron variant may achieve good therapeutic efficacy.

Potential prognosis and immunotherapy predictor TFAP2A in pan-cancer.

BACKGROUND: TFAP2A is critical in regulating the expression of various genes, affecting various biological processes and driving tumorigenesis and tumor development. However, the significance of TFAP2A in carcinogenesis processes remains obscure. METHODS: In our study, we explored multiple databases including TCGA, GTEx, HPA, cBioPortal, TCIA, and other well-established databases for further analysis to expound TFAP2A expression, genetic alternations, and their relationship with the prognosis and cellular signaling network alternations. GO term and KEGG pathway enrichment analysis as well as GSEA were conducted to examine the common functions of TFAP2A. RT-qPCR, Western Blot and Dual Luciferase Reporter assay were employed to perform experimental validation. RESULTS: TFAP2A mRNA expression level was upregulated and its genetic alternations were frequently present in most cancer types. The enrichment analysis results prompted us to investigate the changes in the tumor immune microenvironment further. We discovered that the expression of TFAP2A was significantly associated with the expression of immune checkpoint genes, immune subtypes, ESTIMATE scores, tumor-infiltrating immune cells, and the possible role of TFAP2A in predicting immunotherapy efficacy. In addition, high TFAP2A expression significantly correlated with several ICP genes, and promoted the expression of PD-L1 on mRNA and protein levels through regulating its expression at the transcriptional level. TFAP2A protein level was upregulated in fresh colon tumor tissue samples compared to that in the adjacent normal tissues, which essentially positively correlated with the expression of PD-L1. CONCLUSIONS: Our study suggests that targeting TFAP2A may provide a novel and effective strategy for cancer treatment.

In-situ bio-assembled specific Au NCs-Aptamer-Pyro conjugates nanoprobe for tumor imaging and mitochondria-targeted photodynamic therapy.

Mitochondrion has emerged as a promising drug target for photodynamic therapy (PDT), due to its significant role in supporting life activities and being reactive oxygen species (ROS)-sensitive. Herein, we establish a new strategy that in-situ bio-synthesized Au NCs combine with mitochondria-targeted aptamer-Pyro conjugates (ApPCs) for specific tumor imaging and PDT. The prepared ApPCs can serve as template for the in-situ bio-synthesis of Au NCs, thereby facilitating the generation of Au NCs-ApPCs assemblies in unique tumor microenvironment. Compared with highly negatively charged ApPCs, bio-synthesized nanoscale Au NCs-ApPCs assemblies are conducive to cell uptake, which consequently benefits the delivery of ApPCs. After dissociated from Au NCs-ApPCs, internalized ApPCs can selectively accumulate in mitochondria and generate excess ROS to disrupt the mitochondrial membrane upon irradiation, thus inducing efficient cell killing. In vitro assays demonstrated that the fluorescent Au NCs-ApPCs assemblies could be specifically produced in cancerous cells, indicating the specific tumor imaging ability, while intracellular ApPCs co-localized well with mitochondria. CCK-8 results revealed over 80% cell death after PDT. In vivo study showed that fluorescent Au NCs-ApPCs assemblies were exclusively generated in tumor and achieved long-term retention; tumor growth was significantly inhibited after 15-day PDT treatment. All these evidences suggest that in-situ bio-synthesized Au NCs-ApPCs assembly is a potent mitochondria-targeted nanoprobe to boost the PDT efficacy of cancers.

Oridonin attenuates dextran sulfate sodium­induced ulcerative colitis in mice via the Sirt1/NF­κB/p53 pathway.

Ulcerative colitis (UC) is a serious chronic inflammatory bowel disease. Oridonin (Ori) has anti­inflammatory, antibacterial and antitumor activities. The current study aimed to investigate the regulatory role of Ori in UC. BALB/C mice were induced to form a model of UC using dextran sulfate sodium (DSS), after which UC mice received high­(Ori­H) and low­doses of Ori (Ori­L). Subsequently, the length of the colon was measured and hematoxylin and, eosin staining was performed to detect colonic injury. Western blot analysis was performed to detect expression level in tight junction­associated proteins in murine colon tissue. Additionally, myeloperoxidase activity and inflammatory factor concentration were detected in colon tissue using ELISA. TUNEL and western blot assays were also performed to detect cell apoptosis, and the expression level of Sirt1/NF­κB/p53 pathway­related proteins was also determined using western blot analysis. The results revealed that Ori ameliorated clinical symptoms and pathological lesions in mice with DSS­induced UC. Furthermore, Ori protected the integrity of the colonic mucosal barrier, reduced the inflammatory response and decreased oxidative stress levels in mice with DSS­induced UC. Ori treatment also inhibited intestinal mucosal cell apoptosis. These effects may have occurred via the Sirtuin­1/NF­κB/p53 pathway. In conclusion, Ori treatment inhibited DSS­induced inflammatory response, oxidative stress and intestinal mucosal apoptosis in UC mice.

Biophysics involved in the process of tumor immune escape.

Much of the current research into immune escape from cancer is focused on molecular and cellular biology, an area of biophysics that is easily overlooked. A large number of immune drugs entering the clinic are not effective for all patients. Apart from the molecular heterogeneity of tumors, the biggest reason for this may be that knowledge of biophysics has not been considered, and therefore an exploration of biophysics may help to address this challenge. To help researchers better investigate the relationship between tumor immune escape and biophysics, this paper provides a brief overview on recent advances and challenges of the biophysical factors and strategies by which tumors acquire immune escape and a comprehensive analysis of the relevant forces acting on tumor cells during immune escape. These include tumor and stromal stiffness, fluid interstitial pressure, shear stress, and viscoelasticity. In addition, advances in biophysics cannot be made without the development of detection tools, and this paper also provides a comprehensive summary of the important detection tools available at this stage in the field of biophysics.

Additive Manufacturing in Orthopedics: A Review.

Additive manufacturing is an advanced manufacturing manner that seems like the industrial revolution. It has the inborn benefit of producing complex formations, which are distinct from traditional machining technology. Its manufacturing strategy is flexible, including a wide range of materials, and its manufacturing cycle is short. Additive manufacturing techniques are progressively used in bone research and orthopedic operation as more innovative materials are developed. This Review lists the recent research results, analyzes the strengths and weaknesses of diverse three-dimensional printing strategies in orthopedics, and sums up the use of varying 3D printing strategies in surgical guides, surgical implants, surgical predictive models, and bone tissue engineering. Moreover, various postprocessing methods for additive manufacturing for orthopedics are described.

Tumor-targeted nano-delivery system of therapeutic RNA.

The birth of RNAi technology has pioneered actionability at the molecular level. Compared to DNA, RNA is less stable and therefore requires more demanding delivery vehicles. With their flexible size, shape, structure, and accessible surface modification, non-viral vectors show great promise for application in RNA delivery. Different non-viral vectors have different ways of binding to RNA. Low immunotoxicity gives RNA significant advantages in tumor treatment. However, the delivery of RNA still has many limitations in vivo. This manuscript summarizes the size-targeting dependence of different organs, followed by a summary of nanovesicles currently in or undergoing clinical trials. It also reviews all RNA delivery systems involved in the current study, including natural, bionic, organic, and inorganic systems. It summarizes the advantages and disadvantages of different delivery methods, which will be helpful for future RNA vehicle design. It is hoped that this will be helpful for gene therapy of clinical tumors.

The regulatory networks of the Hippo signaling pathway in cancer development.

The Hippo signaling pathway is a relatively young tumor-related signaling pathway. Although it was discovered lately, research on it developed rapidly. The Hippo signaling pathway is closely relevant to the occurrence and development of tumors and the maintenance of organ size and other biological processes. This manuscript focuses on YAP, the core molecule of the Hippo signaling pathway, and discussion the upstream and downstream regulatory networks of the Hippo signaling pathway during tumorigenesis and development. It also summarizes the relevant drugs involved in this signaling pathway, which may be helpful to the development of targeted drugs for cancer therapy.

The long noncoding RNA AATBC promotes breast cancer migration and invasion by interacting with YBX1 and activating the YAP1/Hippo signaling pathway.

Long noncoding RNAs (lncRNAs) play an important role in the regulation of gene expression and are involved in several pathological responses. However, many important lncRNAs in breast cancer have not been identified and their expression levels and functions in breast cancer remain unknown. In this study, the lncRNA apoptosis-associated transcript in bladder cancer (AATBC) was found to be significantly highly expressed in breast cancer patients. In vitro and in vivo experiments indicated that AATBC promoted breast cancer metastasis. Further studies revealed that AATBC activated the YAP1/Hippo signaling pathway through the AATBC-YBX1-MST1 axis. This is also an important supplement to the composition of the YAP1/Hippo signaling pathway. The model of "AATBC-YAP1" may bring a new dawn to the treatment of breast cancer.

LncRNA AATBC regulates Pinin to promote metastasis in nasopharyngeal carcinoma.

Long noncoding RNA (lncRNA) have emerged as crucial regulators for a myriad of biological processes, and perturbations in their cellular expression levels have often been associated with cancer pathogenesis. In this study, we identified AATBC (apoptosis-associated transcript in bladder cancer, LOC284837) as a novel lncRNA. AATBC was found to be highly expressed in nasopharyngeal carcinoma (NPC), and increased AATBC expression was associated with poor survival in patients with NPC. Furthermore, AATBC promoted migration and invasion of NPC cells in vitro, as well as metastasis in vivo. AATBC upregulated the expression of the desmosome-associated protein pinin (PNN) through miR-1237-3p sponging. In turn, PNN interacted with the epithelial-mesenchymal transition (EMT) activator ZEB1 and upregulated ZEB1 expression to promote EMT in NPC cells. Collectively, our results indicate that AATBC promotes NPC progression through the miR-1237-3p-PNN-ZEB1 axis. Our findings indicate AATBC as a potential prognostic biomarker or therapeutic target in NPC.

Bio responsive self-assembly of Au-miRNAs for targeted cancer theranostics.

BACKGROUND: MicroRNA (miRNA) therapeutics are a promising approach to cancer treatment. However, this method faces considerable challenges to achieve tissue-specific, efficient, and safe delivery of miRNAs in vivo. METHODS: Herein, we developed a miRNA delivery system based on the in situ self-assembly of Au-miRNA nanocomplexes (Au-miRNA NCs). Within the cancer microenvironment, we constructed in situ self-assembled Au-miRNA NCs by coincubating gold salt and tumor suppressor mimics, such as let-7a, miRNA-34a, and miRNA-200a. FINDINGS: The in vitro experiments demonstrated that characteristic in situ self-assembled Au-miRNA NCs were present in cancer cells and can be taken up to inhibit the proliferation of cancer cells effectively. Most importantly, as proven in subcutaneous tumor treatment models, Au-miRNA NCs were especially useful for accurate target imaging and tumor suppression, with significantly enhanced antitumor effects for combination therapy. INTERPRETATION: These observations highlight that a new strategy for the in situ biosynthesis of Au-let-7a NCs, Au-miR-34a NCs, and Au-miR-200a NCs is feasible, and this may assist in the delivery of more miRNA to tumor cells for cancer treatment. This work opens up new opportunities for the development of miRNA tumor therapy strategies. FUNDING: National Natural Science Foundation of China (91753106); Primary Research & Development Plan of Jiangsu Province (BE2019716); National Key Research and Development Program of China (2017YFA0205300).

Precise therapeutic effect of self-assembling gold nanocluster-PTEN complexes on an orthotropic model of liver cancer.

PURPOSE: Presently, liver cancer is still one of the malignant tumors with high mortality. As far as the treatment of liver cancer is concerned, the most effective method is still liver transplantation. But every year, many liver cancer patients die from the lack of a proper liver transplant, or from waiting for a liver transplant. Therefore, it is very important to find new and effective treatment for patients with liver cancer. METHODS: Herein, the cell model and the orthotropic liver tumor mice model have been performed to verify the results of our treatment. We found that the in situ synthesized gold nanocluster-PTEN (GNC-PTEN) complexes can effectively target and realize the fluorescence imaging of the liver tumor. RESULTS: GNC-PTEN complexes could inhibit the proliferation, invasion, and metastasis of liver cancer cells. And the results also showed that GNC-PTEN complexes could be well targeted liver tumor at 6 h and the liver tumor in mice group treated with GNC-PTEN complexes almost disappeared. CONCLUSION: This is a simply and effectively method to realize liver cancer imaging and inhibition. This may raise the possibility for the accurate image/diagnosis and simultaneously efficient treatment of liver cancer in the relevant clinic application.

Author Correction: 3D Printed Polyvinyl Alcohol Tablets with Multiple Release Profiles.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Manganese oxide doped carbon dots for temperature-responsive biosensing and target bioimaging.

We report on the synthesis of manganese oxide doped CDs (MnOx-CDs) by a hydrothermal strategy using manganese (III) acetylacetonate (Mn(III) (C5H7O2)3) as the only raw materials. The MnOx-CDs exhibit water solubility, favorable biocompatibility, low cytotoxicity, and show blue fluorescence with excitation/emission maxima at 326/442 nm with a quantum yield of 11.3%, allowing efficient cellular imaging. The MnOx-CDs have a reversible temperature-sensitive fluorescent property in vitro within 10-60 °C, which can also be used as a sensitive thermometer in living cells. By a scratch assay, the MnOx-CDs can restrain the migration of HepG2 cancer cells, which make the MnOx-CDs be attractive candidates for liver cancer adjuvant treatment. Besides, the fluorescence of the MnOx-CDs is quenched in the presence of Fe3+ due to the formation of a nonfluorescent MnOx-CDs-Fe3+ complex between oxygen-containing groups on the surface of MnOx-CDs and Fe3+, and the quenched fluorescence of MnOx-CDs can be turn-on by dissociation of MnOx-CDs-Fe3+ complexes by biothiols including L-cysteine, homocysteine and glutathione. Therefore, the Fe3+ and biothiols can be sequentially detected with high reliability and accuracy via exploiting the on-off-on nanosensor at room temperature, respectively. Further application to detection biothiols in human serum indicated that the probe was practicality and feasibility in medical field.

Nanoelectrochemical biosensors for monitoring ROS in cancer cells.

Compared with normal cells, cancer or tumor cells have a specific microenvironment and apparently possess a relatively large amount of ROS/RNS, and their overexpression is one of the important reasons for tumor development and deterioration. Therefore, monitoring the changes of intracellular ROS/RNS can improve the awareness of the clinical manifestations of the disease, which will be beneficial for the early diagnosis of cancer and improving treatment efficiency. Herein, in this study we have exploited and constructed a novel strategy based on the SiC@C nanowire electrode for intracellular electrochemical analysis to monitor ROS levels in cancer or tumor cells. Firstly, the SiC@C nanowire electrode was utilized to detect the intracellular ROS radical changes involved in the relevant biological processes of cancer cells where fluorescent zinc nanoclusters were biosynthesized in situ in target cancer cells by using the intracellular microenvironment and specificity of these cancer cells. By combining a confocal fluorescence microscopy study simultaneously, our observations illustrate that accompanied by the apparent change of the intracellular ROS, these in situ biosynthesized fluorescent nanoclusters gradually accumulate inside the cytosolic area with the increase of the reaction time. Moreover, it is evident that the size of the SiC@C nanoelectrodes can match the single cell dimensions, and its unique high spatial resolution provides the possibility of relevant intracellular molecular detection. These nanoelectrochemical biosensors can be adopted to quantitatively determine the change of the ROS content in target single cells in the relevant biological microenvironment or during the in situ biosynthesis process, and are also beneficial for understanding the related mechanism of some specific biological processes including the in situ synthesis at the single cell level.

In situ self-assembling Au-DNA complexes for targeted cancer bioimaging and inhibition.

Cancer remains one of the most challenging diseases to treat. For accurate cancer diagnosis and targeted therapy, it is important to assess the localization of the affected area of cancers. The general approaches for cancer diagnostics include pathological assessments and imaging. However, these methods only generally assess the tumor area. In this study, by taking advantage of the unique microenvironment of cancers, we effectively utilize in situ self-assembled biosynthetic fluorescent gold nanocluster-DNA (GNC-DNA) complexes to facilitate safe and targeted cancer theranostics. In in vitro and in vivo tumor models, our self-assembling biosynthetic approach allowed for precise bioimaging and inhibited cancer growth after one injection of DNA and gold precursors. These results demonstrate that in situ bioresponsive self-assembling GNC-PTEN (phosphatase and tensin homolog) complexes could be an effective noninvasive technique for accurate cancer bioimaging and treatment, thus providing a safe and promising cancer theranostics platform for cancer therapy.

3D Printed Polyvinyl Alcohol Tablets with Multiple Release Profiles.

The aim of this study was to explore the feasibility of using different 3D printed internal geometries as tablet formulations to obtain controlled release profiles. In order to obtain controllable release profiles, three types of tablet models (Cylinder, Horn and Reversed Horn) with controlled structures were designed. The cylinder model shows a constant release profile and can keep the drug concentration within a certain range. The horn model exhibits an increasing release profile, which is suitable for the patients who have the drug resistance in the course of medication. The reversed horn model has a decreasing release profile that would be applied to hypertension cure. Furthermore, three types of tablets were fabricated successfully by a fused deposition modeling three-dimensional (3D) printer and injected with paracetamol (APAP) -containing gels. The results of in vitro drug release demonstrate that tablets with three kinds of structures can produce constant, gradually increasing, and gradually decreasing release profiles, respectively. The release attributes can be controlled by using different 3D printed geometries as tablet formulations. More importantly, there are no residues after dissolution. The method of preparing customized tablets with distinguished release profiles presented in this study has the promising potential in the fabrication of patient-tailored medicines.