A DNA machine-based magnetic resonance imaging nanoprobe for in vivo microRNA detection.

In situ monitoring microRNA (miRNA) expression in vivo holds immense potential for directly visualizing the occurrence and progression of tumors. However, the significant barrier to developing a probe that can overcome the low abundance of miRNAs while providing an output signal with unlimited tissue penetration depth remains formidable. In this study, we developed a DNA machine-based magnetic resonance imaging nanoprobe (MRINP) for amplified detection of miR-21 in vivo. The MRINP was constructed with superparamagnetic Fe3O4 nanoparticles (NPs), paramagnetic Gd-DOTA complexes, and miR-21-activated DNA machines; the DNA machine was composed of hairpin DNAzyme (HD) strands serving as the DNAzyme walker and hairpin substrate (HS) strands serving as the track. Once uptake into tumor cells, the intracellular miR-21 specifically recognized and hybridized with the HD strand, restoring the activity of DNAzyme. Subsequently, the DNAzyme walker autonomously traveled on the surface of MRINP, and each step movement of the DNAzyme walker resulted in the cleavage of its substrate strands and the ensued release of the Gd-DOTA complex-labeled oligonucleotides, turning on the T1 signal of Gd-DOTA complexes for in situ imaging of miR-21 in tumor-bearing mice. This strategy would offer a promising approach for mapping tumor-specific biomarkers in vivo with unlimited penetration depth.

Trehalose enhanced cold atmospheric plasma-mediated cancer treatment.

Cold atmospheric plasma (CAP) is a unique form of physical plasma that has shown great potential for cancer therapy. CAP uses ionized gas to induce lethal oxidative stress on cancer cells; however, the efficacy of CAP therapy continues to be improved. Here, we report an injectable hydrogel-mediated approach to enhance the anti-tumor efficacy of CAP by regulating the phosphorylation of eIF2α. We discovered that reactive oxygen and nitrogen species (ROS/RNS), two main anti-tumor components in CAP, can lead to lethal oxidative stress on tumor cells. Elevated oxidative stress subsequently induces eIF2α phosphorylation, a pathognomonic marker of immunogenic cell death (ICD). Trehalose, a natural disaccharide sugar, can further enhance CAP-induced ICD by elevating the phosphorylation of eIF2α. Moreover, injectable hydrogel-mediated delivery of CAP/trehalose treatment promoted dendritic cell (DC) maturation, initiating tumor-specific T-cell mediated anti-tumor immune responses. The combination therapy also supported the polarization of tumor-associated macrophages to an M1-like phenotype, reversing the immunosuppressive tumor microenvironment and promoting tumor antigen presentation to T cells. In combination with immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1 antibody, aPD1), CAP/trehalose therapy further inhibited tumor growth. Importantly, our findings also indicated that this hydrogel-mediated local combination therapy engaged the host systemic innate and adaptive immune systems to impair the growth of distant tumors.

Black phosphorus boosts wet-tissue adhesion of composite patches by enhancing water absorption and mechanical properties.

Wet-tissue adhesives have long been attractive materials for realizing complicated biomedical functions. However, the hydration film on wet tissues can generate a boundary, forming hydrogen bonds with the adhesives that weaken adhesive strength. Introducing black phosphorus (BP) is believed to enhance the water absorption capacity of tape-type adhesives and effectively eliminate hydration layers between the tissue and adhesive. This study reports a composite patch integrated with BP nanosheets (CPB) for wet-tissue adhesion. The patch's improved water absorption and mechanical properties ensure its immediate and robust adhesion to wet tissues. Various bioapplications of CPB are demonstrated, such as rapid hemostasis (within ~1-2 seconds), monitoring of physical-activity and prevention of tumour-recurrence, all validated via in vivo studies. Given the good practicability, histocompatibility and biodegradability of CPB, the proposed patches hold significant promise for a wide range of biomedical applications.

Injectable cold atmospheric plasma-activated immunotherapeutic hydrogel for enhanced cancer treatment.

Despite the promise of immune checkpoint blockade (ICB) for cancer treatment, challenges associated with this therapy still exist, including low response rates and severe side effects in patients. Here, we report a hydrogel-mediated combination therapy for enhanced ICB therapy. Specifically, cold atmospheric plasma (CAP), an ionized gas consisting of therapeutically effective reactive oxygen species (ROS) and reactive nitrogen species (RNS), can effectively induce cancer immunogenic cell death, releasing tumor-associated antigens in situ and initiating anti-tumor immune responses, which, therefore, can synergistically augment the efficacy of immune checkpoint inhibitors. To minimize the systemic toxicity of immune checkpoint inhibitors and improve the tissue penetration of CAP, an injectable Pluronic hydrogel was employed as a delivery method. Our results show that major long-lived ROS and RNS in CAP can be effectively persevered in Pluronic hydrogel and remain efficacious in inducing cancer immunogenic cell death after intratumoral injection. Our findings suggest that local hydrogel-mediated combination of CAP and ICB treatment can evoke both strong innate and adaptive, local and systemic anti-tumor immune responses, thereby inhibiting both tumor growth and potential metastatic spread.

COL11A1 as an novel biomarker for breast cancer with machine learning and immunohistochemistry validation.

Machine learning (ML) algorithms were used to identify a novel biological target for breast cancer and explored its relationship with the tumor microenvironment (TME) and patient prognosis. The edgR package identified hub genes associated with overall survival (OS) and prognosis, which were validated using public datasets. Of 149 up-regulated genes identified in tumor tissues, three ML algorithms identified COL11A1 as a hub gene. COL11A1was highly expressed in breast cancer samples and associated with a poor prognosis, and positively correlated with a stromal score (r=0.49, p<0.001) and the ESTIMATE score (r=0.29, p<0.001) in the TME. Furthermore, COL11A1 negatively correlated with B cells, CD4 and CD8 cells, but positively associated with cancer-associated fibroblasts. Forty-three related immune-regulation genes associated with COL11A1 were identified, and a five-gene immune regulation signature was built. Compared with clinical factors, this gene signature was an independent risk factor for prognosis (HR=2.591, 95%CI 1.831-3.668, p=7.7e-08). A nomogram combining the gene signature with clinical variables, showed better predictive performance (C-index=0.776). The model correction prediction curve showed little bias from the ideal curve. COL11A1 is a potential therapeutic target in breast cancer and may be involved in the tumor immune infiltration; its high expression is strongly associated with poor prognosis.

Construction of ceRNA Networks Associated With CD8 T Cells in Breast Cancer.

Background: The infiltration of CD8 T cells is usually linked to a favorable prognosis and may predict the therapeutic response of breast cancer patients to immunotherapy. The purpose of this research is to investigate the competing endogenous RNA (ceRNA) network correlated with the infiltration of CD8 T cells. Methods: Based on expression profiles, CD8 T cell abundances for each breast cancer (BC) patient were inferred using the bioinformatic method by immune markers and expression profiles. We were able to extract the differentially expressed RNAs (DEmRNAs, DEmiRNAs, and DElncRNAs) between low and high CD8 T-cell samples. The ceRNA network was constructed using Cytoscape. Machine learning models were built by lncRNAs to predict CD8 T-cell abundances. The lncRNAs were used to develop a prognostic model that could predict the survival rates of BC patients. The expression of selected lncRNA (XIST) was validated by quantitative real-time PCR (qRT-PCR). Results: A total of 1,599 DElncRNAs, 89 DEmiRNAs, and 1,794 DEmRNAs between high and low CD8 T-cell groups were obtained. Two ceRNA networks that have positive or negative correlations with CD8 T cells were built. Among the two ceRNA networks, nine lncRNAs (MIR29B2CHG, NEAT1, MALAT1, LINC00943, LINC01146, AC092718.4, AC005332.4, NORAD, and XIST) were selected for model construction. Among six prevalent machine learning models, artificial neural networks performed best, with an area under the curve (AUC) of 0.855. Patients from the high-risk category with BC had a lower survival rate compared to those from the low-risk group. The qRT-PCR results revealed significantly reduced XIST expression in normal breast samples, which was consistent with our integrated analysis. Conclusion: These results potentially provide insights into the ceRNA networks linked with T-cell infiltration and provide accurate models for T-cell prediction.

Cold atmospheric plasma for addressing the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has greatly stressed the global community, exposing vulnerabilities in the supply chains for disinfection materials, personal protective equipment, and medical resources worldwide. Disinfection methods based on cold atmospheric plasma (CAP) technologies offer an intriguing solution to many of these challenges because they are easily deployable and do not require resource-constrained consumables or reagents needed for conventional decontamination practices. CAP technologies have shown great promise for a wide range of medical applications from wound healing and cancer treatment to sterilization methods to mitigate airborne and fomite transfer of viruses. This review engages the broader community of scientists and engineers that wish to help the medical community with the ongoing COVID-19 pandemic by establishing methods to utilize broadly applicable CAP technologies.

An Innovative Breast-Conserving Oncoplastic Technique for Treating Small to Medium Volume Breasts With a Tumor in the Lower Quadrant: The Folding Flap Technique.

Background: Here, we describe an innovative oncoplastic technique for small to medium volume breasts with a tumor in the lower quadrant and this technique could provide sufficient tissue to avoid visible defects after tumor removal and help reshape the natural shape of the breast. Methods: A detailed procedure for the folding flap technique is described step by step. Then, the results of a retrospective analysis of patients treated using this technique, including complications and disease recurrence rate, between January 2017 and November 2021 are reported. Aesthetic outcomes were evaluated on a 5-point scale proposed by the Paris Breast Center. Results: A total of 52 patients underwent surgery with the folding flap technique, The average operation time was 98.4 min (range, 75-120 min), and the mean bleeding volume was 56.5 mL (range, 20-100 mL). A margin-positive result was confirmed in 1 patient who underwent re-excision. Short-term postoperative complications were observed in 7 patients, including 4 with fat liquefaction, 2 with seroma, and 1 with skin redness and swelling. No flap necrosis was observed. The median follow-up time was 28.6 months (range, 9-58 months), and 2 patients experienced local recurrence. The mean aesthetic score was 4.7 points, with 36 patients scoring 5 points and 26 patients scoring 4 points, respectively. Conclusions: The folding flap technique, as an innovative and favorable oncoplastic technique for treating small- to medium-volume breasts with a tumor in the lower quadrant, could retain sufficient tissue to fill the residual cavity after the operation while improving the aesthetic outcome of the breast.

Portable air-fed cold atmospheric plasma device for postsurgical cancer treatment.

Surgery represents the major option for treating most solid tumors. Despite continuous improvements in surgical techniques, cancer recurrence after surgical resection remains the most common cause of treatment failure. Here, we report cold atmospheric plasma (CAP)­mediated postsurgical cancer treatment, using a portable air-fed CAP (aCAP) device. The aCAP device we developed uses the local ambient air as the source gas to generate cold plasma discharge with only joule energy level electrical input, thus providing a device that is simple and highly tunable for a wide range of biomedical applications. We demonstrate that local aCAP treatment on residual tumor cells at the surgical cavities effectively induces cancer immunogenic cell death in situ and evokes strong T cell­mediated immune responses to combat the residual tumor cells. In both 4T1 breast tumor and B16F10 melanoma models, aCAP treatment after incomplete tumor resection contributes to inhibiting tumor growth and prolonging survival.

Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy.

Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.

Cold atmospheric plasma and iron oxide-based magnetic nanoparticles for synergetic lung cancer therapy.

Cold atmospheric plasma (CAP) is an emerging biomedical technique that shows great potential for cancer treatment. On the other hand, magnetic nanoparticles open up a wide field of possible applications in medicine. Here we seek to develop a novel dual cancer therapeutic method by integrating promising CAP and iron oxide-based magnetic nanoparticles (MNPs), and evaluate its underlying mechanism for targeted lung cancer treatment. For this purpose, the synergistic effects of CAP and iron oxide-based MNPs on cellular bioactivity, epidermal growth factor receptor (EGFR) expression, and EGFR downstream signaling pathways were investigated. Results showed that the effectiveness of CAP and iron oxide-based MNPs for synergistic strongly killed activity against lung cancer cells, and significantly inhibited cell proliferation via reduction of viability and induction of apoptosis. Importantly, CAP combining with iron oxide-based MNPs induced EGFR downregulation while CAP inhibited lung cancer cells via depressing pERK and pAKT. Translation of these findings to an in vivo setting demonstrates that CAP combining iron oxide-based MNPs is effective at preventing xenograft tumors. Thus, the integration of CAP and iron oxide-based MNPs provides a promising tool for the development of a new cancer treatment strategy.

In vitro Demonstration of Cancer Inhibiting Properties from Stratified Self-Organized Plasma-Liquid Interface.

Experiments on plasma-liquid interaction and formation of thinly stratified self-organized patterns at plasma-liquid interface have revealed a nontrivial cancer-inhibiting capability of liquid media treated at self-organized interfacial patterns. A pronounced cancer suppressing activity towards at least two cancer cells, breast cancer MDA-MB-231 and human glioblastoma U87 cancer lines, was demonstrated in vitro. After a short treatment at the thinly stratified self-organized plasma-liquid interface pattern, the cancer inhibiting media demonstrate pronounced suppressing and apoptotic activities towards tumor cells. Importantly, this would have been impossible without interfacial stratification of plasma jet to thin (of several µm) current filaments, which plays a pivotal role in building up the cancer inhibition properties. Furthermore, thinly stratified, self-organized interfacial discharge is capable to efficiently control the ROS and RNS concentrations in the cancer-inhibiting media. In particular, abnormal ROS/RNS ratios are not achievable in discharges since they do not form stratified thin-filament patterns. Our findings could be tremendously important for understanding the cancer proliferation problem and hence, the potential of this approach in tackling the challenges of high cancer-induced mortality should be explored.

A Novel Micro Cold Atmospheric Plasma Device for Glioblastoma Both In Vitro and In Vivo.

Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. Direct CAP jet irradiation is limited to the skin and it can also be invoked as a supplement therapy during surgery as it only causes cell death in the upper three to five cell layers. However, the current cannulas from which the plasma emanates are too large for intracranial applications. To enhance efficiency and expand the applicability of the CAP method for brain tumors and reduce the gas flow rate and size of the plasma jet, a novel micro-sized CAP device (µCAP) was developed and employed to target glioblastoma tumors in the murine brain. Various plasma diagnostic techniques were applied to evaluate the physics of helium µCAP such as electron density, discharge voltage, and optical emission spectroscopy (OES). The direct and indirect effects of µCAP on glioblastoma (U87MG-RedFluc) cancer cells were investigated in vitro. The results indicate that µCAP generates short- and long-lived species and radicals (i.e., hydroxyl radical (OH), hydrogen peroxide (H2O2), and nitrite (NO2-), etc.) with increasing tumor cell death in a dose-dependent manner. Translation of these findings to an in vivo setting demonstrates that intracranial µCAP is effective at preventing glioblastoma tumor growth in the mouse brain. The µCAP device can be safely used in mice, resulting in suppression of tumor growth. These initial observations establish the µCAP device as a potentially useful ablative therapy tool in the treatment of glioblastoma.

Treatment of gastric cancer cells with nonthermal atmospheric plasma generated in water.

Nonthermal atmospheric plasma (NTAP) can be applied to living tissues and cells as a novel technology for cancer therapy. The authors report on a NTAP argon solution generated in deionized (DI) water for treating human gastric cancer cells (NCI-N87). Our findings show that the plasma generated in DI water with 30-min duration has the strongest effect on apoptosis in precultured human gastric cancer cells. This result can be attributed to the presence of reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced in water during treatment. Furthermore, the data show that the elevated levels of RNS may play a more significant role than ROS in the rate of cell death.