Upconversion nanoparticle platform for efficient dendritic cell antigen delivery and simultaneous tracking.

Upconversion nanoparticles (UCNPs) represent a group of NPs that can convert near-infrared (NIR) light into ultraviolet and visible light, thus possess deep tissue penetration power with less background fluorescence noise interference, and do not induce damage to biological tissues. Due to their unique optical properties and possibility for surface modification, UCNPs can be exploited for concomitant antigen delivery into dendritic cells (DCs) and monitoring by molecular imaging. In this study, we focus on the development of a nano-delivery platform targeting DCs for immunotherapy and simultaneous imaging. OVA 254-267 (OVA24) peptide antigen, harboring a CD8 T cell epitope, and Pam3CysSerLys4 (Pam3CSK4) adjuvant were chemically linked to the surface of UCNPs by amide condensation to stimulate DC maturation and antigen presentation. The OVA24-Pam3CSK4-UCNPs were thoroughly characterized and showed a homogeneous morphology and surface electronegativity, which promoted a good dispersion of the NPs. In vitro experiments demonstrated that OVA24-Pam3CSK4-UCNPs induced a strong immune response, including DC maturation, T cell activation, and proliferation, as well as interferon gamma (IFN-γ) production. In vivo, highly sensitive upconversion luminescence (UCL) imaging of OVA24-Pam3CSK4-UCNPs allowed tracking of UCNPs from the periphery to lymph nodes. In summary, OVA24-Pam3CSK4-UCNPs represent an effective tool for DC-based immunotherapy.

NOX4- and Nrf2-mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells.

It has been widely reported that silver nanoparticles (AgNPs) induce oxidative stress in various cell lines. However, the mechanism for this effect and its consequences for cellular signaling are poorly understood. In this study, human umbilical vein endothelial cells (HUVECs) were used to assess the toxicity and investigate the associated molecular mechanisms caused by exposure to AgNPs. We demonstrated that AgNP exposure significantly and dose-dependently decreased the cell viability, induced reactive oxygen species (ROS) generation and led to early apoptosis in HUVECs. Our findings showed that AgNPs induced excess ROS production that affected the signaling pathways by a mechanism that depended on activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity through upregulation of NADPH oxidase 4 (NOX4) protein expressions. Moreover, AgNPs could disrupt the inactivation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response, which is considered another important element for oxidative stress caused by AgNPs in HUVECs. The redox imbalance between NOX4 and Nrf2 was an important cause for the ROS overproduction that led to cell injury in HUVECs. The results provided insight into the mechanisms of oxidative stress induced by AgNPs in vascular endothelial cells.

Correction: Yu et al. Achieving Effective Multimodal Imaging with Rare-Earth Ion-Doped CaF2 Nanoparticles. Pharmaceutics 2022, 14, 840.

There was an error in the original publication [...].

SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells.

SGT1 (suppressor of G2 allele of Skp1) plays a role in various cellular processes including kinetochore assembly and protein ubiquitination by interacting with Skp1, a component of SCF E3 ligase complex. However, the function of SGT1 in cancer is largely unknown. Here, we showed that SGT1 was over-expressed in gastric cancer tissues and silencing of SGT1 by siRNAs significantly inhibited the growth and colony formation of gastric cancer cells. We further showed that SGT1 could regulate Akt signaling pathway by modulating Akt ser473 phosphorylation status. Moreover, we found that SGT1 was able to regulate the stability of PHLPP1, which is the direct phosphatase for Akt ser473 phosphorylation. Immunoprecipitation assay revealed that SGT1 could enhance the binding between PHLPP1 and beta-TrCP which has been documented to be able to target PHLPP1 for destruction. Decreased PHLPP1 in SGT1 over-expressed gastric cancer cells failed to dephosphorylate Akt and resulted in increased Akt ser473 phosphorylation and amplified downstream Akt signaling. Thus, our data revealed a previously uncovered role of SGT1 in gastric cancer development, and suggested that SGT1 could be a promising anti-cancer target to against gastric cancer.

Effective breast cancer therapy based on palmitic acid-loaded PLGA nanoparticles.

Although new strategies for breast cancer treatment have yielded promising results, most drugs can lead to serious side effects when applied systemically. Doxorubicin (DOX), currently the most effective chemotherapeutic drug to treat breast cancer, is poorly selective towards tumor cells and treatment often leads to the development of drug resistance. Recent studies have indicated that several fatty acids (FAs) have beneficial effects on inhibiting tumorigenesis. The saturated FA palmitic acid (PA) showed anti-tumor activities in several types of cancer, as well as effective repolarization of M2 macrophages towards the anti-tumorigenic M1 phenotype. However, water insolubility and cellular impermeability limit the use of PA in vivo. To overcome these limitations, here, we encapsulated PA into a poly(d,l-lactic co-glycolic acid) (PLGA) nanoparticle (NP) platform, alone and in combination with DOX, to explore PA's potential as mono or combinational breast cancer therapy. Our results showed that PLGA-PA-DOX NPs and PLGA-PA NPs significantly reduced the viability and migratory capacity of breast cancer cells in vitro. In vivo studies in mice bearing mammary tumors demonstrated that PLGA-PA-NPs were as effective in reducing primary tumor growth and metastasis as NPs loaded with DOX, PA and DOX, or free DOX. At the molecular level, PLGA-PA NPs reduced the expression of genes associated with multi-drug resistance and inhibition of apoptosis, and induced apoptosis via a caspase-3-independent pathway in breast cancer cells. In addition, immunohistochemical analysis of residual tumors showed a reduction in M2 macrophage content and infiltration of leukocytes after treatment of PLGA-PA NPs and PLGA-PA-DOX NPs, suggesting immunomodulatory properties of PA in the tumor microenvironment. In conclusion, the use of PA alone or in combination with DOX may represent a promising novel strategy for the treatment of breast cancer.

Correction: Yu et al. Rare-Earth-Metal (Nd3+, Ce3+ and Gd3+)-Doped CaF2: Nanoparticles for Multimodal Imaging in Biomedical Applications. Pharmaceutics 2022, 14, 2796.

In the original publication [...].

Identification of Genes Predicting Poor Response of Trastuzumab in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer.

Objective: To identify trastuzumab-resistant genes predicting drug response and poor prognosis in human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Methods: Gene expression profiles from the GEO (Gene Expression Omnibus) database were obtained and analyzed. Differentially expressed genes (DEGs) between the pathological complete response (pCR) group and non-pCR group in a trastuzumab neoadjuvant therapy cohort and DEGs between Herceptin-resistant and wild-type cell lines were detected and evaluated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were performed to select the functional hub genes. The hub genes' prognostic power was validated by another trastuzumab adjuvant treatment cohort. Results: Fifty upregulated overlapping DEGs were identified by analyzing two trastuzumab resistance-related GEO databases. Functional analysis picked out ten hub genes enriched in mitochondrial function and metabolism pathways: ASCL1, CPT2, DLD, ELVOL7, GAMT, NQO1, SLC23A1, SPR, UQCRB, and UQCRQ. These hub genes could distinguish patients with trastuzumab resistance from the sensitive ones. Further survival analysis of hub genes showed that DLD overexpression was significantly associated with an unfavorable prognosis in HER2+ breast cancer patients. Conclusion: Ten novel trastuzumab resistance-related genes were discovered, of which DLD could be used for trastuzumab response prediction and prognostic prediction in HER2+ breast cancer.

Photodynamic Therapy in Combination with the Hepatitis B Core Virus-like Particles (HBc VLPs) to Prime Anticancer Immunity for Colorectal Cancer Treatment.

Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8+ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy.

Achieving Effective Multimodal Imaging with Rare-Earth Ion-Doped CaF2 Nanoparticles.

Nowadays, cancer poses a significant hazard to humans. Limitations in early diagnosis techniques not only result in a waste of healthcare resources but can even lead to delays in diagnosis and treatment, consequently reducing cure rates. Therefore, it is crucial to develop an imaging probe that can provide diagnostic information precisely and rapidly. Here, we used a simple hydrothermal method to design a multimodal imaging probe based on the excellent properties of rare-earth ions. Calcium fluoride co-doped with ytterbium, gadolinium, and neodymium (CaF2:Y,Gd,Nd) nanoparticles (NPs) is highly crystalline, homogeneous in morphology, and displays a high biosafety profile. In addition, in vitro and ex vivo experiments explored the multimodal imaging capability of CaF2:Y,Gd,Nd and demonstrated the efficient performance of CaF2:Y,Gd,Nd during NIR-II fluorescence/photoacoustic/magnetic resonance imaging. Collectively, our novel diagnosis nanoparticle will generate new ideas for the development of multifunctional nanoplatforms for disease diagnosis and treatment.

Combinatorial Therapeutic Approaches with Nanomaterial-Based Photodynamic Cancer Therapy.

Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies.

Rare-Earth-Metal (Nd3+, Ce3+ and Gd3+)-Doped CaF2: Nanoparticles for Multimodal Imaging in Biomedical Applications.

Here, we describe the synthesis of a novel type of rare-earth-doped nanoparticles (NPs) for multimodal imaging, by combining the rare-earth elements Ce, Gd and Nd in a crystalline host lattice consisting of CaF2 (CaF2: Ce, Gd, Nd). CaF2: Ce, Gd, Nd NPs are small (15-20 nm), of uniform shape and size distribution, and show good biocompatibility and low immunogenicity in vitro. In addition, CaF2: Ce, Gd, Nd NPs possess excellent optical properties. CaF2: Ce, Gd, Nd NPs produce downconversion emissions in the second near-infrared window (NIR-II, 1000-1700 nm) under 808 nm excitation, with a strong emission peak at 1056 nm. Excitation in the first near- infrared window (NIR-I, 700-900 nm) has the advantage of deeper tissue penetration power and reduced autofluorescence, compared to visible light. Thus, CaF2: Ce, Gd, Nd NPs are ideally suited for in vivo fluorescence imaging. In addition, the presence of Gd3+ makes the NPs intrinsically monitorable by magnetic resonance imaging (MRI). Moreover, next to fluorescence and MR imaging, our results show that CaF2: Ce, Gd, Nd NPs can be used as imaging probes for photoacoustic imaging (PAI) in vitro. Therefore, due to their biocompatibility and suitability as multimodal imaging probes, CaF2: Ce, Gd, Nd NPs exhibit great potential as a traceable imaging agent in biomedical applications.

Integrated Bioinformatics and Experimental Approaches Identified the Role of NPPA in the Proliferation and the Malignant Behavior of Breast Cancer.

Breast cancer is the 3rd most common type of malignant tumor worldwide with high heterogeneity, frequent recurrence, and high metastasis tendency. In this study, we aimed to demonstrate the value of extracellular matrix- (ECM-) related genes in breast cancer patients. The overall expression of ECM is assessed with a novel SC3 clustering method, and patients were divided into two clusters with diverse recurrence rate. We established the Cox regression model in breast cancer patients and identified NPPA as an independent prognostic marker. The NPPA expression is downregulated in breast cancer patients, independent of the ER status, PR status, stemness score, and immune infiltrating condition. And we observed the enhanced proliferation, migration, and invasion potential of breast cancer cells after NPPA depletion. Further, we predicted the transcription modulation of NPPA with PROMO and JASPAR. And we further validated the binding of MZF1 to the -318 bp~-452 bp region of the NPPA promoter with chromatin immunoprecipitation and dual luciferase assay. Together, our study identified NPPA as a potential prognostic biomarker for breast cancer patients, whose downregulation is associated with an enhanced malignant behavior of breast cancer cells both in vivo and in vitro and identified the transcription regulation of NPPA by MZF1.

Hypericin-mediated photodynamic therapy for the treatment of cancer: a review.

OBJECTIVES: Hypericin is a polycyclic aromatic naphthodianthrone that occurs naturally. It is also an active ingredient in some species of the genus Hypericum. Emerging evidence suggests that hypericin has attracted great attention as a potential anticancer drug and exhibits remarkable antiproliferative effect upon irradiation on various tumour cells. This paper aims to summarise the anticancer effect and molecular mechanisms modulated by hypericin-medicated photodynamic therapy and its potential role in the cancer treatment. KEY FINDINGS: Hypericin-medicated photodynamic therapy could inhibit the proliferation of various tumour cells including bladder, colon, breast, cervical, glioma, leukaemia, hepatic, melanoma, lymphoma and lung cancers. The effect is primarily mediated by p38 mitogen-activated protein kinase (MAPK), JNK, PI3K, CCAAT-enhancer-binding protein homologous protein (CHOP)/TRIB3/Akt/mTOR, TRAIL/TRAIL-receptor, c-Met and Ephrin-Eph, the mitochondria and extrinsic signalling pathways. Furthermore, hypericin-medicated photodynamic therapy in conjunction with chemotherapeutic agents or targeted therapies is more effective in inhibiting the growth of tumour cells. SUMMARY: During the past few decades, the anticancer properties of photoactivated hypericin have been extensively investigated. Hypericin-medicated photodynamic therapy can modulate a variety of proteins and genes and exhibit a great potential to be used as a therapeutic agent for various types of cancer.

Recent Advances in Rare-Earth-Doped Nanoparticles for NIR-II Imaging and Cancer Theranostics.

Fluorescence imaging in the second near infrared window (NIR-II, 1,000-1,700 nm) has been widely used in cancer diagnosis and treatment due to its high spatial resolution and deep tissue penetration depths. In this work, recent advances in rare-earth-doped nanoparticles (RENPs)-a novel kind of NIR-II nanoprobes-are presented. The main focus of this study is on the modification of RENPs and their applications in NIR-II in vitro and in vivo imaging and cancer theranostics. Finally, the perspectives and challenges of NIR-II RENPs are discussed.

Metallic contamination in soils around a municipal solid waste incineration site: a case study in northeast China.

An investigation of 45 soil samples collected from the surface soil around a municipal solid waste incinerator, in northeast China, was performed to understand the status of metallic contamination in the soil. Methods such as inverse distance weighting, pollution index, potential ecological risk, and statistical analysis were used to investigate metallic contamination in soils around municipal solid waste incineration sites. Both grade II and background concentrations were employed as reference standards to evaluate the levels of metallic contamination in soils. The results revealed that the metal concentrations and contamination levels were both the highest near the centre of the MSWI and decreased away from the centre of the MSWI. The source identification results demonstrated that the MSWI, natural sources and complicated sources represented the three primary sources, accounting for 59.08 %, 11.17 %, and 10.43 % of the contamination, respectively. The most heavily polluted samples were located to the south of the MSWI. When the grade II values were used as references, the metals in soils, except for Cd, Zn, and Cu in some samples, exhibited low contamination levels and ecological risks. Soils were polluted by the metals to various degrees based on the background reference values. Additionally, the potential ecological risk analysis further suggested that the study area was at considerable risk, especially for Cd pollution. These results are critical for protecting the environment in the vicinity of a MSWI and providing basic data for policy-makers to formulate viable regulations in the future.

Correction: Zn2SnO4:Cr,Eu ultra-small nanoparticles as new near infrared-emitting persistent luminescent nanoprobes for cellular and deep tissue imaging at 800 nm.

Correction for 'Zn2SnO4:Cr,Eu ultra-small nanoparticles as new near infrared-emitting persistent luminescent nanoprobes for cellular and deep tissue imaging at 800 nm' by Hongwu Zhang et al., Nanoscale, 2017, 9, 8631-8638.

Luminescence enhancement of CaF2:Nd3+ nanoparticles in the second near-infrared window for in vivo imaging through Y3+ doping.

In vivo luminescent imaging in the second biological window (1000-1400 nm, NIR-II) has attracted increasing attention since it can provide high sensitivity to deep tissue in vivo imaging. Herein, we synthesized approximately 10-15 nm-sized NIR-II luminescent nanoparticles (CaF2:Nd3+ NPs). Furthermore, co-doped Y3+ was utilized to enhance the NIR-II luminescence of the CaF2:Nd3+ NPs via breaking the aggregation of Nd3+. The appearance of a (200) diffraction peak and the broadening of the interplanar spacing of the (111) plane both showed that the incorporated Y3+ can dissolve in CaF2 by occupying the Ca2+ sites to form a CaF2-YF3 solid solution. In particular, the addition of Y3+ can greatly enhance the of the NIR-II luminescence of CaF2:Nd3+ NPs. When the Y3+ doped concentration reached 0.30, the luminescence intensity of CaF2:Y3+,Nd3+ NPs was about 65 times that of CaF2:Nd3+ NPs. In addition, the quantum yield of Ca0.68Y0.30Nd0.02F2.32 NPs was 9.30% under the excitation of an 808 nm laser with 483 mW cm-2 power, which was about 3 times higher than that of CaF2:Nd3+ NPs (3.10%). The in vivo imaging results revealed that the in vivo imaging intensity of Ca0.68Y0.30Nd0.02F2.32 NPs was about 2.38-fold stronger than that of Ca0.98F2.02:Nd3+ 0.02 NPs. All of these results indicated that CaF2:Y3+,Nd3+ NPs can be regarded as potential in vivo imaging probes for biological imaging.

Five-nanometer ZnSn2O4:Cr,Eu ultra-small nanoparticles as new near infrared-emitting persistent luminescent nanoprobes for cellular and deep tissue imaging at 800 nm.

Until now, the afterglow emissions of most developed near infrared (NIR)-emitting persistent luminescent nanoparticles (NPLNPs) were located at approximately 700 nm, at the edge of the first tissue transparency window (from 650 to 900 nm), which resulted in relatively low tissue penetration and signal-to-noise ratio (SNR) for in vivo imaging. Herein, 5 nm ZnSn2O4:Cr,Eu (ZSO) NPLNPs with NIR afterglow emission at 800 nm are synthesized via a direct aqueous-phase synthesis method. The longer NIR afterglow emission of ZSO NPLNPs can easily penetrate approximately 3 cm of pork tissue. Furthermore, even though the backbones blocked part of the NIR afterglow light, high SNR (25.5) in vivo images of the backs of mice can be observed and can be maintained for more than 15 min. The ZSO nanoprobes conjugated with folic acid exhibited excellent in vitro and in vivo tumor targeting capacity, which was advantageous for accurate tumor diagnosis. More importantly, the ZSO NPLNPs can be re-excited in situ and in vivo using NIR light to realize renewable near-infrared persistent luminescence in vivo, which was helpful for very long term and higher SNR in vitro and in vivo imaging.

Transareola single-site endoscopic thyroidectomy: clinical study of 28 cases with thyroid nodules.

OBJECTIVES: To investigate the feasibility and safety of transareola single-site endoscopic thyroidectomy. SUBJECTS AND METHODS: Twenty-eight patients with thyroid nodules were involved in this study. An incision was cut on a single areola, and a laparoendoscope apparatus and an operating apparatus were implanted. The thyroid gland was exposed using the neck suture suspension technique, and the damaged thyroid gland was removed with an ultrasonic scalpel. The operation time, intraoperative bleeding volume, postoperative pain score, and cosmetic satisfaction score were calculated. RESULTS: Unilateral subtotal thyroidectomy was performed in 12 cases, unilateral partial thyroidectomy in 14 cases, and bilateral partial thyroidectomy in 2 cases. For the former 14 cases, the operation time was 145-205 minutes, with a mean duration of 170 minutes; the operation time ranged from 125 to 150 minutes, with a mean of 135 minutes, for the latter 14 cases. The intraoperative bleeding volume was 15-40 mL, with a mean of 25 mL. The total postoperative wound drainage was 80-135 mL, with a mean of 110 mL. The drainage tube was removed 3-4 days after surgery. The visual analog scale score was 1-5 at 24 hours postoperatively, with a mean score of 3.10. Postoperative pathological examination diagnosed thyroid adenoma in 11 cases and nodular goiter in 17 cases. CONCLUSIONS: Transareola single-site endoscopic thyroidectomy is feasible and safe and has the advantages of a covert incision, small subcutaneous separation area, and high cosmetic satisfaction. The operation time shortens with the increasing number of patients undergoing operations.