Computed Tomography Imaging Guided Microenvironment-Responsive Ir@WO3-x Dual-Catalytic Nanoreactor for Selective Radiosensitization.

Radiotherapy (RT) is often administered, either alone or in combination with other therapies, for most malignancies. However, the degree of tumor oxygenation, damage to adjacent healthy tissues, and inaccurate guidance remain issues that result in discontinuation or failure of RT. Here, a multifunctional therapeutic platform based on Ir@WO3-x is developed which simultaneously addresses these critical issues above for precision radiosensitization. Ir@WO3-x nanoreactors exhibit strong absorption of X-ray, acting as radiosensitizers. Moreover, ultrasmall Ir enzyme-mimic nanocrystals (NCs) are decorated onto the surface of the nanoreactor, where NCs have catalyst-like activity and are sensitive to H2O2 in the tumor microenvironment (TME) under near infrared-II (NIR-II) light stimulation. They efficiently catalyze the conversion of H2O2 to O2, thereby ameliorating hypoxia, inhibiting the expression of HIF-1α, and enhancing RT-induced DNA damage in cancerous tissue, further improving the efficiency of RT. Additionally, in response to high H2O2 levels in TME, the Ir@WO3-x nanoreactor also exerts peroxidase-like activity, boosting exogenous ROS, which increases oxidative damage and enhances ROS-dependent death signaling. Furthermore, Ir@WO3-x can serve as a high-quality computed tomography contrast agent due to its high X-ray attenuation coefficient and generation of pronounced tumor-tissue contrast. This report highlights the potential of advanced health materials to enhance precision therapeutic modalities.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells.

Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer. Currently, therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape, which leads to enhanced aggressive behaviors compared with CSCs that have never been treated. However, the underlying mechanisms regulating the therapeutic escape remain unknown. To this end, we established a model to isolate the therapeutic escaped CSCs (TSCSCs) from breast CSCs and performed the transcription profile to reveal the mechanism. Mechanistically, we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway, resulting in TSCSCs exhibiting enhanced motility and metastasis. Notably, blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo, which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition (EMT)-related proteins vimentin and N-cadherin. The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

Nocardiosis and other common diseases of cultured golden pompano (Trachinotus blochii) in Taiwan.

Golden pompano (Trachinotus blochii) is a carnivorous teleost cultured in the Asia-Pacific region. Fish culture in high densities and numbers results in disease outbreaks, causing huge economic losses. Here, we collected cultured golden pompanos from 2021 to 2022 and identified the pathogens isolated from the diseased fish. Out of a total of 64 clinical cases observed in both sea cages and fish ponds, it was found that Nocardia seriolae was the predominant pathogen (26%), followed by Lactococcus garvieae (13%). Trichodina spp. was the most prevalent parasite in sea cages and earthen ponds (21%), while Neobenedenia spp. was the primary parasitic pathogen (16%) in sea cages. Given these findings, further investigations were conducted, including antibiotic susceptibility and pathogenicity tests specific to N. seriolae in golden pompanos. Antibiotic susceptibility tests of N. seriolae revealed that all strains were susceptible to doxycycline, oxytetracycline, florfenicol and erythromycin but resistant to amoxicillin and ampicillin. Additionally, a pathogenicity assessment was carried out by administering an intraperitoneal injection of 0.1 mL containing 107 CFU of N. seriolae per fish. The mortality rates observed varied between 40% and 90%, with the P2 strain exhibiting the highest level of virulence, resulting in a cumulative mortality of 90%. Therefore, disease outbreaks in fish can be minimized by developing effective treatments and prevention methods.

First report of a Kudoa lutjanus outbreak in farmed Chicken Grunts Parapristipoma trilineatum.

OBJECTIVE: As part of the National Disease Surveillance Program for Taiwanese Aquaculture, we investigated the causative agent of disease outbreaks in farmed Chicken Grunts Parapristipoma trilineatum. METHODS: In this study, outbreak cases on two separate farms were noticed in coastal Pingtung County, Taiwan. In total, 50 juvenile fish showing clinical signs (such as emaciation and erratic swimming behavior) and broodstock (two females and two males) from both farms were collected to perform gross lesion assessment, histopathological examination, and molecular identification of the pathogen. RESULT: Clinical symptoms were infected fish exhibited erratic swimming behavior, such as whirling and floating on the surface of the water. In the following months, cumulative mortality had reached 19% and 24%, respectively. The gross lesions in the infected fish included white oval cysts in the muscle, serosa of the internal organs, sclera of the eyes, and cerebral meninges. After conducting a wet mount examination of cysts using a light microscope, we observed a significant quantity of spores with morphological characteristics, suggesting their affiliation with the Myxosporea group. The spores were semiquadrate, with four tiny suture notches at the periphery; the mean spore length was 7.3 µm (SD = 0.5), and the mean spore width was 8.2 µm (SD = 0.6). The mean length and width of the pyriform polar capsules (nematocysts) were 3.6 µm (SD = 0.5) and 2.2 µm (SD = 0.5), respectively. The 18S and 28S ribosomal RNA sequences of these specimens were identical to those of Kudoa lutjanus. CONCLUSION: As this was the first time an outbreak of K. lutjanus in Chicken Grunts was confirmed, its reappearance with substantial mortality should serve as a warning to the aquaculture industry.

First identification, molecular characterization, and pathogenicity assessment of Lactococcus garvieae isolated from cultured pompano in Taiwan.

Lactococcosis, caused by Lactococcus garvieae, is an acute hemorrhagic septicemia in fish recorded in marine and freshwater aquaculture during the summer months. In 2020-2021, several sea cage Pompano farms recorded sudden fish mortality events. Based on the results of phenotypic and biochemical tests, L. garvieae was predicted to be the cause. PCR with L. garvieae specific primers (pLG1 and pLG2) targeting the 16S rRNA region further confirmed the etiological agent as L. garvieae after amplifying an 1100 base pairs (bp) product. Furthermore, the 16S rRNA sequences of the two representative strains (AOD109-196-2B and AOD110-215-2B) shared 99.81% identity with L. garvieae (GenBank accession number: MT597707.1). The genetic profiles of the strains were classified using pulsed-field gel electrophoresis after digestion with SmaI and ApaI, which clustered our strains under the same pulsotype. Multiplex PCR targeting the capsule gene cluster and serotype-specific PCR collectively showed that the strains were non-capsulated; thus, they belonged to serotype I. An experimental infection was designed to fulfil Koch's postulates by infecting healthy Pompano with case-driven L. garvieae strains (AOD109-196-2B and AOD110-215-2B) with a cumulative mortality of 70%. Overall, L. garvieae infection in Pompano emphasizes the need for better monitoring and control procedures in aquaculture settings.

Multifunctional Gold Nanoclusters for Effective Targeting, Near-Infrared Fluorescence Imaging, Diagnosis, and Treatment of Cancer Lymphatic Metastasis.

Developing effective lymph-node (LN) targeting and imaging probes is crucial for the early detection and diagnosis of tumor metastasis to improve patient survival. Most current clinical LN imaging probes are based on small organic dyes (e.g., indocyanine green) or radioactive 99mTc-complexes, which often suffer from limitations, such as rapid photobleaching, poor signal contrast, and potential biosafety issues. Moreover, these probes cannot easily incorporate therapeutic functions to realize beneficial theranostics without affecting their LN-targeting ability. Herein, we have developed dual-ligand-/multiligand-capped gold nanoclusters (GNCs) for specific targeting, near-infrared (NIR) fluorescence imaging, diagnosis, and treatment of LN cancer metastasis in in vivo mouse models. By optimizing the surface ligand coating, we have prepared Au25(SR1)n(SR2)18-n (where SR1 and SR2 are different functional thiol ligands)-type GNCs, which display highly effective LN targeting, excellent stability and biocompatibility, and optimal body-retention time. Moreover, they can provide continuous NIR fluorescence imaging of LNs for >3 h from a single dose, making them well-suited for fluorescence-guided surgery. Importantly, we have further incorporated methotrexate, a chemotherapeutic drug, into the GNCs without affecting their LN-targeting ability. Consequently, they can significantly improve the efficiency of methotrexate delivery to target LNs, achieving excellent therapeutic efficacy with up to 4-fold lower hepatotoxicity. Thus, the GNCs are highly effective and safe theranostic nanomedicines against cancer lymphatic metastasis.

Controlling the pyridinium-zwitterionic ligand ratio on atomically precise gold nanoclusters allowing for eradicating Gram-positive drug-resistant bacteria and retaining biocompatibility.

Infections caused by multidrug-resistant (MDR) bacteria are an increasing global healthcare concern. In this study, we developed a dual-ligand-functionalised Au25(SR1) x (SR2)18-x -type gold nanocluster and determined its antibacterial activity against MDR bacterial strains. The pyridinium ligand (SR1) provided bactericidal potency and the zwitterionic ligand (SR2) enhanced the stability and biocompatibility. By optimising the ligand ratio, our gold nanocluster could effectively kill MDR Gram-positive bacteria via multiple antibacterial actions, including inducing bacterial aggregation, disrupting bacterial membrane integrity and potential, and generating reactive oxygen species. Moreover, combining the optimised gold nanocluster with common antibiotics could significantly enhance the antibacterial activity against MDR bacteria both in in vitro and animal models of skin infections. Furthermore, the fluorescence of the gold nanocluster at the second near-infrared (NIR-II) biological window allowed for the monitoring of its biodistribution and body clearance, which confirmed that the gold nanoclusters had good renal clearance and biocompatibility. This study provides a new strategy to combat the MDR challenge using multifunctional gold nanomaterials.

Reversing the Chirality of Surface Ligands Can Improve the Biosafety and Pharmacokinetics of Cationic Gold Nanoclusters.

Severe toxicity and rapid in vivo clearance of cationic nanomaterials seriously hinder their clinical translation. Present strategies to improve the biosafety and in vivo performance of cationic nanomaterials require neutralization of positive charge, which often compromises their efficacy. Herein, we report that substituting L-glutathione (L-GSH) on cationic gold nanoclusters (GNCs) with its D-counterpart can effectively improve the biosafety and pharmacokinetics. Compared with L-GNCs, D-GNCs do not exhibit cellular cytotoxicity, hemolysis, or acute damage to organs. Cationic D-GNCs show less cell internalization than L-GNCs, and do not induce cellular apoptosis. In vivo, the chirality of surface ligands distinctly affects the pharmacokinetics and tumor targeting abilities of D-/L-GNCs. D-GNCs show higher extended circulation time in blood plasma compared to similarly-sized and poly (ethylene glycol)-modified gold nanoparticles. This work demonstrates that the choice of chirality of surface ligands can determine toxicities and pharmacokinetics of cationic nanomaterials.

Four-in-One: Advanced Copper Nanocomposites for Multianalyte Assays and Multicoding Logic Gates.

The usage of non-noble-metal nanomaterials for nanoprobes or functional modules is still a big challenge because of their poor stability, functionality, and surface plasmon resonance property. In this work, copper ion, mercaptosuccinic acid, and nanocrystalline cellulose are combined for facile one-step synthesis and self-assembly of ultrasmall copper nanoparticles to produce supercolloidal particles (NCC@MSA-Cu SPs). Cu SPs show advanced multifunctionality for fast point-of-care tests (POCTs) of four metal ions (Hg2+, Pb2+, Ag+, and Zr4+). These selective recognitions integrate four different chemical reaction mechanisms (ion etching, core-shell deposition, templated synthesis, and precipitation) to produce four distinct readout signals. The multisignal mode-guided multianalyte sensing strategy can effectively avoid interference that affects single signal mode-based sensing. Benefiting from the creative multi-input and multireadout abilities, the visual multicoding logic gates of OR, NOR, AND, and INHIBIT are built based on optical responses of Cu SPs.

Multifunctional Magnetic Nanoplatform Eliminates Cancer Stem Cells via Inhibiting the Secretion of Extracellular Heat Shock Protein 90.

Cancer stem cells (CSCs) are responsible for malignant tumor initiation, recurrences, and metastasis. Therefore, targeting CSCs is a promising strategy for the development of cancer therapies. A big challenge for CSC-based cancer therapy is the overexpression of therapeutic stress protein, heat shock protein 90 (Hsp90), which protects CSCs from further therapeutic-induced damage, leading to the failure of treatment. Thus, efficient strategies to target CSCs are urgently needed for cancer therapy. To this end, a multifunctional nanoparticle (MNP) for CSC-based combined thermotherapy and chemotherapy is reported. This strategy dramatically suppresses tumor growth in breast CSC xenograft-bearing mice. Furthermore, a new mechanism is present that the MNP exerts its striking effects on CSCs by inhibiting the secretion of extracellular Hsp90 (eHsp90), resulting in the interruption of several key signaling pathways. These findings open new perspectives on the use of an MNP for effective CSC-based cancer treatment by inhibiting the function of eHsp90.

Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy.

Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy.

Biomimetic O2-Evolving metal-organic framework nanoplatform for highly efficient photodynamic therapy against hypoxic tumor.

Improving the supply of O2 and the circulation lifetime of photosensitizers for photodynamic therapy (PDT) in vivo would be a promising approach to eliminate hypoxic tumors. Herein, by taking advantage of the significant gas-adsorption capability of metal-organic frameworks (MOFs), a biomimetic O2-evolving photodynamic therapy (PDT) nanoplatform with long circulating properties was fabricated. Zirconium (IV)-based MOF (UiO-66) was used as a vehicle for O2 storing, then conjugated with indocyanine green (ICG) by coordination reaction, and further coated with red blood cell (RBC) membranes. Upon 808 nm laser irradiation, the initial singlet oxygen (1O2) generated by ICG would decompose RBC membranes. At the same time, The photothermal property of ICG could facilitate the burst release of O2 from UiO-66. Subsequently, the generated O2 could significantly improve the PDT effects on hypoxic tumor. Owing to the advantages of long circulation and O2 self-sufficient, the designed nanotherapeutic agent can improve the efficiency of treatment against hypoxia tumor via PDT. Hence, this study presents a new paradigm for co-delivery of O2 and photosensitizers, and provides a new avenue to eliminate hypoxic tumors.

Two-photon fluorescent probe for detection of nitroreductase and hypoxia-specific microenvironment of cancer stem cell.

Hypoxia plays a crucial role in cancer progression, and it has great significance for monitoring hypoxic level in biosystems. Cancer stem cells (CSCs) represent a small population of tumour cells that regard as the key to seed tumours. The survival of CSCs depend on the tumour microenvironment, which is distinct region has the hypoxic property. Therefore, the detection of the hypoxic CSC niche plays a pivotal role in the destructing the 'soil' of CSCs, and eliminating CSCs population. Numerous one-photon excited fluorescent probes have been developed to indicate the hypoxic status in tumours through the detection of nitroreductase (NTR) level. However, the biomedical application of one-photon fluorescent probes is limited due to the poor tissue penetration. In the present work, we reported a two-photon fluorescent probe to detect the NTR in CSCs and monitor the hypoxic microenvironment in vivo. The two-photon fluorescent molecular probe with a hypoxic specific response group can be reduced by NTR under hypoxic conditions. We used the two-photon probe to detect the hypoxia status of 3D cultured-CSCs in vitro and in vivo CSCs' microenvironment in tumour. The two-photon absorption cross section extends fluorescent excitation spectra to the near infrared region, which dramatically promotes the tissue penetration for hypoxic microenvironment detection of CSC in vivo.

Biomimetic mineralized strontium-doped hydroxyapatite on porous poly(l-lactic acid) scaffolds for bone defect repair.

INTRODUCTION: poly(l-lactic acid) (PLLA) has been approved for clinical use by the US Food and Drug Administration (FDA); however, their stronger hydrophobicity and relatively fast degradation rate restricted their widespread application. In consideration of the composition of bone, the inorganic-organic composite has a great application prospect in bone tissue engineering. Many inorganic-organic composite scaffolds were prepared by directly mixing the active ingredient, but this method is uncontrolled and will lead to lack of homogeneity in the polymer matrix. Strontium (Sr) is an admirable addition to improve the bioactivity and bone induction of hydroxyapatite (HA). To our knowledge, the application of biomimetic mineralized strontium-doped hydroxyapatite on porous poly(l-lactic acid) (Sr-HA/PLLA) scaffolds for bone defect repair has never been reported till date. Biomimetic mineralized Sr-HA/PLLA porous scaffold was developed in this study. The results indicated that the Sr-HA/PLLA porous scaffold could improve the surface hydrophobicity, reduce the acidic environment of the degradation, and enhance the osteoinductivity; moreover, the ability of protein adsorption and the modulus of compression were increased. The results also clearly showed the effectiveness of the Sr-HA/PLLA porous scaffold in promoting cell adhesion, proliferation, and alkaline phosphatase (ALP) activity. The micro computed tomography (micro-CT) results showed that more new bones were formed by Sr-HA/PLLA porous scaffold treatment. The histological results confirmed the osteoinductivity of the Sr-HA/PLLA porous scaffold. The results suggested that the Sr-HA/PLLA porous scaffold has a good application prospect in bone tissue engineering in the future. PURPOSE: The purpose of this study was to promote the bone repair. MATERIALS AND METHODS: Surgical operation of rabbits was carried out in this study. RESULTS: The results showed that formation of a large number of new bones by the Sr-HA/PLLA porous scaffold treatment is possible. CONCLUSION: Biomimetic mineralized Sr-HA/PLLA porous scaffold could effectively promote the restoration of bone defects in vivo.

[Efficacy and safety of sildenafil in the treatment of high altitude heart disease associated with severe pulmonary arterial hypertension in children: a preliminary evaluation].

OBJECTIVE: To observe the clinical efficacy and safety of sildenafil in the treatment of high altitude heart disease associated with severe pulmonary arterial hypertension (PAH) in children. METHODS: Fifty children (aged 2 months to 2 years) with high altitude heart disease associated with severe PAH, who were continuously transferred to the Intensive Care Unit between January 2011 and October 2013, were randomly assigned to observation and control groups. The control group was given conventional treatment, while the observation group received oral sildenafil [1 mg/(kg . d)] three times daily for 7-10 days in addition to the conventional treatment. Before and after treatment, hemodynamics, blood gas, routine blood parameters, and blood biochemical parameters were recorded. RESULTS: After treatment, the observation group had a significantly higher decrease in mean pulmonary artery pressure and significantly higher increases in arterial partial pressure of oxygen, cardiac output, cardiac index, and oxygenation index compared with the control group (P<0.05). In the observation group, there were no significant changes in mean arterial pressure, routine blood parameters and blood biochemical parameters (P>0.05), and no obvious adverse reactions were found. CONCLUSIONS: For children with high altitude heart disease associated with severe PAH, sildenafil can effectively reduce pulmonary artery pressure and improve cardiac function and does not cause adverse reactions. This therapy has good safety according to the preliminary evaluation.