Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo.

Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

Cellular Process of Polystyrene Nanoparticles Entry into Wheat Roots.

Nanoscale plastic particles are widely found in the terrestrial environment and being increasingly studied in recent years. However, the knowledge of their translocation and accumulation mechanism controlled by nanoplastic characterizations in plant tissues is limited, especially in plant cells. Here, 20 mg L-1 polystyrene nanoparticles (PS NPs) with different sizes and amino/carboxy groups were employed to investigate the internalization process in wheat roots and cells. From the results, we found that the uptake of small-size PS NPs in the root tissues was increased compared to that of large-size ones, but no PS NPs were observed in the vascular cylinder. Similar results were observed in their cellular uptake process. Besides, the cell wall could block the entry of large-size PS NPs while the cell membrane could not. The -NH2 group on the PS NPs surface could benefit their tissular/cellular translocation compared to the -COOH group. The internalization of PS NPs was controlled by both particle size and surface functional group, and the size should be the primary factor. Our findings offer important information for understanding the PS NPs behaviors in plant tissues, especially at the cellular level, and assessing their potential risk to food safety, quality, and agricultural sustainability.

Synergistic Chemoimmunotherapy Augmentation via Sequential Nanocomposite Hydrogel-Mediated Reprogramming of Cancer-Associated Fibroblasts in Osteosarcoma.

In osteosarcoma, immunotherapy often faces hurdles posed by cancer-associated fibroblasts (CAFs) that secrete dense extracellular matrix components and cytokines. Directly removing CAFs may prove ineffective and even promote tumor metastasis. To address this challenge, a sequential nanocomposite hydrogel that reshapes CAF behavior is developed, enhancing tumor-infiltrating T-cells in osteosarcoma. The approach utilizes an injectable blend of carboxymethyl chitosan and tetrabasic polyethylene glycol, forming a hydrogel for controlled release of a potent CAF suppressor (Nox4 inhibitor, Nox4i) and liposomal Doxorubicin (L-Dox) to induce immunogenic cell death (ICD) upon in situ administration. Nox4i effectively counters CAF activation, overcoming T-cell exclusion mechanisms, followed by programmed L-Dox release for ICD induction in stroma-rich osteosarcoma models. Combining the co-delivery gel with αPD-1 checkpoint inhibitor further enhances its effectiveness in an orthotopic osteosarcoma model. Immunophenotyping data underscore a significant boost in tumor T-cell infiltration and favorable anti-tumor immunity at the whole-animal level.

Macrophage-Inspired marine antifouling coating with dynamic surfaces based on regulation of dynamic covalent bonds.

Macrophages can kill bacteria and viruses by releasing free radicals, which provides a possible approach to construct antifouling coatings with dynamic surfaces that release free radicals if the breaking of dynamic covalent bonds is precisely regulated. Herein, inspired by the defensive behavior of macrophages of releasing free radicals to kill bacteria and viruses, a marine antifouling coating composed of polyurethane incorporating dimethylglyoxime (PUx-DMG) is prepared by precise regulation of dynamic oxime-urethane covalent bonds. The obtained alkyl radical (R·) derived from the cleavage of the oxime-urethane bonds manages to effectively suppress the attachment of marine biofouling. Moreover, the intrinsic dynamic surface makes it difficult for biofouling to adhere and ultimately achieves sustainable antifouling property. Notably, the PU50-DMG coating not only presents efficient antibacterial and antialgae properties, but also prevents macroorganisms from settling in the sea for up to 4 months. This provides a pioneer broad-spectrum strategy to explore the marine antifouling coatings.

In vitro wheat protoplast cytotoxicity of polystyrene nanoplastics.

Nanoplastics are an emerging environmental pollutant, having a potential risk to the terrestrial ecosystem. In the natural environment, almost all the micro-or nano-plastics will be aged by many factors and their characterizations of the surface will be modified. However, the toxicity and mechanism of the modified polystyrene nanoparticles (PS-NPs) to plant cells are not clear. In the study, the amino- and carboxyl-modified PS-NPs with different sizes (20 and 200 nm) were selected as the typical representatives to investigate their effects on protoplast cell viability, reactive oxygen species (ROS) production in the cell and the leakage of cell-inclusion and apoptosis. The results indicated that the 20 nm amino-modified PS-NPs (PS-20A) could significantly damage the structure of the cell, especially the cell membrane, chloroplast and mitochondrion. After being modified by amino group, smaller size nanoplastics had the potential to cause more severe damage. In addition, compared with carboxyl-modified PS-NPs, the amino-modified PS-NPs induced more ROS production and caused higher membrane permeability/lactate dehydrogenase (LDH) leakage. Apoptosis assay indicated that the proportion of viable cells in the PS-20A treatment decreased significantly, and the proportion of necrotic cells increased by four times. This study provides new insights into the toxicity and damage mechanism of PS-NPs to terrestrial vascular plants at the cellular level, and guides people to pay attention to the quality and safety of agricultural products caused by nanoplastics.

A high-flux antibacterial poly(amidoxime)-polyacrylonitrile blend membrane for highly efficient uranium extraction from seawater.

Uranium is an important fuel for nuclear power, with 4.5 billion tons of it stored in the oceans, 1,000 times more than on land. Polymer membrane materials are widely used in the marine resources fields, due to their convenient collection, good separation and can work continuously. Herein, a poly(amidoxime)-polyacrylonitrile blend membrane (PCP) with high flux, excellent antibacterial properties and uranium adsorption performance has been prepared by using the phase inversion method, and the prepared membrane was used for highly efficient uranium extraction from seawater. In static adsorption experiments, the PCP membrane reached adsorption equilibrium after 48 h, and the adsorption capacity was 303.89 mg/g (C0 =50 mg/L). In dynamic adsorption experiments, it was found that the lower flow rate and higher number of membrane layers were favorable for dynamic adsorption. In addition, the water flux of the PCP membrane was 7.4 times higher than that of the PAN membrane. The adsorption mechanism can be attributed to the chelation between amino and hydroxyl groups in CS, amidoxime group in poly(amidoxime) and uranyl ions. The simple preparation process coupled with the excellent adsorption performance indicated that the PCP membrane would be a promising material for the uranium extraction from seawater.

Microplastics lag the leaching of phenanthrene in soil and reduce its bioavailability to wheat.

Microplastics wildly occur in soil and they can become the carriers of persistent contaminants. However, the influence of microplastics on polycyclic aromatic hydrocarbons vertical translocation in the soil system after rainfall is limitedly understood. Here, experiments were conducted to study the influence of polyethylene (PE), polystyrene (PS) and polyvinyl chloride (PVC) microplastics on the leaching behavior and bioavailability of phenanthrene (Phe). The adsorption capacity of phenanthrene on the microplastics followed the order of PS > PE > PVC. The Phe concentrations in the top soil layer after 15 days of leaching with water were 30.25, 28.32 and 27.25 mg kg-1 for the treatments of Phe-PS, Phe-PE and Phe-PVC respectively, which is consistent with the adsorption capacities of microplastics. The concentrations of Phe were correlated with the microplastic adsorption capacities at soil depths of 5-45 cm. Under long-term leaching, Phe could reach the deeper soil layer. Phe concentrations significantly decreased in the leachate over time. Phe concentrations in wheat had a positive correlation with that in leachate/leached top soil layer. Our findings are beneficial to accurately evaluate the ecological risk of the combined contamination of PAHs and microplastics, and improve the understanding of the environmental behaviors of different microplastics.

Mussel-inspired polydopamine microspheres self-adhered on natural hemp fibers for marine uranium harvesting and photothermal-enhanced antifouling properties.

The rapid development of nuclear energy and the accelerated consumption of uranium (U(VI)) ores have forced researchers to turn to marine U(VI) harvesting. However, the performance of marine U(VI) harvesting materials was challenged by the combination of ultralow concentrations of U(VI), high concentrations of various interfering ions and biofouling from abundant marine living organisms. Natural abundant hemp fibers (HFs) were adhered by mussel-inspired polydopamine microspheres (HFMPDA) during self-polymerization. Both HFs and PDA are derived from natural products with low-cost and eco-friendly properties to guarantee compatibility with biological marine environments. HFMPDA exhibits an outstanding distribution coefficient of 10.51 ± 0.51 L g-1 for U(VI) and great fouling resistance. The coordination forms between the U(VI) ion and HFMPDA were investigated by density functional theory (DFT), and the antifouling property was simulated by molecular dynamics (MD) calculations. The adsorption capacity of HFMPDA is 128.43 ± 3.26 µg g-1, which is 1.75 and 6.05 times higher than that of HFPDA (only covered by PDA) and V(V), respectively, after immersion for 34 days in the Yellow Sea, China. These polydopamine microspheres adhered to HF will be a photothermal marine U(VI) harvesting material with enhanced selectivity and fouling resistance.

Microplastic particles alter wheat rhizosphere soil microbial community composition and function.

The wide existence of microplastics (MPs) in the terrestrial systems is proved by -many studies, and their presence could potentially change the soil chem-physical properties and processes. Various types of microplastics may have different behaviors, inducing distinct effects on the soil ecosystems. However, the knowledge of microplastic impacts on rhizosphere soil bacterial community structure is limited. In our study, three types of microplastics, i.e., polyethylene (PE), polyvinylchloride (PVC) and polystyrene (PS), with the same particle size (200 µm) and concentration (2%) were used to investigate their influences on the rhizosphere soil bacterial communities. Results revealed that the alpha diversities (richness, evenness and diversity) of microbiota in the rhizosphere soil were variously decreased by the microplastics, especially the PE MPs. The relative abundance of some various phyla and genera related to pollution degradation was miscellaneously increased, indicating that the MPs with different characterizations may have miscellaneous biodegradation pathways. Moreover, the PICRUSt2 analysis demonstrated that PS decreased most functional category levels and led to a decrease of bacterial genus number, however, PE and PVC improved metabolic pathways and xenobiotics biodegradation and metabolism. Our findings offer important knowledge of how the microplastics with different characterizations influence rhizosphere soil bacterial communities and their related function.

Constructing an Amino-reinforced amidoxime swelling layer on a Polyacrylonitrile surface for enhanced uranium adsorption from seawater.

Polyacrylonitrile (PAN)-based materials have been studied for decades as uranium (U(VI)) adsorbents, because the further products of abundant nitrile groups, amidoxime (AO) groups, show great affinity for U(VI) ions. However, excessive amidoximation could cause the shrinkage of PAN fibers, resulting in decreased adsorption performance. Hence, an amino-reinforced amidoxime (ARAO) swelling layer was constructed on the PAN fiber surface (PAN-NH2-AO) by modification of the strongly hydrophilic amino group to prevent shrinkage. The molecular chains in the ARAO swelling layer would be swelled due to the adsorption of a large amount of water. Simultaneously, U(Ⅵ) ions can penetrate into the ARAO swelling layer with water molecules and coordinate with amino or AO groups, leading to increased adsorption performance. PAN-NH2-AO exhibited maximum U(VI) and water adsorption capacities of 492.61 mg g-1 and 20.32 g g-1 at 25 â„ƒ with a swelling ratio of 20.73%, respectively. The adsorption capacity of PAN-NH2-AO was 0.312 mg g-1 after a 91-day immersion in Yellow Sea, China. The study of the adsorption thermodynamics and kinetics of PAN-NH2-AO showed that the adsorption process was spontaneous homogeneous chemical adsorption. This paper proposes a novel method to obstruct amidoximation induced shrinkage and to maximize the potential application of PAN-based materials.

The joint toxicity of polyethylene microplastic and phenanthrene to wheat seedlings.

Due to wide distribution, easy production, and difficult degradation, microplastic pollution has become a new environmental problem that has attracted worldwide attention. However, there is little information about the effects of microplastics in soil and their combined pollution with other organic pollutants on crop growth. In this study, we conducted soil culture experiments to evaluate the effects of polyethylene microplastics (PE-MPs) (0.5%, 1%, 2%, 5%, 8% w/w) individual and combined with phenanthrene (100 mg kg-1) on wheat growth for 15 days. Under PE-MPs alone and combined with phenanthrene exposure, dose-dependent toxicities in biomass, shoot height and root length were observed. Over 1% PE-MPs stimulate wheat root elongation. Compared with single phenanthrene treatment, the co-contamination of PE-MPs and phenanthrene reduces the accumulation of phenanthrene in wheat roots and leaves. In the range of 0-5%, the activity of wheat root antioxidant enzymes increases with increasing PE-MP concentration; but both phenanthrene and high concentrations (8%) of PE-MPs cause damage to the antioxidant system in wheat roots. In the presence or absence of phenanthrene, the photosynthetic pigment concentration of wheat leaves shows a dual concentration effect of low promotion and high inhibition under PE-MPs stress. The single pollution of PE-MPs destroys the photosynthetic system of wheat leaves, while the co-contamination of PE-MPs and phenanthrene exacerbates this destruction. Therefore, the co-contamination of PE-MPs and phenanthrene causes greater damage to wheat growth. Our findings can help to evaluate the individual and comprehensive toxicity of microplastics and polycyclic aromatic hydrocarbons to crops.

Changes in epidemiological features of vaccine preventable infectious diseases among three eras of national vaccination strategies from 1953 to 2018 in Shanghai, China.

BACKGROUND: Recurring outbreaks of infectious diseases highlight the importance of population vaccination strategies. We aimed to assess the impact of national vaccination strategies on vaccine-preventable infectious diseases (VPDs) in Shanghai, China and to identify vulnerable groups that may benefit from future vaccination policies. METHODS: Infectious disease data from 1953 to 2018 was obtained from Xuhui District Center for Disease Control and Prevention, Shanghai China. We used joinpoint regression to show incidence, mortality and fatality trends and to determine annual percent change in incidence of 12 VPDs among three eras of national immunization strategies: (1)1953-1977, (2)1978-2007, and(3)2008-2018. FINDINGS: Incidence, mortality, and fatality from VPDs have decreased drastically over the three eras, despite the inclusion of more diseases over time. Strikingly, the overall yearly incidence of VPDs shows an increasing trend from 2000 to 2018 in Shanghai (annual percentage changes, APC:7.7, p = 0.025). In the third era (2008-2018), the three VPDs with the highest incidence were varicella (80.2 cases/100,000), hand, foot, and mouth disease (HFMD) (73.6 cases/100,000), and hepatitis (43.5 cases/100,000). A significant upward trend was also observed in hepatitis (APC:24.9, p<0.001), varicella (APC:5.9, p = 0.006), and HFMD (APC:11.8, p = 0.003) from 2008-2018. Hepatitis and tuberculosis are the only VPDs with fatality cases in this period. INTERPRETATION: Focus is needed in controlling adult hepatitis and tuberculosis, either by introducing adult booster vaccines or by research into more effective vaccines. Varicella and HFMD are on the rise, but vaccines for these are not included in national programs. Strategies funded by government agencies or encouraged by research incentives are needed for varicella and HFMD, such as two-dose and novel multi-valent vaccines, respectively. FUNDING: Chinese Ministry of Education, Shanghai Municipal Government.

Efficacy of Traditional Chinese Medicine, Maxingshigan-Weijing in the management of COVID-19 patients with severe acute respiratory syndrome: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We aimed to test our expectation that additional administration of Traditional Chinese medicine (TCM), maxingshigan-weijing decoction, is more effective in the management of COVID-19 patients compared to those treated with routine supportive care alone. TRIAL DESIGN: This is a multicenter, open-label 2-arm (1:1 ratio) randomized controlled trial. PARTICIPANTS: Patients will be recruited from 3 hospitals in Wenzhou China: the First Affiliated Hospital of Wenzhou Medical University, the Second Affiliated Hospital of Wenzhou Medical University and Wenzhou Center Hospital. The inclusion and exclusion criteria are as follows: Inclusion criteria 1. Participants are 18-85 years of age, either male or female. 2. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3. Symptomatic. Mild (mild clinical symptoms without signs of pneumonia in chest X-ray) and Moderate (fever or respiratory symptom with signs of pneumonia in chest X-ray) . 1. Signed the informed consent before treatment. 2. Agreed not to enroll in any other clinical trials. 3. Inpatients Exclusion criteria 1. < 18 or > 85 years old. 2. Pregnancy and lactation. 3. Serious heart, liver, kidney and hematopoietic system diseases, abnormal liver or kidney function. 4. Suffering from other known virus pneumonia. 5. Allergic to Chinese herbal medicine or suffering from allergies. 6. Critical patients (respiratory failure treated by mechanical ventilation or shock or multiple organ failure). INTERVENTION AND COMPARATOR: Patients in the control group will receive routine supportive clinically care including the therapies of anti-viral, anti-bacterial and ameliorating the related symptoms, while patients in TCM group will be asked to take maxingshigan-weijing decoction (composed of 14 Chinese herbal medicines), orally 200 mL 2 times daily, for 14 consecutive days in addition to routine supportive care as mentioned above. Maxingshigan-weijing decoction consists of 10 g of Herba Ephedra (Mahuang), 10 g of Amygdalus Communis Vas (Xingren), 45 g of Gypsum Fibrosum (Shigao), 30 g of Rhizoma phragmitis (Lugen), 20 g of Peach kernel (Taoren), 20 g of Winter Melon kernel (Dongguaren), 30 g of Trichosanthes Kirilowii Maxim (Gualou), 12 g of Pericarpium Citri Reticulatae (Chenpi), 12 g of Rhizoma Pinelliae (Jiangbanxia), 12 g of caulis bambusae in taeniis (Zhuru), 30 g of semen lepidii (Tingliz), 15 g of semen lepidii (Shichangpu), 10 g of curcuma zedoary (ezhu) and 5 g of Radix Glycyrrhizae (Gancao). MAIN OUTCOMES: The primary outcome will be the number of days until the clinical symptom of fever improves in the first 14 days of treatment following randomisation. Fever will be defined as an improvement when the temperature is less than 37°C. Secondary outcomes will be TCM Syndrome Scores, the time it takes until individuals have negative test results for SARS-CoV-2 nucleic acid, the proportion of cases with chest X-ray improvements and the rate of symptom (fever, cough, malaise, shortness of breath) recovery. TCM Syndrome Scoring System is a checklist covering 4 main, 7 secondary and 13 accompanying items. The 4 main items consisting of fever, cough, malaise and shortness of breath, use a four-point scale (0, 2, 4 and 6) depending on the severity; the 7 secondary items including dysphoria, diarrhea, pharyngalgia, expectoration, muscular soreness, nasal obstruction and rhinorrhoea use 0-3-point scale; the 13 accompanying items contain chest pain, headache, aversion to cold, dizziness, nausea and vomiting, anorexia, abdominal distension, dry mouth, anxiety, spontaneous sweating, insomnia, wheezing and blood tinged sputum, and each item is rated on 0-1 scale ( 0 stands for asymptomatic, 1 stands for symptomatic ). The total scores sum up to a range from 0 to 58, with higher scores indicating more severe levels of disease. RANDOMIZATION: Minimization method will be used, balancing the two arms for pneumonia severity. Patients are randomized (1:1 ratio) to each group. Clinical researchers will get a random sequence number which is automatically generated by a random number generator (IBM Corp., Armonk, NY, USA), and sequentially number them in an opaque envelope. Researchers will open random allocation envelopes and assign participants accordingly. Eligible patients will be randomly divided into a routine supportive care group and a routine supportive care plus oral administration of traditional Chinese medicine group, with 70 patients in each group. BLINDING (MASKING): This is an open-label study. The statistical analysis will be carried out by the Professor of Statistics at Wenzhou Medical University, who is blinded to patient allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The previous study reported the efficacy of TCM for COVID-19 and H1N1 influenza patients, the median survival time in the TCM group is estimated as 3 days; this time will be 1.5 times longer in the control group. Accordingly, Kaplan-Meier method and log-rank test will be used. And assuming a statistical power of 70% (one-sided type-1 error of α = 5%, ß = 30%) and a rate of withdrawal and loss to follow-up of 10%, we plan to include 140 participants in both groups ( TCM group = 70, control group = 70). TRIAL STATUS: The trial protocol is Version 2.0, October 14, 2020. Recruitment began March, 2020, and is anticipated to be completed by December 31, 2020. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000030759 . Registered on 13 March 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.