A thermoresponsive nanocomposite integrates NIR-II-absorbing small molecule with lonidamine for pyroptosis-promoted synergistic immunotherapy.

Photothermal immunotherapy is regarded as the ideal cancer therapeutic modality to against malignant solid tumors; however, its therapeutic benefits are often modest and require improvement. In this study, a thermoresponsive nanoparticle (BTN@LND) composed of a photothermal agent (PTA) and pyroptosis inducer (lonidamine) were developed to enhance immunotherapy applications. Specifically, our "two-step" donor engineering strategy produced the strong NIR-II-absorbing organic small-molecule PTA (BTN) that exhibited high NIR-II photothermal performance (ε1064 = 1.51 × 104 M-1 cm-1, η = 75.8%), and this facilitates the diagnosis and treatment of deep tumor tissue. Moreover, the fabricated thermally responsive lipid nanoplatform based on BTN efficiently delivered lonidamine to the tumor site and achieved spatiotemporal release triggered by the NIR-II photothermal effect. In vitro and in vivo experiments demonstrated that the NIR-II photothermal therapy (PTT)-mediated on-demand release of cargo effectively faciliated tumor cell pyroptosis, thereby intensifying the immunogenic cell death (ICD) process to promote antitumor immunotherapy. As a result, this intelligent component bearing photothermal and chemotherapy can maximally suppress the growth of tumors, thus providing a promising approach for pyroptosis/NIR-II PTT synergistic therapy against tumors.

Characterization of viscoelastic behavior of basalt fiber asphalt mixtures based on discrete and continuous spectrum models.

In order to analyze the differences between the master curves of relaxation modulus E(t) and creep compliance J(t) obtained from discrete and continuous spectrum models, and to comprehensively evaluate the effect of basalt fiber content on the viscoelastic behavior of asphalt mixtures, complex modulus tests were conducted for asphalt mixtures with fiber content of 0%, 0.1%, 0.2% and 0.3%, respectively. Consequently, the master curves of Viscoelastic Parameters of asphalt mixtures were constructed according to the generalized Sigmoidal model(GSM) and the approximate Kramers-Kronig (K-K) relationship. Then, transformation of master curves using discrete and continuous spectrum models to obtain the models of E(t) and J(t) containing all viscoelastic information. Also, the accuracy of the models of E(t) and J(t) was evaluated. The results show that the addition of basalt fibers improves the strength, stress relaxation and deformation resistance of asphalt mixtures. It is worth noting that basalt fibers achieve the improvement of asphalt mixtures by changing their internal structure. Considering the different viscoelastic master curves at four dosages, the optimum fiber dosage was 0.2%. In addition, both discrete and continuous model conversion methods can obtain high accuracy conversion results.

Phenylboronic Acid-Modified Near-Infrared Region II Excitation Donor-Acceptor-Donor Molecule for 2-Deoxy-d-Glucose Improved Starvation/Chemo/Photothermal Combination Therapy.

Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side effects. However, the chemo/PTT combination therapy suffers from limited penetration depth, thermoresistance performance of tumor cells, and low drug bioavailability. Herein, multifunctional nanoparticles (BTP/DOX/2DG NPs) coloaded with near-infrared region II (NIR-II) light excitation donor-acceptor-donor (D-A-D) small molecules, doxorubicin (DOX), and 2-deoxy-d-glucose (2-DG) are developed for reinforced starvation/chemo/NIR-II PTT combination therapy. The synthesized phenylboronic acid (PBA)-modified water-soluble D-A-D molecule (BBT-TF-PBA) not only exhibits high binding ability to DOX and 2-DG through donor-acceptor coordination interactions PBA-diol bonds but also serves as a photoactive agent for NIR-II fluorescence imaging, NIR-II photoacoustic imaging, and NIR-II PTT. Under the acidic and oxidizing conditions in the tumor microenvironment, donor-acceptor coordination interactions and PBA-diol bond are decomposed, simultaneously releasing DOX and 2-DG from BTP/DOX/2DG NPs to achieve effective chemotherapy and starvation therapy. 2-DG also effectively inhibits the expression of heat shock protein and further enhances NIR-II PTT and chemotherapy efficiency. In vitro and in vivo experiments demonstrate the combination effect of BTP/DOX/2DG NPs for chemotherapy, NIR-II PTT, and starvation therapy.

Caffeic acid phenethyl ester loaded in a targeted delivery system based on a solid-in-oil-in-water multilayer emulsion: Characterization, stability, and fate of the emulsion during in vivo digestion.

Many studies have shown that caffeic acid phenethyl ester (CAPE) has various functions, such as antioxidant, anti-inflammatory and anticancer activity, but its low bioavailability and stability limit its application. In this study, the colorectal targeted delivery system for CAPE based on a solid-in-oil-in-water (S/O/W) multilayer emulsion was prepared using CAPE-loaded nanoparticles as the solid phase, coconut oil as the oil phase, and a mixture of lecithin and sodium caseinate as the aqueous phase. The stability of the O/W interfacial layer was improved by using a sodium casein-lecithin mixture as the aqueous surface layer in the preparation. This S/O/W emulsion is a spherical droplet with an S/O/W trilayer structure with a particle size of 155.5 ± 0.72 nm and a polydispersity index (PDI) of 0.24 ± 0.01. The Fourier transform infrared (FTIR) results confirmed that CAPE was successfully loaded into the S/O/W emulsion. This S/O/W emulsion was able to maintain a stable liquid state at pH 6.00-7.4 or cholate concentration of 0-50 mg/mL but showed a gel state at pH 2.0-3.0. The storage experiments demonstrated that the S/O/W emulsion was stable for 15 days at 4 °C, but was prone to agglomeration and emulsion breakage at 25 °C. The in vivo digestion process indicated that the S/O/W emulsion was gradually digested in the digestive tract and released solid phase nanoparticles in the large intestine. Therefore, this newly developed targeted delivery system can effectively deliver CAPE to the colorectum and achieve a 12-hour delayed release, which improved the bioavailability and activity of CAPE.

Microbial mechanism of biochar addition on nitrogen leaching and retention in tea soils from different plantation ages.

The effect of biochar additions on N leaching and retention in tea soils and its microbial mechanism are still unclear. In this study, effects of biochar additions at rates of 0, 3% and 6% on N leaching, N retention and microbial responses in two tea soils with 20- and 60-year plantation ages were investigated under application with 15N-labeled urea. The results showed that cumulative mass of leached NH4+-N, NO3--N and TN was reduced by 20.9%-91.9%, 35.1%-66.9% and 40.0%-72.8% under biochar additions, respectively. The retention of TN in soil was increased by 1.2%-5.8% under biochar amendment. Fertilizer-N in the leachate was reduced by 28.8%-62.1%, while fertilizer-N retention in the soils was enhanced by 3.2%-23.9% with biochar application. Biochar addition of 6% showed the highest mitigation of N leaching and enhancement of TN retention across the two soils. Biochar additions increased soil microbial biomass and enzyme activities and changed the bacterial community composition, indicating that biochar addition increased the microbial N requirement, stimulated soil N cycling, including nitrification and denitrification processes, and enhanced microbial N immobilization in the tea soils. Those microbial responses to biochar addition were higher in 60-year-old soil relative to 20-year-old soil, leading to a higher enhancement of N retention and mitigation of N leaching. Soil pH was the prime factor that influenced soil microbes, and it strongly correlated with microbial biomass, enzyme activity, the relative abundance of dominant phyla and α-diversity indices. Therefore, the enhancement of microbial biomass, activity and shifts of bacterial community composition related to N cycling in response to biochar additions that increased the soil pH could be an important mechanism to better understand the biochar-induced N leaching mitigation and N retention enhancement in tea soils under different plantation ages.

Smart Nanosacrificial Layer on the Bone Surface Prevents Osteoporosis through Acid-Base Neutralization Regulated Biocascade Effects.

Osteoporosis is a global chronic disease characterized by severe bone loss and high susceptibility to fragile fracture. It is widely accepted that the origin acidified microenvironment created by excessive osteoclasts causes irreversible bone mineral dissolution and organic degradation during osteoclastic resorption. However, current clinically available approaches are mainly developed from the perspective of osteoclast biology rather than the critical acidified niche. Here, we developed a smart "nanosacrificial layer" consisting of sodium bicarbonate (NaHCO3)-containing and tetracycline-functionalized nanoliposomes (NaHCO3-TNLs) that can target bone surfaces and respond to external secreted acidification from osteoclasts, preventing osteoporosis. In vitro and in vivo results prove that this nanosacrificial layer precisely inhibits the initial acidification of osteoclasts and initiates a chemically regulated biocascade to remodel the bone microenvironment and realize bone protection: extracellular acid-base neutralization first inhibits osteoclast function and also promotes its apoptosis, in which the apoptosis-derived extracellular vesicles containing RANK (receptor activator of nuclear factor-κ B) further consume RANKL (RANK ligand) in serum, achieving comprehensive osteoclast inhibition. Our therapeutic strategy for osteoporosis is based on original and precise acid-base neutralization, aiming to reestablish bone homeostasis by using a smart nanosacrificial layer that is able to induce chemically regulated biocascade effects. This study also provides a novel understanding of osteoporosis therapy in biomedicine and clinical treatments.

A Retrospective Study of Gemcitabine and Carboplatin With or Without Intravenous Vitamin C on Patients With Advanced Triple-Negative Breast Cancer.

Background: This is a retrospective study to examine the effect of chemotherapy with or without intravenous vitamin C (IVC) on women with advanced triple-negative breast cancer (TNBC). Methods: From 2008 to 2016, a total of 113 patients with pathologically confirmed TNBC at Clifford Hospital were evaluated, and 70 patients were matched and divided into IVC (treatment group) and non-IVC groups (control group). The match was according to age, menopausal status, and metastatic sites. In the control group, 35 patients received gemcitabine and carboplatin. In the treatment group, 35 patients received the same chemotherapy plus IVC. Results: Baseline characteristics were not significantly different between the 2 groups. According to the criteria of RECIST 1.1 (Response Evaluation Criteria in Solid Tumors), enhanced computed tomography scan was compared after 2 cycles of chemotherapy. In the treatment group, 2/35 cases had a complete remission (CR), 15/35 cases had partial remission (PR), and 13/35 cases had stable disease (SD). The response rate was 48.6%. In the control group, there were no CR cases, 14/35 cases had PR, 14/35 cases had SD, and the response rate was 40.0% (P > .05). The median progression-free survival time and median overall survival time was 7 months (95% confidence interval [CI] =1.5-28.5 months) and 27 months (95% CI = 4-40 months) in the treatment group compared with 4.5 months (95% CI = 1.5-8 months) and 18 months (95% CI = 3-26 months) in the control group (P < .05). All patients experienced diverse reactions in the gastrointestinal tract and myelosuppression. The incidence of adverse reactions in the treatment group was significantly lower than that of the control group (P < .05). Conclusion: IVC may have an effect on improving the prognosis of patients with advanced TNBC.

Facile construction of reduced graphene oxide supported three-dimensional polyaniline/WO2.72 nanobelt-flower as a full solar spectrum light response catalyst for efficient photocatalytic conversion of bromate.

As a carcinogenic byproduct in drinking water treatment, bromate has raised global concerns on environmental and health hazard, calling for effective treatments. In the current work, a novel reduced graphene oxide supported polyaniline/WO2.72 nanobelt-flower (RGO/PANI/WO2.72) ternary composite was prepared through a solvent volatilization method for photocatalytic reduction of bromate. The prepared sample was characterized, and the influence of aqueous pH, ions and dissolved oxygen on the bromate reduction was explored. As expected, the introduction of RGO and PANI on the WO2.72 exhibited great synergistic effects on the separation of photogenerated carriers. The calculated reduction rate constant of RGO/PANI/WO2.72 was about six times as high as that of pure WO2.72. Specially, the prepared photocatalyst possessed strong optical absorption in a broad range of 250-2500 nm, and thus displaying excellent catalytic performance in utilization of all solar spectrum energy. Moreover, the RGO/PANI/WO2.72 exhibited stable photocatalytic activity in cycling test. Considered holistically, the present study offered a valuable approach for rational construction of heterogeneous structure in the development of bromate-catalyzed reduction.

Sensitive analysis of curcuminoids via micellar electrokinetic chromatography with laser-induced native fluorescence detection and mixed micelles-induced fluorescence synergism.

Curcuminoids, the major bioactive constituents of traditional medicine known as turmeric, have exhibited extensive therapeutic benefits. Excited by violet-blue light, curcuminoids can emit native fluorescence, making them possible to be detected with high sensitivity and specificity by laser-induced native fluorescence (LINF). Here, a commercial 445 nm laser diode was used as an excitation source to construct a confocal laser-induced fluorescence (LIF) detector and then a complete capillary electrophoresis (CE) system coupled with LIF detection was established. With three major curcuminoids, curcumin, demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC) as target analytes, a micellar electrokinetic chromatography (MEKC) method was proposed using mixed micelles consisting of Triton X-100 and SDS to sensitize the native fluorescence of curcuminoids and enhance their separation efficiency. Fluorescence spectra revealed that the mixed micelles induced fluorescence synergism could enhance the signals of three curcuminoids by 77-, 57-, and 47-fold for curcumin, DMC, and BDMC. After systematic investigation, the optimal separation buffer for curcuminoids was chosen as follows: 20 mM Triton X-100, 20 mM SDS, 30% (v/v) methanol in 10 mM borax solution at pH 10.0. Under these conditions, a baseline separation of three curcuminoids was achieved within 10 min and the detection limits were found to be 4.1, 2.6, and 0.4 ng/mL for curcumin, DMC, and BDMC, respectively. Furthermore, the developed MEKC-LINF method was validated in terms of precision, linearity, accuracy and successfully applied for the determination of three curcuminoids in turmeric, medicinal turmeric liniment, curry seasoning, and human urine samples.

Upregulation of IL-6 is involved in moderate hyperthermia induced proliferation and invasion of hepatocellular carcinoma cells.

Increasing evidences suggested that insufficient radiofrequency ablation (RFA) can paradoxically promote tumor invasion and metastatic processes, while the effects of moderate hyperthermia on cancer progression are not well illustrated. Our present study confirmed moderate hyperthermia treatment can promote the proliferation, migration and invasion of hepatocellular carcinoma (HCC) cells, which was evidenced by the results that moderate hyperthermia induced up regulation of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2). Cellular studies indicated that moderate hyperthermia treatment can increase the mRNA and protein expression of IL-6 and IL-10, while not IL-2, IL-4, IL-8, IL-22, VEGF, TGF-ß, or TNF-α, in HCC cells. Silencing of IL-6, while not IL-10, attenuated moderate hyperthermia treatment induced proliferation and cell invasion. Furthermore, our data revealed the inhibition of NF-κB, while not ERK1/2 or PI3K/Akt, abolished moderate hyperthermia treatment induced production of IL-6. Collectively, our data showed that activation of NF-κB/IL-6 is involved in moderate hyperthermia treatment induced progression of HCC cells.

The antitumor effect of arsenic trioxide on hepatocellular carcinoma is enhanced by andrographolide.

High concentrations of arsenic trioxide (As2O3) are used to treat acute promyelocytic leukemia and solid tumors, with negative side effects to normal cells. Andrographolide is a traditional Chinese medicine that exerts anti-cancer, anti-inflammatory, anti-virus, and anti-diabetic effects. Here, we tested the effects of combined andrographolide with As2O3 against hepatocellular carcinoma (HCC). We found that by increasing apoptosis, andrographolide synergistically enhanced the anti-tumor effects of As2O3 in HepG2 cells in vitro and in vivo. Furthermore, results from our microarray assays and experiments with mouse xenografts showed that EphB4 was downregulated by the combination of As2O3 plus andrographolide. These findings suggest that the combination of andrographolide and As2O3 could yield therapeutic benefits in the treatment of HCC.

Efficacy and safety of probiotic-supplemented triple therapy for eradication of Helicobacter pylori in children: a systematic review and network meta-analysis.

AIM: The aim of this study was to identify the best probiotic supplementation in triple therapy for pediatric population with Helicobacter pylori infection. METHODS: Eligible trials were identified by comprehensive searches. Relative risks with 95% confidence intervals and relative ranks with P scores were assessed. RESULTS: Twenty-nine trials (3122 participants) involving 17 probiotic regimens were identified. Compared with placebo, probiotic-supplemented triple therapy significantly increased H. pylori eradication rates (relative ratio (RR) 1.19, 95% CI 1.13-1.25) and reduced the incidence of total side effects (RR 0.49, 95% CI 0.38-0.65). Furthermore, to supplemented triple therapy, Lactobacillus casei was identified the best for H. pylori eradication rates (P score = 0.84), and multi-strain of Lactobacillus acidophilus and Lactobacillus rhamnosus for total side effects (P score = 0.93). As for the subtypes of side effects, multi-strain of Bifidobacterium infantis, Bifidobacterium longum, L. acidophilus, L. casei, Lactobacillus plantarum, Lactobacillus reuteri, L. rhamnosus, Lactobacillus salivarius, Lactobacillus sporogenes, and Streptococcus thermophilus was the best to reduce the incidence of diarrhea; multi-strain of Bacillus mesentericus, Clostridium butyricum, and Streptococcus faecalis for loss of appetite; multi-strain of B. longum, Lactobacillus bulgaricus, and S. thermophilus for constipation; multi-strain of Bifidobacterium bifidum, B. infantis, L. acidophilus, L. bulgaricus, L. casei, L. reuteri, and Streptococcus for taste disturbance; Saccharomyces boulardii for bloating; and multi-strain of Bifidobacterium breve, B. infantis, L. acidophilus, L. bulgaricus, L. casei, L. rhamnosus, and S. thermophilus for nausea/vomiting. CONCLUSIONS: Probiotics are recommended to supplement triple therapy in pediatrics, and the effectiveness of triple therapy is associated with specific probiotic supplementation.

Local modulated electro-hyperthermia in combination with traditional Chinese medicine vs. intraperitoneal chemoinfusion for the treatment of peritoneal carcinomatosis with malignant ascites: A phase II randomized trial.

The purpose of this study was to develop a safe and non-toxic alternative to the conventional conservative treatment of peritoneal carcinomatosis with malignant ascites (PCMA) by investigating the efficacy and safety of local modulated electro-hyperthermia (mEHT) combined with the traditional Chinese medicine (TCM) 'Shi Pi' herbal decoction, compared with standard intraperitoneal chemoinfusion (IPCI). A randomized, controlled, single-center, open-label clinical trial (phase II) with two parallel groups (allocation ratio, 1:1) was conducted to investigate the efficacy and safety of mEHT+TCM (study group, SG) vs. standard IPCI (control group, CG) in patients with PCMA by intention-to-treat analysis. A total of 260 patients with PCMA were randomly allocated into the two groups (130/130); mEHT was applied for 60 min per session every second day for 4 weeks, for a total of 14 sessions. The TCM decoction was administered orally, at 400 ml daily. In CG, occlusive IPCI with cisplatin (30-60 mg) and fluorouracil (500-600 mg/m2) was applied twice, biweekly. The objective response rate (ORR), quality of life (QoL) and adverse event rate (AER) in the two groups were evaluated 1 month after treatment, analyzed and compared. The present study is registered on ClinicalTrials.gov (NCT02638051). No case was lost or excluded (0/260). The ORR in SG was 77.69% (101/130) vs. 63.85% (73/130) in CG (P<0.05). The QoL in SG was 49.23% vs. 32.3% in CG (P<0.05). The AER in SG was 2.3% (3/130) vs. 12.3% (16/130) in CG (P<0.05). All the adverse events were grade I. In conclusion, the combination of mEHT with TCM achieves better control of PCMA compared with standard IPCI, with less toxicity. Both components of the combination are non-toxic treatments easily tolerated by patients. Thus, this combined treatment may be preferred due to the better benefit-harm balance.

Intra-articular delivery of sinomenium encapsulated by chitosan microspheres and photo-crosslinked GelMA hydrogel ameliorates osteoarthritis by effectively regulating autophagy.

Reduced expression of autophagy regulators has been observed in pathological cartilage in humans and mice. The present study aimed to investigate the synergistic therapeutic effect of promotion of chondrocyte autophagy via exposure to sinomenium (SIN) encapsulated by chitosan microspheres (CM-SIN) and photo-crosslinked gelatin methacrylate (GelMA) hydrogel, with the goal of evaluating CM-SIN as a treatment for patients with osteoarthritis. First, we fabricated and characterized GelMA hydrogels and chitosan microspheres. Next, we measured the effect of SIN on cartilage matrix degradation induced by IL1-ß in chondrocytes and an ex vivo model. SIN ameliorated the pathological changes induced by IL1-ß at least partially through activation of autophagy. Moreover, we surgically induced osteoarthritis in mice, which were injected intra-articularly with CM-SIN and GelMA. Cartilage matrix degradation and chondrocyte autophagy were evaluated 4 and 8 weeks after surgery. Treatment with the combination of CM-SIN and GelMA retarded the progression of surgically induced OA. SIN ameliorated cartilage matrix degradation at least partially by inducing autophagy in vivo. Our results demonstrate that injection of the combination of GelMA hydrogel and CM-SIN could be a promising strategy for treating patients with osteoarthritis.

[Real-time analysis of soil N and P with near infrared diffuse reflectance spectroscopy].

Improving the efficiency of fertilization is an effective method of enhancing income for farmers, but it depends on measuring the soil nutrients accurately and rapidly. Near infrared reflectance spectroscopy (NIRS) is a fast method to detect the soil nutrients. In order to evaluate the feasibility of using NIRS to determine the soil N and P contents, the soil samples were collected from different LULC (land use and land cover) types in Daxing district, Beijing, and their biochemical parameters were determined by traditional chemical method. Then, the near infrared reflectance spectra of the samples were acquired, and NIRS models were built using partial least square regression (PLS) and Fourier transform technology for the total N and total P. The determination coefficients of cross validation for the total N and total P were 0.862 6 and 0.668 5 respectively. Ten samples were used to test the performance of the models. The coefficients of correlation between the chemically determined value and the NIRS predicted one were 0.969 8(N) and 0.830 7(P) respectively. The root mean standard error of prediction for N and P were 0.009 5(%) and 0.008 6(%), respectively. The ratios of RMSEP to SD(RPD) were 3.78(N) and 1.69(P). The results showed that the NIRS could be used to evaluate the soil N accurately and the soil P roughly.