Loosely-packed dynamical structures with partially-melted surface being the key for thermophilic argonaute proteins achieving high DNA-cleavage activity.

Prokaryotic Argonaute proteins (pAgos) widely participate in hosts to defend against the invasion of nucleic acids. Compared with the CRISPR-Cas system, which requires a specific motif on the target and can only use RNA as guide, pAgos exhibit precise endonuclease activity on any arbitrary target sequence and can use both RNA and DNA as guide, thus rendering great potential for genome editing applications. Hitherto, most in-depth studies on the structure-function relationship of pAgos were conducted on thermophilic ones, functioning at ∼60 to 100°C, whose structures were, however, determined experimentally at much lower temperatures (20-33°C). It remains unclear whether these low-temperature structures can represent the true conformations of the thermophilic pAgos under their physiological conditions. The present work studied three pAgos, PfAgo, TtAgo and CbAgo, whose physiological temperatures differ significantly (95, 75 and 37°C). By conducting thorough experimental and simulation studies, we found that thermophilic pAgos (PfAgo and TtAgo) adopt a loosely-packed structure with a partially-melted surface at the physiological temperatures, largely different from the compact crystalline structures determined at moderate temperatures. In contrast, the mesophilic pAgo (CbAgo) assumes a compact crystalline structure at its optimal function temperature. Such a partially-disrupted structure endows thermophilic pAgos with great flexibility both globally and locally at the catalytic sites, which is crucial for them to achieve high DNA-cleavage activity. To further prove this, we incubated thermophilic pAgos with urea to purposely disrupt their structures, and the resulting cleavage activity was significantly enhanced below the physiological temperature, even at human body temperature. Further testing of many thermophilic Agos present in various thermophilic prokaryotes demonstrated that their structures are generally disrupted under physiological conditions. Therefore, our findings suggest that the highly dynamical structure with a partially-melted surface, distinct from the low-temperature crystalline structure, could be a general strategy assumed by thermophilic pAgos to achieve the high DNA-cleavage activity.

Effects of guanidinoacetic acid supplementation on lactation performance, nutrient digestion and rumen fermentation in Holstein dairy cows.

BACKGROUND: Considering the high energy demand of lactation and the potential of guanidinoacetic acid (GAA) addition on the increase in creatine supply for cows, the present study investigated the effects of 0, 0.3, 0.6 and 0.9 g kg-1 dry matter (DM) of GAA supplementation on lactation performance, nutrient digestion and ruminal fermentation in dairy cows. The study used 40 mid-lactation multiparous Holstein cows and the study duration was 100 days. RESULTS: DM intake was not affected, but milk and milk component yields and feed efficiency increased linearly with increasing GAA addition. The total-tract digestibility of DM, organic matter, neutral detergent fibre, acid detergent fibre and non-fibre carbohydrates increased linearly and that of crude protein increased quadratically with increasing GAA addition. When the addition level of GAA increased, ruminal pH, molar percentages of butyrate, isobutyrate and isovalerate and the acetate-to-propionate ratio decreased linearly, and the total volatile fatty acids concentration and propionate molar percentage also increased linearly, whereas the acetate molar percentage and ammonia-N concentration were unaltered. The activities of fibrolytic enzymes, α-amylase and protease increased linearly. The populations of total bacteria, fungi, Ruminococcus albus, Fibrobacter succinogenes, Ruminococcus flavefaciens, Ruminobacter amylophilus and Prevotella ruminicola increased linearly, whereas protozoa and methanogens decreased linearly with increasing GAA addition. As for the blood metabolites, concentrations of glucose, urea nitrogen and methionine were unchanged, total protein, albumin, creatine and homocysteine increased linearly, and folate decreased linearly with increasing GAA supply. CONCLUSION: The results of the present study indicate that supplementation of GAA improved milk performance and rumen fermentation in lactating dairy cows. © 2022 Society of Chemical Industry.

Effects of folic acid and cobalt sulphate supplementation on growth performance, nutrient digestion, rumen fermentation and blood metabolites in Holstein calves.

To investigate the influences of cobalt (Co) and folic acid (FA) on growth performance and rumen fermentation, Holstein male calves (n 40) were randomly assigned to four groups according to their body weights. Cobalt sulphate at 0 or 0·11 mg Co/kg DM and FA at 0 or 7·2 mg/kg DM were used in a 2 × 2 factorial design. Average daily gain was elevated with FA or Co supplementation, but the elevation was greater for supplementing Co in diets without FA than with FA. Supplementing FA or Co increased DM intake and total-tract nutrient digestibility. Rumen pH was unaltered with FA but reduced with Co supplementation. Concentration of rumen total volatile fatty acids was elevated with FA or Co inclusion. Acetate percentage and acetate to propionate ratio were elevated with FA inclusion. Supplementing Co decreased acetate percentage and increased propionate percentage. Activities of xylanase and α-amylase and populations of total bacteria, fungi, protozoa, Ruminococcus albus, Fibrobacter succinogenes and Prevotella ruminicola increased with FA or Co inclusion. Activities of carboxymethyl-cellulase and pectinase increased with FA inclusion and population of methanogens decreased with Co addition. Blood folates increased and homocysteine decreased with FA inclusion. Blood glucose and vitamin B12 increased with Co addition. The data suggested that supplementing 0·11 mg Co/kg DM in diets containing 0·09 mg Co/kg DM increased growth performance and nutrient digestibility but had no improvement on the effects of FA addition in calves.

Using machine-learning algorithms to identify patients at high risk of upper gastrointestinal lesions for endoscopy.

BACKGROUND AND AIM: Endoscopic screening for early detection of upper gastrointestinal (UGI) lesions is important. However, population-based endoscopic screening is difficult to implement in populous countries. By identifying high-risk individuals from the general population, the screening targets can be narrowed to individuals who are in most need of an endoscopy. This study was designed to develop an artificial intelligence (AI)-based model to predict patient risk of UGI lesions to identify high-risk individuals for endoscopy. METHODS: A total of 620 patients (from 5300 participants) were equally allocated into 10 parts for 10-fold cross validation experiments. The machine-learning predictive models for UGI lesion risk were constructed using random forest, logistic regression, decision tree, and support vector machine (SVM) algorithms. A total of 48 variables covering lifestyles, social-economic status, clinical symptoms, serological results, and pathological data were used in the model construction. RESULTS: The accuracies of the four models were between 79.3% and 93.4% in the training set and between 77.2% and 91.2% in the testing dataset (logistics regression: 77.2%; decision tree: 87.3%; random forest: 88.2%; SVM: 91.2%;). The AUCs of four models showed impressive predictive ability. Comparing the four models with the different algorithms, the SVM model featured the best sensitivity and specificity in all datasets tested. CONCLUSIONS: Machine-learning algorithms can accurately and reliably predict the risk of UGI lesions based on readily available parameters. The predictive models have the potential to be used clinically for identifying patients with high risk of UGI lesions and stratifying patients for necessary endoscopic screening.

Effects of sodium selenite addition on ruminal fermentation, microflora and urinary excretion of purine derivatives in Holstein dairy bulls.

Researches on sodium selenite (SS) mainly focus on production performance and rumen fermentation in ruminants, and the influence of dietary Se addition on ruminal microbial population and enzyme activity in dairy bulls is scarce. This study mainly evaluated the effects of SS on ruminal fermentation, microflora and urinary excretion of purine derivatives (PD) in dairy bulls. Eight ruminally cannulated dairy bulls were used in a replicated 4 × 4 Latin square design. Treatments were control, low SS (LSS), medium SS (MSS) and high SS (HSS) with 0, 0.1, 0.3 and 0.5 mg/kg of selenium (Se) from SS in dietary dry matter (DM), respectively. The supplement of SS (1.0 g/kg of Se) was mixed into the first third of the daily ration. Bulls were fed a total mixed ration with corn silage to concentrate ratio of 50:50 on a DM basis. Dry matter intake was not affected, average daily gain linearly increased, while feed conversion ratio quadratically decreased with increasing Se addition. The linearly increased digestibility of DM, organic matter, crude protein, ether extract, neutral detergent fibre and acid detergent fibre was observed. Both ruminal pH and ammonia-N concentration linearly decreased, whereas total volatile fatty acid concentration linearly increased. A lower acetate to propionate ratio was observed due to the unchanged acetate proportion and increased propionate proportion. Activity of cellobiase, xylanase, pectinase, α-amylase and protease, populations of total bacteria, fungi, protozoa, Ruminococcus (R.) albus, R. flavefaciens, Fibrobacter succinogenes, Butyrivibrio fibrisolvens and Ruminobacter amylophilus as well as urinary total PD excretion linearly increased, whereas populations of total methanogens and Prevotella ruminicola linearly decreased. The data indicated that dietary Se addition stimulated ruminal microbial growth and enzyme activity, and resulting in the increased nutrient digestion and growth performance, and the optimum supplementary dose of Se was 0.3 mg/kg dietary DM from SS in dairy bulls.

Application of data mining methods to improve screening for the risk of early gastric cancer.

BACKGROUND: Although gastric cancer is a malignancy with high morbidity and mortality in China, the survival rate of patients with early gastric cancer (EGC) is high after surgical resection. To strengthen diagnosing and screening is the key to improve the survival and life quality of patients with EGC. This study applied data mining methods to improve screening for the risk of EGC on the basis of noninvasive factors, and displayed important influence factors for the risk of EGC. METHODS: The dataset was derived from a project of the First Hospital Affiliated Guangdong Pharmaceutical University. A series of questionnaire surveys, serological examinations and endoscopy plus pathology biopsy were conducted in 618 patients with gastric diseases. Their risk of EGC was categorized into low and high risk of EGC by the results of endoscopy plus pathology biopsy. The synthetic minority oversampling technique (SMOTE) was used to solve imbalance categories of the risk of EGC. Four classification models of the risk of EGC was established, including logistic regression (LR) and three data mining algorithms. RESULTS: The three data mining models had higher accuracy than the LR model. Gain curves of the three data mining models were convexes more closer to ideal curves by contrast with that of the LR model. AUC of the three data mining models were larger than that of the LR model as well. The three data mining models predicted the risk of EGC more effectively in comparison with the LR model. Moreover, this study found 16 important influence factors for the risk of EGC, such as occupations, helicobacter pylori infection, drinking hot water and so on. CONCLUSIONS: The three data mining models have optimal predictive behaviors over the LR model, therefore can effectively evaluate the risk of EGC and assist clinicians in improving the diagnosis and screening of EGC. Sixteen important influence factors for the risk of EGC were illustrated, which may helpfully assess gastric carcinogenesis, and remind to early prevention and early detection of gastric cancer. This study may also be conducive to clinical researchers in selecting and conducting the optimal predictive models.

Electrospun poly(l-lactide)/zein nanofiber mats loaded with Rana chensinensis skin peptides for wound dressing.

Electrospun nanofiber mats can display impressive performance as an ideal wound dressing. In this study, poly(l-lactide)(PLLA)/zein nanofiber mats loaded with Rana chensinensis skin peptides (RCSPs) were successfully produced by two different electrospinning techniques, blend and coaxial, with the goal of developing a wound dressing material. The nanofiber mats were investigated by environmental scanning electron microscope (ESEM), transmission electron microscopy (TEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC), water contact angle, mechanical tests and cell viability. The resulting nanofiber mats exhibited smooth surfaces, tiny diameters and different cross-sectional shapes from pure PLLA and zein nanofibers. The FTIR result showed that PLLA, zein and RCSPs were well dispersed, without chemical interactions. Compared with coaxial nanofiber mats, blending zein-RCSPs with PLLA enhanced hydrophilicity but decreased mechanical properties. Adding RCSPs into the electrospun nanofibers significantly improved the mechanical properties of the mats. Cell viability studies with human foreskin fibroblasts demonstrated that cell growth on PLLA/zein-RCSPs nanofiber mats was significantly higher than that on PLLA/zein nanofiber mats. The results indicate that nanofiber mats containing RCSPs are potential candidates for wound dressing.

Enhancing Thermal Conductivity in Polymer Composites through Molding-Assisted Orientation of Boron Nitride.

Incrementing thermal conductivity in polymer composites through the incorporation of inorganic thermally conductive fillers is typically constrained by the requirement of high filler content. This necessity often complicates processing and adversely affects mechanical properties. This study presents the fabrication of a polystyrene (PS)/boron nitride (BN) composite exhibiting elevated thermal conductivity with a modest 10 wt% BN content, achieved through optimized compression molding. Adjustments to molding parameters, including molding-cycle numbers, temperature, and pressure, were explored. The molding process, conducted above the glass transition temperature of PS, facilitated orientational alignment of BN within the PS matrix predominantly in the in-plane direction. This orientation, achieved at low filler loading, resulted in a threefold enhancement of thermal conductivity following a single molding time. Furthermore, the in-plane alignment of BN within the PS matrix was found to intensify with increased molding time and pressure, markedly boosting the in-plane thermal conductivity of the PS/BN molded composites. Within the range of molding parameters examined, the highest thermal conductivity (1.6 W/m·K) was observed in PS/BN composites subjected to five molding cycles at 140 °C and 10 MPa, without compromising mechanical properties. This study suggests that compression molding, which allows low filler content and straightforward operation, offers a viable approach for the mass production of polymer composites with superior thermal conductivity.

Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP1R) agonists have been approved by Food and Drug Administration for management of obesity. However, the causal relationship of GLP1R agonists (GLP1RA) with cancers still unclear. METHODS: The available cis-eQTLs for drugs target genes (GLP1R) were used as proxies for exposure to GLP1RA. Mendelian randomizations (MR) were performed to reveal the association of genetically-proxied GLP1RA with 14 common types cancer from large-scale consortia. Type 2 diabetes was used as positive control, and the GWASs data including 80 154 cases and 853 816 controls. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, all the related randomized controlled trails (RCTs) on GLP1RA were systematically searched from PubMed, Embase, and the Cochrane Library to comprehensively synthesize the evidence to validate any possible association with cancers. RESULT: A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instrument. The association of genetically-proxied GLP1RA with significantly decreased type 2 diabetes risk [OR (95%)=0.82 (0.79-0.86), P<0.001], which ensuring the effectiveness of identified genetic instruments. The authors found favorable evidence to support the association of GLP1RA with reduced breast cancer and basal cell carcinoma risk [0.92 (0.88-0.96), P<0.001, 0.92 (0.85-0.99), P=0.029, respectively], and with increased colorectal cancer risk [1.12 (1.07-1.18), P<0.001]. In addition, there was no suggestive evidence to support the association of GLP1RA with ovarian cancer [0.99 (0.90-1.09), P=0.827], lung cancer [1.01 (0.93-1.10), P=0760], and thyroid cancer [0.83 (0.63-1.10), P=0.187]. Our findings were consistent with the meta-analysis. Finally, 80 RCTs were included in the systematic review, with a low incidence of different kinds of cancer. CONCLUSIONS: Our study suggests that GLP1RA may decrease the risk of breast cancer and basal cell carcinoma, but increase the risk of colorectal cancer. However, according to the systematic review of RCTs, the incidence of cancer in patients treated with GLP1RA is low. Larger sample sizes of RCTs with long-term follow-up are necessary to establish the incidence of cancers and evaluate the risk-benefit ratios.

Case Report: Toripalimab: a novel immune checkpoint inhibitor in advanced nasopharyngeal carcinoma and severe immune-related colitis.

Toripalimab, a specific immune checkpoint inhibitor targeting the programmed death 1 (PD-1) receptor, represents a novel immunotherapeutic approach for advanced nasopharyngeal carcinoma, showing promising curative potential. However, it is not without drawbacks, as some patients experience immune-related adverse events (irAEs) associated with this treatment, and there remains a limited body of related research. Here, we present a case of advanced nasopharyngeal carcinoma in a patient who developed colitis as an irAE attributed to Toripalimab. Subsequent to Toripalimab treatment, the patient achieved complete remission. Notably, the development of colitis was accompanied by inflammatory manifestations evident in colonoscopy and pathology results. Further investigation revealed cytomegalovirus (CMV) infection, detected through immunohistochemistry in 11 colon biopsies. Subsequent treatment with ganciclovir and steroids resulted in symptom relief, and colonoscopy indicated mucosal healing. Our case highlights the association between irColitis induced by Toripalimab and CMV infection. Toripalimab demonstrates remarkable efficacy in treating advanced nasopharyngeal carcinoma, albeit with a notable risk of irAEs, particularly in the form of colitis. The link between symptoms and endoscopic pathology findings in irColitis is noteworthy. Standardized biopsy procedures can effectively confirm the diagnosis of CMV infection. Our findings may provide valuable guidance for managing acute CMV infection and irAEs associated with Toripalimab in the treatment of nasopharyngeal carcinoma in the future.

High-Dose immunoglobulin Intervention as an effective and simple strategy for donor specific Anti-HLA antibody desensitization in haploidentical transplant.

Donor-specific anti-HLA antibody (DSA) is a significant obstacle to successful haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and is associated with poor engraftment rates. DSA strongly positive patients with a mean fluorescence intensity (MFI) over 5000 have a primary poor graft function (PGF) rate of over 60%. Currently, there is no consensus on the desensitization of DSA, and existing strategies are complex and have limited effectiveness. To address this issue, we conducted a retrospective study on 19 patients with strongly positive DSA (MFI over 5000) who underwent haplo-HSCT and were treated with intravenous immunoglobulin (IVIg)-based therapy. We also included 38 baseline-matched patients with DSA-negative as controls. Our findings revealed that the cumulative incidence of engraftment, PGF, graft-versus-host disease (GVHD), virus infection, overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) in the DSA strongly positive group after desensitization were comparable to those in the DSA negative group (P > 0.05). Our multivariable analysis showed that disease remission was a protective factor against PGF (P = 0.005, OR = 0.019, 95% CI 0.001-0.312). Subgroup analysis revealed that the desensitization efficacy was equal regardless of DSA type against HLA-I or II, and MFI value over 5000 or not. In conclusion, we propose a simple and effective DSA desensitization strategy based on immunoglobulin to ensure successful engraftment and improve patient prognosis.

Developing Thermal Regulating and Electromagnetic Shielding Nacre-Inspired Graphene-Conjugated Conducting Polymer Film via Apparent Wiedemann-Franz Law.

In this work, we observed size-dependent behavior of filler on both the thermal and electrical conductivities of nacre-like graphene-conjugated conducting polymer films and demonstrated the display of apparent Wiedemann-Franz law and tunability of Lorenz constant in such films. The maximum thermal and electrical conductivities of as-fabricated films can reach over 73 W·m-1·K-1 and 1200 S·cm-1, respectively. Furthermore, the maximum value of electromagnetic interference shielding reaches 54 dB with SSE/t over 16000 dB·cm2·g-1. These films can not only show high-quality electromagnetic interference shielding performance with small thickness and low filler ratio but also achieve simultaneous thermal management during electromagnetic shielding. The findings in this work offer new insight into designing flexible graphene-conjugated polymers with customizable thermal and electrical properties in the broad fields of thermal management systems, electromagnetic defense systems, and flexible electronic systems.

Dexamethasone-loaded zeolitic imidazolate frameworks nanocomposite hydrogel with antibacterial and anti-inflammatory effects for periodontitis treatment.

Periodontitis is a bacterial-induced, chronic inflammatory disease characterized by progressive destruction of tooth-supporting structures. Pathogenic bacteria residing in deep periodontal pockets after traditional manual debridement can still lead to local inflammatory microenvironment, which remains a challenging problem and an urgent need for better therapeutic strategies. Here, we integrated the advantages of metal-organic frameworks (MOFs) and hydrogels to prepare an injectable nanocomposite hydrogel by incorporating dexamethasone-loaded zeolitic imidazolate frameworks-8 (DZIF) nanoparticles into the photocrosslinking matrix of methacrylic polyphosphoester (PPEMA) and methacrylic gelatin (GelMA). The injectable hydrogel could be easily injected into deep periodontal pockets, achieving high local concentrations without leading to antibiotic resistance. The nanocomposite hydrogel had high antibacterial activity and constructs with stable microenvironments maintain cell viability, proliferation, spreading, as well as osteogenesis, and down-regulated inflammatory genes expression in vitro. When evaluated on an experimental periodontitis rat model, micro-computed tomography and histological analyses showed that the nanocomposite hydrogel effectively reduced periodontal inflammation and attenuated inflammation-induced bone loss in a rat model of periodontitis. These findings suggest that the nanocomposite hydrogel might be a promising therapeutic candidate for treating periodontal disease.

[Evaluation of shensongyangxin capsules in the treatment of paroxysmal atrial fibrillation: a randomized, double-blind and controlled multicenter trial].

OBJECTIVE: To evaluate the efficacy and safety of Chinese medicinal shensongyangxin capsules in the treatment of paroxysmal atrial fibrillation. METHODS: From August 2007 to July 2008, Beijing Chaoyang Hospital conducted a multicenter study, select the eleven hospital's outpatient subjects, aged 18 to 75 years old, male or female, paroxysmal atrial fibrillation (at least one electrocardiogram diagnosis) seizure frequency ≥ 2 times/month, according to the ratio 1:1:1, subjects were randomly divided into three groups: a. shensongyangxin group, taking shensongyangxin capsule 4 + propafenone analogues 150 mg, 3 times a day; b. propafenone group, taking propafenone tablets 150 mg + 4 shensongyangxin analogues, 3 times a day; shensongyangxin capsule + propafenone group, taking shensongyangxin capsule 4 + propafenone 150 mg, 3 times a day. The treatment course is 8 weeks, with 3 times of follow-up. RESULTS: Total of 349 cases of paroxysmal atrial fibrillation, which 117 cases in shensongyangxin group, 115 cases in propafenone group; 117 cases in shensongyangxin + propafenone group. The baseline data analysis showed that there were no significantly difference (P > 0.05) among the three groups of atrial fibrillation seizure frequency, vital signs, general condition, medical history, 24-hour ambulatory ECG, 12-lead normal electrocardiogram, cardiac ultrasound and symptoms. The comparison before and after (8 weeks) treatment showed that the frequency (from 6 times/m to 2 times/m in each group, P < 0.01), number of cases [from 46 (43.3%) to 22 (20.8%), 43 (43.4%) to 25 (25.3%), and 40 (40.6%) to 31 (29.2%), respectively P < 0.01] and duration time of attack of atrial fibrillation (from 4 h to 0.5 h, 4 h to 0.5 h, and 4.25 h to 0.5 h, respectively P < 0.01) all decreased in three groups. No significant difference among the three groups comparing the overall effect (62.3%, 58.6%, and 58.5%, respectively, P > 0.05), while the efficacy of TCM symptoms in shensongyangxin group (80.2%) was better than that of propafenone group (67.7%) (P < 0.05). Safety evaluation showed that adverse reaction rate was 1.8% in shensongyangxin group, and 8.2% and 5.4% in propafenone group and shensongyangxin + propafenone group. CONCLUSION: Shensongyangxin capsules and propafenone have comparable efficacies in the treatment of PAF. The efficacy of TCM symptoms is better than propafenone. Shensongyangxin capsules have an excellent profile of safety.

Silver-hydroxyapatite nanocomposites prepared by three sequential reaction steps in one pot and their bioactivities in vitro.

Hydroxyapatite (HA) combined with antimicrobial agents for biomedical application can effectively avoid the bacteria infection, while HA have the good performance. In this study, we prepared silver-hydroxyapatite (Ag-HA) nanocomposites using a one-pot method consisting of three sequential steps of wet chemical precipitation, ion exchange, and a silver mirror reaction. The HA nanoparticles used as the precursor for Ag ion doping were first synthesised by wet chemical precipitation. Next, Ag+ absorbed on HA surface through ion exchange reaction. Glucose was then added to initiate the silver mirror reaction, which made the Ag+ ions reduce to Ag0 and Ag nanoparticles in situ formed on HA nanoparticles. Subsequently, Ag-HA nanocomposites with different Ag content were prepared. X-ray diffraction, SEM, EDX mapping and TEM imaging confirmed that spherical Ag nanoparticles ~20-40 nm in diameter were adhered to the surface of HA nano-rods (0.4-0.8 µm in length and 15-40 nm in diameter). The Ag content (1.9-15.2 wt%) in the Ag-HA nanocomposites was adjusted by varying the feeding Ag/Ca molar ratio (2.0-20%). The cell viability evaluation in vitro proved that Ag-HA nanocomposites had low cytotoxicity to L929 normal cells. Meanwhile, the antibacterial examinations in vitro demonstrated that Ag-HA nanocomposites had obvious antibacterial effects on Gram-positive bacteria, Gram-negative bacteria, and fungus. The antibacterial results were dose-dependent on the accumulation of silver content. The Ag-HA nanocomposites loaded PMMA resins also demonstrated a potential antibacterial activity against S. mutans. This paper presents a convenient and bio-friendly approach for preparing Ag-HA nanocomposites with adjustable Ag content, which are a promising material for biomedical applications.

Hydroxyapatite-Bovine Serum Albumin-Paclitaxel Nanoparticles for Locoregional Treatment of Osteosarcoma.

Osteosarcoma is the most primary type of bone tumor occurring in the pediatric and adolescent age groups. In order to obtain the most appropriate prognosis, both tumor recurrence inhibition and bone repair promotion are required. In this study, a ternary nanoscale biomaterial/antitumor drug complex including hydroxyapatite (HA), bovine serum albumin (BSA) and paclitaxel (PTX) is prepared for post-surgical cancer treatment of osteosarcoma in situ. The HA-BSA-PTX nanoparticles, about 55 nm in diameter with drug loading efficiency (32.17 wt%), have sustained release properties of PTX and calcium ions (Ca2+ ) and low cytotoxicity to human fetal osteoblastic (hFOB 1.19) cells in vitro. However, for osteosarcoma (143B) cells, the proliferation, migration, and invasion ability are significantly inhibited. The in situ osteosarcoma model studies demonstrate that HA-BSA-PTX nanoparticles have significant anticancer effects and can effectively inhibit tumor metastasis. Meanwhile, the detection of alkaline phosphatase activity, calcium deposition, and reverse transcription-polymerase chain reaction proves that the HA-BSA-PTX nanoparticles can promote the osteogenic differentiation. Therefore, the HA-BSA-PTX nanodrug delivery system combined with sustained drug release, antitumor, and osteogenesis effects is a promising agent for osteosarcoma adjuvant therapy.

Chlorin e6 and polydopamine modified gold nanoflowers for combined photothermal and photodynamic therapy.

Combinational photo-based approaches with enhanced efficacy for cancer therapy have garnered increasing attention in recent years. In this work, a multifunctional system for synergistic photothermal and photodynamic cancer therapy was successfully prepared. The system consists of gold nanoflowers (AuNFs) conjugated with Chlorin e6 (Ce6), and then coated with a polydopamine (PDA) layer. AuNFs with diameters around 80 nm and a broad absorbance in the visible-near infrared (Vis-NIR) range of 500 to 800 nm, were successfully synthesized by a two-step process at 0 °C, using HAuCl4, ascorbic acid (AA), and hydroxylamine hydrochloride (NH2OH·HCl) as the reactants. Glutathione (GSH) molecules chemically anchored to the gold surfaces were used to provide addressable sites for Ce6 conjugated to GSH-AuNFs through an amidation reaction. A PDA layer was then wrapped outside the Ce6-GSH-AuNFs via self-polymerization of dopamine, which provided additional chemical modification and functionalization. Finally, the multifunctional PDA-Ce6-GSH-AuNFs were obtained. The content of Ce6 incorporated into the AuNFs was 14.0 wt%, and the singlet oxygen yield of PDA-Ce6-GSH-AuNFs was approximately 91.0% of that of free Ce6. PDA-Ce6-GSH-AuNFs showed better photothermal conversion efficiency (η = 23.6%), lower cytotoxicity, and faster cell internalization. Both in vitro and in vivo investigation of the combined treatment with a near-infrared (NIR) laser (660 nm for photodynamic therapy, and 808 nm for photothermal therapy) demonstrated that PDA-Ce6-GSH-AuNFs had excellent phototoxicity and synergistic effects of killing cancer cells. Hence, PDA-Ce6-GSH-AuNFs are a dual phototherapeutic agent that exhibits photodynamic and photothermal therapeutic effects and has potential application in enhanced cancer therapy.

An enzyme-responsive membrane for antibiotic drug release and local periodontal treatment.

Periodontitis is a chronic, destructive inflammatory disease that injures tooth- supporting tissues, eventually leading to tooth loss. Complete eradication of periodontal pathogenic microorganisms is fundamental to allow periodontal healing and commonly precedes periodontal tissue regeneration. To address this challenge, we report a strategy for developing an enzyme-mediated periodontal membrane for targeted antibiotic delivery into infectious periodontal pockets; the unique components of the membrane will also benefit periodontal alveolar bone repair. In this approach, a chitosan membrane containing polyphosphoester and minocycline hydrochloride (PPEM) was prepared. Physical, morphological, and ultrastructural analyses were carried out in order to assess cellular compatibility, drug release and antibacterial activity in vitro. Additionally, the functionality of the PPEM membrane was evaluated in vivo with a periodontal defect model in rats. The results confirm that the PPEM membrane exhibits good physical properties with excellent antibacterial activity and successfully promotes periodontal tissue repair, making it promising for periodontal treatment.

Paclitaxel/Chitosan Nanosupensions Provide Enhanced Intravesical Bladder Cancer Therapy with Sustained and Prolonged Delivery of Paclitaxel.

Bladder cancer (BC) is a very common cancer. Nonmuscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. After postoperative tumor resection, chemotherapy intravesical instillation is recommended as a standard treatment to significantly reduce recurrences. Nanomedicine-mediated delivery of a chemotherapeutic agent targeting cancer could provide a solution to obtain longer residence time and high bioavailability of an anticancer drug. The approach described here provides a nanomedicine with sustained and prolonged delivery of paclitaxel and enhanced therapy of intravesical bladder cancer, which is paclitaxel/chitosan (PTX/CS) nanosupensions (NSs). The positively charged PTX/CS NSs exhibited a rod-shaped morphology with a mean diameter about 200 nm. They have good dispersivity in water without any protective agents, and the positively charged properties make them easy to be adsorbed on the inner mucosa of the bladder through electrostatic adsorption. PTX/CS NSs also had a high drug loading capacity and can maintain sustained release of paclitaxel which could be prolonged over 10 days. Cell experiments in vitro demonstrated that PTX/CS NSs had good biocompatibility and effective bladder cancer cell proliferation inhibition. The significant anticancer efficacy against intravesical bladder cancer was verified by an in situ bladder cancer model. The paclitaxel/chitosan nanosupensions could provide sustained delivery of chemotherapeutic agents with significant anticancer efficacy against intravesical bladder cancer.

Micro-/nanofibers prepared via co-assembly of paclitaxel and dextran.

In this paper, we reported the preparation of micro-/nanofibers via co-assembly with paclitaxel (PTX) and dextran (DEX). The co-assembly fibers formed in PTX and DEX mixture solution via non-covalent interactions including hydrophilic/hydrophobic interactions and π-π stacking. The micro-/nanofibers could be obviously observed when the mixed solution became turbid and ivory-white in color. The properties of fibers were characterized by SEM, TEM, FTIR, DSC, XRD, in vitro release and MTT assay. The length of fibers could reach several centimeters. The diameter of microfibers and nanofibers was about 800nm and 80nm, respectively. In addition, the PTX loading efficiency was over 78% in co-assembly fibers and up to 84% when PTX and DEX (Mw: 40,000) both were 2mg/mL. The sustained drug release and low cytotoxicity in vitro of PTX/DEX fibers were also demonstrated. Therefore, we believe that PTX/DEX micro-/nanofibers would have great potential for drug delivery of PTX.