A Comprehensive Investigation on Potential Risk Factors for NSCL/P in a Rural District of Hebei Province, China.

Non syndromic cleft lip with or without palate (NSCL/P), one of the most common birth defects, is closely related to various risk factors. However, information regarding risk factors for NSCL/P in rural districts in China is very limited thus far. The objective of this study was designed to identify the potential risk factors for NSCL/P in rural districts.A comprehensive retrospective investigation including 435 NSCL/P patients and 402 healthy children was carried out in Hebei Province, China. Multiple logistic regression analysis and transmission disequilibrium test (TDT) were respectively used to identify non-genetic and genetic risk factors for NSCL/P, and then PLINK was used to explore the relationship between non-genetic and genetic risk factors.The results showed that maternal periconceptional exposure to pesticides and herbicides, as well as low parental education level were involved in the increased risk of NSCL/P, whereas maternal folic acid and multivitamin supplementation use during preconception period were associated with the reduced risk of NSCL/P. TDT analysis identified 2 single nucleotide polymorphisms (SNPs) (rs7078160 and rs4752028) in VAX1 and one SNP (rs17563) in BMP4 as the genetic risk factors for NSCL/P. Further analysis showed that the genetic risk factors were closely related with the negative non-genetic risk factors.Our study identified the potential risk factors for NSCL/P in rural districts, thus providing a theoretical basis for the prevention of NSCL/P occurrence.

Enhanced anti-tumor activity of a drug through pH-triggered release and dual targeting by calcium phosphate-covered mesoporous silica vehicles.

Rapid release and clearance of antitumor drugs in vivo are the main factors used to evade the effectiveness of chemotherapeutics. Targeted delivery and controlled release of drugs are the most pressing dilemmas in cancer therapy. Herein we report the design and fabrication of multifunctional mesoporous silica nanoparticles coated with poly(N-isopropylacrylamide)-co-acrylic acid and calcium phosphate (MSCNs) with pH-triggered chemotherapeutic release and dual-targeting functions. By decorating the nanoparticle surface with a transferrin (Tf)/RGD ligand, these nanoparticles are capable of not only recognizing the intrinsic pH difference between tumor and normal tissues, but also targeting the lesion location. It was shown that Tf/RGD-MSCNs delivered the anti-tumor drug doxorubicin more efficiently into lysosomes and the resulting DOX-loaded nanoparticles (DOX-Tf/RGD-MSCNs) showed a stronger inhibitory effect towards tumor cell growth than free DOX and DOX delivered by unmodified MSNs. Moreover, the nanoparticles are more biocompatible than uncoated mesoporous silica nanoparticles. All these results indicate that Tf/RGD-MSCNs have great potential as a novel drug carrier in therapeutic applications against cancers.

Castleman's disease with submaxillary lymphadenectasis as the main manifestation: a case report.

Castleman's disease is a lymphoproliferative disease that is rare and hard to diagnose. As a result of untypical manifestations, missed diagnosis and misdiagnosis of Castleman's disease are common in clinical practice. In this paper, we report one patient with clinical manifestations of painless submaxillary lymphadenectasis. The patient was finally diagnosed with Castleman's disease by clinical, laboratory, and pathological examinations. This report may promote the understanding and diagnosis of Castleman's disease for clinicians.

Effect of Different Salt Concentrations on Dimethyl Sulfoxide (DMSO) Nanocluster Structures by Molecular Dynamics Simulations.

We performed MD simulations to examine dimethyl sulfoxide (DMSO) nanocluster structures in NaCl aqueous solution with different concentrations (0.45 g/100 mL, 0.9 g/100 mL, 1.8 g/100 mL, 2.7 g/100 mL, and 3.6 g/100 mL). Results showed that interaction between Na+ and DMSO at the first solvation shells was weakened due to acceleration rotational influence of ion driven by NaCl concentration. We investigated the tetrahedral order parameter and average H-B number of water molecules. These results indicated that NaCl influenced the solvation structure of water cluster, but that of DMSO was not affected by NaCl. We also found that Na+ was prior solvated by water solution in these mixture systems, and Cl- only existed in the water cluster in our simulation systems. Consequently, we herein proposed a decentralized model that depicts microphysical structure images of DMSO in NaCl aqueous solution systems.

Risk Assessment of Nanoparticle Exposure in a Calcium Carbonate Manufacturing Workshop with Six Control Banding Tools.

With wide production and use, nanometer calcium carbonate (nano-CaCO3) has attracted much more concerns due to its potential inhalation toxicity in the occupational setting. It is of great significance to protect exposure workers by scientifically measuring the concentration of aerosol nano-CaCO3 particles, evaluating the risk levels at the production sites and accordingly providing suggestions of improvement. In this study, the aerosol particle concentrations of six operating procedures in a nano-CaCO3 production workshop were determined, including digesting, carbonization, modification, pressure filtration, drying and packaging. The relevant occupational exposure risk was assessed by six control banding (CB) tools, CB Nanotool, Stoffenmanager Nano, Nanosafer, the Guidance on Working Safely with Nanomaterials and Nanoproducts (GWSNN), French Agency for Food, Environmental and Occupational Health and Safety method (ANSES) and Precautionary Matrix for Synthetic Nanomaterials (Precautionary Matrix). It was found that there are quite high concentrations of airborne nanoparticles released from the nano-CaCO3 production procedures in this workshop. Most aerosol particles were agglomerated with the sizes of primary particles about 100 nm. The number concentration of aerosol particles at packaging site is 407000 particles/cm³ in size range of 0.02-1.0 µm, which is 10 times higher than the aerosol particle concentration at the digestion site. Furthermore, there is a significant correlation between the metrics of number and surface area concentrations detected in this workshop. The risk assessment results indicate that this workshop has medium or high exposure risks of the occupational nanoparticle exposure. Detailed engineering control or personal occupational protection should be implemented to protect the occupational health in this workshop. Similar and comparable judgment results were obtained, although the input parameters for six risk assessment CB tools are different. It was found that Stoffenmanager nano and Nanosafer are more suitable for the risk assessment of this workshop comparing to the other four tools. It is recommended a wide applications of risk assessment tools to various nanotechnology related occupational settings for controlling the occupational health risks.

Evaluation of Turning-Sized Gold Nanoparticles on Cellular Adhesion by Golgi Disruption in Vitro and in Vivo.

In contrast to the booming production and application of nanomaterials, research on the toxicological impacts and possible hazards of nanoparticles to tissues and organs is still in its infancy. Golgi apparatus is one of the most important organelles in cells and plays a key role in intracellular protein processing. The structural integrity of Golgi is vital for its normal function, and Golgi disturbance could result in a wide range of diseases and disorders. In this study, for the first time we found gold nanoparticles (Au NPs) induced size-dependent cytoplasmic calcium increase and Golgi fragmentation, which hampers normal Golgi functions, leads to abnormal protein processing, and causes cellular adhesion decrease, while cell viability was not significantly compromised. Additionally, early renal pathological changes were induced in vivo. This work is significant to nanoparticle research because it illustrates the important role of size on Au NP-induced changes in Golgi morphology and their consequences in vitro and in vivo, which has important implications for the biological applications of nanomaterials.

Through-Bond Energy Transfer Cassette with Dual-Stokes Shifts for "Double Checked" Cell Imaging.

Organic dyes generally suffer from small Stokes shift that usually leads to self-quenching and -gaining errors during the fluorescent imaging process. Here, a through-bond energy transfer (TBET) cassette is developed with large Stokes shift to pursue precise cell imaging. The TBET is constructed by covalently conjugated tetraphenylethene (acts as donor) and rhodamine (acceptor) through an acetylene bond. The constructed TBET cassette distinctly behaves as dual-Stokes shifts, including a large pseudo-Stokes shift caused by energy transfer, from donor's absorption to acceptor's emission (up to 260 nm) and a smaller Stokes shift of acceptor molecules itself. Due to the intrinsic dual-Stokes shifts, TBET cassette exhibits specific "dual distinct absorbances, single shared emission" properties, which can be excitated under two different laser channels. By colocalization of the imaging readouts of these two channels, the precisely "double checked" fluorescent imaging is achieved in living cells.

Overcoming resistance to cisplatin by inhibition of glutathione S-transferases (GSTs) with ethacraplatin micelles in vitro and in vivo.

Platinum-based DNA-adducting agents are used extensively in the clinic for cancer chemotherapy. However, the anti-tumor efficacy of these drugs is severely limited by cisplatin resistance, and this can lead to the failure of chemotherapy. One of cisplatin resistance mechanisms is associated with overexpression of glutathione S-transferases (GSTs), which would accelerate the deactivation of cisplatin and decrease its antitumor efficiency. Nanoscale micelles encapsulating ethacraplatin, a conjugate of cisplatin and ethacrynic acid (an effective GSTs inhibitor), can enhance the accumulation of active cisplatin in cancer cells by inhibiting the activity of GSTs and circumventing deactivation of cisplatin. In vitro and in vivo results provide strong evidence that GSTs inhibitor-modified cisplatin prodrug combined with nanoparticle encapsulation favor high effective platinum accumulation, significantly enhanced antitumor efficacy against cisplatin-resistant cancer and decreased system toxicity. It is believed that these ethacraplatin-loaded micelles have the ability of overcoming resistance of cancers toward cisplatin and will improve the prospects for chemotherapy of cisplatin-resistant cancers in the near future.

P-gp Inhibition and Mitochondrial Impairment by Dual-Functional Nanostructure Based on Vitamin E Derivatives To Overcome Multidrug Resistance.

Vitamin E derivatives possess many essential features for drug-delivery applications, such as biocompatibility, stability, improvement of water solubility of hydrophobic compounds, anticancer activity, and the ability to overcome multidrug resistance (MDR). Herein, vitamin E derivatives are used to overcome MDR through a combined P-glycoprotein (P-gp) inhibition and mitochondrial impairment strategy. A novel nanomicellar drug-delivery system as a carrier for doxorubicin (DOX) was developed, in which d-α-tocopheryl polyethylene glycol 1000 succinate was used as a P-gp inhibitor, α-tocopheryl succinate was introduced as a mitochondrial disrupting agent, and d-α-tocopheryl polyethylene glycol 2000 succinate was used as the main building block of micelles. The optimal ratio between the components of the nanocarrier was determined. The resultant DOX-loaded mixed micelles exhibited a suitable size of 52.08 nm, high drug-loading encapsulation efficiency (>98%), high stability, and pH-dependent drug release. In vitro experiments demonstrated a significantly increased cytotoxic activity of DOX-loaded mixed micelles against resistant MCF-7/Adr cells (45-fold higher than DOX after 48 h of treatment). In vivo studies revealed superior antitumor efficiency with less cardio- and hepatotoxicities of DOX-loaded micelles compared with that of free DOX. These results highlight that the developed DOX-loaded mixed micelles have a promising potential to overcome MDR in chemotherapy for clinical usage.

Nanotechnology-based strategies for treatment of ocular disease.

Ocular diseases include various anterior and posterior segment diseases. Due to the unique anatomy and physiology of the eye, efficient ocular drug delivery is a great challenge to researchers and pharmacologists. Although there are conventional noninvasive and invasive treatments, such as eye drops, injections and implants, the current treatments either suffer from low bioavailability or severe adverse ocular effects. Alternatively, the emerging nanoscience and nanotechnology are playing an important role in the development of novel strategies for ocular disease therapy. Various active molecules have been designed to associate with nanocarriers to overcome ocular barriers and intimately interact with specific ocular tissues. In this review, we highlight the recent attempts of nanotechnology-based systems for imaging and treating ocular diseases, such as corneal d iseases, glaucoma, retina diseases, and choroid diseases. Although additional work remains, the progress described herein may pave the way to new, highly effective and important ocular nanomedicines.

Virus-Inspired Self-Assembled Nanofibers with Aggregation-Induced Emission for Highly Efficient and Visible Gene Delivery.

High-efficiency gene transfer and suitably low cytotoxicity are the main goals of gene transfection systems based on nonviral vectors. In addition, it is desirable to track the gene transfer process in order to observe and explain the mechanism. Herein, inspired by viral structures that are optimized for gene delivery, we designed a small-molecule gene vector (TR4) with aggregation-induced emission properties by capping a peptide containing four arginine residues with tetraphenylethene (TPE) and a lipophilic tail. This novel vector can self-assemble with plasmid DNA to form nanofibers in solution with low cytotoxicity, high stability, and high transfection efficiency. pDNA@TR4 complexes were able to transfect a variety of different cell lines, including stem cells. The self-assembly process induces bright fluorescence from TPE, which makes the nanofibers visible by confocal laser scanning microscopy (CLSM). This allows us for the tracking of the gene delivery process.

An Amphiphilic Ruthenium Polymetallodrug for Combined Photodynamic Therapy and Photochemotherapy In Vivo.

An amphiphilic Ru-containing block copolymer is used as a photoactivated polymetallodrug for anticancer phototherapy. The block copolymer self-assembles into nanoparticles, which can accumulate at tumor sites in a mouse model. Red light irradiation of the block copolymer nanoparticles releases anticancer Ru complexes and generates cytotoxic 1 O2 , both of which can inhibit tumor growth.

Acute localized exanthematous pustulosis caused by cefoperazone and sodium sulbactam

Abstract Acute localized exanthematous pustulosis is a localized variant of acute generalized exanthematous pustulosis, which is characterized by the eruption of multiple scattered pustules following drug administration. A 72-year-old woman presented with multiple erythematous pustules on her face, which had appeared two days after using cefoperazone and sodium sulbactam. Histopathological findings showed subcorneal pustules and mixed inflammatory cell infiltration in the dermis. The pustules resolved within about two weeks after the patient discontinued the antibiotics. This report discusses the case of a woman with a cutaneous drug reaction consistent with acute localized exanthematous pustulosis that occurred after cefoperazone and sodium sulbactam were administered.

Tunable self-assembly of Irinotecan-fatty acid prodrugs with increased cytotoxicity to cancer cells.

The development of a clinical chemotherapeutic is not an easy task. One challenge is how to deliver the agent to cancer cells. Nano-formulation of prodrugs, which combines the strengths of nanotechnology and prodrugs, possesses many advantages for chemotherapeutic drug delivery, including high drug loading efficiency, improved drug availability and enhanced accumulation in cancer cells. Here, we have constructed a small library of Irinotecan-derived prodrugs, in which the 20-hydroxyl group was derived with fatty-acid moieties through esterification. This conjugation fine-tuned the polarity of the Irinotecan molecule, thus enhancing the lipophilicity of the prodrugs and inducing their self-assembly into nanoparticles with different morphologies. These nano-formulated prodrugs accumulated at higher levels in cancer cells and were much more cytotoxic than free drugs. The rational design of prodrug-based nano-formulations opens a new avenue for the engineering of more efficient drug-delivery systems.

Zinc Oxide Nanoparticles as Adjuvant To Facilitate Doxorubicin Intracellular Accumulation and Visualize pH-Responsive Release for Overcoming Drug Resistance.

Multidrug resistance (MDR) of cancer is a challenge to effective chemotherapeutic interventions. The stimulus-responsive drug delivery system (DDS) based on nanotechnology provides a promising approach to overcome MDR. Through the development of a doxorubicin delivery system based on zinc oxide nanomaterials, we have demonstrated that MDR in breast cancer cell line can be significantly circumvented by a combination of efficient cellular uptake and a pH-triggered rapid drug release due to degradation of nanocarriers in acidic environment. Doxorubicin and zinc oxide nanoparticles, compared with free doxorubicin, effectively enhanced the intracellular drug concentration by simultaneously increasing cell uptake and decreasing cell efflux in MDR cancer cells. The acidic environment-triggered release of drug can be tracked real-time by the doxorubicin fluorescence recovery from its quenched state. Therefore, with the combination of therapeutic potential and the capacity to track release of drug in cancer cells, our system holds great potential in nanomedicine by serving dual roles of overcoming drug resistance and tracking intracellular drug release from the DDS.

A Photosensitizer-Loaded DNA Origami Nanosystem for Photodynamic Therapy.

Photodynamic therapy (PDT) offers an alternative for cancer treatment by using ultraviolet or visible light in the presence of a photosensitizer and molecular oxygen, which can produce highly reactive oxygen species that ultimately leading to the ablation of tumor cells by multifactorial mechanisms. However, this technique is limited by the penetration depth of incident light, the hypoxic environment of solid tumors, and the vulnerability of photobleaching reduces the efficiency of many imaging agents. In this work, we reported a cellular level dual-functional imaging and PDT nanosystem BMEPC-loaded DNA origami for photodynamic therapy with high efficiency and stable photoreactive property. The carbazole derivative BMEPC is a one- and two-photon imaging agent and photosensitizer with large two-photon absorption cross section, which can be fully excited by near-infrared light, and is also capable of destroying targets under anaerobic condition by generating reactive intermediates of Type I photodynamic reactions. However, the application of BMEPC was restricted by its poor solubility in aqueous environment and its aggregation caused quenching. We observed BMEPC-loaded DNA origami effectively reduced the photobleaching of BMEPC within cells. Upon binding to DNA origami, the intramolecular rotation of BMEPC became proper restricted, which intensify fluorescence emission and radicals production when being excited. After the BMEPC-loaded DNA origami are taken up by tumor cells, upon irradiation, BMEPC could generate free radicals and be released due to DNA photocleavage as well as the following partially degradation. Apoptosis was then induced by the generation of free radicals. This functional nanosystem provides an insight into the design of photosensitizer-loaded DNA origami for effective intracellular imaging and photodynamic therapy.

Acute localized exanthematous pustulosis caused by cefoperazone and sodium sulbactam.

Acute localized exanthematous pustulosis is a localized variant of acute generalized exanthematous pustulosis, which is characterized by the eruption of multiple scattered pustules following drug administration. A 72-year-old woman presented with multiple erythematous pustules on her face, which had appeared two days after using cefoperazone and sodium sulbactam. Histopathological findings showed subcorneal pustules and mixed inflammatory cell infiltration in the dermis. The pustules resolved within about two weeks after the patient discontinued the antibiotics. This report discusses the case of a woman with a cutaneous drug reaction consistent with acute localized exanthematous pustulosis that occurred after cefoperazone and sodium sulbactam were administered.

Correction: Tunable self-assembly of Irinotecan-fatty acid prodrugs with increased cytotoxicity to cancer cells.

Correction for 'Tunable self-assembly of Irinotecan-fatty acid prodrugs with increased cytotoxicity to cancer cells' by Chunqiu Zhang et al., J. Mater. Chem. B, 2016, DOI: .

Engineered biomaterials for development of nucleic acid vaccines.

Nucleic acid vaccines have attracted many attentions since they have presented some superiority over traditional vaccines. However, they could only induce moderate immunogenicity. The route and formulation of nucleic acid vaccines have strong effects on the immune response and efficiency. Numerous biomaterials are used as a tool to enhance the immunogenicity of antigens. They deliver the antigens into the cells through particle- and non-particle-mediated pathway. However, challenges remain due to lack of comprehensive understanding of the actions of these biomaterials as a carrier/adjuvant. Herein, this review focuses on the evolution of biomaterials used for nucleic acid vaccines, discusses the advantages and disadvantages for gene delivery and immunostimulation of variety of structures of the biomaterials, in order to provide new thought on rational design of carrier/adjuvant and better understanding of mechanism of action in both immunostimulatory and delivery methods.