Cascade Catalytic Nanoparticles Selectively Alkalize Cancerous Lysosomes to Suppress Cancer Progression and Metastasis.

Lysosomes are critical in modulating the progression and metastasis for various cancers. There is currently an unmet need for lysosomal alkalizers that can selectively and safely alter the pH and inhibit the function of cancer lysosomes. Here an effective, selective, and safe lysosomal alkalizer is reported that can inhibit autophagy and suppress tumors in mice. The lysosomal alkalizer consists of an iron oxide core that generates hydroxyl radicals (•OH) in the presence of excessive H+ and hydrogen peroxide inside cancer lysosomes and cerium oxide satellites that capture and convert •OH into hydroxide ions. Alkalized lysosomes, which display impaired enzyme activity and autophagy, lead to cancer cell apoptosis. It is shown that the alkalizer effectively inhibits both local and systemic tumor growth and metastasis in mice. This work demonstrates that the intrinsic properties of nanoparticles can be harnessed to build effective lysosomal alkalizers that are both selective and safe.

Co-Delivery of Metabolic Modulators Leads to Simultaneous Lactate Metabolism Inhibition and Intracellular Acidification for Synergistic Cancer Therapy.

Simultaneous lactate metabolism inhibition and intracellular acidification (LIIA) is a promising approach for inducing tumor regression by depleting ATP. However, given the limited efficacy of individual metabolic modulators, a combination of various modulators is required for highly efficient LIIA. Herein, a co-delivery system that combines lactate transporter inhibitor, glucose oxidase, and O2 -evolving nanoparticles is proposed. As a vehicle, a facile room-temperature synthetic method for large-pore mesoporous silica nanoparticles (L-MSNs) is developed. O2 -evolving nanoparticles are then conjugated onto L-MSNs, followed by immobilizing the lactate transporter inhibitor and glucose oxidase inside the pores of L-MSNs. To load the lactate transporter inhibitor, which is too small to be directly loaded into the large pores, it is encapsulated in albumin by controlling the albumin conformation before being loaded into L-MSNs. Notably, inhibiting lactate efflux shifts the glucose consumption mechanism from lactate metabolism to glucose oxidase reaction, which eliminates glucose and produces acid. This leads to synergistic LIIA and subsequent ATP depletion in cancer cells. Consequently, L-MSN-based co-delivery of modulators for LIIA shows high anticancer efficacy in several mouse tumor models without toxicity in normal tissues. This study provides new insights into co-delivery of small-molecule drugs, proteins, and nanoparticles for synergistic metabolic modulation in tumors.

Penetrative and Sustained Drug Delivery Using Injectable Hydrogel Nanocomposites for Postsurgical Brain Tumor Treatment.

Postsurgical treatment of glioblastoma multiforme (GBM) by systemic chemotherapy and radiotherapy is often inefficient. Tumor cells infiltrating deeply into the brain parenchyma are significant obstacles to the eradication of GBM. Here, we present a potential solution to this challenge by introducing an injectable thermoresponsive hydrogel nanocomposite. As a liquid solution that contains drug-loaded micelles and water-dispersible ferrimagnetic iron oxide nanocubes (wFIONs), the hydrogel nanocomposite is injected into the resected tumor site after surgery. It promptly gelates at body temperature to serve as a soft, deep intracortical drug reservoir. The drug-loaded micelles target residual GBM cells and deliver drugs with a minimum premature release. Alternating magnetic fields accelerate diffusion through heat generation from wFIONs, enabling penetrative drug delivery. Significantly suppressed tumor growth and improved survival rates are demonstrated in an orthotopic mouse GBM model. Our system proves the potential of the hydrogel nanocomposite platform for postsurgical GBM treatment.

Geometric Tuning of Single-Atom FeN4 Sites via Edge-Generation Enhances Multi-Enzymatic Properties.

Single-atom nanozymes (SAzymes) are considered promising alternatives to natural enzymes. The catalytic performance of SAzymes featuring homogeneous, well-defined active structures can be enhanced through elucidating structure-activity relationship and tailoring physicochemical properties. However, manipulating enzymatic properties through structural variation is an underdeveloped approach. Herein, the synthesis of edge-rich Fe single-atom nanozymes (FeNC-edge) via an H2 O2 -mediated edge generation is reported. By controlling the number of edge sites, the peroxidase (POD)- and oxidase (OXD)-like performance is significantly enhanced. The activity enhancement results from the presence of abundant edges, which provide new anchoring sites to mononuclear Fe. Experimental results combined with density functional theory (DFT) calculations reveal that FeN4 moieties in the edge sites display high electron density of Fe atoms and open N atoms. Finally, it is demonstrated that FeNC-edge nanozyme effectively inhibits tumor growth both in vitro and in vivo, suggesting that edge-tailoring is an efficient strategy for developing artificial enzymes as novel catalytic therapeutics.

Localized Delivery of Theranostic Nanoparticles and High-Energy Photons using Microneedles-on-Bioelectronics.

The low delivery efficiency of light-responsive theranostic nanoparticles (NPs) to target tumor sites, particularly to brain tumors due to the blood-brain barrier, has been a critical issue in NP-based cancer treatments. Furthermore, high-energy photons that can effectively activate theranostic NPs are hardly delivered to the target region due to the strong scattering of such photons while penetrating surrounding tissues. Here, a localized delivery method of theranostic NPs and high-energy photons to the target tumor using microneedles-on-bioelectronics is presented. Two types of microneedles and flexible bioelectronics are integrated and mounted on the edge of surgical forceps. Bioresorbable microneedles containing theranostic NPs deliver the NPs into target tumors (e.g., glioblastoma, pituitary adenoma). Magnetic resonance imaging can locate the NPs. Then, light-guiding/spreading microneedles deliver high-energy photons from bioelectronics to the NPs. The high-energy photons activate the NPs to treat tumor tissues by photodynamic therapy and chemotherapy. The controlled thermal actuation by the bioelectronics accelerates the diffusion of chemo-drugs. The proposed method is demonstrated with mouse tumor models in vivo.

Evaluation of crude protein levels in White Pekin duck diet for 21 days after hatching.

In poultry diets, a requirement of crude protein is one of the most important factors in poultry productivity. Besides, the Pekin duck requirement of crude protein is still not clear. This experiment was conducted to determine the crude protein requirement of Pekin duck on diet formulation by investigation of growth performance, carcass trait, and analysis of blood parameter for a hatch to 21-day (d) of age. A total of 432 male White Pekin ducks were randomly allocated to six levels of crude protein (i.e., 15%, 17%, 19%, 21%, 23%, and 25%) to give six replicate pens per treatment with 12 ducklings per each pen. Body weight and feed intake were measured weekly by calculating feed conversion ratio and protein intake. Two ducklings each pen was euthanized via cervical dislocation for analysis of carcass trait and plasma blood on 21-d of age. Data were applied on both prediction linear-plateau and quadratic-plateau models by estimation of the crude protein requirements. Data were applied on both prediction linear-plateau and quadratic-plateau models by estimation of the crude protein requirements. The level of crude protein requirements of Pekin ducks for 21 days after the hatch was estimated to be 20.63% and 23.25% diet for maximum daily gain, and minimum feed conversion ratio, respectively.

Performance of and methanogenic communities involved in an innovative anaerobic process for the treatment of food wastewater in a pilot plant.

In this study, dual-cylindrical anaerobic digesters were designed and built on the pilot plant scale for the improvement of anaerobic digestion efficiency. The removal efficiency of organics, biogas productivity, yield, and microbial communities was evaluated as performance parameters of the digester. During the stable operational period in the continuous mode, the removal efficiencies of chemical oxygen demand and total solids were 74.1 and 65.1%, respectively. Biogas productivities of 63.9 m(3)/m(3)-FWW and 1.3 m(3)/kg-VSremoved were measured. The hydrogenotrophic methanogen orders, Methanomicrobiales and Methanobacteriales, were predominant over the aceticlastic methanogen order, Methanosarcinaceae, probably due to the tolerance of the hydrogenotrophs to environmental perturbation in the field and their faster growth rate compared with that of the aceticlastics.

A blind algorithm for reverberation-time estimation using subband decomposition of speech signals.

An algorithm for blind estimation of reverberation time (RT) in speech signals is proposed. Analysis is restricted to the free-decaying regions of the signal, where the reverberation effect dominates, yielding a more accurate RT estimate at a reduced computational cost. A spectral decomposition is performed on the reverberant signal and partial RT estimates are determined in all signal subbands, providing more data to the statistical-analysis stage of the algorithm, which yields the final RT estimate. Algorithm performance is assessed using two distinct speech databases, achieving 91% and 97% correlation with the RTs measured by a standard nonblind method, indicating that the proposed method blindly estimates the RT in a reliable and consistent manner.

The effect of gender on EC(50) of remifentanil to prevent pain during injection of microemulsion propofol.

BACKGROUND: Propofol injection pain is an unpleasant experience to patients and its prevalence can be influenced by age and gender. We determined the half maximal effective concentration (EC(50)) of remifentanil for preventing the microemulsion propofol injection pain in the male and female adult groups. METHODS: After institutional review board approval, a total of 60 patients were assigned into 2 groups depending on their gender: group M (male, 20-65 yr) and group F (female, 20-65 yr). Anesthesia was induced with propofol and remifentanil, by a target-controlled infusion. Target effect-site concentration (Ce) of propofol and remifentanil for the first patient started at 4.0 ug/ml and 4.0 ng/ml. Ce of remifentanil for each subsequent patient was determined by the response of the previous patient by the Dixon's up-and-down method (DUDM) with an interval of 0.2 ng/ml. After equilibration of plasma and effect site remifentanil concentration, propofol was administered, and the pain responses were observed. RESULTS: The remifentanil EC(50) was 3.8 ± 0.2 and 2.7 ± 0.2 ng/ml in groups M and F, respectively, by DUDM. From Probit regression model, the remifentanil EC(50) was 3.7 (3.0-4.3) and 2.7 (1.8-2.9) ng/ml in groups M and F, respectively. CONCLUSIONS: The remifentanil EC(50) for preventing the moderate to severe injection pain of propofol was higher in males than in females.