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Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.

Biochar, as a soil additive, will inevitably affect the transformation process of soil and water interactions. Biochar plays an important role in reducing soil degradation. The capillary water in soil affects the stability of the soil structure. The characteristics of the capillary force between the soil and biochar particles are investigated in this study. Based on an advanced capillary force measurement system, biochar and soil particles are simplified as spherical particles of equal size. The image of the liquid bridge between different particles is recorded by a high-speed camera (AOSVI-HD202WF). Based on digital image processing technology, the fractal dimension of the image is calculated, and the influence of the liquid volume and particle properties is analyzed. The results indicate that the capillary force between the particles decreases with increase in interparticle distance. Due to the increase of the liquid volume, the initial capillary force between the biochar and soil particles is increased from 3.6×10−4 to 4.4×10−4 N, and the fracture distance of the liquid bridge is increased from 0.41 to 0.70 mm, respectively, for a liquid volume from 0.8 to 2.4 ul. The fractal dimension of morphology of the liquid bridge between the particles increased and decreased in a cycle (C). It is found that the variation of the liquid bridge between the particles is stable with a high liquid volume (≥2.4 ul). It is also found that the cycle period of the liquid bridge between the biochar and soil particles is not affected by the liquid volume. The calculated capillary forces between the biochar and soil particles by using a Laplace-Young equation have been well verified by the experimental data. Biochar has an effect on the stability of the capillary force of the liquid bridge between the soil particles. Biochar-soil particles can be effectively combined to improve the capillary force and water retention capacity of the soil.

SUMMARY The conserved GATOR1 complex consisting of NPRL2-NPRL3-DEPDC5 inhibits mammalian target of rapamycin complex 1 (mTORC1) in response to amino acid insufficiency. Here, we show that loss of NPRL2 and GATOR1 function in skeletal muscle causes constitutive activation of mTORC1 signaling in the fed and fasted states. Muscle fibers of NPRL2 knockout animals are significantly larger and show altered fiber-type composition, with more fast-twitch glycolytic and fewer slow-twitch oxidative fibers. NPRL2 muscle knockout mice also have altered running behavior and enhanced glucose tolerance. Furthermore, loss of NPRL2 induces aerobic glycolysis and suppresses glucose entry into the TCA cycle. Such chronic activation of mTORC1 leads to compensatory increases in anaplerotic pathways to replenish TCA intermediates that are consumed for biosynthetic purposes. These phenotypes reveal a fundamental role for the GATOR1 complex in the homeostatic regulation of mitochondrial functions (biosynthesis versus ATP) to mediate carbohydrate utilization in muscle., In Brief Dutchak et al. investigate how mTORC1 activation rewires cellular metabolism in skeletal muscle by analyzing the consequences of loss of NPRL2, a component of the GATOR1 complex that is a conserved negative regulator of mTORC1.

With recent advances in understanding the genomic underpinnings and oncogenic drivers of pathogenesis in different subtypes, it is increasingly clear that proper pretreatment diagnostics are essential for the choice of appropriate treatment options for non-small cell lung cancer (NSCLC). Tumor tissue preservation in optimal cutting temperature (OCT) compound is commonly used in the surgical suite. However, proteins recovered from OCT-embedded specimens pose a challenge for LC-MS/MS experiments, due to the large amounts of polymers present in OCT. Here we present a simple workflow for whole proteome analysis of OCT-embedded NSCLC tissue samples, which involves a simple trichloroacetic acid precipitation step. Comparisons of protein recovery between frozen versus OCT-embedded tissue showed excellent consistency with more than 9200 proteins identified. Using an isobaric labeling strategy, we quantified more than 5400 proteins in tumor versus normal OCT-embedded core needle biopsy samples. Gene ontology analysis indicated that a number of proliferative as well as squamous cell carcinoma (SqCC) marker proteins were overexpressed in the tumor, consistent with the patient's pathology based diagnosis of "poorly differentiated SqCC". Among the most downregulated proteins in the tumor sample, we noted a number of proteins with potential immunomodulatory functions. Finally, interrogation of the aberrantly expressed proteins using a candidate approach and cross-referencing with publicly available databases led to the identification of potential druggable targets in DNA replication and DNA damage repair pathways. We conclude that our approach allows LC-MS/MS proteomic analyses on OCT-embedded lung cancer specimens, opening the way to bring powerful proteomics into the clinic. Graphical Abstract ᅟ.

In the version of the Supplementary Information originally published, in Supplementary Fig. 8a, in the bottom row, the left-most image ('Control') was not the correct image; this has now been replaced.

Using a validated, three-dimensional, coupled physical-biogeochemical model, this study examines the dynamics of dissolved inorganic carbon (DIC) in the South China Sea (SCS). The model identifies characteristic differences in DIC concentrations between the SCS and adjacent West Philippine Sea (WPS), showing an increase in DIC of up to 140 μmol kg−1 in the upper 2000 m layer from the WPS to the vicinity of the northern SCS. This increasing pattern continues from the northern to the southern SCS, but to a much lower degree ( 1600 m. Exports of DIC occur through other straits and the SCS intermediate water outflow (600 m to 1600 m) via the Luzon Strait. The model shows upward transport of DIC in the upper 400 m and below 1100 m, in contrast to downward DIC transport between 400 m and 1100 m. Seasonally, both DIC concentrations and fluxes in the upper layer have larger dynamic ranges in winter than in summer, attributable to the combined effects of enhanced Kuroshio intrusion, stronger vertical upwelling and greater biogeochemical alterations. A balance of various constitutive DIC terms revealed that horizontal and vertical advection is an order of magnitude greater than the other terms of the DIC budget, which has an opposite sign and thus tends to neutralize each other. The model indicated a decrease in the DIC inventory in the euphotic zone in spring and summer caused by net DIC consumption, and a contrasting increase in fall and winter primarily influenced by DIC vertical transport. In intermediate and deep layers, physical transport processes play a dominant role in the seasonal variation of DIC inventories. In the upper 150 m, DIC fluxes and their stoichiometry with nutrient fluxes, which potentially impact the air-sea CO2 fluxes, are largely driven by excess vertical DIC fluxes compared to horizontal fluxes via the Luzon Strait.

The East China Sea (ECS) and the South China Sea (SCS) are two major marginal seas of the north Pacific with distinct seasonal primary productivity. Based upon field observation in December 2008–January 2009 covering both the ECS and the northern SCS (NSCS) in wintertime, we examined southward long-range nutrient-transport from the ECS to the northeast SCS (NESCS) carried by the China Coastal Current (CCC) driven by the northeast prevailing monsoon. These nutrients escaped from the cold ECS shelf to refuel the primary production on the NESCS shelf where river-sourced nutrients were limited yet water temperature remained favorable. By coupling the field observation of nitrate + nitrite (DIN) with the volume transport of the CCC, we derived a first order estimate of DIN flux of ~ 1430 ± 260 mol s−1. This DIN flux was ~ 7 times the wintertime DIN input from the Pearl River, a primary riverine nutrient source to the NSCS. By assuming DIN was the limiting nutrient, such southward DIN transport would have stimulated ~ 8.8 ± 1.6 × 1011 gC of new production (NP), accounting for ~ > 58 ± 10% of the total NP or ~ 38 ± 7–24 ± 4% of primary production on the NESCS shelf shallower than 100 m.

Nogo-B receptor (NgBR) plays fundamental roles in regulating angiogenesis, vascular development, and the epithelial-mesenchymal transition (EMT) of cancer cells. However, the therapeutic effect of NgBR blockade on tumor vasculature and malignancy is unknown, investigations on which requires an adequate delivery system for small interfering RNA against NgBR (NgBR siRNA). Here a surface charge switchable polymeric nanoparticle that was sensitive to the slightly acidic tumor microenvironment was developed for steady delivery of NgBR siRNA to tumor tissues. The nanoformulation was constructed by conjugating 2, 3-dimethylmaleic anhydride (DMMA) molecules to the surface amines of micelles formed by cationic co-polymer poly(lactic-co-glycolic acid)2-poly(ethylenimine) and subsequent absorption of NgBR siRNAs. The nanoparticles remained negatively charged in physiological condition and smartly converted to positive surface charge due to tumor-acidity-activated shedding of DMMA. The charge conversion facilitated cellular uptake of siRNAs and in turn efficiently depleted the expression of NgBR in tumor-bearing tissues. Silencing of NgBR suppressed endothelial cell migration and tubule formation, and reverted the EMT process of breast cancer cells. Delivery of the nanoformulation to mice bearing orthotopic breast carcinoma showed no effect on tumor growth, but led to remarkable decrease of distant metastasis by normalizing tumor vessels and suppressing the EMT of breast cancer cells. This study demonstrated that NgBR is a promising therapeutic target in abnormal tumor vasculature and aggressive cancer cells, and the tumor-responsive nanoparticle with the feature of charge transformation offers great potential for tumor-specific delivery of gene therapeutics.

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer-lipid-peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid-peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.

Peptide therapeutics hold great promise for the treatment of cancer due to low toxicity, high specificity, and ease of synthesis and modification. However, the unfavorable pharmacokinetic parameters strictly limit their therapeutic efficacy and clinical translation. Here, we tailor-designed an amphiphilic chimeric peptide through conjugation of functional 3-diethylaminopropyl isothiocyanate (DEAP) molecules to a short antitumor peptide, C16Y. The ultimate DEAP–C16Y peptides self-assembled into spherical nanostructures at physiologic conditions, which dissociated to release individual peptide molecules in weakly acidic tumors. DEAP–C16Y peptides showed negligible cytotoxicity but impaired vascular endothelial cell migration and tubule formation by inactivation of the focal adhesion kinase and PI3K–Akt pathways, as well as tumor cell invasion by decreasing invadopodia formation. Compared with C16Y, the systemically administered DEAP–C16Y nanostructures exhibited superior stability, thereby allowing prolonged treatment interval and resulting in significant decreases in microvessel density, tumor growth, and distant metastasis formation in orthotopic mammary tumor models. Through encapsulation of hydrophobic doxorubicin, DEAP–C16Y nanostructure served as a smart carrier to achieve targeted drug delivery and combination therapy. Our study, for the first time, demonstrates that a simple nanoformulation using a functional antitumor peptide as the building block can show innate antitumor activity and also provide a nanoplatform for combination therapy, opening a new avenue for the design of antitumor nanotherapeutics. Mol Cancer Ther; 14(10); 2390–400. ©2015 AACR.