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A simple and efficient method for the copper-catalyzed selective C5-H bromination and difluoromethylation of 8-aminoquinoline amides using ethyl bromodifluoroacetate as the bifunctional reagent.

A series of hollow carbon nanospheres embedded with MRI agents γ-Fe2O3 and GdPO4 nanoparticles (Fe–Gd/HCS), were prepared and applied to in vitro/vivo evaluation with well defined sizes of ∼100 nm, ∼200 nm, ∼300 nm, respectively.

Esophageal cancer has high incidence rate in China. Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for esophageal squamous cell carcinoma (ESCC). However, there are few reliable epigenetic parameters for patients with ESCC undergoing neoadjuvant therapy. Genomic extract from tumor tissue was amplified and sequenced using the Illumina HiSeq4000 to quantify genes associated methylation or hydromethylation in 12 patients with ESCC undergoing nCRT. The genome-wide hydroxymethylation were analyzed by methylated and hydroxymethylated DNA immunoprecipitation sequencing by MACS2 software and UCSC RefSeq database. Abnormal DNA methylation was statistically different between nCRT-well (showed a pathological complete response to nCRT) and nCRT-poor (showed incomplete pathological response to nCRT) patients. Levels of ten-eleven translocation 1, 2 and 3 mRNA and protein were higher in tumor tissue in nCRT-well group patients than in nCRT-poor group patients. Illumina HiSeq 4000 sequencing identified 2925 hypo-differentially hydroxymethylated region (DhMRs) and 292 hyper-DhMRs in promoter between nCRT-well and nCRT-poor patients. Biological processes associated with hyper-DhMRs included 'snRNA processing', 'hormone-mediated signaling pathway' and 'cellular response'. Metabolic processes were associated with hypo-DhMRs. These data may explain the functional response to nCRT in patients with abnormal promoter of methylation gene-associated mRNA expression. The present results implied that hyper-DhMRs and hypo-DhMRs affect molecular pathways, such as hippo and Notch signaling pathways, highlighting epigenetic modifications associated with clinical response to nCRT in patients with esophageal cancer.

Palladium nanosheets (Pd NSs) are well-investigated photothermal therapy agents, but their catalytic potential for tumor therapy has been underexplored owing to the inactive dominant (111) facets. Herein, lattice tensile strain is introduced by surface reconstruction to activate the inert surface, endowing the strained Pd NSs (SPd NSs) with photodynamic, catalase-like, and peroxidase-like properties. Tensile strain promoting the photodynamic and enzyme-like activities is revealed by density functional theory calculations. Compared with Pd NSs, SPd NSs exhibit lower photothermal effect, but approximately five times higher tumor inhibition rate. This work calls for further study to activate nanomaterials by strain engineering and surface reconstruction for catalytic therapy of tumors.

This study aims to investigate the feasibility and potential of sparse random arrays driven by the particle swarm optimization (PSO) algorithm to generate multiple-focus patterns and a large scanning range without grating lobes, which extends the scanning range of focused ultrasound in the treatment of brain tumors, opening the blood-brain barrier, and neuromodulation. Operating at 1.1 MHz, a random spherical array with 200 square elements (sparseness 58%) and a sparse random array with 660 square elements (sparseness 41%) driven by PSO are employed to simulate different focus patterns. With the same radius of curvature and diameter of transducer and element size, the scanning range of the off-axis single focus of a random 200-element array is two times that of an ordinary array using symmetric arrangement. The focal volume of multiple-focus patterns of the random array is 18 times that of the single focus. The single focus of the sparse random array with 660 elements could steer up to ±23 mm in the radial direction, without grating lobes. The maximum distance between two foci in a multiple-focus "S"-shaped deflection is approximately 25 mm. Simulation results illustrate the capability of a focused beam steered in 3-D space. Multiple-focus patterns could significantly increase the focal volume and shorten the treatment time for large target volumes. Simulation results show the feasibility and potential of the method combining PSO with a sparse random array to generate flexible focus patterns that can adapt to different needs in different tissue treatments.

Cancer stem cells (CSCs), a type of cell with self-renewal, unlimited proliferation, and insensitivity to common physical and chemical factors, are the key to cancer metastasis, recurrence, and chemo-resistance. Available CSCs inhibition strategies are mainly based on small molecule drugs, yet are limited by their off-target toxicity. The link between CSCs and non-CSCs interconversion is difficult to sever. In this work, a nanotherapeutic strategy based on MnO

Objective. Histotripsy is a non-invasive focused ultrasound ablation method that can mechanically disintegrate tissues. This study aims to verify that ultrasound-guided histotripsy using millisecond-length two-stage ultrasound pulses combined with fundamental and second harmonic superposition can enhance treatment in rabbit kidneys in vivo. Approach. Rabbit kidneys (n = 10) were treated using a custom-designed 1.1/2.2 MHz two-element confocal-annular array, with lateral and axial full width at half-maximum pressure dimensions of approximately 1.0 and 6.0 mm. Two-stage ultrasound pulses were applied: stage 1 used 60–80 pulses with a pulse duration of 6 ms and a pulse repetition frequency of 10 Hz. Meanwhile, stage 2 consists of 2–4 periods, each period consists of a concentrated pulse train of localized high DC of 6% and an off-time of 3–5 s, with an average DC of 1%–1.5%. B-mode ultrasound imaging was used to guide and monitor the boiling and cavitation bubbles. Main results. Ultrasound-guided treatment was successful in all rabbits, and the ablation rate is about seven times that of single-frequency combined two-stage pulses, achieving enhanced histotripsy. The regular elliptical lesions with dimensions of 10.6 ± 0.8 mm × 3.9 ± 0.6 mm (axial × lateral) were generated, and a large-volume lesion was generated by multi-point treatment. The size of most lysates was about 2.5 μm. Histologically, lesions were completely homogenized and well demarcated between treated-untreated areas. There was no apparent damage to critical structures surrounding lesions. Nonlinear simulations revealed that it may be the interaction between shock front and the cavitation and boiling bubbles generated by the dual-frequency effect enhanced the treatment efficiency. Significance. The novel histotripsy could improve treatment efficiency and generate regular elliptical lesions with controllable shape and axial dimensions, which may be a useful tool in treating renal cell carcinoma.

The size modulation of hollow carbon nanospheres (HCSs) has attracted great interest in the contexts of cellular uptake, drug delivery and bioimaging. In this study, a facile fabrication method was specifically used to minimize all influencing factors except for the particle size. A series of nanoparticles of hollow carbon nanospheres embedded with magnetic resonance imaging (MRI) nanoagent γ-Fe

Citrullinated histone H3 (H3Cit) is the product of the conversion of peptidylarginine to citrulline in histone H3. We evaluated the H3Cit level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) tissues and assessed its association with Beclin1 messenger RNA (mRNA) (a key autophagic regulator). The level of H3Cit was detected by a capture enzyme-linked immunosorbent assay, while Beclin1 mRNA was determined by real-time polymerase chain reaction in 80 HBV-related patients with HCC. We found that the mean level of H3Cit was 72.25 ng/mg in HCC and 44.02 ng/mg in nontumor tissues. The mean HCC/nontumor ratio of Beclin1 mRNA was higher (0.096) in tumor samples than in nontumor specimens (0.056). Specifically, Beclin1 mRNA was elevated in 51 HCC cases (63.75%) and decreased in 29 cases (36.25%). Moreover, the levels of H3Cit and Beclin1 mRNA were significantly associated with vascular invasion and serum AFP levels. A shorter survival (19 months) was associated with a high H3Cit level. We also found increased levels of Beclin1 mRNA in the H3Cit (high) group compared with the H3Cit (low) group. The results implied that elevated histone H3 citrullination is associated with increased Beclin1 expression during the development of HBV-related HCC.

Ammonium (NH

Background Epigenetic alterations of tumor-associated genes contribute to the pathogenesis of virtually all cancer types. We evaluated the methylation status of the interleukin-10 (IL-10) gene promoter and assessed its association with IL-10 mRNA expression and clinical prognosis in hepatocellular carcinoma (HCC) patients. Methods Methylation-specific polymerase chain reaction (MSP) and real-time polymerase chain reaction (PCR) were used to define the methylation index (MI) of the IL-10 gene and quantify IL-10 mRNA expression in 120 HCC samples and paired non-tumor tissues. Results Mean MI was 0.47 in HCC specimens and 0.59 in non-tumor controls, and was associated with metastasis classification and serum α-fetoprotein (AFP) levels. IL-10 mRNA levels [mean –∆∆Ct of 1.678 in HCC cases with hypomethylation (∆MI ≤0) and –0.18 in HCC cases with hypermethylation (∆MI >0)] also correlated with metastasis classification and serum AFP. An association was detected between IL-10 mRNA and its gene’s MI in HCC. Also, an association was found between IL-10 hypomethylation, but not IL-10 mRNA expression and reduced postoperative HCC survival. Conclusions These results indicate that IL-10 promoter hypomethylation is associated with increased IL-10 mRNA levels and indicative of poor survival in HCC.

A novel histotripsy approach based on fundamental and second harmonic superposition and incorporating hundred-microsecond-long pulses and two-stage pulse protocol is proposed in this study to rapidly generate mechanically homogenized lesions. Two pulse stages were applied: stage 1, pulses with a pulse duration of 500-600 μs and pulse repetition frequency of 100 Hz, and stage 2, multiple periods, each composed of multiple pulses with the same pulse duration and pulse repetition frequency as those in stage 1, but with an off-time of 600 ms between periods. A custom-designed 1.1/2.2-MHz two-element confocal-annular array, with an f-number of 0.69, and lateral and axial full width at half-maximum pressure dimensions of approximately 1.0 and 6.0 mm, was used. The peak positive/negative pressures at the focus were +22/-7 MPa for 1.1 MHz and +56/-14 MPa with shock wave for 2.2 MHz. To investigate the feasibility of this approach, experiments were designed and performed in tissue-mimicking polyacrylamide gel phantoms with bovine serum albumin and in ex vivo porcine tissues. Cavitation and boiling activities were observed through high-speed photography, and the corresponding acoustic emissions were recorded through passive cavitation detection. Ex vivo experimental results revealed that complete tissue homogeneous regions with regular long tear shape and typical dimensions of 5.80 ± 0.19 mm in axial and 2.20 ± 0.26 mm in lateral were successfully generated in porcine kidney samples. The hematoxylin and eosin staining evidenced that the lesions were thoroughly homogenized and sharply demarcated from untreated regions. These results indicated that the histotripsy approach using fundamental and second harmonic superposition combined with hundred-microsecond pulses and two-stage pulse protocol can efficiently obtain a mechanical disruption of soft tissues with spatial precision, and this approach may have the potential to be developed as a useful tool for precise tumor treatment.

Breast cancer is the cancer with the highest incidence all over the world. Phosphatidylinositol 3-kinase is an important regulator of intracellular signaling pathways, which is frequently mutated and overexpressed in majority of human breast cancers, and the inhibition of PI3K has been considered as a promising approach for the treatment of the cancer. Here, we report our design and synthesis of new 7-azaindole derivatives as PI3K inhibitors through the scaffold hopping strategy. By varying the groups at the 3-position of 7-azaindole, we identified a series of potent PI3K inhibitors, whose antiproliferative activities against two human breast cancer MCF-7 and MDA-MB-231 cell lines were evaluated. Representative derivatives FD2054 and FD2078 showed better activity than BKM120 in antiproliferation, reduced the levels of phospho-AKT and induced cell apoptosis. All these results suggested that FD2054 and FD2078 are potent PI3K inhibitors that could be considered as potential candidates for the development of anticancer agents.

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29–51 fold over other PI3K isoforms) against PI3Kδ, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, in vivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3Kδ inhibitor for the treatment of leukemia such as AML.

Cinnoline is a potential pharmacophore which has rarely been reported for uses as PI3K inhibitors. In this study, a series of cinnoline derivatives were developed as PI3K inhibitors and evaluated for enzymatic and cellular activities. Most compounds displayed nanomolar inhibitory activities against PI3Ks, among which 25 displayed high LLE and micromolar inhibitory potency against three human tumor cell lines (IC50 = 0.264 μM, 2.04 μM, 1.14 μM).

The viscoelastic properties of tissues can reflect human physiological and pathological conditions. During and after the high-intensity focused ultrasound (HIFU) treatment, measuring the viscoelasticity of HIFU ablated tissue is important for therapy evaluation. Two-dimensional Fourier transform (2DFT) method has been reported to quantify elasticity and viscosity. However, a deviation is induced by under-sampling in practical application. This work proposes an approach based on the convolution theorem and model fitting to solve the finite spatial data problem. A model using the convolution theorem was constructed, and mean-square error (MSE) was calculated to determine the optimal fitting between the model and experimental data. For validation, HIFU therapeutic experiments were conducted in polyacrylamide-bovine serum (BAS) transparent tissue-mimicking phantoms. This approach was used to quantify the viscoelasticity of HIFU ablation and untreated phantoms. Acoustic-radiation-force (ARF) shear wave was generated by the same HIFU therapeutic transducer, and laser Doppler vibrometer (LDV) was used for the high-resolution measurement of shear wave signals. Results suggest that the shear elasticity and viscosity of untreated phantoms are generally smaller than those of HIFU ablation. Thus, the proposed method may be helpful for HIFU treatment monitoring.

Key Findings: Combining physical fractionation and pyrolysis&ndash, gas chromatography/mass spectrometry (py-GC/MS) technique can help better understand the dynamics of soil organic matter (SOM). Background and Objectives: SOM plays a critical role in the global carbon (C) cycle. However, its complexity remains a challenge in characterizing chemical molecular composition within SOM and under nitrogen (N) deposition. Materials and Methods: Three particulate organic matter (POM) fractions within SOM and under N treatments were studied from perspectives of distributions, C contents and chemical signatures in a subtropical forest. N addition experiment was conducted with two inorganic N forms (NH4Cl and NaNO3) applied at three rates of 0, 40, 120 kg N ha&minus, 1 yr&minus, 1. Three particle-size fractions (&gt, 250 &mu, m, 53&ndash, m and &lt, 53 &mu, m) were separated by a wet-sieving method. Py-GC/MS technique was used to differentiate between chemical composition. Results: A progressive proportion transfer of mineral-associated organic matter (MAOM) to fine POM under N treatment was found. Only C content in fine POM was sensitive to N addition. Principal component analyses (PCA) showed that the coarse POM had the largest plant-derived markers (lignins, phenols, long-chain n-alkanes, and n-alkenes). Short-chain n-alkanes and n-alkenes, benzofurans, aromatics and polycyclic aromatic hydrocarbons mainly from black carbon prevailed in the fine POM. N compounds and polysaccharides from microbial products dominated in the MAOM. Factor analysis revealed that the degradation extent of three fractions was largely distinct. The difference in chemical structure among three particulate fractions within SOM was larger than treatments between control and N addition. In terms of N treatment impact, the MAOM fraction had fewer benzofurans compounds and was enriched in polysaccharides, indicating comparatively weaker mineralization and stronger stabilization of these substances. Conclusions: Our findings highlight the importance of chemical structure in SOM pools and help to understand the influence of N deposition on SOM transformation.

Intracerebral hemorrhage is a life-threatening acute cerebrovascular disease characterized by a 30-d mortality rate of 40% and substantial disability for those who survive. The objective of this study is to investigate the feasibility of histotripsy-mediated efficient and fine liquefaction of large-volume hematoma by utilizing a protocol of millisecond-length ultrasound pulse groups combined with fundamental and second harmonic superposition. Experiments were initially performed in an in vitro hematoma phantom, using a two-element confocal-annular array. Results showed that a single ellipsoid shape, histotripsy lesion with major dimensions of 10.8 ± 1.2 mm axially and 4.8 ± 0.2 mm laterally was successfully generated. Controllability of the lesion shape and size could be realized by modulating treatment parameters in single-spot experiments. Large-volume hematomas were efficiently and finely liquefied through multisonications via a treatment strategy under the relatively optimized treatment parameters. Liquefied contents were evacuated and analyzed using a particle sizing system. The size of the lysates for the most part ranged from 4-8 μm, with more than 99% of them being smaller than 10 μm. Experiments were then conducted in an optically transparent tissue phantom to explore the liquefaction mechanisms. The phantom was composed of polyacrylamide hydrogel, embedded with bovine serum albumin (BSA), and a thin phantom layer consisted of red blood cells in the BSA polyacrylamide gel was inlayed in the BSA gel phantom. The related mechanisms, such as the frequent boiling that occurred at multiple positions and the enhanced cavitation, revealed the quick development of the lesion in the phantom and the efficient liquefaction of the clot. These results indicated that the proposed histotripsy approach is feasible for the efficient, precise and fine liquefaction of large-volume hematoma and may be developed as a useful tool for intracerebral hemorrhage treatment.

A novel strategy for enhancing the activity and stability of metal-activated enzymes by allosteric control and confinement of metal-nulceobase hybrid coordination was reported in this study. Despite the lack of active Mg2+ ions, methionine adenosyltransferase (MAT) immobilized by Zn2(adenine) still exhibited robust catalytic activity and stability at pH 3 and 80 °C.

External inorganic and organic nitrogen (N) inputs can contrastingly affect the transformation and availability of N in forest soils. Studies have mainly focused on the effects of inorganic N enrichment, whereas little is known about the effects of organic N input on soil gross N transformation and the underlying microbial mechanisms. Here we conducted a laboratory 15N tracing study in a temperate needle-broadleaved mixed forest with a fertilization rate of 0, 20, 60, and 120 kg urea-N ha−1 yr−1 over three years. We investigated the key drivers of soil N transformation processes using a 15N tracing model in the context of selected soil chemical properties and microbial characteristics. Urea addition did not change soil gross N mineralization rates, while stimulating mineralization of labile organic N (MNlab). Urea addition at a rate of 120 kg N ha−1 yr−1 significantly increased autotrophic nitrification and gross nitrification rates by 88% and 96%, respectively. In contrast, all the three levels of urea addition significantly reduced gross microbial N immobilization by 28% to 52%, leading to an increase in the accumulation of soil NO3−-N in the top 10 cm soil layer by 38% to 88%. The changes in autotrophic nitrification were primarily driven by acid-tolerant ammonia-oxidizing archaea (AOA). Fungi were responsible for the change in heterotrophic nitrification under organic N enrichment. Gross N transformation rates were predominately regulated by AOA and fungal abundances as well as soil NO3−-N content under high level of organic N addition. The response of soil N transformation to exogenous organic N input depended on N addition level with the threshold rate being estimated to be 60–120 kg N ha−1 yr−1. All lines of evidence showed that the temperate needle-broadleaved mixed forest is moving towards an opener microbial N cycle under elevated organic N deposition. Our finding suggests that the effect of organic N input on soil gross N transformation is different from that of inorganic N input, which should be considered in ecosystem process models.