PET-MR Guided, Pre-targeted delivery to HER2(+) Breast Cancer Model.

Purpose: HER2(+) metastatic breast cancer (mBC) is one of the most aggressive and lethal cancer types among females. While initially effective, targeted therapeutic approaches with trastuzumab and pertuzumab antibodies and antibody-drug conjugates (ADC) lack long-term efficacy against HER2(+) mBC and can cause severe systemic toxicity due to off-target effects. Therefore, the development of novel targeted delivery platforms that minimize toxicity and increase therapeutic efficacy is critical to the treatment of HER2(+) breast cancer (BC). A pretargeting delivery platform can minimize the non-specific accumulation and off-target toxicity caused by traditional one-step delivery method by separating the single delivery step into a pre-targeting step with high-affinity biomarker binding ligand followed by the subsequent delivery step of therapeutic component with fast clearance. Each delivery component is functionalized with bioorthogonal reactive groups that quickly react in situ, forming cross-linked clusters on the cell surface, which facilitates rapid internalization and intracellular delivery of therapeutics. Procedures: We have successfully developed a click chemistry-based pretargeting platform for HER2(+) BC enabling PET-MR image guidance for reduced radiation dose, high sensitivity, and good soft tissue contrast. Radiolabeled trastuzumab and superparamagnetic iron-oxide carriers (uSPIO) were selected as pretargeting and delivery components, respectively. HER2(+) BT-474 cell line and corresponding xenografts were used for in vitro and in vivo studies. Results: An enhanced tumor accumulation as well as tumor-to-organ accumulation ratio was observed in pretargeted mice up to 24 h post uSPIO injection. A 40% local T1 decrease in the pretargeted mice tumor was observed within 4 h, and an overall 15% T1 drop was retained for 24 h post uSPIO injection. Conclusions: Prolonged tumor retention and increased tumor-to-organ accumulation ratio provided a solid foundation for pretargeted image-guided delivery approach for in vivo applications.

The First Genome-Wide Survey of Shortbelly Eel (Dysomma anguillare Barnard, 1923) to Provide Genomic Characteristics, Microsatellite Markers and Complete Mitogenome Information.

Dysomma anguillare is a demersal eel widespread distributing in tropical waters of the Indo-West Pacific and Atlantic. As an important component of the coastal fishery and marine ecosystem, the lack of genomic information for this species severely restricts the progress of relevant researches. In this study, the abecedarian genome-wide characteristics and phylogenetic relationships analyses were carried out based on next-generation sequencing (NGS) platform. The revised genome size was approximately 1 310 Mb, with the largest scaffold length reaching 23 878 bp through K-mer (K = 17) method. The heterozygosity, repetitive rate and average GC content were about 0.94%, 51.93% and 42.23%, respectively. A total of 1 160 104 microsatellite motifs were identified from the de novo assembled genome of D. anguillare, in which dinucleotide repeats accounted for the largest proportion (592 234, 51.05%), the highest occurrence frequency (14.58%) as well as the largest relative abundance (379.27/Mb). The high-polymorphic and moderate-polymorphic loci composed around 73% of the total single sequence repeats (SSRs), showing a latent capacity for subsequent population genetic structure and genetic diversity appraisal researches. Another byproduct of whole-genome sequencing, the double-stranded and circular mitogenome (16 690 bp) was assembled to investigate the evolutionary relationships of D. anguillare. The phylogenic tree constructed with maximum likelihood (ML) method showed that D. anguillare was closely related to Synaphobranchidae species, and the molecular systematic results further supported classical taxonomy status of D. anguillare.

Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling.

Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.

VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation.

The availability of nanoparticles (NPs) to deliver small interfering RNA (siRNA) has significantly expanded the specificity and range of 'druggable' targets for precision medicine in cancer. This is especially important for cancers such as triple negative breast cancer (TNBC) for which there are no targeted treatments. Our purpose here was to understand the role of tumor vasculature and vascular endothelial growth factor (VEGF) overexpression in a TNBC xenograft in improving the delivery and function of siRNA NPs using in vivo as well as ex vivo imaging. We used triple negative MDA-MB-231 human breast cancer xenografts derived from cells engineered to overexpress VEGF to understand the role of VEGF and vascularization in NP delivery and function. We used polyethylene glycol (PEG) conjugated polyethylenimine (PEI) NPs to deliver siRNA that downregulates choline kinase alpha (Chkα), an enzyme that is associated with malignant transformation and tumor progression. Because Chkα converts choline to phosphocholine, effective delivery of Chkα siRNA NPs resulted in functional changes of a significant decrease in phosphocholine and total choline that was detected with 1H magnetic resonance spectroscopy (MRS). We observed a significant increase in NP delivery and a significant decrease in Chkα and phosphocholine in VEGF overexpressing xenografts. Our results demonstrated the importance of tumor vascularization in achieving effective siRNA delivery and downregulation of the target gene Chkα and its function.

Ultrasmall Superparamagnetic Iron Oxide Nanoparticles as Nanocarriers for Magnetic Resonance Imaging: Development and In Vivo Characterization.

Ultrasmall superparamagnetic iron oxide nanoparticles (uSPIOs) are attractive platforms for the development of smart contrast agents for magnetic resonance imaging (MRI). Oleic acid-capped uSPIOs are commercially available yet hydrophobic, hindering in vivo applications. A hydrophilic ligand with high affinity toward uSPIO surfaces can render uSPIOs water-soluble, biocompatible, and highly stable under physiological conditions. A small overall hydrodynamic diameter ensures optimal pharmacokinetics, tumor delivery profiles, and, of particular interest, enhanced T 1 MR contrasts. In this study, for the first time, we synthesized a ligand that not only fulfills the as-proposed properties but also provides multiple reactive groups for further modifications. The synthesis delivers a facile approach using commercially available reactants, with resultant uSPIO-ligand constructs assembled through a single-step ligand exchange process. Structural and molecular size analyses confirmed size uniformity and small hydrodynamic diameter of the constructs. On average, 43 reactive amine groups were present per uSPIO nanoparticle. Its r 1 relaxivity has been tested on a 7 Tesla MR instrument and is comparable to that of the clinically available T 1 gadolinium-based contrast agent GBCA (1 vs 3 mM-1 s-1, respectively). A significant decrease in tumor T1 (15%) within 1 h of injection and complete signal recovery after 2 h were detected with a dose of 7 µg Fe/g mouse. The agent also has high r 2 relaxivity and can be used for T 2 contrast-enhanced MRI. Taken together, good relaxation and delivery properties and the presence of multiple surface reactive groups can facilitate its application as a universal MRI-compatible nanocarrier platform.

Dual-Modality PET-SPECT Image-Guided Pretargeting Delivery in HER2(+) Breast Cancer Models.

Pretargeted drug delivery has been explored for decades as a promising approach in cancer therapy. An image-guided pretargeting strategy significantly enhances the intrinsic advantages of this approach since imaging the pretargeting step can be used for diagnostic purposes, while imaging of the drug delivery step can be utilized to evaluate drug distribution and assess therapeutic response. A trastuzumab (Tz)-based HER2 pretargeting component (Tz-TCO-[89Zr-DFO]) was developed by conjugating with trans-cyclooctene (TCO) bioorthogonal click chemistry functional groups and deferoxamine (DFO) to enable radiolabeling with a 89Zr PET tracer. The drug delivery component (HSA-DM1-Tt-[99mTc-HyNic]) was developed by conjugating human serum albumin (HSA) with mertansine (DM1), tetrazine (Tt) functional groups, and a HyNic chelator and radiolabeling with 99mTc. For ex vivo biodistribution studies, pretargeting and delivery components (without drug) were administered subsequently to mice bearing human HER2(+) breast cancer xenografts, and a high tumor uptake of Tz-TCO-[89Zr-DFO] (26.4% ID/g) and HSA-Tt-[99mTc-HyNic] (4.6% ID/g) was detected at 24 h postinjection. In vivo treatment studies were performed in the same HER2(+) breast cancer model using PET-SPECT image guidance. The increased tumor uptake of the pretargeting and drug delivery components was detected by PET-CT and SPECT-CT, respectively. The study showed a significant 92% reduction of the relative tumor volume in treated mice (RTV = 0.08 in 26 days), compared to the untreated control mice (RTV = 1.78 in 11 days) and to mice treated with only HSA-DM1-Tt-[99mTc-HyNic] (RTV = 1.88 in 16 days). Multimodality PET-SPECT image-guided and pretargeted drug delivery can be utilized to maximize efficacy, predict therapeutic response, and minimize systemic toxicity.

Two-Electron Interference in Strong-Field Ionization of He by a Short Intense Extreme Ultraviolet Laser Pulse.

Double ionization of helium by a single intense (above 10^{18} W/cm^{2}) linearly polarized extreme ultraviolet laser pulse is studied by numerically solving the full-dimensional time-dependent Schrödinger equation. For the laser intensities well beyond the perturbative limit, novel gridlike interference fringes are found in the correlated energy spectrum of the two photoelectrons. The interference can be traced to the multitude of two-electron wave packets emitted at different ionization times. A semianalytical model for the dressed two-photon double ionization is shown to qualitatively account for the interference patterns in the joint energy spectrum. Similar signatures of interferences between transient induced time-delayed ionization bursts are expected for other atomic and molecular multielectron systems.

Photon Momentum Transfer in Single-Photon Double Ionization of Helium.

We theoretically and experimentally investigate the photon momentum transfer in single-photon double ionization of helium at various large photon energies. We find that the forward shifts of the momenta along the light propagation of the two photoelectrons are roughly proportional to their fraction of the excess energy. The mean value of the forward momentum is about 8/5 of the electron energy divided by the speed of light. This holds for fast and slow electrons despite the fact that the energy sharing is highly asymmetric and the slow electron is known to be ejected by secondary processes of shake off and knockout rather than directly taking its energy from the photon. The biggest deviations from this rule are found for the region of equal energy sharing where the quasifree mechanism dominates double ionization.

[The effects of multi-mode audio frequency pulse modulating laser together with electrical stimulation on blood pressure and hemorrheology of the spontaneously hypertensive rats].

In order to explore new ways in restraining the ascending blood pressure, this paper reports a research on the effects of multi-mode audio frequency pulse modulating laser irradiation with electrical stimulation on the hemorrheology and blood pressure of the spontaneously hypertensive rats (SHR). Forty male SHR were randomly divided into four groups: Group A (control), Group B (treated with electrical stimulation on stomach 36 point (ST-36)), Group C (treated with low level pulse laser irradiation on Erjian acupuncture point), Group D (low level laser irradiation together with electrical stimulation on Erjian acupuncture point and ST-36). Laser irradiation lasted for 45 min/ day, while electrical stimulation lasted for 30 min/day. After 10 days' treatment, we compared the hemorrheology and blood pressure of the rats in the four groups. The results were that values of hemorrheology in group A and group C were obviously improved compared with those in the other two groups. Meanwhile, the blood pressures in the three treated groups (B, C, and D) were lower than in the control group after the treatment, and the value of the rats in group A was the lowest. In conclusion, the treatment the laser irradiation combined with electrodes stimulation on spontaneously hypertensive rats brought better results of hemorrheology and blood pressure in the tested rats.

[Study on spectral measurement methods in identification of maize variety authenticity based on near infrared spectra of single kernels].

In order to establish the better maize variety identification models based on single kernel samples, the near-infrared spectral measurement methods were studied by comparing the direction of the maize seed's embryo, diffuse reflectance and transmission mode, devices of holding the sample according to their impacts on the performance of variety identification models. Partial least squares-discriminant analysis (PLSDA) was used to compress the pretreated spectral data into 9 variables, and then the identification models were built based on biomimetic pattern recognition (BPR). The results show that with the maize grain's embryo facing the light source the models can be made perform better than with embryo backing toward the light source, diffuse reflectance mode is better than transmission mode, and small sample pool performs better than the small aperture. The measurement method of acquiring the diffuse reflectance near infrared spectra of maize by small pool with the seed embryo facing the light source can make models have the best performance. The average correct identification rate of the models is 94.6%, and the average correct rejection rates for the varieties not belonging to the models reached 96.5%.