Delafossite-structured CuAlO2 materials with and without vacancy defects were investigated comparatively using the first principle calculation method. The method based on the density functional ...theory, has been carried out to search the systems’ ground states and supplies the corresponding electronic properties. In the process of calculations, ultrasoft pseudo-potentials and PBE-GGA functionals are chosen for the atoms and exchange-correlation interactons between electrons, respectively. The geometry optimization shows the Al vacancy causes a larger lattice deformation than the vacancies of Cu and O atoms. The results of Mulliken charge also verify this conclusion. The calculations of vacancy formation energy and elastic constants indicate the Cu vacancy has the lowest formation energy, the highest Pugh ratio and the smallest Zener anisotropy factor, which means the introduction of Cu vacancy can improve the functional applications of Cu-based delafossites, e.g. p-type conductivity, ductility, etc.
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, ...represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
Multifunctional theranostic nanoplatforms integrated of imaging function, multi-modality therapy, stimuli-responsiveness, and targeted delivery are of highly desirable attributes in achieving precise ...medicine. However, preparation of multifunctional nanoplatforms often involves laborious, multiple steps and inevitably utilizes low-biocompatible or non-functional components. Herein we report a facile, one-step self-assembly strategy to fabricate hyaluronic acid (HA)-based multifunctional tumor theranostic nanoplatform by employing magnetic resonance imaging (MRI) agent Mn2+ as a reversible crosslink agent for histidine-grafted HA, along with simultaneously loading chemotherapeutic agent doxorubicin hydrochloride (DOX) and photodynamic therapy agent chlorin e6, to realize MRI-guided targeted chemo-photodynamic cancer therapy. The targeted delivery and stimuli-responsive payload release were demonstrated in vitro and in vivo. Furthermore, the combined chemo-photodynamic therapy of the nanoassembly dramatically improved the cancer therapeutic outcome, in comparison with that of free DOX and nanoplatform solely loaded DOX in a melanoma bearing mice. Our one step assemble strategy is of great potential in clinic transformation.
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•One-step strategy was employed to prepare multifunctional hyaluronic acid nanogels.•No extra low-biocompatible or non-functional components were used in this process.•Such platform achieved MRI-guided responsive chemo-photodynamic cancer therapy.
Despite recent advancements in colorectal cancer (CRC) treatment, the prognosis remains unfavorable primarily due to high recurrence and liver metastasis rates. Fluorescence molecular imaging ...technologies, combined with specific probes, have gained prominence in facilitating real-time tumor resection guided by fluorescence. Hepatocyte growth factor (HGF) is overexpressed in CRC, but the advancement of HGF fluorescent probes has been impeded by the absence of effective HGF-targeting small-molecular ligands. Herein, we present the targeted capabilities of the novel V-1-GGGK-MPA probe labeled with a near-infrared fluorescent dye, which targets HGF in CRC. The V-1-GGGK peptide exhibits high specificity and selectivity for HGF-positive in vitro tumor cells and in vivo tumors. Biodistribution analysis of V-1-GGGK-MPA revealed tumor-specific accumulation with low background uptake, yielding signal-to-noise ratio (SNR) values of tumor-to-colorectal >6 in multiple subcutaneous CRC models 12 h postinjection. Quantitative analysis confirmed the probe’s high uptake in SW480 and HT29 orthotopic and liver metastatic models, with SNR values of tumor-to-colorectal and -liver being 5.6 ± 0.4, 4.6 ± 0.5, and 2.1 ± 0.3, 2.0 ± 0.5, respectively, enabling precise tumor visualization for surgical navigation. Pathological analysis demonstrated the excellent tumor boundaries discrimination capacity of the V-1-GGGK-MPA probe at the molecular level. With its rapid tumor targeting, sustained tumor retention, and precise tumor boundary delineation, V-1-GGGK-MPA merges as a promising HGF imaging agent, enriching the toolbox of intraoperative navigational fluorescent probes for CRC.
Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal ...antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC.
Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS).
In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%).
Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.
Antimony-doped tin oxide nanopowders were synthesized by the hydrothermal method. Porous antimony-doped tin oxide ceramics with variant porosity were obtained by controlling the spark plasma ...sintering temperatures. It was found that antimony doping can effectively improve the electric conductivity of SnO
2
, while the nanosized pores sufficiently reduce the thermal conductivity. An extremely low thermal conductivity of 0.79 W m
-
1
K
-
1
is obtained at room temperature in the sample sintered at 500
∘
C with porosity of 32.2%. However, the porous sample exhibits poor electrical conductivity. With increasing sintering temperature, the porosity of ceramic samples decreases gradually. Consequently, the lattice thermal conductivity increases monotonically. Meanwhile, both electrical conductivity and Seebeck coefficient show improvement with increasing sintering temperature. After sintering at 1000
∘
C, Sn
0.99
Sb
0.01
O
2
sample still owns a porosity of 7.2% and the lattice thermal conductivity is still as low as 4.2 W m
-
1
K
-
1
. As a result, a maximum ZT of
∼
0.05 is achieved at 500
∘
C for Sn
0.99
Sb
0.01
O
2
sintered at 1000
∘
C, which is higher than the ZT value ever reported for SnO
2
.
Nano-graphene oxide (NGO) has attracted increasing attention as an advanced drug delivery system. However, the current surface functionalization and drug-loading of NGO either rely on π-π stacking ...that is limited to aromatic molecules, or covalent conjugation that requires tedious synthesis. Herein, we developed the first cucurbit7uril (CB7)-conjugated NGO (NGO-CB7) that allows non-covalent, modular surface functionalization and drug loading via not only traditional π-π stacking interactions between the NGO surface and functional molecules, but also strong host-guest interactions between CB7 and guest payloads or adamantane (ADA)-tagged functional molecules, for more versatile biomedical applications. To this end, chlorin e6 (Ce6, a photosensitizer), banoxantrone dihydrochloride (AQ4N, a hypoxia-responsive prodrug) and oxaliplatin (OX, a guest of CB7) were co-loaded onto NGO-CB7 via π-π stacking and host-guest interactions, respectively. Subsequently, ADA-tagged hyaluronic acid (ADA-HA) wrapped NGO-CB7 non-covalently via CB7-ADA host-guest interactions to improve the physiological stability and overall biocompatibility of this supramolecular nanosystem, and to enable targeted delivery into cancer cells with CD44 receptors overexpressed. Remarkably, this supramolecular nanomedicine exhibited significant antitumor efficacy via combined photothermal/photodynamic therapy (PTT/PDT) from NGO/Ce6, as well as dual chemotherapy from OX and AQ4N (activated by PDT-enhanced hypoxia), in vitro and in vivo. This study not only offers a new supramolecular inorganic/organic hybrid nanosystem for multi-modality cancer therapy, but may also provide important new insights into noncovalent functionalization of other carbon nanomaterials and inorganic nanomaterials leading to multifunctional drug delivery systems.
Despite advancements in pancreatic cancer treatment, it remains one of the most lethal malignancies with extremely poor diagnosis and prognosis. Herein, we demonstrated the efficiency of a novel ...peptide GB-6 labeled with a near-infrared (NIR) fluorescent dye 3H-indolium, 2-2-2-(2-carboxyethyl)thio-3-2-1,3-dihydro-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-2H-indol-2-ylideneethylidene-1-cyclohexen-1-ylethenyl-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-, inner salt (MPA) and radionuclide technetium-99m (99mTc) as targeting probes using the gastrin-releasing peptide receptor (GRPR) that is overexpressed in pancreatic cancer as the target. A short linear peptide with excellent in vivo stability was identified, and its radiotracer 99mTcTc-HYNIC-PEG4-GB-6 and the NIR probe MPA-PEG4-GB-6 exhibited selective and specific uptake by tumors in an SW1990 pancreatic cancer xenograft mouse model. The favorable biodistribution of the tracer 99mTcTc-HYNIC-PEG4-GB-6 in vivo afforded tumor-specific accumulation with high tumor-to-muscle and -bone contrasts and renal body clearance at 1 h after injection. The biodistribution analysis revealed that the tumor-to-pancreas and -intestine fluorescence signal ratios were 5.2 ± 0.3 and 6.3 ± 1.5, respectively, in the SW1990 subcutaneous xenograft model. Furthermore, the high signal accumulation in the orthotopic pancreatic and liver metastasis tumor models with tumor-to-pancreas and -liver fluorescence signal ratios of 7.66 ± 0.48 and 3.94 ± 0.47, respectively, enabled clear tumor visualization for intraoperative navigation. The rapid tumor targeting, precise tumor boundary delineation, chemical versatility, and high potency of the novel GB-6 peptide established it as a high-contrast imaging probe for the clinical detection of GRPR, with compelling additional potential in molecular-targeted therapy.
Solute and vacancy depletion have long been investigated to reveal the formation mechanism of grain boundary precipitate-free zones (GB-PFZ) during ageing, yet there is no conclusive explanation due ...to the simultaneous appearance of the two in GB-PFZ. In this study, the evolution of GB-PFZs and solute distributions in the vicinity of grain boundaries (GBs) were studied during the homogenisation of an Al–Cu–Mg–Mn alloy using transmission electron microscopy, high-angle annular dark field scanning transmission electron microscopy, and energy-dispersive X-ray spectroscopy. Results indicated that the evolution of GB-PFZ during homogenisation can be divided into the following three stages: Stage I, formation and recession of GB-PFZ; Stage II, absence of GB-PFZ, and Stage III, the reappearance and broadening of GB-PFZ. The results also revealed that the GB-PFZ in Stage I is totally devoid of solute depletion and its formation can be attributed to vacancy depletion alone. The GB-PFZ at Stage III solely caused by solute depletion and excludes vacancy depletion.
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