Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an ...antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
Background
The aim of this study was to investigate the prevalence of epidemiologic and physician‐diagnosed pollen‐induced AR (PiAR) in the grasslands of northern China and to study the impact of the ...intensity and time of pollen exposure on PiAR prevalence.
Methods
A multistage, clustered and proportionately stratified random sampling with a field interviewer‐administered survey study was performed together with skin prick tests (SPT) and measurements of the daily pollen count.
Results
A total of 6043 subjects completed the study, with a proportion of 32.4% epidemiologic AR and 18.5% PiAR. The prevalence was higher in males than females (19.6% vs 17.4%, P = .024), but no difference between the two major residential and ethnic groups (Han and Mongolian) was observed. Subjects from urban areas showed higher prevalence of PiAR than rural areas (23.1% vs 14.0%, P < .001). Most PiAR patients were sensitized to two or more pollens (79.4%) with artemisia, chenopodium, and humulus scandens being the most common pollen types, which were similarly found as the top three sensitizing pollen allergens by SPT. There were significant regional differences in the prevalence of epidemiologic AR (from 18.6% to 52.9%) and PiAR (from 10.5% to 31.4%) among the six areas investigated. PiAR symptoms were positively associated with pollen counts, temperature, and precipitation (P < .05), but negatively with wind speed and pressure P < .05).
Conclusion
Pollen‐induced AR (PiAR) prevalence in the investigated region is extremely high due to high seasonal pollen exposure, which was influenced by local environmental and climate conditions.
Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that ...small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with (125)I-CGRP binding to the human CGRP receptor, with a Ki of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (>5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.
Mg-based materials are promising candidates for high capacity hydrogen storage. However, their poor hydrogenation/dehydrogenation kinetics and high desorption temperature are the main obstacles to ...their applications. This paper reports a method for in situ formation of cycle stable CeH2.73-MgH2-Ni nanocomposites, from the hydrogenation of as-melt Mg80Ce18Ni2 alloy, with excellent hydrogen storage performance. The nanocomposites demonstrate reversible hydrogen storage capacity of more than 4.0 wt %, at a low desorption temperature with fast kinetics and long cycle life. The temperature for the full hydrogenation/dehydrogenation cycle of the composites is significantly decreased to 505 K, which is about 100 K lower than that for pure Mg. The hydrogen desorption activation energy is 63 ± 3 kJ/mol H2 for the composites, which is significantly lower than those of Mg3Ce alloy and pure Mg (104 ± 7 and 158 ± 2 kJ/mol H2, respectively). X-ray diffraction and transmission electron microscopy have been used to reveal the mechanism that delivers this excellent cycle stability and fast hydriding/dehydriding kinetics. It is found that the hydriding/dehydriding process is catalyzed by the combination of in situ formed extremely fine CeH2/CeH2.73 and Ni to Mg/MgH2. In addition, this nanocomposite structure can effectively suppress Mg/MgH2 grain growth and enable the material to maintain its high performance for more than 500 hydrogenation dehydrogenation cycles.
Graphene nanosheets (GNs) were synthesized and used as a substitute for platinum as counter-electrode materials for dye-sensitized solar cells (DSSCs). The as-synthesized GNs were dispersed in a ...mixture of terpineol and ethyl cellulose. GN films were screen-printed on fluorine-doped tin oxide (FTO) slides using the formed GN dispersions. GN counter-electrodes were produced by annealing the GN films at different temperatures. The annealed GN films revealed an unusual 3D network structure. Structural and electrochemical properties of the formed GN counter-electrodes were examined by field emission scanning electron microscopy, Raman spectroscopy and electrochemical impedance spectroscopy. It was found that the annealing temperature of GN materials played an important role in the quality of the GN counter-electrode and the photovoltaic performance of the resultant DSSC. The grown DSSCs with graphene-based counter-electrodes exhibited a conversion efficiency high up to 6.81%.
Huanglongbing (HLB) causes extensive damage in citrus orchards worldwide. Symptoms include blotchy mottle leaf (BML) and little leaf chlorosis (LLC), and nutrient deficiency usually occurs ...concurrently. However, the relationship between plant mineral content and infection with Candidatus Liberibacter asiaticus (CLas) is not clearly established.
We sampled 7‐month‐old autumn shoots with three characteristic phenotypes, asymptomatic leaf (AL), BML and LLC, representing HLB disease progression, and further divided samples into CLas‐infected and uninfected based on PCR analysis.
HLB infection decreased transfer coefficients of Mg and K from leaf to phloem tissues through regulation of the transporter genes Cs3g03790.1 and PtrMGT5, increasing the content of leaf Mg and K. HLB infection also decreased leaf Zn, xylem Ca and phloem Ca and Zn content. Leaf Ca, Mg, Zn and B content decreased while leaf K content increased significantly as symptoms progressed from AL to LLC. The transport of P from leaf to phloem tissue, as evaluated by the transfer coefficient, was regulated by the transporter CsiPT2, resulting in irregular levels of leaf P.
Our results provide insights into the nutrient dynamics in Citrus in response to CLas infection and the progression of HLB symptoms.
The levels and distribution of various nutrients, like Phosphorus, Manganese, and Boron, varied with symptom emergence and later progression, while the contents and distribution of other nutrients, like Potassium, Calcium, Magnesium, and Zinc, were affected by both symptom development and the presence of the HLB pathogen.
Optical coherence tomography (OCT) has several advantages over other imaging modalities, such as angiography and ultrasound, due to its inherently high
resolution, which allows for the identification ...of morphological tissue structures. Optical coherence elastography (OCE) benefits from the superior spatial resolution of OCT and has promising applications, including cancer diagnosis and the detailed characterization of arterial wall biomechanics, both of which are based on the elastic properties of the tissue under investigation. We present OCE principles based on techniques associated with static and dynamic tissue excitation, and their corresponding elastogram image-reconstruction algorithms are reviewed. OCE techniques, including the development of intravascular- or catheter-based OCE, are in their early stages of development but show great promise for surgical oncology or intravascular cardiology applications.
Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic ...effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.
The high-temperature stability and mechanical properties of refractory molybdenum alloys are highly desirable for a wide range of critical applications. However, a long-standing problem for these ...alloys is that they suffer from low ductility and limited formability. Here we report a nanostructuring strategy that achieves Mo alloys with yield strength over 800 MPa and tensile elongation as large as ~ 40% at room temperature. The processing route involves a molecular-level liquid-liquid mixing/doping technique that leads to an optimal microstructure of submicrometre grains with nanometric oxide particles uniformly distributed in the grain interior. Our approach can be readily adapted to large-scale industrial production of ductile Mo alloys that can be extensively processed and shaped at low temperatures. The architecture engineered into such multicomponent alloys offers a general pathway for manufacturing dispersion-strengthened materials with both high strength and ductility.
The impact of central Asian aridification on the low latitude North Pacific Ocean since the late Miocene remains unclear. To address this question, we systematically studied an abyssal manganese ...nodule from the northwestern Pacific Ocean, which is expected to be sensitive to eolian dust sourced from central Asia. Geochemical variations and the fossilized remains of magnetotactic bacteria within the studied nodule manifest two prominent Asian aridification events at ∼8–7 Ma and 3.6–0 Ma. These results suggest that central Asian aridification impacted both primary productivity and abyssal microbial activity in the NW Pacific Ocean via eolian dust inputs. In contrast to the Pliocene aridification event, the late Miocene event was associated with a primary productivity bloom that is not evident in coeval global primary productivity records, which indicates that the ∼8–7 Asian aridification event was likely due to NE Tibetan Plateau uplift rather than to global cooling.
Plain Language Summary
Central Asian aridification since the late Miocene has had a significant influence on climate, temperature, and North Pacific Ocean productivity through eolian dust inputs transported by westerlies. However, it is unclear whether the low latitude of NW Pacific Ocean responded to this aridification. We systematically analyzed the geochemistry and magnetism of a NW Pacific manganese nodule, and find that Asian aridification since, the late Miocene impacted biogeochemical cycling and abyssal microbial activity in the NW Pacific Ocean via eolian dust input. Our results imply that these two prominent Asian aridification events at around 8–7 Ma and ca. 3.6 Ma can be attributed to the NE Tibetan Plateau uplift and global cooling, respectively.
Key Points
A manganese nodule from the NW Pacific carries a paleoclimatic record of Asian aridification since the Late Miocene
Asian aridification impacted biogeochemical cycling and abyssal microbial activity in the NW Pacific Ocean
Major Asian aridification events at ∼8–7 Ma and ∼3.6–0 Ma may be attributed to NE Tibetan Plateau uplift and global cooling, respectively
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