The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the ...oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.
ABSTRACT
The predicted nature of the candidate redback pulsar 3FGL J2039.6–5618 was recently confirmed by the discovery of γ-ray millisecond pulsations (Clark et al., hereafter Paper I), which ...identify this γ-ray source as PSR J2039–5617. We observed this object with the Parkes radio telescope in 2016 and 2019. We detect radio pulsations at 1.4 and 3.1 GHz, at the 2.6 ms period discovered in γ-rays, and also at 0.7 GHz in one 2015 archival observation. In all bands, the radio pulse profile is characterized by a single relatively broad peak which leads the main γ-ray peak. At 1.4 GHz, we found clear evidence of eclipses of the radio signal for about half of the orbit, a characteristic phenomenon in redback systems, which we associate with the presence of intra-binary gas. From the dispersion measure of 24.57 ± 0.03 pc cm−3, we derive a pulsar distance of 0.9 ± 0.2 or 1.7 ± 0.7 kpc, depending on the assumed Galactic electron density model. The modelling of the radio and γ-ray light curves leads to an independent determination of the orbital inclination, and to a determination of the pulsar mass, qualitatively consistent to the results in Paper I.
The clinical use of anticancer drugs necessitates new technologies for their safe, sensitive, and selective detection. In this article, lanthanide (Eu3+ and Tb3+)-loaded γ-cyclodextrin ...nano-aggregates (ECA and TCA) are reported, which sensitively detects the anticancer drug irinotecan by fluorescence intensity changes. Fluorescent lanthanide (Eu3+ and Tb3+) complexes exhibit high fluorescence intensity, narrow and distinct emission bands, long fluorescence lifetime, and insensitivity to photobleaching. However, these lanthanide (Eu3+ and Tb3+) complexes are essentially hydrophobic, toxic, and non-biocompatible. Lanthanide (Eu3+ and Tb3+) complexes were loaded into naturally hydrophilic γ-cyclodextrin to form fluorescent nano-aggregates. The biological nontoxicity and cytocompatibility of ECA and TCA fluorescent nanoparticles were demonstrated by cytotoxicity experiments. The ECA and TCA fluorescence nanosensors can detect irinotecan selectively and sensitively through the change of fluorescence intensity, with detection limits of 6.80 μM and 2.89 μM, respectively. ECA can safely detect irinotecan in the cellular environment, while TCA can detect irinotecan intracellularly and is suitable for cell labeling.
BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and ...tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.
•Accurate control of plasmonic absorption peak by Ag-Au alloying.•With the tunable absorption, jetting is witnessed with the maximum velocity over 1 cm/s driven by both 450 and 532 nm lasers.•Water ...jetting with Ag-rich alloy shows enhanced stability with excitation of 450 nm laser.•The jetting stability is studied based on the morphological evolution of jetting point leaded by thermal conductivities.
Photoacoustic micro-fluidic pumps (PMPs) based on localized surface plasmon resonance (LSPR) of nanoparticles (NPs) can convert photo energy into kinetic energy of fluidic jetting therefore attracted considerable attentions in microfluidics and optofluidics. In this work, PMPs are fabricated using Ag-Au alloy NPs. Through solid-state-dewetting, alloy NPs are prepared of variable component ratios for tunable LSPR absorption between 440 and 530 nm. The relationship between NP morphology and optical properties are studied with the assistant of finite-difference time-domain (FDTD) simulation. Photoacoustic jets are observed through the excitation of both 450 and 532 nm lasers. Noticeably, with 450 nm laser, long lasting jets over 1 h are excited on Ag0.9Au0.1, which sharply contrast to the duration within 1 min on Ag0.2Au0.8 NPs with 532 nm laser, indicating the importance of material selection in performance improvement. Further investigation on jetting stability is performed according to the morphological evolution by laser striking, suggesting the enhanced stability can be related to the increased melting-point and thermal-stability of alloys.
ABSTRACT We present multi-wavelength observations of the unassociated γ-ray source 3FGL J2039.6−5618 detected by the Fermi Large Area Telescope. The source γ-ray properties suggest that it is a ...pulsar, most likely a millisecond pulsar, for which neither radio nor γ-ray pulsations have been detected. We observed 3FGL J2039.6−5618 with XMM-Newton and discovered several candidate X-ray counterparts within/close to the γ-ray error box. The brightest of these X-ray sources is variable with a period of 0.2245 0.0081 days. Its X-ray spectrum can be described by a power law with photon index ΓX = 1.36 0.09, and hydrogen column density NH < 4 × 1020 cm−2, which gives an unabsorbed 0.3-10 keV X-ray flux of 1.02 × 10−13 erg cm−2 s−1. Observations with the Gamma-Ray Burst Optical/Near-Infrared Detector discovered an optical counterpart to this X-ray source, with a time-averaged magnitude g′ ∼ 19.5. The counterpart features a flux modulation with a period of 0.22748 0.00043 days that coincides, within the errors, with that of the X-ray source, confirming the association based on the positional coincidence. We interpret the observed X-ray/optical periodicity as the orbital period of a close binary system where one of the two members is a neutron star. The light curve profile of the companion star, which has two asymmetric peaks, suggests that the optical emission comes from two regions with different temperatures on its tidally distorted surface. Based upon its X-ray and optical properties, we consider this source as the most likely X-ray counterpart to 3FGL J2039.6−5618, which we propose to be a new redback system.
Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical ...trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.
Copper (II) complexes containing mixed ligands were synthesized in dimethyl formamide (DMF). The intense cyan emission at an ambient temperature is observed for solid copper (II) complexes with ...salicylic acid and a 12% quantum yield with a fluorescent lifetime of approximately 10 ms. Hence, copper (II) complexes with salicylic acid are excellent candidates for photoactive materials. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) reveal that the divalent copper metal centers coordinate with the nitrogen and oxygen lone pairs of conjugate ligands. XPS binding energy trends for core electrons in lower-lying orbitals are similar for all three copper (II) complexes: nitrogen 1s and oxygen 1s binding energies increase relative to those for undiluted ligands, and copper 2p3/2 binding energies decrease relative to that for CuCl2. The thermal behavior of these copper complexes reveals that the thermal stability is characterized by the following pattern: Cu(1,10-phenanthroline)(salicylic acid) > Cu(1,10-phenanthroline)(2,2’-bipyridine) > Cu(1,10-phenanthroline)(1-benzylimidazole)2.
Purpose
Graves’ ophthalmopathy (GO) is an autoimmune disease that affects orbital soft tissues and represents the most common extrathyroidal manifestation of Graves’ disease (GD). The European Group ...of Graves’ Ophthalmopathy (EUGOGO) has attempted to shed light on the European epidemiological picture of GO, suggesting that GO in newly diagnosed patients in recent years has a trend towards a less severe clinical presentation. There are no studies that focus this issue on the population of our area; we aimed to evaluate the trend of GO clinical presentation in our outpatient clinic through an observation period of 10 years.
Methods
We compared 55 consecutive patients, 11 males (F) and 44 females (M), who came to our observation from January 2005 to December 2006 Group 1 (G1), with 56 patients, 15 males, and 41 females, who were referred to us from 2015 to 2016 Group 2 (G2). We studied the following putative predictors of GO presentation and severity: thyroid function, smoking, diabetes, hypercholesterolemia, time from GO diagnosis to referral to our thyroid centre (TGOD), sex and age.
Results
GO severity was significantly reduced in G2 vs. G1 (
p
= 0.04). TGOD ≥ 3 months was related to clinical characteristics of GO (severity and Clinical Activity Score ≥ 4) and was an independent predictor of GO severity (
p
= 0.01). The other variables evaluated had no independent effects.
Conclusions
We found that GO severity at presentation was significantly reduced over a ten-year observation period (2005–2006 vs. 2015–2016) in GO patients referred to our tertiary thyroid centre. TGOD ≥ 3 months was an independent predictor of GO severity.
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