Low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin.

Exposure to cadmium (Cd) has been associated with development of chronic obstructive lung disease (COPD). The mechanisms and signaling pathways whereby Cd causes pathological peribronchiolar fibrosis, airway remodeling, and subsequent airflow obstruction remain unclear. We aimed to evaluate whether low-dose Cd exposure induces vimentin phosphorylation and Yes-associated protein 1 (YAP1) activation leading to peribronchiolar fibrosis and subsequent airway remodeling. Our data demonstrate that Cd induces myofibroblast differentiation and extracellular matrix (ECM) deposition around small (<2 mm in diameter) airways. Upon Cd exposure, α-smooth muscle actin (α-SMA) expression and the production of ECM proteins, including fibronectin and collagen-1, are markedly induced in primary human lung fibroblasts. Cd induces Smad2/3 activation and the translocation of both Smad2/3 and Yes-associated protein 1 (YAP1) into the nucleus. In parallel, Cd induces AKT and cdc2 phosphorylation and downstream vimentin phosphorylation at Ser39 and Ser55, respectively. AKT and cdc2 inhibitors block Cd-induced vimentin fragmentation and secretion in association with inhibition of α-SMA expression, ECM deposition, and collagen secretion. Furthermore, vimentin silencing abrogates Cd-induced α-SMA expression and decreases ECM production. Vimentin-deficient mice are protected from Cd-induced peribronchiolar fibrosis and remodeling. These findings identify two specific sites on vimentin that are phosphorylated by Cd and highlight the functional significance of vimentin phosphorylation in YAP1/Smad3 signaling that mediates Cd-induced peribronchiolar fibrosis and airway remodeling.

Mid-IR spectroscopy of Fe:ZnSe quantum dots.

We report spectroscopic characterization of Fe:ZnSe quantum dots (for 2% of Zn/Fe molar ratio) fabricated by microemulsion hydrothermal synthesis. Mid-IR photoluminescence of the 5E↔5T2 transition of Fe2+ ions over 3.5-4.5 µm spectral range was observed in Fe:ZnSe quantum dot samples and kinetics of luminescence have been characterized at temperatures of 30-300 K under direct (2.788 µm) mid-IR excitation and indirect (0.355 µm) photoionization excitation. The radiative lifetime (τrad) was estimated from these measurements to be 48 µs while lifetime at room temperature was measured to be 440 ns. This agrees closely with the behavior of bulk material.

Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice.

Pulmonary exposure to cadmium, a major component of cigarette smoke, has a dramatic impact on lung function and the development of emphysema. Cigarette smoke exposure induces heme oxygenase-1 (HO-1), a cytoprotective enzyme. In this study, we employed a truncated mouse model of emphysema by intratracheal instillation of cadmium (CdCl2) solution (0.025% per 1 mg/kg body wt) in HO-1(+/+), HO-1(-/-), and overexpressing humanized HO-1 bacterial artificial chromosome (hHO-1BAC) mice. We evaluated the role of HO-1 in cadmium-induced emphysema in mice by analyzing histopathology, micro-computed tomography scans, and lung function tests. CdCl2-exposed HO-1(-/-) mice exhibited more severe emphysema compared with HO-1(+/+) or hHO-1BAC mice. Loss of pulmonary endothelial cells (PECs) from the alveolar capillary membrane is recognized to be a target in emphysema. PECs from HO-1(+/+), HO-1(-/-), and hHO-1BAC were employed to define the underlying molecular mechanism for the protection from emphysema by HO-1. Electron microscopy, expression of autophagic markers (microtubule-associated protein 1B-light chain 3 II, autophagy protein 5, and Beclin1) and apoptotic marker (cleaved caspase 3) suggested induction of autophagy and apoptosis in PECs after CdCl2 treatment. CdCl2-treated HO-1(-/-) PECs exhibited downregulation of autophagic markers and significantly increased cleaved caspase 3 expression and activity (∼4-fold higher). Moreover, hHO-1BAC PECs demonstrated upregulated autophagy and absence of cleaved caspase 3 expression or activity. Pretreatment of HO-1(+/+) PECs with rapamycin induced autophagy and resulted in reduced cell death upon cadmium treatment. Induction of autophagy following CdCl2 treatment was found to be protective from apoptotic cell death. HO-1 induced protective autophagy in PECs and mitigated cadmium-induced emphysema.

A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression.

PURPOSE: Nanoparticle (NP)-enabled near infrared (NIR) photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies. METHODS: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG)-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm(2). Tumor response was measured for 10-15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed. RESULTS: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a comparison to the average of all three control groups over time (P<0.01). CONCLUSION: Photothermal nanotherapy, or intratumoral nanorod injections followed by NIR laser irradiation of tumors and tumor margins, demonstrate the potential of NIR photothermal therapy as a viable localized treatment approach for primary and early stage tumors, and prevents NP uptake by the reticuloendothelial system.

Compact Cr:ZnS channel waveguide laser operating at 2,333 nm.

A compact mid-infrared channel waveguide laser is demonstrated in Cr:ZnS with a view to power scaling chromium laser technology utilizing the thermo-mechanical advantages of Cr:ZnS over alternative transition metal doped II-VI semiconductor laser materials. The laser provided a maximum power of 101 mW of CW output at 2333 nm limited only by the available pump power. A maximum slope efficiency of 20% was demonstrated.

Energy scaling of 4.3 µm room temperature Fe:ZnSe laser.

We demonstrate a fourfold increase of the output energy of the gain-switched mid-IR Fe:ZnSe laser. Iron doping of the ZnSe polycrystalline samples was realized using a postgrowth thermal-diffusion method from the metal film. Gain-switched Er:Cr:YSGG (2.8 µm) laser pumped Fe:ZnSe lasing was studied in a Fabry-Perot cavity over a 236-300 K temperature range. The maximum output energy reached 4.7 mJ at 4.3 µm and 3.6 mJ at 4.37 µm at 236 K and 300 K and was limited only by available pump energy. The laser threshold was about 8 mJ and was practically unchanged over the studied temperature range. The laser slope efficiencies, measured with respect to the input pump energy, decreased from 19% to 16% with an increase of temperature from 236 to 300 K. The output radiation featured a Gaussian spatial profile with M(2) = 2.6.

Semiconductor disk laser pumped Cr2+:Znse lasers.

A new flexible pump source, the optically-pumped semiconductor disk laser (SDL), for the Cr(2+):ZnSe laser is reported. The SDL provides up to 6W output power at a free running central wavelength of 1.98 microm. The Cr(2+):ZnSe laser operated at an output power of 1.8W and a slope efficiency of approximately 50% with respect to absorbed pump power whilst maintaining a low output intensity noise figure of <0.14% RMS. The system required no optical isolation even under the situation of significant optical feedback.

Limitations of Adenoviral Vector-Mediated Delivery of Gold Nanoparticles to Tumors for Hyperthermia Induction.

Novel combinatorial treatment strategies are desired to achieve tumor eradication. In this regard, nanotechnology and gene therapy hold the potential to expand the available tumor treatment options. In particular, gold nanoparticles (AuNPs) have been utilized for hyperthermic tumor cell ablation. Similarly, adenoviral (Ad) vectors have been utilized for targeting, imaging, and cancer gene therapy. Thus, to combine AuNP-mediated hyperthermia with Ad vector-based gene therapy, we have previously coupled AuNPs to Ad vectors. Herein we tested the capability of these AuNP-coupled Ad vectors for hyperthermic tumor cell ablation. Towards this end, we compared absorption characteristics of different sized AuNPs and determined that in our system 20 nm diameter AuNPs are suitable for laser induced hyperthermic tumor cell killing. In addition, we observed that AuNPs outside and inside the cell contribute differentially towards hyperthermia induction. Unfortunately, due to the limitation of delivery of required amounts of AuNPs to cells, we observed that AuNP-coupled Ad vectors are unable to kill tumor cells via hyperthermia. However, with future technological advances, it may become possible to realize the potential of the multifunctional AuNP-coupled Ad vector system for simultaneous targeting, imaging, and combined hyperthermia and gene therapy of tumors.

Highly efficient, narrow-linewidth, and single-frequency actively and passively Q-switched fiber-bulk hybrid Er:YAG lasers operating at 1645 nm.

High power, highly efficient single frequency oscillation of Er:YAG fiber-bulk hybrid laser at 1645 nm is demonstrated in actively and passively Q-switched operation modes. The slope efficiencies in the active and passive Q-switched operation reached 75% and 20%, respectively, with the record output powers in the narrow-linewidth and single longitudinal mode regimes of operation.