Integrating the microneedles with carboplatin to facilitate the therapeutic effect of radiotherapy for skin cancers.

In most skin cancer patients, excisional surgery is required to remove tumorous tissue. However, the risk of locoregional recurrence after surgery alone is relatively high, particularly for a locally advanced stage of melanoma. Therefore, additional adjuvant treatments, such as radiotherapy, can be used after surgery to inhibit recurrent melanoma after surgical removal. To enhance local radiotherapy, we present the combined X-ray radiation and radiosensitizers (carboplatin) through microneedles (MNs) to treat melanoma. The MNs could be beneficial to precisely delivering carboplatin into the sub-epidermal layer of the melanoma region and alleviate patients' fear and discomfort during the drug administration compared to the traditional local injection. The carboplatin was loaded into the tips of dissolving gelatin MNs (carboplatin-MNs) through the molding method. The results show gelatin MNs have sufficient mechanical strength and can successfully administer carboplatin into the skin. Both in vitro and in vivo studies suggest that carboplatin can enhance radiotherapy in melanoma treatment. With a combination of radiotherapy and carboplatin, the inhibition effect of carboplatin delivered into the B16F10 murine melanoma model through MNs administration (1.2 mg/kg) is equivalent to that through an intravenous route (5 mg/kg). The results demonstrate a promise of combined carboplatin and X-ray radiation treatment in treating melanoma by MNs administration.

S- Cis Diene Conformation: A New Bathochromic Shift Strategy for Near-Infrared Fluorescence Switchable Dye and the Imaging Applications.

In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S- cis diene conformer. This is the first example where a fluorescent dye adopts the stable S- cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S- cis diene conformation can lead to new strategies for the design of near-IR dyes.

Evaluation of LPS-Induced Acute Lung Injury Attenuation in Rats by Aminothiazole-Paeonol Derivatives.

Paeonol is a key phenolic compound in the root bark of Moutan Cortex Radicis that has been used in traditional Chinese Medicine to ameliorate inflammation. A series of aminothiazole-paeonol derivatives (APDs) were synthesized in this work and subjected to preliminary evaluation in cells followed by verification in animals. Quantification of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) in culture media of LPS-activated A549 cells, a lung epithelial adenocarcinoma cell line, were used to investigate the anti-inflammatory capability of APDs. ALI-bearing rats were employed to verify therapeutic efficacy of APDs according to observations of total cells, protein amounts, MCP-1 and IL-6 in bronchoalveolar lavage fluid (BALF). Histopathological examinations of lung tissues were consequently applied for validation of APDs. Among these compounds, 2-(2-aminothiazol-4-yl)-5-methoxyphenol (4) had the most potent activity, showing comparable inhibition of MCP-1/IL-6 and superior elimination of neutrophil infiltration and protein exudation in lungs compared to others as well as dexamethasone. This study demonstrated a comprehensive strategy to evaluate APDs through integration of cell-based screening and animal-based verification. In order to fulfill unmet needs of treating acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), APDs introduced in this work could be promising lead compounds to develop high potent anti-inflammation agents.

Pulmonary Hypertension in Hemodialysis Patients Following Repeated Endovascular Thrombectomy.

BACKGROUND: The prevalence of pulmonary hypertension is unusually high in Taiwanese patients with end-stage renal disease. Thrombosis of hemodialysis grafts is common and pulmonary embolism has been reported after endovascular thrombectomy. The aim of this study was to evaluate the relationship between pulmonary hypertension and endovascular thrombectomy of hemodialysis grafts. METHODS: One hundred and ten patients on hemodialysis via arteriovenous grafts were enrolled in our study. The mean pulmonary artery pressure (PAP) was measured by right heart catheterization. Clinical information was collected by review of medical records. Comorbid cardiopulmonary disease was evaluated by echocardiography and chest X-ray. The history of patient vascular access thrombosis was reviewed from database, hemodialysis records, and interviews with staff at hemodialysis centers. RESULTS: Fifty-two participants (47%) had pulmonary hypertension diagnosed by right heart catheterization. There was no difference in the number of thrombectomy procedures between patients with and without pulmonary hypertension. Based on multivariate analysis, the number of prior endovascular thrombectomy procedures did not correlate with mean PAP (F-value = 1.10, p = 0.30) nor was it associated with pulmonary hypertension (odds ratio = 0.92, p = 0.17). CONCLUSIONS: Prior endovascular arteriovenous graft thrombectomies were not associated with pulmonary hypertension or increased mean PAP in end-stage renal disease patients on maintenance hemodialysis.

Synthesis and Evaluation of Aminothiazole-Paeonol Derivatives as Potential Anticancer Agents.

In this study, novel aminothiazole-paeonol derivatives were synthesized and characterized using ¹H-NMR, (13)C-NMR, IR, mass spectroscopy, and high performance liquid chromatography. All the new synthesized compounds were evaluated according to their anticancer effect on seven cancer cell lines. The experimental results indicated that these compounds possess high anticancer potential regarding human gastric adenocarcinoma (AGS cells) and human colorectal adenocarcinoma (HT-29 cells). Among these compounds, N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]-4-methoxybenzenesulfonamide (13c) had the most potent inhibitory activity, with IC50 values of 4.0 µM to AGS, 4.4 µM to HT-29 cells and 5.8 µM to HeLa cells. The 4-fluoro-N-[4-(2-hydroxy-4-methoxyphenyl)thiazol-2-yl]benzenesulfonamide (13d) was the second potent compound, showing IC50 values of 7.2, 11.2 and 13.8 µM to AGS , HT-29 and HeLa cells, respectively. These compounds are superior to 5-fluorouracil (5-FU) for relatively higher potency against AGS and HT-29 human cancer cell lines along with lower cytotoxicity to fibroblasts. Novel aminothiazole-paeonol derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating gastrointestinal adenocarcinoma.

Establishment of a trimodality analytical platform for tracing, imaging and quantification of gold nanoparticles in animals by radiotracer techniques.

This study aims to establish a (198)Au-radiotracer technique for in vivo tracing, rapid quantification, and ex vivo visualization of PEGylated gold nanoparticles (GNPs) in animals, organs and tissue dissections. The advantages of GNPs lie in its superior optical property, biocompatibility and versatile conjugation chemistry, which are promising to develop diagnostic probes and drug delivery systems. (198)Au is used as a radiotracer because it simultaneously emits beta and gamma radiations with proper energy and half-life; therefore, (198)Au can be used for bioanalytical purposes. The (198)Au-tagged radioactive gold nanoparticles ((198)Au-GNPs) were prepared simply by irradiating the GNPs in a nuclear reactor through the (197)Au(n,γ)(198)Au reaction and subsequently the (198)Au-GNPs were subjected to surface modification with polyethylene glycol to form PEGylated (198)Au-GNPs. The (198)Au-GNPs retained physicochemical properties that were the same as those of GNP before neutron irradiation. Pharmacokinetic and biodisposition studies were performed by intravenously injecting three types of (198)Au-GNPs with or without PEGylation into mice; the γ radiation in blood specimens and dissected organs was then measured. The (198)Au-radiotracer technique enables rapid quantification freed from tedious sample preparation and shows more than 95% recovery of injected GNPs. Clinical gamma scintigraphy was proved feasible to explore spatial- and temporal-resolved biodisposition of (198)Au-GNPs in living animals. Moreover, autoradiography, which recorded beta particles from (198)Au, enabled visualizing the heterogeneous biodisposition of (198)Au-GNPs in different microenvironments and tissues. In this study, the (198)Au-radiotracer technique facilitated creating a trimodality analytical platform for tracing, quantifying and imaging GNPs in animals.

Directly thiolated modification onto the surface of detonation nanodiamonds.

An efficient method for modifying the surface of detonation nanodiamonds (5 and 100 nm) with thiol groups (-SH) by using an organic chemistry strategy is presented herein. Thiolated nanodiamonds were characterized by spectroscopic techniques, and the atomic percentage of sulfur was analyzed by elemental analysis and X-ray photoelectron spectroscopy. The conjugation between thiolated nanodiamonds and gold nanoparticles was elucidated by transmission electron microscopy and UV-vis spectrometry. Moreover, the material did not show significant cytotoxicity to the human lung carcinoma cell line and may prospectively be applied in bioconjugated technology. The new method that we elucidated may significantly improve the approach to surface modification of detonation nanodiamonds and build up a new platform for the application of nanodiamonds.

Drug delivery system design and development for boron neutron capture therapy on cancer treatment.

We have already synthesized a boron-containing polymeric micellar drug delivery system for boron neutron capture therapy (BNCT). The synthesized diblock copolymer, boron-terminated copolymers (Bpin-PLA-PEOz), consisted of biodegradable poly(D,l-lactide) (PLA) block and water-soluble polyelectrolyte poly(2-ethyl-2-oxazoline) (PEOz) block, and a cap of pinacol boronate ester (Bpin). In this study, we have demonstrated that synthesized Bpin-PLA-PEOz micelle has great potential to be boron drug delivery system with preliminary evaluation of biocompatibility and boron content.

Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress.

Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53-p21-Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity.

Plasma proteome of severe acute respiratory syndrome analyzed by two-dimensional gel electrophoresis and mass spectrometry.

We have investigated the plasma proteome by using 2D gel electrophoresis and MS from patients with severe acute respiratory syndrome (SARS). A complete proteomic analysis was performed on four patients with SARS in different time courses, and a total of 38 differential spots were selected for protein identification. Most of the proteins identified are acute phase proteins, and their presence represents the consequence of serial cascades initiated by SARS-coronavirus infection. There are several proteins that have never been identified in plasma before using 2D gel electrophoresis, among which peroxiredoxin II was chosen for further study by analyzing additional 20 plasma samples from patients with probable and suspected SARS and patients with fever, respectively. The results showed that the level of plasma peroxiredoxin II in patients with SARS is significantly high and could be secreted by T cells. Taken together, our findings indicate that active innate immune responses, along with the oxidation-associated injuries, may play a major role in the pathogenesis of SARS.

Microsatellite alteration at chromosome 11 in primary human nasopharyngeal carcinoma in Taiwan.

Nasopharyngeal carcinoma (NPC) is one of the common cancers in Taiwan but is rare in western countries. The development of NPC involves multiple genetic changes in tumorigenesis and progression of the disease. To better understand genetic alterations in chromosome 11 which occur in human (NPC), we examined tumor specimens and corresponding non-cancerous tissue from 30 cases of NPC, using five microsatellite polymorphic markers whose location has previously been defined. To determine the clinical characteristics of MSI(+) or LOH, we performed correlation analysis of the findings with clinicopathological parameters. Loss of heterozygosity (LOH) was identified in 18 (60%) of 30 cases on at least one of the five markers. A high frequency of LOH was found at the two loci: D11S912 (7/30, 23.33%) and D11S934 (6/30, 20.00%), both of which are located within 11q23-24. We also found that 14 specimens (14/30, 46.67%) exhibited microsatellite instability (MSI(+)). Five (5/30, 16.67%) specimens exhibited MSI(+) in the transformation growth factor beta receptor type II (TGF-beta RII) exon 3 which also exhibited on chromosome 11. LOH was found to be significantly correlated with the T (tumor size) value (P=0.022) of Ho's system. MSI(+) showed a significant correlation with the N (lymph node) value of the UICC system (P=0.031). Our results suggest that multiple putative tumor suppressor genes on chromosome 11 play a role in the development of NPC. MSI(+) expression showed a predisposition to occur in the late stage of NPC while LOH tended to occur in early stages of NPC. The behavior of mutated TGF-beta RII exon 3, which appeared to serve as a dysfunction brake during nasopharyngeal carcinogenesis, may be a target gene in the defected mismatch repair system.