Activation of apoptosis, the cell death machinery, in tumor cells by organelle specific delivery of antitumor theranostic agent is utmost challenge in cancer therapy. Herein, we developed a highly efficient mitochondria targeting antitumor theranostic prodrug 7 that contain two molecules of drug 5'-deoxy-5-fluorouridine, and an apoptotic marker ethidium for self-monitoring intrinsic (mitochondrial) apoptosis after its activation in tumor cells. Theranostic 7 was activated by endogenously produced mitochondrial-overexpressed H2O2 and release drug 5'-deoxy-5-fluorouridine and apoptotic marker ethidium to the tumor cells. The in vitro and in vivo drug release was monitored by observing the fluorescence changes of ethidium. Theranostic 7 exhibited an enhanced cytotoxicity over commercial 5-fluorouracil (an active drug of 5'-deoxy-5-fluorouridine) leading to intrinsic apoptosis monitored by in situ generated ethidium. Enhanced expres-sion of mitochondria-mediated apoptotic genes (NOXA, PUMA, BID, BAX, and BAK), Cyt C, Caspase-3 and -9, and cell surface death receptors was observed after theranostic 7 activation in tumor cells. In vivo and ex-vivo xenografts re-vealed that theranostic 7 significantly inhibited tumor progression and cured the tumor-bearing mice. Such organelle specific theranostic strategies have great potential for the early diagnosis and precise treatment of cancer.
We propose a novel structure that includes two compact, simply structured, and lossy waveguides for reducing back reflection in MMI combiners. The preferred lossy waveguide consists of a bend section and a tapered section. Theoretical calculations and 2D FDTD analysis were used to confirm the properties of our proposed structure. Significantly and interestingly, for TE modes, the optimized bend radius is about 7.5 µm and the specific back reflectance depends on taper end width. For TM modes, to achieve a back reflection value smaller than -30 dB, the taper length of 30 µm is desired regardless of bend radius. Moreover, the introduction of the lossy waveguide influences neither the MMI design nor its operation.
There is growing evidence that the human brain is a large scale complex network. The structural network is reported to be disrupted in cognitively impaired patients. However, there have been few studies evaluating the effects of amyloid and small vessel disease (SVD) markers, the common causes of cognitive impairment, on structural networks. Thus, we evaluated the association between amyloid and SVD burdens and structural networks using diffusion tensor imaging (DTI). Furthermore, we determined if network parameters predict cognitive impairments. Graph theoretical analysis was applied to DTI data from 232 cognitively impaired patients with varying degrees of amyloid and SVD burdens. All patients underwent Pittsburgh compound-B (PiB) PET to detect amyloid burden, MRI to detect markers of SVD, including the volume of white matter hyperintensities and the number of lacunes, and detailed neuropsychological testing. The whole-brain network was assessed by network parameters of integration (shortest path length, global efficiency) and segregation (clustering coefficient, transitivity, modularity). A greater PiB retention ratio was not associated with any white matter network parameters. Greater white matter hyperintensity volumes or lacunae numbers were significantly associated with decreased network integration (increased shortest path length, decreased global efficiency) and increased network segregation (increased clustering coefficient, increased transitivity, increased modularity). Decreased network integration or increased network segregation were associated with poor performances in attention, language, visuospatial, memory, and frontal-executive functions. Our results suggest that amyloid burden disrupts white matter network integration, while SVD alters white matter network integration and segregation, which further predicts cognitive dysfunction.
Quantitative determination of specific analytes is essential for a variety of applications ranging from life sciences to environmental monitoring. Optical sensing allows non-invasive measurements within biological milieus, parallel monitoring of multiple samples, and less invasive imaging. Among the optical sensing methods currently being explored, ratiometric fluorescence sensing has received particular attention as a technique with the potential to provide precise and quantitative analyses. Among its advantages are high sensitivity and inherent reliability, which reflect the self-calibration provided by monitoring two (or more) emissions. A wide variety of ratiometric sensing probes using small fluorescent molecules have been developed for sensing, imaging, and biomedical applications. In this research highlight, we provide an overview of the design principles underlying small fluorescent probes that have been applied to the ratiometric detection of various analytes, including cations, anions, and biomolecules in solution and in biological samples. This highlight is designed to be illustrative, not comprehensive.
A pyrenyl-appended calixtriazolearene displaying excellent selectivity for Cu(2+) over other metal ions in pyrenyl excimer emission changes was synthesized. The binding mode with Cu(2+) was supported through nuclear magnetic resonance (NMR) studies and density functional theory (DFT) calculations. Fluorescence imaging demonstrates that this new copper sensor is capable of detecting intracellular copper in living cells. Furthermore, through colocalization of the probe with organelle trackers as a function of time, it was observed that copper initially accumulates in lysosomes and then decreases. These results provide evidence for a close relationship between copper and lysosomes in Wilson's disease. This system is the first Cu(2+) ion-induced fluorescent turn-on system used for imaging copper trafficking over time in a Wilson's disease model.
Metastatic cancers have historically been difficult to treat. However, metastatic tumors have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antimetastatic therapy. In this study, prodrug 7 was designed to be activated by H2O2-mediated boronate oxidation, resulting in activation of the fluorophore for detection and release of the therapeutic agent, SN-38. Drug release from prodrug 7 was investigated by monitoring fluorescence after addition of H2O2 to the cancer cells. Prodrug 7 activated by H2O2, selectively inhibited tumor cell growth. Furthermore, intratracheally administered prodrug 7 showed effective antitumor activity in a mouse model of metastatic lung disease. Thus, this H2O2-responsive prodrug has therapeutic potential as a novel treatment for metastatic cancer via cellular imaging with fluorescence as well as selective release of the anticancer drug, SN-38.
Outer membrane vesicles (OMVs) are produced by various pathogenic Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. In this study, we isolated OMVs from a representative soil bacterium, Pseudomonas putida KT2440, which has a biodegradative activity toward various aromatic compounds. Proteomic analysis identified the outer membrane proteins (OMPs) OprC, OprD, OprE, OprF, OprH, OprG, and OprW as major components of the OMV of P. putida KT2440. The production of OMVs was dependent on the nutrient availability in the culture media, and the up- or down-regulation of specific OMPs was observed according to the culture conditions. In particular, porins (e.g., benzoate-specific porin, BenF-like porin) and enzymes (e.g., catechol 1,2-dioxygenase, benzoate dioxygenase) for benzoate degradation were uniquely found in OMVs prepared from P. putida KT2440 that were cultured in media containing benzoate as the energy source. OMVs of P. putida KT2440 showed low pathological activity toward cultured cells that originated from human lung cells, which suggests their potential as adjuvants or OMV vaccine carriers. Our results suggest that the protein composition of the OMVs of P. putida KT2440 reflects the characteristics of the total proteome of P. putida KT2440.
We report here a mitochondria-targetable pH-sensitive probe that allows for a quantitative measurement of mitochondrial pH changes, as well as the real-time monitoring of pH-related physiological effects in live cells. This system consists of a piperazine-linked naphthalimide as a fluorescence off-on signaling unit, a cationic triphenylphosphonium group for mitochondrial targeting, and a reactive benzyl chloride subunit for mitochondrial fixation. It operates well in a mitochondrial environment within whole cells and displays a desirable off-on fluorescence response to mitochondrial acidification. Moreover, this probe allows for the monitoring of impaired mitochondria undergoing mitophagic elimination as the result of nutrient starvation. It thus allows for the monitoring of the organelle-specific dynamics associated with the conversion between physiological and pathological states.
The cerebellum (CB) consists of complex anatomical and functional subregions. To better investigate the complicated functional anatomy, a detailed subregional analysis and/or a precise spatial normalization of the fluorine-18 fluorodeoxyglucose (F-FDG) PET imaging data are essential. Here, the 28 MRIcron CB volumes of interests (VOIs) template merged into eight cerebellar subregional VOIs (bilateral anterior, superior, and inferior posterior lobes of the CB cortex, and the superior and inferior vermis) on mean F-FDG PET templates. We also developed a new spatial normalization method using a study-specific and CB-specific template (CBSST) to better localize the VOIs and to minimize interparticipant differences for the locations of whole and subregional CB VOIs, as well as to increase the accuracy of the subregional mean F-FDG uptake. Using VOIs of individual F-FDG PET images normalized to the F-FDG template, we analyzed subregional cerebellar glucose metabolism in patients with spinocerebellar ataxia, a representative disease involving the spinocerebellum, and compared them with age-matched and sex-matched healthy normal controls. We achieved significant improvement over the Montreal Neurological Institute template in spatial normalization accuracy using our CBSST approach for CB VOI location agreement increases (79 vs. 90%) and VOI uptake error decreases in many CB subregions. We also found significant decreases in the anterior/posterior ratio of F-FDG uptake in patients with spinocerebellar ataxia (0.45) compared with those in normal controls (0.73) only using our CBSST approach. Therefore, we established an accurate CB subregional VOI analysis framework, and this may be useful for understanding and differentiating many of the cerebellar ataxia diseases.
We herein report a fluorescent bimodal probe (1) capable of determining ER viscosity and polarity changes using FLIM and fluorescence ratiometry, respectively; during ER stress caused by tunicamycin, the viscosity was increased from ca. 129.5 to 182.0 cP and the polarity of the ER (dielectric constant, ?) enhanced from 18.5 to 21.1.
Rhodamine-labelled dieckol (1) synthesized through a click reaction was found to be localized in the endoplasmic reticulum (ER) of RAW 264.7 cells. Anti-inflammatory activity of compound was considerably greater than that of dieckol itself.
Spatial normalization of C-Pittsburgh Compound B (PiB) images is challenging for an automatic quantitative analysis without magnetic resonance imaging (MRI) because of different distribution patterns between amyloid positive and negative images. To overcome this issue, we evaluated a selective positron emission tomography template (SPT) method.
Endoplasmic reticulum (ER) stress is implicated in the development of type 2 diabetes mellitus. ER stress activates the unfolded protein response pathway, which contributes to apoptosis and insulin resistance. We investigated the roles of cytochrome P450 4A (CYP4A) in the regulation of hepatic ER stress, insulin resistance, and the development of diabetes in mice.
Herein, we present a fluorescent-peptide drug delivery system composed of biotin-naphthalimide-HJ inhibitor peptide2, prodrug 1. Treatment of 1 to biotin receptor-positive HepG2 cells, which are resistant to high concentrations of the HJ inhibitor peptide2, decreased cell viability and increased intracellular fluorescence.
Thioredoxin (Trx) is a redox-active protein that plays a key role in mitigating the effects of oxidative stress. The secretion of Trx on the plasma membrane has been suggested as a distinctive feature of inflammation. However, selective monitoring of membrane-associated Trx activity has proved challenging because of the ubiquity of Trx action in cells. Here, we report a Trx-specific probe that allows visualization of Trx activity associated with the membranes via fluorescence microscopy. The ability of this probe to act as a possible screening tool for agents that modulate Trx secretion was demonstrated in HeLa cells under oxidative stress conditions and in a cellular hepatosteatosis model. Control experiments serve to confirm that the response seen for the present probe is due to Trx and that it is selective over various potentially competing metabolites, including thiol-containing small molecules and test proteins.
Drug-induced parkinsonism (DIP) is the common cause of parkinsonism. It is difficult to make a differentiation between DIP and Parkinson's disease (PD) because there are no notable differences in the clinical characteristics between the two entities. In this study, we examined the relationship between the characteristics of [(18)F] fluorinated-N-3-fluoropropyl-2-?-carboxymethoxy-3-?-(4-iodophenyl)nortropane (FP-CIT) positron emission tomography (PET) images and clinical features in DIP patients. We retrospectively studied 76 patients with DIP who underwent [(18)F] FP-CIT PET. We also enrolled 16 healthy controls who underwent it. We compared the clinical characteristics between the DIP patients with normal [(18)F] FP-CIT PET scans and those with abnormal ones. Symmetric parkinsonism was more frequent in the patients with normal [(18)F] FP-CIT PET scans as compared with those with abnormal ones. Interval from drug intake to onset of parkinsonism was longer in the patients with abnormal [(18)F] FP-CIT PET scans as compared with those with normal ones. A semi-quantitative analysis showed that specific to non-specific binding ratios in the putamen was lower in the patients with abnormal [(18)F] FP-CIT PET scans as compared with those with normal ones and the age-matched control group. Our results suggest that symmetric parkinsonism was more prevalent, and the duration of drug exposure before the onset of parkinsonism was shorter in the patients with normal [(18)F] FP-CIT PET scans as compared with those with abnormal ones.
To evaluate the usefulness of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured by pretreatment fluorine 18-fluorodeoxyglucose ((18) F-FDG) positron emission tomography (PET)/computed tomography (CT) as predictors of clinical outcome in hypopharyngeal squamous cell carcinoma (HPSCC).
We herein report a fluorescence probe 1 capable of detecting water-soluble oligomeric A? aggregates and A? fibrils. Upon injection into A?42-challenged mouse brains, probe 1 shows increased fluorescence intensity, indicating its facile binding to extracellular A? fibrils in brain tissues.
In the past few decades, the development of chemosensors for neurotransmitters has emerged as a research area of significant importance, which attracted a tremendous amount of attention due to its high sensitivity and rapid response. This current review focuses on various neurotransmitter detection based on fluorescent or colorimetric spectrophotometry published for the last 12 years, covering biogenic amines (dopamine, epinephrine, norepinephrine, serotonin, histamine and acetylcholine), amino acids (glutamate, aspartate, GABA, glycine and tyrosine), and adenosine.
Environment-related parameters, including viscosity, polarity, temperature, hypoxia, and pH, play pivotal roles in controlling the physical or chemical behaviors of local molecules. In particular, in a biological environment, such factors predominantly determine the biological properties of the local environment or reflect corresponding status alterations. Abnormal changes in these factors would cause cellular malfunction or become a hallmark of the occurrence of severe diseases. Therefore, in recent years, they have increasingly attracted research interest from the fields of chemistry and biological chemistry. With the emergence of fluorescence sensing and imaging technology, several fluorescent chemosensors have been designed to respond to such parameters and to further map their distributions and variations in vitro/in vivo. In this work, we have reviewed a number of various environment-responsive chemosensors related to fluorescent recognition of viscosity, polarity, temperature, hypoxia, and pH that have been reported thus far.
Fluorine 18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) is used to identify index or second primary cancer (SP) of the head and neck (HN) through changes in (18)F-FDG uptake. However, both physiologic and abnormal lesions increase (18)F-FDG uptake. Therefore, we evaluated (18)F-FDG uptake in the HN region to determine clinical values of abnormal tracer uptake.
To investigate whether the magnitude of presynaptic dopamine depletion is a risk factor for the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) by quantitatively analyzing (18)F-FP-CIT PET data.
A progressive reduction in the speed and amplitude of repetitive action is an essential component of bradykinesia, which is called sequence effect (SE). Because SE is specific to Parkinson's disease (PD) and is suggested to be associated with motor arrest, its features are of great interest. The aim of this study was, for the first time, to find the neural correlates of SE and to demonstrate whether dopaminergic deficit is correlated with SE.
Brunner gland hyperplasia, a rare duodenal tumor, usually presents with benign features. A 68-year-old man with a history of anemia presented with a polypoid duodenal mass that was detected by CT and esophagogastroduodenoscopy. This mass showed high F-FDG avidity on PET/CT and was histopathologically confirmed as Brunner gland hyperplasia. We suggest that Brunner gland hyperplasia should be considered in the differential diagnosis of F-FDG-avid duodenal tumors.
Thiacalixarenes, a subclass of "third generation" calixarenes, exhibit many interesting features such as enlarged ring size, facile chemical modification, and metal complexation due to the presence of bridging sulfur atoms. The thiacalixarene scaffold is a unique host with vast possibilities for functionalization not only at the upper and lower rim but also at the bridging sulfide groups. Modified thiacalixarenes have been used for many applications such as the detection and separation of biologically important cations, anions, and bio-analytes, mimicking molecular logic gates and devices, and synthesis of self-assembled coordination cages, multinuclear complexes, magnetic materials and luminescent materials. This review article summarizes recent developments in the derivatization methods of thiacalixarenes and their utilization in various applications.
Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11C-Pittsburgh compound B (PiB) PET. We recruited 53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (? = 7.0 × 10-3, p = 0.034) while no significant correlation was found in APOE4 carriers (? = -9.0 × 10-3, p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD.
(18) F-fluoromisonidazole (FMISO) positron emission tomography (PET) is used to image metabolically compromised but viable hypoxic tissue. We hypothesized that FMISO PET might predict early infarct growth in acute ischemic stroke patients with perfusion-diffusion mismatch in magnetic resonance imaging (MRI).
The presence of common risk factors suggests that there is a relationship between osteoporosis and cardiovascular disease, possibly via dyslipidemia and inflammation. We investigated the relationships among the lipid profile, the inflammation marker high-sensitivity C-reactive protein (hsCRP), bone turnover markers, and bone mineral density (BMD) to assess the correlation between osteoporosis and cardiovascular disease and identify factors predicting osteoporosis.
Cerebrovascular disease (CVD) and Alzheimer disease are significant causes of cognitive impairment in the elderly. However, few studies have evaluated the relationship between CVD and ?-amyloid burden in living humans or their synergistic effects on cognition. Thus, there is a need for better understanding of mild cognitive impairment (MCI) before clinical deterioration begins.
Synchronous colorectal cancer liver metastasis (SCLM) remains a clinical challenge, largely because of the limited availability of tools that use reliable prognostic indicators to guide treatment. This study assessed the prognostic ability of preoperative (18)F-FDG PET/CT in patients with SCLM who had undergone curative-intent colorectal and liver surgery.
A new theranostic strategy is described. It is based on the use of an "all in one" prodrug, namely the biotinylated piperazine-rhodol conjugate 4?a. This conjugate, which incorporates the anticancer drug SN-38, undergoes self-immolative cleavage when exposed to biological thiols. This leads to the tumor-targeted release of the active SN-38 payload along with fluorophore 1?a. This release is made selective as the result of the biotin functionality. Fluorophore 1?a is 32-fold more fluorescent than prodrug 4?a. It permits the delivery and release of the SN-38 payload to be monitored easily in?vitro and in?vivo, as inferred from cell studies and ex?vivo analyses of mice xenografts derived from HeLa cells, respectively. Prodrug 4?a also displays anticancer activity in the HeLa cell murine xenograft tumor model. On the basis of these findings we suggest that the present strategy, which combines within a single agent the key functions of targeting, release, imaging, and treatment, may have a role to play in cancer diagnosis and therapy.
Two novel Cu(2+) sensors, 1 and 2, bearing naphthalimide and a DPA moiety were synthesized to study copper accumulation in organelles by selective Cu(2+) sensing. The ER-selective Cu(2+) sensor 1 that we developed serves as a valuable tool for understanding the subcellular compartmentalization and roles of copper ions in physiology and pathophysiology.
Biotin-disulfide-coumarin conjugates are designed and synthesized as novel fluorescent sensors for cancer targeted intracellular thiol imaging in living organisms. In vitro experiments disclose that probe 6 is preferentially taken up by biotin receptor-positive A549 tumor cells through receptor mediated endocytosis.
To assess the clinical usefulness of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and CT/magnetic resonance (MR) imaging in detecting occult neck metastasis in patients with head and neck squamous cell carcinoma and negative neck palpation findings.
Early detecting of cancer is critical to provide proper treatment and to improve survival of patients. Here, we reported a highly sensitive ratiometric (yellow emission (550 nm) to blue emission (496 nm)) fluorescent probe 1 developed for detection of thiol-containing amino acids. This probe successfully eliminates interference from background autofluorescence, and discriminates between human carcinoma and normal cells by detecting intracellular thiol levels in living cells (P < 0.05). Furthermore, the ability of the probe to identify growing tumors by measuring GSH in the tissues as well as in the fresh blood of tumor xenograft mice. Additionally, the ratio of the emission intensity at two different wavelengths can provide quantitative analysis of glutathione (GSH) in the living systems. It suggests that it represents a promising prognostic and diagnostic marker, with extensive and simple potential clinical applications.
Dopamine transporter (DAT) imaging shows age-related decline of ligand binding in the normal striatum, a decline attributed to regulatory changes. We investigated if similar changes occur in the striatum of Parkinson's disease (PD) patients, using PET and [(18)F]FP-CIT, a ligand for DAT.
Click chemistry, a new strategy for organic chemistry, has been widely used in the chemical modification of calixarenes because of its reliability, specificity, biocompatibility, and efficiency. Click-derived triazoles also play a critical role in sensing ions and molecules. This in-depth review provides an overview of calixarene-based chemosensors that incorporate click-derived triazoles, and their three characteristics (chromogenic, fluorescence, and wettability) are reviewed.
Detection of human epidermal growth factor receptor 2 gene (HER2, also known as erbB2) expression is a preparatory process to decide a treatment strategy for breast cancer patients. 20-30% of breast cancer patients have HER2 overexpression, and they usually show poor recovery rate. For detection of HER2 expression, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods are conventionally used. Although these methods are accurate and reliable, their time-consuming process and high cost need a concise method with high sensitivity and accuracy. As a complementary method to the current IHC/FISH standard techniques, PCR-based methods have been developed. Here we employed a quantitative PCR method to detect HER2 expression in one hundred ninety nine formalin-fixed and paraffin-embedded (FFPE) breast cancer tissue samples from the patients treated over two years at the Yonsei University Severance Hospital, Republic of Korea. Relative expression of HER2 mRNA in the FFPE samples was analyzed using a quantitative RT-PCR (RT-qPCR) method and the obtained HER2 expression levels were compared with those from IHC/FISH methods. Our results show that the RT-qPCR method was highly concordant with IHC/FISH methods for detecting HER2 expression. Overall sensitivity and specificity of the BrightGen HER2 RT-qDx assay kit (Syantra, Calgary, Canada), which is a kit we used for RT-qPCR analyses, were 93.0% and 89.8% (P < 0.0001), respectively. The diagnostic cut-off value of HER2 RT-qDx for the clinical samples was determined by likelihood ratio, among which the highest likelihood ratio of relative HER2 mRNA levels was over 105.5 (AUC = 0.9466) with the highest sensitivity and specificity. Our study indicates that quantification of HER2 mRNA expression with the RT-qPCR could be an alternative method of conventional IHC/FISH methods.
The self-assembly features of the bis-pyrene methyl amide functionalized pyridine and benzene "tweezers" 1 and 2 were studied in organic solution and in the solid state. These systems were found to display remarkably different self-association features and optical properties, which was rationalized by control experiments using compounds bearing pyrenemethyl esters, alkyl groups, or a single pyrene substituent (3-6). As dilute solutions in chloroform, tweezers 1 displays both pyrene monomer and excimer emission features reflecting intramolecular contacts between the pyrene subunits. At higher concentrations in chloroform, as well as in the solid state, tweezers 1 self-assembles to form a linear supramolecular polymer. In contrast, tweezers 2 does not interact in an intermolecular fashion and photoexcitation produces emission features characteristic of a pyrene monomer. DFT (density functional theory) and TDDFT (time dependent density functional theory) calculations revealed that the lowest vertical transitions are forbidden and that S1 of 1 is an emissive state. In contrast to 1 and 2, both pyrene-free control systems 5 and 6 were found to form linearly self-assembled supramolecular arrays in the solid state, albeit of differing structure. Upon exposure to trinitrobenzene (TNB), the self-assembled structures formed from 1 undergo deaggregation to form TNB complexes. This change is reflected in both an easily discernible color change and a quenching of the fluorescence emission intensity. Changes in the optical features were also seen in the case of 2. However, notable differences between these two ostensibly similar systems were seen.
We propose and analyze a compact polarizing beam splitter (PBS) based on a metal-insulator-metal (MIM) structure inserted into a multimode interference coupler (MMI). Owing to the MIM structure, the TE polarized state is reflected by the cut-off condition while the TM polarized state is transmitted by the surface plasmon polariton, and the two polarized states can thus be separated. In this paper, the dependence of the reflected TE and transmitted TM field intensities on the MIM length and the gap thickness has been studied systematically. The proposed PBS structure, with a total size of 4 × 0.7 × 44 µm(3) is designed with MIM length, gap thickness, and metal thickness of 0.6 µm, 0.5 µm, and 0.05 µm, respectively. In the designed PBS, the transmittance for the TM polarized light, reflectance for the TE polarized light, extinction ratio, and insertion losses of the TE and TM modes are obtained using a 3D finite-difference time-domain method to be 0.9, 0.88, 12.55 dB, and 1.1 dB and 0.9 dB, respectively. The designed PBS has a much shorter length, 44 µm, compared to previous PBS devices.
A water-soluble T1 magnetic resonance imaging contrast agent (1) has been synthesized. The bimodal contrast agent 1 responds to the Cu(2+) ion in living cells by enhancing the MRI modality signal whereas the optical signal gradually drops. This dual modality probe response depends on the cellular free copper ions in RAW 264.7 cells even at the micromolar level.
Both total plasma and tumor-derived microvesicle (TMV)-associated miRNAs have been proposed as potential blood-based biomarkers for cancer diagnosis. However, there has been no comparison of the two types of miRNAs for biomarker discovery because of technological challenges of isolating TMVs from human plasma. The effective isolation of TMVs can be hardly achieved with conventional immunobead-based methods due to the high content of plasma proteins. In the current study, zwitterionic sulfobetaine-conjugated immunobeads are prepared using cluster of differentiation 83 (CD83) as a candidate protein marker for breast cancer-derived microvesicles. The zwitterionic immunobeads are more than 10-fold efficient for isolating TMVs from clinical plasma samples by suppressing nonspecific protein binding than conventional immunobeads. Early-stage breast cancer can be distinguished from benign breast disease by using the sulfobetaine-modified immunobeads, whereas conventional immunobeads show poor discriminatory performance. Further, we demonstrate that miRNAs in the form of TMVs offer a major improvement over total plasma miRNAs for early cancer detection. The analyses of miRNA expression levels show that in total, 6 miRNAs are significantly upregulated in the CD83-positive microvesicles of breast cancer patients, whereas differential miRNA expression is not detected on using total plasma RNA. The results indicate that our zwitterionic immunobead platform may constitute a powerful tool to identify circulating biomarkers and open a new avenue for highly sensitive blood-based cancer diagnostics.
The identification of novel diagnostic markers of pathogenic bacteria is essential for improving the accuracy of diagnoses and for developing targeted vaccines. Streptococcus pneumoniae is a significant human pathogenic bacterium that causes pneumonia. N-acetylglucosamine-6-phosphate deacetylase (NagA) was identified in a protein mixture secreted by S. pneumoniae and its strong immunogenicity was confirmed in an immuno-proteomic assay against the anti-serum of the secreted protein mixture. In this study, recombinant S. pneumoniae NagA protein was expressed and purified to analyze its protein characteristics, immunospecificity, and immunogenicity, thereby facilitating its evaluation as a novel diagnostic marker for S. pneumoniae. Mass spectrometry analysis showed that S. pneumoniae NagA contains four internal disulfide bonds and that it does not undergo post-translational modification. S. pneumoniae NagA antibodies successfully detected NagA from different S. pneumoniae strains, whereas NagA from other pathogenic bacteria species was not detected. In addition, mice infected with S. pneumoniae generated NagA antibodies in an effective manner. These results suggest that NagA has potential as a novel diagnostic marker for S. pneumoniae because of its high immunogenicity and immunospecificity.
Visual hallucination (VH) is a common psychotic symptom in patients with Parkinsons disease (PD) and may be a significant predictor of cognitive impairment (CI) in such patients. Objective: This study aimed to investigate the pattern of glucose metabolism of VH and the relationship between VH and CI in PD.
Pyrene-appended calixtriazolearene capable of bimodal sensing has been synthesized. Upon addition of Zn(2+) (or Cd(2+)), it selectively exhibits an enhanced monomeric emission (~13-20-fold) over other metal ions. On the other hand, it displays excellent selectivity for Fe(2+) over other metal ions (even over Fe(3+)) from the angle of excimeric emissions (10-fold enhancement). Density Functional Theory (DFT) based theoretical calculations distinguished the bimodal activity of the probe and supported the experimental observations.
This study evaluated the efficacy and safety of S-1 combined with docetaxel (SD) following doxorubicin plus cyclophosphamide (AC) as neoadjuvant therapy in patients with HER2-negative, stage II-III breast cancer.
A series of heptamethine cyanine (1-3) derivatives bearing a carbamate ethyl disulfide group and gemcitabine, an anticancer drug, have been newly synthesized. Their disulfide bonds are readily cleaved by various thiols including glutathione, to result in a subsequent decomposition of the carbamate into amine followed by release of the active gemcitabine, which can be monitored by the fluorescence changes. In the biological experiment, prodrug 1 is preferentially up-taken by folate-positive KB cells over folate-negative A549 cells via receptor-mediated endocytosis to release gemcitabine causing cell death and to emit fluorescence in endoplasmic reticulum. Moreover, it is selectively accumulated in the KB cells which were treated to mice by dorsal subcutaneous injection. This drug delivery system is a new theranostic agent, wherein both therapeutic effect and drug uptake can be easily monitored at the subcellular level, by in vivo and in vitro fluorescence imaging.
Mouse double minute 2 (Mdm2) is a negative regulator of the tumor suppressor p53. The p53-Mdm2 pathway may play a role in cancer development and prognosis, although the role of p53-Mdm2 in breast cancer remains unclear.
We present the design, synthesis, optical properties and in vitro biological assessments of the theranostic prodrug in which a near IR fluorophore is conjugated with a cancer cell-directing biotin unit; further it is linked with the anti-cancer drug gemcitabine via a self-immolative spacer, a disulfide bond. The prodrug is able to monitor drug delivery and cellular imaging.
The aim of this study was to evaluate 3-deoxy-3-(18)F-fluorothymidine ((18)F-FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX).
Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) from (18)F-FDG PET/CT are emerging prognostic biomarkers in human solid cancers; yet few studies have investigated their clinical and prognostic significance in oral cavity squamous cell carcinoma (OSCC). The present retrospective study evaluated the utility of pretreatment MTV and TLG measured by (18)F-FDG PET/CT to predict survival and occult metastasis (OM) in OSCC.
A self-calibrating bipartite viscosity sensor 1 for cellular mitochondria, composed of coumarin and boron-dipyrromethene (BODIPY) with a rigid phenyl spacer and a mitochondria-targeting unit, was synthesized. The sensor showed a direct linear relationship between the fluorescence intensity ratio of BODIPY to coumarin or the fluorescence lifetime ratio and the media viscosity, which allowed us to determine the average mitochondrial viscosity in living HeLa cells as ca. 62 cP (cp). Upon treatment with an ionophore, monensin, or nystatin, the mitochondrial viscosity was observed to increase to ca. 110 cP.
To investigate the prognostic value of tumor markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels at diagnosis of systemic recurrence. After primary treatments of locoregional breast cancers, serum CA 15-3 and/or CEA concentrations were regularly measured, and systemic recurrences were identified in 351 patients between January 1999 and December 2009. The association between tumor marker levels at systemic recurrence and survival were investigated by univariate and multivariate analyses. Elevated CA 15-3 and CEA levels were identified in 194 of 349 (55.6 %) and 111 of 308 (36.0 %) patients, respectively, at diagnosis of systemic recurrence. Elevated levels of CA 15-3 and CEA were correlated with visceral or multiple recurrences and elevated preoperative levels. Elevation of CA 15-3 was more prominent in younger patients and in primary node-positive tumors, while CEA was elevated in older patients at diagnosis and in estrogen receptor (ER)-positive tumors. Elevated tumor markers as well as ER negativity, short disease-free interval, and advanced stage at initial diagnosis showed independent prognostic significance on multivariate analysis. Among 306 patients for whom levels of both tumor markers at recurrence were available, 106 patients without elevation of either marker showed significantly better overall survival than those with elevated levels of either one or both markers, and the significance persisted in multivariate analysis. Elevated serum CA 15-3 and CEA levels at recurrence suggest increased tumor burden and may be prognostic for survival for metastatic breast cancer patients.
In the past few decades, the development of optical probes for thiols has attracted great attention because of the biological importance of the thiol-containing molecules such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). This tutorial review focuses on various thiol detection methods based on luminescent or colorimetric spectrophotometry published during the period 2010-2012. The discussion covers a diversity of sensing mechanisms such as Michael addition, cyclization with aldehydes, conjugate addition-cyclization, cleavage of sulfonamide and sulfonate esters, thiol-halogen nucleophilic substitution, disulfide exchange, native chemical ligation (NCL), metal complex-displace coordination, and nanomaterial-related and DNA-based chemosensors.
Lotus-leaf-like structured poly(?-caprolactone)-block-poly(l-lactic acid) copolymer (PCL-b-PLLA) films cast using the solvent-nonsolvent casting method. PCL-b-PLLA was synthesized by the well-known copolymerization process, and was confirmed by (1)H NMR analysis. The molecular weight of the synthesized PCL-b-PLLA was measured by gel permeation chromatography (GPC). The number-average (Mn), weight-average (Mw) molecular weights and polydispersity (Mw/Mn) were 3.9×10(4), 5.1×10(4), and 1.3, respectively. PCL-b-PLLA films were cast in vacuum conditions with various nonsolvent ratios. Tetrahydrofuran (THF) was used as solvent and ethanol was used as nonsolvent. Surface hydrophobicity was confirmed by the water contact angle. The water contact angle was increased from 90.9°±4.2° to 130.2°±3.6°. Water contact angle was found to be influenced by surface topography. The prepared film surfaces were characterized by scanning electron microscopy (SEM). Changes in crystalline property were characterized by X-ray diffraction (XRD). Platelet adhesion tests of the modified PCL-b-PLLA film surfaces were evaluated by platelet-rich plasma (PRP) and whole blood. Cell adhesive behavior on the modified film surfaces was evaluated by fibroblast cell culture. The prepared lotus-leaf-like structured film surfaces exhibited reduced platelet adhesion and an increased fibroblast cell proliferation ratio.
Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from (18)F-FDG PET/CT are emerging prognostic biomarkers in various human cancers. This study examined the prognostic value of these metabolic tumor parameters measured by pretreatment (18)F-FDG PET/CT in patients with salivary gland carcinomas.
Breast-conserving surgery (BCS) in patients with large tumors shrunk by neoadjuvant chemotherapy (NCT) remains controversial. We investigated oncologic outcomes of BCS in patients receiving NCT to treat locally advanced breast cancer (LABC).
The relationship between the apolipoprotein E ?4 allele (APOE4) and factors associated with vascular cognitive impairment (VCI) is unclear. We aimed to examine the effects of APOE4 on brain amyloid beta using Pittsburg compound B (PiB) and subcortical cerebrovascular disease, as assessed by lacunes and white matter hyperintensities (WMH) in subcortical VCI (SVCI) patients. We recruited 230 subjects with normal cognition, 111 subjects with cognitive impairment due to clinically defined Alzheimers disease (ADCI), and 134 subjects with clinically defined SVCI. A PiB retention ratio greater than 1.5 was considered to be PiB positive. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each cognitive impairment group. Multiple linear regression analysis was performed to investigate whether APOE4 was associated with brain amyloid beta, lacunes, and WMH. APOE4 did not increase the risk of PiB(-) SVCI (odds ratio [OR], 1.50; 95% confidence interval [CI], 0.79-2.84), whereas APOE4 increased the risk of PiB(+) SVCI (OR, 4.52; 95% CI, 1.70-11.97) and PiB(+) ADCI (odds ratio, 4.84; 95% CI, 2.54-7.91). In SVCI patients, APOE4 was positively associated with PiB retention ratio, whereas APOE4 was not associated with the number of lacunes or with WMH volume. Our results suggest that amyloid beta burden can occur in patients with and without subcortical cerebrovascular disease, and that it is associated with APOE4. However APOE4 might be independent of subcortical cerebrovascular disease.
Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB-positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.
Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment.
We present here, the design, synthesis, spectroscopic characterization, and in vitro biological assessment of a gemcitabine-coumarin-biotin conjugate (5). Probe 5 is a multifunctional molecule composed of a thiol-specific cleavable disulfide bond, a coumarin moiety as a fluorescent reporter, gemcitabine (GMC) as a model active drug, and biotin as a cancer-targeting unit. Upon addition of free thiols that are relatively abundant in tumor cells, disulfide bond cleavage occurs as well as active drug GMC release and concomitantly fluorescence intensity increases. Confocal microscopic experiments reveal that 5 is preferentially taken up by A549 cells rather than WI38 cells. Fluorescence-based colocalization studies using lysosome- and endoplasmic reticulum-selective dyes suggest that thiol-induced disulfide cleavage of 5 occur in the lysosome possibly via receptor-mediated endocytosis. The present drug delivery system is a new theranostic agent, wherein both a therapeutic effect and drug uptake can be readily monitored at the subcellular level by two photon fluorescence imaging.
The multitopic ion-pair receptor 2 is able to recognize and extract various cesium and potassium salts via three different ion recognition modes. Furthermore, it is capable of extracting and then releasing KNO(3)via ion-pair metathesis with CsClO(4), allowing KNO(3) recovery.
Despite many neuropsychological studies to differentiate subcortical vascular dementia (SVaD) from Alzheimer disease (AD), previous studies did not eliminate confounding effects of mixed Alzheimer and vascular pathology. We aimed to investigate neuropsychological differences between patients with Pittsburgh compound B (PiB)-negative SVaD and those with PiB-positive AD.
Central compartment lymph node metastasis (CLNM) in patients with laryngeal, hypopharyngeal, or cervical esophageal squamous cell carcinoma is associated with unfavorable clinical outcomes, but cannot be reliably detected using computed tomography (CT)/magnetic resonance imaging (MRI). Therefore, we assessed the clinical utility of using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT to identify CLNM in these patients.
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