Cardiac Dose Predicts the Response to Concurrent Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

Definitive concurrent chemoradiation (CCRT) is the standard treatment for cervical esophageal cancer and non-surgical candidates. Initial treatment response affects survival; however, few validated markers are available for prediction. This study evaluated the clinical variables and chemoradiation parameters associated with treatment response. Between May 2010 and April 2016, 86 completed CCRT patients' clinical, dosimetric, and laboratory data at baseline and during treatment were collected. Cox regression analysis assessed the risk factors for overall survival (OS). A receiver operating characteristic curve with Youden's index was chosen to obtain the optimal cut-off value of each parameter. Treatment response was defined per Response Evaluation Criteria in Solid Tumors v.1.1 at the first post-CCRT computed tomography scan. Responders had complete and partial responses; non-responders had stable and progressive diseases. Logistic regression (LR) was used to evaluate the variables associated with responders. The Cox regression model confirmed the presence of responders (n = 50) vs. non-responders (n = 36) with a significant difference in OS. In multivariate LR, cardiac dose-volume received ≥10 Gy; the baseline hemoglobin level, highest neutrophil to lymphocyte ratio during CCRT, and cumulative cisplatin dose were significantly associated with the responders. The initial clinical treatment response significantly determines disease outcome. Cardiac irradiation may affect the treatment response.

Carpal tunnel syndrome in dentists compared to other populations: A nationwide population-based study in Taiwan.

BACKGROUND: Dentists may be at a higher risk of developing carpal tunnel syndrome (CTS) because of their use of frequent wrist and vibratory instruments at work; however, this issue remains unclear. Therefore, we conducted this study to clarify it. METHODS: Taiwan National Health Insurance Research Database was used for this nationwide population-based study. We identified 11,084 dentists, 74,901 non-dentist healthcare professionals (HCPs), and identical number of age- and sex-matched participants from the general population. Participants who had the diagnosis of CTS before 2007 were excluded. Between 2007 and 2011, the risk of developing CTS among dentists, non-dentist HCPs, and the general population was compared by following their medical histories. RESULTS: The cumulative incidence rate of CTS among dentists was 0.5% during the 5-year follow-up period. In dentists, the risk was higher in women (women: 0.7%; men: 0.4%) and older individuals (≥60 years: 1.0%; <60 years: 0.4%). After adjusting for age, sex, and underlying comorbidities, dentists had a lower risk of CTS than the general population (adjusted odds ratio [AOR]: 0.65, 95% confidence interval [CI]: 0.45-0.92). Dentists had a higher risk for CTS compared with non-dentist HCPs, although the difference was not statistically significant (AOR: 1.21; 95% CI: 0.90-1.64). CONCLUSIONS: In CTS, dentists had a lower risk than the general population and a trend of higher risk than non-dentist HCPs. The difference between dentists and non-dentist HCPs suggests that we should pay attention to dentists for potential occupational risk of this disease. However, further studies are warranted to better clarify it.

Inhibition of Retinal Ganglion Cell Loss By a Novel ROCK Inhibitor (E212) in Ischemic Optic Nerve Injury Via Antioxidative and Anti-Inflammatory Actions.

Purpose: This study investigated the neuroprotective effects of administration of ROCK inhibitor E212 on ischemic optic neuropathy. Methods: Rats received an intravitreal injection of either E212 or PBS immediately after optic nerve infarct. The oxidative stress in the retina was detected by performing superoxide dismutase activity and CellROX assays. The integrity of retinal pigment epithelium was determined by staining of zona occludens 1. The visual function, retinal ganglion cell (RGC) density, and RGC apoptosis were determined by using flash visual-evoked potential analysis, retrograde FluoroGold labeling, and TdT-dUTP nick end-labeling assay. Macrophage infiltration was detected by staining for ED1. The protein levels of TNF-α, p-CRMP, p-AKT1, p-STAT3, and CD206 were evaluated using Western blotting. Results: Administration of E212 resulted in a 1.23-fold increase in the superoxide dismutase activity of the retina and 2.28-fold decrease in RGC-produced reactive oxygen species as compared to the levels observed upon treatment with PBS (P < 0.05). Moreover, E212 prevented the disruption of the blood-retinal barrier (BRB) in contrast to PBS. The P1-N2 amplitude and RGC density in the E212-treated group were 1.75- and 2.05-fold higher, respectively, than those in the PBS-treated group (P < 0.05). The numbers of apoptotic RGCs and macrophages were reduced by 2.93- and 2.54-fold, respectively, in the E212-treated group compared with those in the PBS-treated group (P < 0.05). The levels of p-AKT1, p-STAT3, and CD206 were increased, whereas those of p-PTEN, p-CRMP2, and TNF-α were decreased after treatment with E212 (P < 0.05). Conclusions: Treatment with E212 suppresses oxidative stress, BRB disruption, and neuroinflammation to protect the visual function in ischemic optic neuropathy.

Low cardiac dose and neutrophil-to-lymphocyte ratio predict overall survival in inoperable esophageal squamous cell cancer patients after chemoradiotherapy.

We aimed to determine the prognostic significance of cardiac dose and hematological immunity parameters in esophageal cancer patients after concurrent chemoradiotherapy (CCRT). During 2010-2015, we identified 101 newly diagnosed esophageal squamous cell cancer patients who had completed definitive CCRT. Patients' clinical, dosimetric, and hematological data, including absolute neutrophil count, absolute lymphocyte count, and neutrophil-to-lymphocyte ratio (NLR), at baseline, during, and post-CCRT were analyzed. Cox proportional hazards were calculated to identify potential risk factors for overall survival (OS). Median OS was 13 months (95% confidence interval [CI]: 10.38-15.63). Univariate analysis revealed that male sex, poor performance status, advanced nodal stage, higher percentage of heart receiving 10 Gy (heart V10), and higher NLR (baseline and follow-up) were significantly associated with worse OS. In multivariate analysis, performance status (ECOG 0 & 1 vs. 2; hazard ratio [HR] 3.12, 95% CI 1.30-7.48), heart V10 (> 84% vs. ≤ 84%; HR 2.24, 95% CI 1.26-3.95), baseline NLR (> 3.56 vs. ≤ 3.56; HR 2.36, 95% CI 1.39-4.00), and follow-up NLR (> 7.4 vs. ≤ 7.4; HR 1.95, 95% CI 1.12-3.41) correlated with worse OS. Volume of low cardiac dose and NLR (baseline and follow-up) were associated with worse patient survival.

The Benefits and Hazards of Intravitreal Mesenchymal Stem Cell (MSC) Based-Therapies in the Experimental Ischemic Optic Neuropathy.

Mesenchymal stem cell (MSC) therapy has been investigated intensively for many years. However, there is a potential risk related to MSC applications in various cell niches. METHODS: The safety of intravitreal MSC application and the efficacy of MSC-derived conditioned medium (MDCM) were evaluated in the normal eye and the diseased eye, respectively. For safety evaluation, the fundus morphology, visual function, retinal function, and histological changes of the retina were examined. For efficacy evaluation, the MDCM was intravitreally administrated in a rodent model of anterior ischemic optic neuropathy (rAION). The visual function, retinal ganglion cell (RGC) density, and neuroinflammation were evaluated at day 28 post-optic nerve (ON) infarct. RESULTS: The fundus imaging showed that MSC transplantation induced retinal distortion and venous congestion. The visual function, retinal function, and RGC density were significantly decreased in MSC-treated eyes. MSC transplantation induced astrogliosis, microgliosis, and macrophage infiltration in the retina due to an increase in the HLA-DR-positive MSC proportion in vitreous. Treatment with the MDCM preserved the visual function and RGC density in rAION via inhibition of macrophage infiltration and RGC apoptosis. CONCLUSIONS: The vitreous induced the HLA-DR expression in the MSCs to cause retinal inflammation and retina injury. However, the MDCM provided the neuroprotective effects in rAION.

Algae Oil Treatment Protects Retinal Ganglion Cells (RGCs) via ERK Signaling Pathway in Experimental Optic Nerve Ischemia.

BACKGROUND: We investigated the therapeutic effects and related mechanisms of algae oil (ALG) to protect retinal ganglion cells (RGCs) in a rat model of anterior ischemic optic neuropathy (rAION). METHODS: Rats were daily gavaged with ALG after rAION induction for seven days. The therapeutic effects of ALG on rAION were evaluated using flash visual evoked potentials (FVEPs), retrograde labeling of RGCs, TUNEL assay of the retina, and ED1 staining of optic nerves (ONs). The levels of inducible nitric oxide synthase (iNOS), IL-1ß, TNF-α, Cl-caspase-3, ciliary neurotrophic factor (CNTF), and p-ERK were analyzed by using western blots. RESULTS: Protection of visual function in FVEPs amplitude was noted, with a better preservation of the P1-N2 amplitude in the ALG-treated group (p = 0.032) than in the rAION group. The density of RGCs was 2.4-fold higher in the ALG-treated group compared to that in the rAION group (p < 0.0001). The number of ED1-positive cells in ONs was significantly reduced 4.1-fold in the ALG-treated group compared to those in the rAION group (p = 0.029). The number of apoptotic RGCs was 3.2-fold lower in number in the ALG-treated group (p = 0.001) than that in the rAION group. The ALG treatment inhibited ERK activation to reduce the levels of iNOS, IL-1ß, TNF-α, and Cl-caspase-3 and to increase the level of CNTF in the rAION model. CONCLUSION: The treatment with ALG after rAION induction inhibits ERK activation to provide both anti-inflammatory and antiapoptotic effects in rAION.

Cyanine-Based Polymer Dots with Long-Wavelength Excitation and Near-Infrared Fluorescence beyond 900 nm for In Vivo Biological Imaging.

Bioimaging in the near-infrared window is of great importance to study the dynamic processes in vivo with deep penetration, high spatiotemporal resolution, and minimal tissue absorption, scattering, and autofluorescence. In spite of the huge progress on the synthesis of small organic fluorophores and inorganic nanomaterials with emissions beyond 900 nm, it remains a tough challenge to synthesize semiconducting polymers with fluorescence over this region. Here, we synthesized a series of heptamethine cyanine-based polymers with both absorption and emission in the near-infrared region. We prepared these polymers as semiconducting polymer dots (Pdots) in pure water with great biocompatibility. The fluorescence quantum yield of the Pdots can be as high as 14% with a full width at half-maximum of 53 nm, and their single-particle brightness is more than 20 times higher than commercial quantum dots or ∼300 times brighter than Food and Drug Administration (FDA)-approved indocyanine green (ICG) dyes. We further demonstrated the use of cyanine-based Pdots for specific cellular labeling and long-term tumor targeting in mice. We anticipate that these cyanine-based ultrabright Pdots could open up an avenue for next generations of near-infrared fluorescent agents.

Therapeutic Effects of Puerarin Against Anterior Ischemic Optic Neuropathy Through Antiapoptotic and Anti-Inflammatory Actions.

Purpose: This study investigated the therapeutic effects of puerarin (PR) on a rat model of anterior ischemic optic neuropathy (rAION). Methods: The neuroprotective effects of PR on rAION were evaluated using flash visual-evoked potentials (FVEP), retrograde labeling of retinal ganglion cells (RGCs), TUNEL assay of the retina, optical coherence tomography (OCT) images of optic nerve width, and ED1 staining of the optic nerve (ON). The inflammatory response of ON and Akt signaling pathways were analyzed through Western blot. M2 polarization was determined by immunostaining and immunoblotting in ONs. Results: In FVEP analysis, the amplitude of P1-N2 and the RGC density in the PR-treated group were 2.3- and 1.6-fold higher than those in the PBS-treated group, respectively (P < 0.05). The number of apoptotic RGC in the PR-treated group was 2.8-fold lower than that in the PBS-treated group. OCT images demonstrated that PR treatment-reduced ON edema in the acute phase compared to PBS treatment (P < 0.05). Macrophage infiltration was reduced by 5.2-fold by PR treatment compared with the PBS treatment (P < 0.05). PR treatment inhibited the levels of iNOS, IL-1ß, and TNF-α, induced the levels of IL-10, Arg1, and Fizz1 in the rAION model. The levels of p-Akt1 and C/EBPß in the PR-treated group increased by 3.4-fold and 5.89-fold compared with those in the PBS-treated group (P < 0.05). Inhibition of Akt activation reduced the number of M2 macrophage in the PR-treated group (P < 0.05). Conclusions: PR treatment provided the neuroprotective effects in the rAION model, which may lead to new clinical applications.

Ultrabright Fluorescent Polymer Dots with Thermochromic Characteristics for Full-Color Security Marking.

Innovative and scalable security technologies are in high demand to deter increasing counterfeiting in modern society. Here, we report the first example of thermochromic-fluorescent ink based on semiconducting polymer dots (Pdots) by taking advantage of the unique optical properties of Pdots. We designed and synthesized two types of thermochromic molecules and then incorporated them with multicolor fluorescent Pdots. The resulting Pdots exhibited colorimetric and fluorescent dual-readout abilities in response to different temperatures which greatly increase the security level for anticounterfeiting applications. These multifunctional Pdots can be easily doped into flexible substrates or prepared as inks. These full-color inks can be further loaded into marker pens for handwriting or cartridges for inkjet printing with excellent signal-to-background contrast. Moreover, complex and delicate full-color images can be printed on security documents or currency for practical use. We anticipate that this first example of thermoresponsive dual-readout methodology based on Pdots will have broad use in advanced security marking technologies.

Molecular Regulation of Bone Metastasis Pathogenesis.

Distant metastases are the major cause of mortality in cancer patients. Bone metastases may cause bone fractures, local pain, hypercalcemia, bone marrow aplasia, and spinal cord compression. Therefore, the management of bone metastases is important in cancer treatment. Normal bone remodeling is regulated by osteoprotegerin ligand (OPGL), receptor activator of NF-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and other cytokines. In the tumor microenvironment, tumor cells induce a vicious cycle that promotes osteoblastic and osteolytic lesions. Studies support the idea that distant metastases may occur due to the immunosuppressive function of myeloid-derived suppressor cells (MDSCs). These cells inhibit T cells and natural killer (NK) cells and differentiate into tumor-associating macrophages (TAMs), monocytes, and dendritic cells (DCs). In this review, we summarize studies focusing on the role of MDSCs in bone metastasis and provide a strong foundation for developing anticancer immune treatments and anticancer therapies, in general.

Effects of intramolecular hydrogen bonding on the excited state dynamics of phenol chromophores.

The theoretical prediction and experimental confirmation of the 1πσ* excited state of phenol which is repulsive along the O-H bond has a large impact on the interpretation of phenol and tyrosine photochemistry. In this work, we demonstrate that this excited state changes significantly if the OH functional group is involved in the formation of an intramolecular hydrogen bond in the ground state. We investigate the excited state dynamics of 2-, 3-, and 4-hydroxyacetophenone (HAP) separately in a molecular beam at 193 nm using multimass ion imaging techniques. H atom elimination from the repulsive excited state and Norrish type I reactions are the major dissociation channels of 3-HAP and 4-HAP which do not have intramolecular hydrogen bonding. However, the H atom elimination channel is completely quenched for 2-HAP which shows intramolecular hydrogen bonding. In addition, the ground state and the excited state potential energy surfaces (PESs) of HAP, 2-hydroxybenzoyl fluoride, 2-hydroxybenzoyl chloride, and 2-hydroxybenzamide are investigated using ab initio calculations. The results also show that the excited state potential along the O-H bond distance of the hydroxyl group changes significantly for molecules with intramolecular hydrogen bonding. The changes include: (a) the repulsive potential energy surface becomes an attractive potential near the ground state equilibrium geometry, (b) the conical intersection between the first and the second excited states along the O-H bond moves to a much higher energy level, and (c) the conical intersection between the repulsive excited state and the ground state along the O-H bond distance disappears. The results suggest that the interpretation of the photochemistry for molecules with a phenol chromophore must take these effects into consideration.

Photodissociation dynamics of methoxybenzoic acid at 193 nm.

The theoretical prediction and experimental confirmation of the 1πσ* repulsive excited state along O-H bond of phenol have large impact on the interpretation of phenol and tyrosine photochemistry. In this work, we investigated the photodissociation dynamics of 2-, 3-, and 4-methoxybenzoic acid (MOBA) in a molecular beam at 193 nm using multimass ion imaging techniques. In addition, the ground state and the excited state potential energy surfaces of MOBA were investigated using ab initio calculations, and branching ratios were predicted by Rice-Ramsperger-Kassel-Marcus theory. The results show that (1) the excited state potential of 1πσ* along O-CH(3) bond remains similar to that of phenol and anisole, (2) CH(3) elimination is the major channel for three MOBA isomers, and (3) photofragment translational energy distributions show bimodal distributions, representing the dissociation on the ground state and repulsive excited state, respectively. Comparison to the study of hydroxbenzoic acid [Y. L. Yang, Y. A. Dyakov, Y. T. Lee, C. K. Ni, Y. L. Sun, and W. P. Hu, J. Chem. Phys. 134, 034314 (2011)] shows that only the intramolecular hydrogen bonding has significant effects on the excited state dynamics of phenol chromophores.

Photostability of amino acids: photodissociation dynamics of phenylalanine chromophores.

The theoretical prediction of H atom elimination on the excited state of phenol, imidazole and indole, the respective chromophores for the amino acids tyrosine, histidine and tryptophan, and the confirmation of theoretical prediction by experimental observations have a great impact on the explanation of photostability of amino acids upon irradiation with UV photons. On the other hand, no theoretical prediction of the excited state photodissociation dynamics has been made on the other aromatic amino acid, phenylalanine. In this work, photodissociation dynamics for various phenylalanine chromophores, including, phenylethylamine, N-methyl-phenylethylamine, and N-acetyl phenylalanine methyl ester was investigated in a molecular beam at 248 and 193 nm using multimass ion imaging techniques. The major dissociation channel for these compounds is the C-C bond cleavage. However, the photofragment translational energy distribution of phenylethylamine contains two components. The slow component corresponds to the dissociation on the ground state surface after internal conversion, and the fast component represents the dissociation from an excited state with a large exit barrier. The competition between the dissociation on the ground state and on the excited state changes as the size of chromophores increases. Internal conversion to the ground state prior to dissociation becomes the major nonradiative process for large chromophores. This study reveals the size-dependent photostability for these amino acid chromophores.