Conserved charged amino acid residues in the extracellular region of sodium/iodide symporter are critical for iodide transport activity

<p>Abstract</p> <p>Background</p> <p>Sodium/iodide symporter (NIS) mediates the active transport and accumulation of iodide from the blood into the thyroid gland. His-226 located in the extracellular region of NIS has been demonstrated to be critical for iodide transport in our previous study. The conserved charged amino acid residues in the extracellular region of NIS were therefore characterized in this study.</p> <p>Methods</p> <p>Fourteen charged residues (Arg-9, Glu-79, Arg-82, Lys-86, Asp-163, His-226, Arg-228, Asp-233, Asp-237, Arg-239, Arg-241, Asp-311, Asp-322, and Asp-331) were replaced by alanine. Iodide uptake abilities of mutants were evaluated by steady-state and kinetic analysis. The three-dimensional comparative protein structure of NIS was further modeled using sodium/glucose transporter as the reference protein.</p> <p>Results</p> <p>All the NIS mutants were expressed normally in the cells and targeted correctly to the plasma membrane. However, these mutants, except R9A, displayed severe defects on the iodide uptake. Further kinetic analysis revealed that mutations at conserved positively charged amino acid residues in the extracellular region of NIS led to decrease NIS-mediated iodide uptake activity by reducing the maximal rate of iodide transport, while mutations at conserved negatively charged residues led to decrease iodide transport by increasing dissociation between NIS mutants and iodide.</p> <p>Conclusions</p> <p>This is the first report characterizing thoroughly the functional significance of conserved charged amino acid residues in the extracellular region of NIS. Our data suggested that conserved charged amino acid residues, except Arg-9, in the extracellular region of NIS were critical for iodide transport.</p

18F-FDG PET/CT-based gross tumor volume definition for radiotherapy in head and neck Cancer: a correlation study between suitable uptake value threshold and tumor parameters

<p>Abstract</p> <p>Background</p> <p>To define a suitable threshold setting for gross tumor volume (GTV) when using ¹⁸Fluoro-deoxyglucose positron emission tomography and computed tomogram (PET/CT) for radiotherapy planning in head and neck cancer (HNC).</p> <p>Methods</p> <p>Fifteen HNC patients prospectively received PET/CT simulation for their radiation treatment planning. Biological target volume (BTV) was derived from PET/CT-based GTV of the primary tumor. The BTVs were defined as the isodensity volumes when adjusting different percentage of the maximal standardized uptake value (SUVmax), excluding any artifact from surrounding normal tissues. CT-based primary GTV (C-pGTV) that had been previously defined by radiation oncologists was compared with the BTV. Suitable threshold level (sTL) could be determined when BTV value and its morphology using a certain threshold level was observed to be the best fitness of the C-pGTV. Suitable standardized uptake value (sSUV) was calculated as the sTL multiplied by the SUVmax.</p> <p>Results</p> <p>Our result demonstrated no single sTL or sSUV method could achieve an optimized volumetric match with the C-pGTV. The sTL was 13% to 27% (mean, 19%), whereas the sSUV was 1.64 to 3.98 (mean, 2.46). The sTL was inversely correlated with the SUVmax [sTL = -0.1004 Ln (SUVmax) + 0.4464; R²= 0.81]. The sSUV showed a linear correlation with the SUVmax (sSUV = 0.0842 SUVmax + 1.248; R²= 0.89). The sTL was not associated with the value of C-pGTVs.</p> <p>Conclusion</p> <p>In PET/CT-based BTV for HNC, a suitable threshold or SUV level can be established by correlating with SUVmax rather than using a fixed threshold.</p

Missing Teeth and Restoration Detection Using Dental Panoramic Radiography Based on Transfer Learning With CNNs

Common dental diseases include caries, periodontitis, missing teeth and restorations. Dentists still use manual methods to judge and label lesions which is very time-consuming and highly repetitive. This research proposal uses artificial intelligence combined with image judgment technology for an improved efficiency on the process. In terms of cropping technology in images, the proposed study uses histogram equalization combined with flat-field correction for pixel value assignment. The details of the bone structure improves the resolution of the high-noise coverage. Thus, using the polynomial function connects all the interstitial strands by the strips to form a smooth curve. The curve solves the problem where the original cropping technology could not recognize a single tooth in some images. The accuracy has been improved by around 4% through the proposed cropping technique. For the convolutional neural network (CNN) technology, the lesion area analysis model is trained to judge the restoration and missing teeth of the clinical panorama (PANO) to achieve the purpose of developing an automatic diagnosis as a precision medical technology. In the current 3 commonly used neural networks namely AlexNet, GoogLeNet, and SqueezeNet, the experimental results show that the accuracy of the proposed GoogLeNet model for restoration and SqueezeNet model for missing teeth reached 97.10% and 99.90%, respectively. This research has passed the Research Institution Review Board (IRB) with application number 202002030B0

Tooth Position Determination by Automatic Cutting and Marking of Dental Panoramic X-ray Film in Medical Image Processing

This paper presents a novel method for automatic segmentation of dental X-ray images into single tooth sections and for placing every segmented tooth onto a precise corresponding position table. Moreover, the proposed method automatically determines the tooth’s position in a panoramic X-ray film. The image-processing step incorporates a variety of image-enhancement techniques, including sharpening, histogram equalization, and flat-field correction. Moreover, image processing was implemented iteratively to achieve higher pixel value contrast between the teeth and cavity. The next image-enhancement step is aimed at detecting the teeth cavity and involves determining the segment and points separating the upper and lower jaw, using the difference in pixel values to cut the image into several equal sections and then connecting each cavity feature point to extend a curve that completes the description of the separated jaw. The curve is shifted up and down to look for the gap between the teeth, to identify and address missing teeth and overlapping. Under FDI World Dental Federation notation, the left and right sides receive eight-code sequences to mark each tooth, which provides improved convenience in clinical use. According to the literature, X-ray film cannot be marked correctly when a tooth is missing. This paper utilizes artificial center positioning and sets the teeth gap feature points to have the same count. Then, the gap feature points are connected as a curve with the curve of the jaw to illustrate the dental segmentation. In addition, we incorporate different image-processing methods to sequentially strengthen the X-ray film. The proposed procedure had an 89.95% accuracy rate for tooth positioning. As for the tooth cutting, where the edge of the cutting box is used to determine the position of each tooth number, the accuracy of the tooth positioning method in this proposed study is 92.78%

Comparison of Immediate and 2-Year Outcomes between Excimer Laser-Assisted Angioplasty with Spot Stent and Primary Stenting in Intermediate to Long Femoropopliteal Disease

Background. To compare the clinical outcomes between excimer laser-assisted angioplasty (ELA) with spot stent (group A) and primary stenting (group B) in intermediate to long femoropopliteal disease. Methods. Outcomes of 105 patients totaling 119 legs treated with two different strategies were analyzed retrospectively in a prospectively maintained database. Results. Baseline characteristics were similar in both groups. Better angiographic results and lesser increase of serum C-reactive protein levels (0.60 ± 0.72 versus 2.98 ± 0.97 mg/dL, P<0.001) after the intervention were obtained in Group B. Group A had inferior 1-year outcomes due to higher rate of binary restenosis (67% versus 32%, P=0.001) and lower rate of primary patency (40% versus 58%, P=0.039). Rates of amputation-free survival, target vessel revascularization, assisted primary patency, and stent fracture at 24 months were similar in both groups (80% versus 82%, P=0.979, 65% versus 45%, P=0.11, 78% versus 80%, P=0.75 and 6.3% versus 6.8%, P=0.71, resp.). Conclusion. Greater vascular inflammation after ELA with spot stent resulted in earlier restenosis and inferior 1-year clinical outcomes than primary stenting. This benefit was lost in the primary stenting group at 2 years due to late catch-up restenosis. Active surveillance with prompt intervention was required to maintain the vessel patency

Toxic risk of stereotactic body radiotherapy and concurrent helical tomotherapy followed by erlotinib for non-small-cell lung cancer treatment - case report

<p>Abstract</p> <p>Background</p> <p>Stereotactic body radiation therapy (SBRT) applied by helical tomotherapy (HT) is feasible for lung cancer in clinical. Using SBRT concurrently with erlotinib for non-small cell lung cancer (NSCLC) is not reported previously.</p> <p>Case Presentation</p> <p>A 77-year-old man with stage III NSCLC, received erlotinib 150 mg/day, combined with image-guided SBRT via HT. A total tumor dose of 54 Gy/9 fractions was delivered to the tumor bed. The tumor responded dramatically and the combined regimen was well tolerated. After concurrent erlotinib-SBRT, erlotinib was continued as maintenance therapy. The patient developed dyspnea three months after the combined therapy and radiation pneumonitis with interstitial lung disease was suspected.</p> <p>Conclusions</p> <p>Combination SBRT, HT, and erlotinib therapy provided effective anti-tumor results. Nonetheless, the potential risks of enhanced adverse effects between radiation and erlotinib should be monitored closely, especially when SBRT is part of the regimen.</p

C-reactive protein concentration as a significant correlate for metabolic syndrome: a Chinese population-based study. Endocrine 43

Abstract Increasing evidence suggests that chronic, lowgrade inflammation may be a common soil involving the pathogenesis of metabolic syndrome (MetS) and cardiovascular disease. We examined the association between C-reactive protein (CRP) concentration, an extensively studied biomarker of low-grade inflammation, and the MetS in a representative sample of Chinese adults in Taiwan. We performed a cross-sectional analysis of data from 4234 subjects [mean (±SD) age, 47.1 (±18.2) years; 46.4 % males] who participated in a population-based survey on prevalences of hypertension, hyperglycemia, and hyperlipidemia in Taiwan. CRP levels were measured by the immunoturbidimetric CRP-latex high-sensitivity assay. The MetS was defined by an unified criteria set by several major organizations. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated with logistic regression model. Overall, there were 938 subjects with MetS among 4,234 participants, resulting in a prevalence rate of 22.1 %. A significantly progressive increase in the prevalence of MetS across quartiles of CRP was observed (p for trend \0.001). Participants in the second, third, and upper quartiles of CRP had significantly higher risk of having MetS when compared with those in the lowest quartile [adjusted ORs (95 % CIs) were 2.18 (1.62-2.94), 4.39 (3.31-5.81), and 7.11 (5.39-9.38), respectively; p for trend \0.001]. Furthermore, there was a strong stepwise increase in CRP levels as the number of components of the MetS increased. The prevalence of MetS showed a graded increase according to CRP concentrations. The possible utility of CRP concentration as a marker for MetS risk awaits further evaluation in prospective studies

Image-guided intensity modulated radiotherapy with helical tomotherapy for postoperative treatment of high-risk oral cavity cancer

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to assess the treatment results and toxicity profiles of helical tomotherapy (HT) for postoperative high-risk oral cavity cancer.</p> <p>Methods</p> <p>From December 6, 2006 through October 9, 2009, 19 postoperative high-risk oral cavity cancer patients were enrolled. All of the patients received HT with (84%) or without (16%) chemotherapy.</p> <p>Results</p> <p>The median follow-up time was 17 months. The 2-year overall survival, disease-free survival, locoregional control, and distant metastasis-free rates were 94%, 84%, 92%, and 94%, respectively. The package of overall treatment time > 13 wk, the interval between surgery and radiation ≤ 6 wk, and the overall treatment time of radiation ≤ 7 wk was 21%, 84%, and 79%, respectively. The percentage of grade 3 mucositis, dermatitis, and leucopenia was 42%, 5% and 5%, respectively.</p> <p>Conclusions</p> <p>HT achieved encouraging clinical outcomes for postoperative high-risk oral cavity cancer patients with high compliance. A long-term follow-up study is needed to confirm these preliminary findings.</p

A Novel Histone Deacetylase Inhibitor Exhibits Antitumor Activity via Apoptosis Induction, F-Actin Disruption and Gene Acetylation in Lung Cancer

BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxicity effect of OSU-HDAC-44 was examined in three human NSCLC cell lines including A549 (p53 wild-type), H1299 (p53 null), and CL1-1 (p53 mutant). The antiproliferative mechanisms of OSU-HDAC-44 were investigated by flow cytometric cell cycle analysis, apoptosis assays and genome-wide chromatin-immunoprecipitation-on-chip (ChIP-on-chip) analysis. Mice with established A549 tumor xenograft were treated with OSU-HDAC-44 or vehicle control and were used to evaluate effects on tumor growth, cytokinesis inhibition and apoptosis. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, cytokinesis was inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. ChIP-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. CONCLUSIONS/SIGNIFICANCE: OSU-HDAC-44 significantly suppresses tumor growth via induction of cytokinesis defect and intrinsic apoptosis in preclinical models of NSCLC. Our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy

Mitochondrial Apoptosis and FAK Signaling Disruption by a Novel Histone Deacetylase Inhibitor, HTPB, in Antitumor and Antimetastatic Mouse Models

BACKGROUND: Compound targeting histone deacetylase (HDAC) represents a new era in molecular cancer therapeutics. However, effective HDAC inhibitors for the treatment of solid tumors remain to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we propose a novel HDAC inhibitor, N-Hydroxy-4-(4-phenylbutyryl-amino) benzamide (HTPB), as a potential chemotherapeutic drug for solid tumors. The HDAC inhibition of HTPB was confirmed using HDAC activity assay. The antiproliferative and anti-migratory mechanisms of HTPB were investigated by cell proliferation, flow cytometry, DNA ladder, caspase activity, Rho activity, F-actin polymerization, and gelatin-zymography for matrix metalloproteinases (MMPs). Mice with tumor xenograft and experimental metastasis model were used to evaluate effects on tumor growth and metastasis. Our results indicated that HTPB was a pan-HDAC inhibitor in suppressing cell viability specifically of lung cancer cells but not of the normal lung cells. Upon HTPB treatment, cell cycle arrest was induced and subsequently led to mitochondria-mediated apoptosis. HTPB disrupted F-actin dynamics via downregulating RhoA activity. Moreover, HTPB inhibited activity of MMP2 and MMP9, reduced integrin-β1/focal adhesion complex formation and decreased pericellular poly-fibronectin assemblies. Finally, intraperitoneal injection or oral administration of HTPB efficiently inhibited A549 xenograft tumor growth in vivo without side effects. HTPB delayed lung metastasis of 4T1 mouse breast cancer cells. Acetylation of histone and non-histone proteins, induction of apoptotic-related proteins and de-phosphorylation of focal adhesion kinase were confirmed in treated mice. CONCLUSIONS/SIGNIFICANCE: These results suggested that intrinsic apoptotic pathway may involve in anti-tumor growth effects of HTPB in lung cancer cells. HTPB significantly suppresses tumor metastasis partly through inhibition of integrin-β1/FAK/MMP/RhoA/F-actin pathways. We have provided convincing preclinical evidence that HTPB is a potent HDAC targeted inhibitor and is thus a promising candidate for lung cancer chemotherapy