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Abstract: For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. Curcumin has a unique structure with phenolic hydroxyl group as well as β-diketone moiety in the same molecule, both of which are able to donate electrons to free radicals. However, due to the reactivity toward molecular oxygen, the carbon-centered radical derived from β-diketone moiety do not serve as radical-trapping antioxidants. In this study, we reasoned that stabilization of the carbon-centered radical through substitution with an electron-withdrawing group would enhance the radical-scavenging antioxidative activity of the resulting curcuminoids. Thus, various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) covering broad spectrum of the polar substituent effect were introduced to the central methylene position of both phenolic and non-phenolic curcuminoids. With the free phenolic hydroxyl groups present, the methylene-substituent did not exert significant effect on the antioxidant activity of the curcuminoids (EC50 =23.2–30.3μM) with the exception of the acetoxy-substituted derivative (EC50 =8.7μM) which showed more potent activity than curcumin (EC50 =22.6μM). When substituted to the non-phenolic curcumin scaffold, however, the methylene-substituent enhanced antioxidant activity of the otherwise inactive curcuminoids in the increasing order of methyl

Abstract: Phosphoinositide 3-kinases (PI3Ks) have known to be key enzymes activating intracellular signaling molecules when a number of growth factors bind to their cell surface receptors. PI3Ks are divided into three classes (I, II, and III) and enzymes of each class have different tissue-specificities and physiological functions. Class II PI3Ks consist of three isoforms (α,β,γ). Although the α-isoform (PI3K-C2α) is considered ubiquitous and preferentially activated by insulin rather than the β-isoform, the physiological significance of PI3K-C2α is poorly understood. The present study aimed to determine whether PI3K-C2α is associated with the suppression of apoptotic cell death. Different sense- and antisense oligonucleotides (ODNs) were synthesized based on the sequence of C2 domain of PI3K-C2α gene. Transfection of CHO-IR cells with two different antisense ODNs clearly reduced the protein content as well as mRNA levels of PI3K-C2α whereas neither the nonspecific mock- nor sense ODNs affected. The decrease of PI3K-C2α gene expression was paralleled by cellular changes indicating apoptotic cell death such as nuclear condensation, formation of apoptotic bodies, and DNA fragmentation. PI3K-C2α mRNA levels were also reduced when cells were incubated in growth factor-deficient medium. Supplementing growth factors (serum or insulin) into medium lead to an increase of PI3K-C2α mRNA levels. This finding strongly suggests that PI3K-C2α is a crucial survival factor. [Copyright &y& Elsevier]

Low hemoglobin levels are known to be associated with hematoma expansion (HE) and poor functional outcome in patients with intracerebral hemorrhage (ICH). However, it is not yet known whether low hemoglobin itself causes HE directly or is merely a confounder. Thus, we investigated the mediation effect of the mean Hounsfield unit (HU) of hematoma on the relationship between low hemoglobin and expansion of ICH. Overall, 232 consecutive patients with ICH who underwent non-contrast computed tomography (NCCT) within 12 h since onset were included. The mean HU and hematoma volume on NCCT were investigated using semi-automated planimetry. HE was defined as an increase in hematoma volume > 33% or 6 mL. The respective associations among the hemoglobin level, mean HU, and HE were analyzed using multivariable regression analysis, adjusting for age, sex, and known HE predictors. Mediation analysis was performed to examine the potential causal association among the three. HE occurred in 34.5% of patients; hemoglobin levels were inversely associated with HE occurrence (adjusted odds ratio, 0.90; p = 0.03). The mean HU of the hematoma was lower in patients with HE than in patients without HE (58.5 ± 3.3 vs. 56.8 ± 3.0; p < 0.01). Hemoglobin levels on admission were linearly related to the mean HU (adjusted β, 0.33; p < 0.01) after adjusting for known HE predictors (time from onset to CT, antithrombotic use, hematoma volume). Causal mediation analysis showed a significant mediation effect of the mean HU on the association between hemoglobin levels and HE (p = 0.04). The proportion of indirect effect through the mean HU among the total effect was 19% (p = 0.05). The mediation effect became nonsignificant in the when the multivariable model was adjusted with additional covariates (baseline systolic blood pressure and hematoma location). The mean HU of the hematoma mediated the association between hemoglobin levels and HE occurrence. Therefore, the mean HU of the hematoma may be a potential marker of impaired hemostasis in patients with ICH. [ABSTRACT FROM AUTHOR]

Demonstrates a zero path-length difference interferometry using the filter response of an unbalanced interferometer to the spontaneous/spontaneous beat noise spectrum of an amplified spontaneous emission source. Application of the method to path-length differences ranging from a few centimeters to several kilometers; Change in the interferometer output due to the frequency modulation.

As patients receiving definitive chemoradiotherapy (dCRT) for oesophageal squamous cell carcinoma (ESCC) are heterogeneous, we aimed to identify prognostic factors and failure patterns after dCRT. From 2006 to 2015, 327 patients who received dCRT for ESCC were reviewed. Treatment response to dCRT was evaluated based on EORTC‐PET criteria with endoscopy and CT results. After dCRT, 296 patients (90.5%) achieved disease stabilisation, with 132 cases of complete response (CR) (40.4%), 158 of partial response (PR) (48.3%) and 6 of stable disease (SD) (1.8%); 31 patients (9.5%) had progressive disease (PD). Median overall survival (OS) from response evaluation was 24.0 months in the overall population. Post‐treatment clinical response was the most significant prognostic factor for OS in the multivariate analysis (median OS, 65.0 months for CR, 17.3 months for PR, 4.4 months for SD and 4.0 months for PD; p < 0.0001). Median progression‐free survival (PFS) in 296 patients who achieved disease stabilisation was 13.1 months, and only clinical response was a significant factor in the multivariate analysis. The median PFS of CR, PR and SD patients were 36.9, 9.2 and 2.8 months, respectively (p < 0.0001). The clinical response was also significantly associated with the predominant failure pattern (locoregional failure [81.6%] in the initial non‐PD group vs. distant metastasis [87.1%] in the initial PD group [p < 0.0001]). In conclusion, definitive chemoradiotherapy‐treated ESCC patients showed highly different prognoses after treatment especially according to the clinical response to chemoradiotherapy. [ABSTRACT FROM AUTHOR]

There are several reports in the literature on the association between non-arteritic retinal artery occlusion (NA-RAO) and acute ischemic stroke. We investigated the burden of small vessel disease (SVD) and cerebral coincident infarction observed on cerebral magnetic resonance imaging (MRI) in patients with newly diagnosed NA-RAO. In this retrospective, observational, case-series study, consecutive patients with NA-RAO who underwent cerebral MRI within one month of diagnosis between September 2003 and October 2018 were included. The classification of NA-RAO was based on ophthalmologic and systemic examinations. We also investigated the co-incident infarction and burden of underlying SVD, which were categorized as white matter hyperintensity lesion (WMH), cerebral microbleeds (CMB), and silent lacunar infarction (SLI). Among the 272 patients enrolled in the study, 18% presented co-incident infarction and 73% had SVD, which included WMH (70%), CMB (14%), and SLI (30%). Co-incident infarction, WMH, and SLI significantly increased with age: co-incident infarction was observed in 8% of young (< 50 years) patients and 30% of old (≥ 70 years) patients. The embolic etiology of RAO (large artery atherosclerosis, cardioembolism, and undetermined etiology) was significantly associated with the prevalence of SVD (82%: 70%: 64%, P = 0.002) and co-incident infarction (30%: 19%: 8%; P = 0.009). Therefore, high co-incidence of acute cerebral infarction and underlying SVD burden warrant careful neurologic examination and appropriate brain imaging, followed by management of NA-RAO. Urgent brain imaging is particularly pertinent in elderly patients with NA-RAO. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance. [ABSTRACT FROM AUTHOR]

Abnormalities in body composition are associated with poor prognosis in cancer patients. We investigated the association between body composition and 90-day mortality in cancer patients who developed septic shock. We included consecutive septic shock patients with active cancer from 2010 to 2017. The muscle area at the level of the third lumbar vertebra was measured by computed tomography upon emergency department admission and adjusted by height squared, yielding the Skeletal Muscle Index (SMI). Hazard ratios (HRs) and 95% confidence intervals (CIs) for 90-day mortality were estimated using a Cox proportional hazards model. Among 478 patients, the prevalence of muscle depletion was 87.7%. Among markers of body composition, the SMI only differed significantly between non-survivors and survivors (mean, 35.48 vs. 33.32 cm2/m2; P = 0.002) and was independently associated with lower 90-day mortality (adjusted HR, 0.970; P = 0.001). The multivariable-adjusted HRs (95% CI) for 90-day mortality comparing quartiles 2, 3, and 4 of the SMI to the lowest quartile were 0.646 (0.916–1.307), 0.620 (0.424–0.909), and 0.529 (0.355–0.788), respectively. The associations were evident in male patients, but not in female patients. The SMI was independently associated with 90-day mortality in cancer patients with septic shock. The graded association between the SMI and 90-day mortality was observed in male patients. [ABSTRACT FROM AUTHOR]

Secreted Protein Acidic and Rich in Cysteine (SPARC)-related modular calcium-binding protein-2 (SMOC2), a secreted matricellular protein, is reported to be involved in various processes related to cancer progression such as regulating the cell cycle, angiogenesis, and invasion. However, its expression and prognostic significance in papillary thyroid carcinomas (PTCs) remains unknown. Using immunohistochemistry, we evaluated the expression profile of SMOC2 and its prognostic value in a large cohort of PTCs. Real time-PCR analysis with fresh-frozen tissues showed that SMOC2 mRNA expression in PTCs was substantially lower than the expression in matched non-cancerous thyroid tissues, consistent with the results from thyroid cancer cell lines. Immunohistochemical analysis demonstrated that SMOC2 was normally present in thyroid follicular epithelial cells and the expression level was maintained in nodular hyperplasia. However, SMOC2 expression was significantly lower in lymphocytic thyroiditis and follicular tumors including follicular adenomas and carcinomas. In particular, 38% of PTCs exhibited a complete loss of SMOC2 expression, which was associated with the presence of BRAF (V600E) mutation. Moreover, SMOC2 further declined during lymph node metastasis in PTCs. DNA methylation chip analysis revealed one hypermethylated CpG site in the promoter region of SMOC2 gene, suggesting an epigenetic regulation of SMOC2 in PTCs. Remarkably SMOC2 positivity was associated with improved recurrence-free survival along with female sex, tumor size, and the N stage. However, SMOC2 was not identified as an independent prognostic marker in multivariate analyses. Taken together, SMOC2 expression is significantly down-regulated in PTCs and SMOC2 positivity is closely associated with better clinical outcomes, suggesting that SMOC2 can be a prognostic marker in PTC patients. [ABSTRACT FROM AUTHOR]

Delayed wound healing after radiation exposure can cause serious cutaneous damage, and its treatment is a major clinical challenge. Although mesenchymal stem cells (MSCs) have emerged as a promising therapeutic agent in regenerative medicine, they alone do not produce satisfactory effects in a combined radiation and wound injury (CRWI) model. Here, we investigated the therapeutic effect of combined umbilical cord blood‐derived (UCB)‐MSCs and platelet‐rich plasma (PRP) treatment on wound healing in a CRWI mouse model. First, we assessed the release of cytokines from UCB‐MSCs cultured with PRP and observed changes in the expression of angiogenic factors. The angiogenic paracrine factors from UCB‐MSCs cultured with PRP were assessed in human umbilical vein endothelial cells (HUVECs). To assess therapeutic efficacy, UCB‐MSCs and PRP were topically implanted into a CRWT mouse model. Vascular endothelial growth factor (VEGF), a pro‐angiogenic growth factor, urokinase‐type plasminogen activator and contributor to VEGF‐induced signalling were more highly expressed in conditioned media of UCB‐MSCs cultured with PRP than in that of UCB‐MSCs alone. Furthermore, conditioned media of UCB‐MSCs cultured with PRP increased the formation of tube‐like structures in HUVECs. Co‐treatment of UCB‐MSCs and PRP in a CRWI mouse model increased the wound closure rate and angiogenesis compared with an untreated irradiated group. Moreover, increased expression of VEGF and CD31 were observed in the wound tissue of co‐treated mice compared with untreated irradiated mice. PRP stimulates the release of angiogenic factors from UCB‐MSCs, and combined therapy of UCB‐MSCs and PRP improves regeneration efficacy by enhancing angiogenesis in a CRWI model. [ABSTRACT FROM AUTHOR]

Background: Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib.Methods: This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients.Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes.Conclusion: Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib. [ABSTRACT FROM AUTHOR]

Periodontitis is an infectious disease that is associated with microorganisms that colonize the tooth surface. Clinically, periodontal condition stability reflects dynamic equilibrium between bacterial challenge and host response. Therefore, periodontal pathogen assessment can assist in the early detection of periodontitis. Here we developed a grading system called the periodontal pathogen index (PPI) by analyzing the copy numbers of multiple pathogens both in healthy and chronic periodontitis patients. We collected 170 mouthwash samples (64 periodontally healthy controls and 106 chronic periodontitis patients) and analyzed the salivary 16S rRNA levels of nine pathogens using multiplex, quantitative real-time polymerase chain reaction. Except for Aggregatibacter actinomycetemcomitans, copy numbers of all pathogens were significantly higher in chronic periodontitis patients. We classified the samples based on optimal cut-off values with maximum sensitivity and specificity from receiver operating characteristic curve analyses (AUC = 0.91, 95% CI: 0.87–0.96) into four categories of PPI: Healthy (1–40), Moderate (41–60), At Risk (61–80), and Severe (81–100). PPI scores were significantly higher in all chronic periodontitis patients than in the controls (odds ratio: 31.7, 95% CI: 13.41–61.61) and were associated with age, scaling as well as clinical characteristics including clinical attachment level and plaque index. Our PPI grading system can be clinically useful for the early assessment of pathogenic bacterial burden and follow-up monitoring after periodontitis treatment. [ABSTRACT FROM AUTHOR]

A radioactive material monitoring system, employing a passive detection technique with multiple gamma spectroscopy detectors and the centroid method for use in large areas, is presented. The system determines the location and the activity of radioisotopes. The proposed system was designed and evaluated using Monte Carlo simulations and experiments. In both simulation and experiment, calculated source locations were well distinguished and the location was determined within less than 1 m range compared to the actual location. The calculated activity was matched to the actual activity within an error of 5%. [ABSTRACT FROM AUTHOR]

Whether admission hyperglycemia is differentially associated with early vascular outcomes in acute ischemic stroke (AIS) depending on stroke subtype has been incompletely delineated. In a multicenter, prospective stroke registry, patients with AIS were categorized based on admission glucose levels into normoglycemia, moderate hyperglycemia, and severe hyperglycemia (<140mg/dl, 140–179mg/dl, and ≥180mg/dl, respectively) groups. Multivariate analysis assessed the interaction between the hyperglycemia and ischemic stroke subtypes of large artery atherothrombosis (LAA), cardioembolism (CE), and small vessel occlusion (SVO) and early vascular outcomes (3-month stroke, all-cause mortality, and composite of stroke, MI, and all-cause mortality). Among the 32,772 patients (age:69.0±12.6yrs, male:58.4%) meeting eligibility criteria, 61.9% were in the normoglycemia group, 19.5% were in the moderate hyperglycemia group, and 18.7% were in the severe hyperglycemia group. Substantial interactions between hyperglycemia groups and stroke subtypes were observed for 3-month stroke (P interaction = 0.003) and composite of stroke, MI, and all-cause mortality (P interaction = 0.001), with differential recurrence strongest among CE, intermediate among LAA, and least among SVO. Hyperglycemia was differently associated with the risk of 3-month stroke by ischemic stroke subtype. The associations of hyperglycemia with 3-month stroke were greatest in CE subtype but not in SVO subtype. These results suggest that the effect of glucose-lowering treatment after AIS may differ according to stroke subtype. [ABSTRACT FROM AUTHOR]

This paper presents the development of filtering methods for positron emission tomography (PET) signals contaminated by radio frequency (RF) pulses for combined PET and clinical 3-T magnetic resonance imaging (MRI). The filtering methods include software, hardware, and hybrid correction methods. In the software correction method, PET signals are assessed, and valid signals are identified based on the characteristics of a typical PET signal using Field-Programmable Gate Array (FPGA)-based programming. The hardware correction method makes use of differential-to-single-ended and low-pass filter circuits for PET analog signals. The hybrid correction method involves the sequential application of both the hardware and software methods. Both valid and contaminated PET signals are measured with an oscilloscope. An evaluation is then made of the performance (energy resolution, photopeak channel, total counts, and coincidence timing resolution) of the PET detector modules with and without various MR sequences (gradient echo, spin echo T1 sequence). For all correction methods, the energy resolution, photopeak position, and coincidence timing resolution with MR sequences are similar (< 3\%) to those without MR sequences. However, the total count of each module depends greatly on the method applied. The hybrid correction method displays an ability to preserve (< 1\%) the total counts of the modules during various MR sequences. The results show that this filtering method, which can reject noise signals and reduce count loss while preserving the valid analog signals of MR sequences, is reliable and useful for the development of simultaneous PET-MRI. [ABSTRACT FROM AUTHOR]

Abstract: Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance. [Copyright &y& Elsevier]

Purpose: In recent times, there has been great interest in the use of Geiger-mode avalanche photodiodes (GAPDs) as scintillator readout in positron emission tomography (PET) detectors because of their advantages, such as high gain, compact size, low power consumption, and magnetic field insensitivity. The purpose of this study was to develop a novel PET system based on GAPD arrays for brain imaging. Methods: The PET consisted of 72 detector modules arranged in a ring of 330 mm diameter. Each PET module was composed of a 4 × 4 matrix of 3 × 3 × 20 mm3 cerium-doped lutetium yttrium orthosilicate (LYSO) crystals coupled with a 4 × 4 array three-side tileable GAPD. The signals from each PET module were fed into preamplifiers using a 3 m long flat cable and then sent to a position decoder circuit (PDC), which output a digital address and an analog pulse of the interacted channel among 64 preamplifier signals tranmitted from four PET detector modules. The PDC outputs were fed into field programmable gate array (FPGA)-embedded data acquisition (DAQ) boards. The analog signal was then digitized, and arrival time and energy of the signal were calculated and stored. Results: The energy and coincidence timing resolutions measured for 511 keV gamma rays were 18.4 ± 3.1% and 2.6 ns, respectively. The transaxial spatial resolution and sensitivity in the center of field of view (FOV) were 3.1 mm and 0.32% cps/Bq, respectively. The rods down to a diameter of 2.5 mm were resolved in a hot-rod phantom image, and activity distribution patterns between the white and gray matters in the Hoffman brain phantom were well imaged. Conclusions: Experimental results indicate that a PET system can be developed using GAPD arrays and the GAPD-based PET system can provide high-quality PET imaging. [ABSTRACT FROM AUTHOR]

Abstract: Currently, for most photomultiplier tube (PMT)-based PET systems, constant fraction discriminators (CFD) and time to digital converters (TDC) have been employed to detect gamma ray signal arrival time, whereas anger logic circuits and peak detection analog-to-digital converters (ADCs) have been implemented to acquire position and energy information of detected events. As compared to PMT the Geiger-mode avalanche photodiodes (GAPDs) have a variety of advantages, such as compactness, low bias voltage requirement and MRI compatibility. Furthermore, the individual read-out method using a GAPD array coupled 1:1 with an array scintillator can provide better image uniformity than can be achieved using PMT and anger logic circuits. Recently, a brain PET using 72 GAPD arrays (4×4 array, pixel size: 3mm×3mm) coupled 1:1 with LYSO scintillators (4×4 array, pixel size: 3mm×3mm×20mm) has been developed for simultaneous PET/MRI imaging in our laboratory. Eighteen 64:1 position decoder circuits (PDCs) were used to reduce GAPD channel number and three off-the-shelf free-running ADC and field programmable gate array (FPGA) combined data acquisition (DAQ) cards were used for data acquisition and processing. In this study, a free-running ADC- and FPGA-based signal processing method was developed for the detection of gamma ray signal arrival time, energy and position information all together for each GAPD channel. For the method developed herein, three DAQ cards continuously acquired 18 channels of pre-amplified analog gamma ray signals and 108-bit digital addresses from 18 PDCs. In the FPGA, the digitized gamma ray pulses and digital addresses were processed to generate data packages containing pulse arrival time, baseline value, energy value and GAPD channel ID. Finally, these data packages were saved to a 128Mbyte on-board synchronous dynamic random access memory (SDRAM) and then transferred to a host computer for coincidence sorting and image reconstruction. In order to evaluate the functionality of the developed signal processing method, energy and timing resolutions for brain PET were measured via the placement of a 6μCi 22Na point source at the center of the PET scanner. Furthermore the PET image of the hot rod phantom (rod diameter: from 2.5mm to 6.5mm) with activity of 1mCi was simulated, and then image acquisition experiment was performed using the brain PET. Measured average energy resolution for 1152 GAPD channels and system timing resolution were 19.5% (FWHM%) and 2.7ns (FWHM), respectively. With regard to the acquisition of the hot rod phantom image, rods could be resolved down to a diameter of 2.5mm, which was similar to simulated results. The experimental results demonstrated that the signal processing method developed herein was successfully implemented for brain PET. This reduced the complexity, cost and developing duration for PET system relative to normal PET electronics, and it will obviously be useful for the development of high-performance investigational PET systems. [Copyright &y& Elsevier]

Abstract: In this study, as a bioisosteric alternative scaffold of the antiviral aryl diketoacids (ADKs), we used 5-hydroxychromone on which two arylmethyloxy substituents were installed. The 5-hydroxychromones (5b–5g) thus prepared showed anti-HCV activity and, depending on the aromatic substituents on the 2-arylmethyloxy moiety, some of the derivatives (5b–5f) were also active against SCV. In addition, unlike the ADKs which showed selective inhibition against the helicase activity of the SCV NTPase/helicase, the 5-hydroxychromones (5b–5f) were active against both NTPase and helicase activities of the target enzyme. Among those, 3-iodobenzyloxy-substituted derivative 5e showed the most potent activity against HCV (EC50 = 4 μM) as well as SCV (IC50 = 4 μM for ATPase activity, 11 μM for helicase activity) and this might be used as a platform structure for future development of the multi-target or broad-spectrum antivirals. [Copyright &y& Elsevier]

Abstract: The authors have previously reported a simulation study on a novel multi-pinhole (MP) collimator that is able to provide improved angular sampling and an enlarged imaging field of view (FOV) when compared to a low-energy high-resolution parallel-hole (LEHR) collimator using a detector of equivalent size. The aim of this study was to develop a miniature single photon emission computerized tomography (SPECT) to verify the performance of the proposed MP collimator with lead vertical septa. A detector with a 70mm×70mm active area that consisted of a 6mm-thick NaI(Tl) crystal coupled to a 127mm-diameter position-sensitive photomultiplier tube (PSPMT) was used. A 7×7 pinhole collimator with a 2mm-diameter pinhole and a focal length of 40mm was fabricated to evaluate the performance as compared to a typical LEHR collimator. Additionally, a detector having a 50mm×50mm active area with 5×5 pinhole and LEHR collimators was investigated to evaluate the enlarged imaging FOV. Planar spatial resolution, sensitivity, and resolution for hot- and cold-rod phantom images were acquired. Images were reconstructed using a dedicated maximum likelihood expectation maximization (MLEM) algorithm with an unmatched projector/backprojector pair. The spatial resolution and sensitivity obtained with both collimators were 4.7mm FWHM and 0.25cps/μCi at a distance of 60mm, respectively. Although the detector size was smaller than the phantom, the MP collimator allowed for imaging of the entire phantom while the image obtained with LEHR collimator suffered from a truncation artifact. The reconstructed images, using 60 and 30 projections with both 7×7 pinhole and LEHR collimators, yielded an image of similar quality to that, which was constructed using 120 projections. However, the images reconstructed with 10 projections using a 7×7 pinhole collimator showed better quality than those that used an LEHR collimator. The reconstructed images that used the MP collimator provided high-quality images with an enlarged imaging FOV, even when insufficient angular sampling data were used, which would be of use in the development of a stationary SPECT. [Copyright &y& Elsevier]

Abstract: A simple and improved digital timing method was developed for positron emission tomography (PET). This method, the so-called ‘initial rise interpolation method’, is based on an important characteristic of gamma signals: a properly pre-amplified and sampled gamma signal pulse can be characterized to arrive with an initial rise from the baseline and then reach a maximum rise. The pulse arrival time was obtained by calculating the intersection of the initial rise line with the baseline for each gamma signal pulse. Using an 8-channel 100MHz free-running ADC and FPGA combined data acquisition (DAQ) card, three digital timing methods were employed to measure the coincidence timing resolution of two types of recently developed 3mm×3mm PET sensors (a fast and a slow GAPD). The results showed that the initial rise interpolation method provides the best timing resolution for both types of GAPDs: 0.7ns FWHM for fast GAPD and 1.5ns FWHM for slow GAPD (digital CFD: 1.5 and 2.2ns FWHM; maximum rise interpolation: 1.8 and 2.7ns FWHM). By implementing the initial rise interpolation method into the FPGA of DAQ card, PET images of two 18F line sources were acquired successfully using a pair of 4×4 GAPD-LYSO array detectors (single pixel size: 3mm×3mm). The acquired image spatial resolution was a 3.1mm FWHM. Furthermore, the simulation was performed to evaluate the effects of the pulse rise time, pulse amplitude and front–end noise level on the timing resolution estimated using the three digital timing methods. In accordance with the measurement results, the simulation results also showed that the initial rise interpolation method provided the best timing resolution. These results show that this simple and improved digital timing method is reliable and useful for the development of high performance PET. [Copyright &y& Elsevier]

Dental caries are one of the chronic diseases caused by organic acids made from oral microbes. However, there was a lack of knowledge about the oral microbiome of Korean children. The aim of this study was to analyze the metagenome data of the oral microbiome obtained from Korean children and to discover bacteria highly related to dental caries with machine learning models. Saliva and plaque samples from 120 Korean children aged below 12 years were collected. Bacterial composition was identified using Illumina HiSeq sequencing based on the V3–V4 hypervariable region of the 16S rRNA gene. Ten major genera accounted for approximately 70% of the samples on average, including Streptococcus, Neisseria, Corynebacterium, and Fusobacterium. Differential abundant analyses revealed that Scardovia wiggsiae and Leptotrichia wadei were enriched in the caries samples, while Neisseria oralis was abundant in the non-caries samples of children aged below 6 years. The caries and non-caries samples of children aged 6–12 years were enriched in Streptococcus mutans and Corynebacterium durum, respectively. The machine learning models based on these differentially enriched taxa showed accuracies of up to 83%. These results confirmed significant alterations in the oral microbiome according to dental caries and age, and these differences can be used as diagnostic biomarkers. [ABSTRACT FROM AUTHOR]

Radiotherapy is one of the major cancer treatment strategies. Exposure to penetrating radiation causes cellular stress, directly or indirectly, due to the generation of reactive oxygen species, DNA damage, and subcellular organelle damage and autophagy. These radiation-induced damage responses cooperatively contribute to cancer cell death, but paradoxically, radiotherapy also causes the activation of damage-repair and survival signaling to alleviate radiation-induced cytotoxic effects in a small percentage of cancer cells, and these activations are responsible for tumor radio-resistance. The present study describes the molecular mechanisms responsible for radiation-induced cellular stress response and radioresistance, and the therapeutic approaches used to overcome radioresistance. [ABSTRACT FROM AUTHOR]

Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to develop a prototype magnetic resonance (MR)-compatible positron emission tomography (PET) that can be inserted into a MR imager and that allows simultaneous PET and MR imaging of the human brain. This paper reports the initial results of the authors' prototype brain PET system operating within a 3-T magnetic resonance imaging (MRI) system using newly developed Geiger-mode avalanche photodiode (GAPD)-based PET detectors, long flexible flat cables, position decoder circuit with high multiplexing ratio, and digital signal processing with field programmable gate array-based analog to digital converter boards. Methods: A brain PET with 72 detector modules arranged in a ring was constructed and mounted in a 3-T MRI. Each PET module was composed of cerium-doped lutetium yttrium orthosilicate (LYSO) crystals coupled to a tileable GAPD. The GAPD output charge signals were transferred to preamplifiers using 3 m long flat cables. The LYSO and GAPD were located inside the MR bore and all electronics were positioned outside the MR bore. The PET detector performance was investigated both outside and inside the MRI, and MR image quality was evaluated with and without the PET system. Results: The performance of the PET detector when operated inside the MRI during MR image acquisition showed no significant change in energy resolution and count rates, except for a slight degradation in timing resolution with an increase from 4.2 to 4.6 ns. Simultaneous PET/MR images of a hot-rod and Hoffman brain phantom were acquired in a 3-T MRI. Rods down to a diameter of 3.5 mm were resolved in the hot-rod PET image. The activity distribution patterns between the white and gray matter in the Hoffman brain phantom were well imaged. The hot-rod and Hoffman brain phantoms on the simultaneously acquired MR images obtained with standard sequences were observed without any noticeable artifacts, although MR image quality requires some improvement. Conclusions: These results demonstrate that the simultaneous acquisition of PET and MR images is feasible using the MR insertable PET developed in this study. [ABSTRACT FROM AUTHOR]