Curcuminoids Inhibit Angiogenic Behaviors of Human Umbilical Vein Endothelial Cells via Endoglin/Smad1 Signaling.

BACKGROUND: Angiogenesis is primarily attributed to the excessive proliferation and migration of endothelial cells. Targeting the vascular endothelial growth factor (VEGF) is therefore significant in anti-angiogenic therapy. Although these treatments have not reached clinical expectations, the upregulation of alternative angiogenic pathways (endoglin/Smad1) may play a critical role in drug (VEGF-neutralizing agents) resistance. Enhanced endoglin expression following a VEGF-neutralizing therapy (semaxanib®) was noted in patients. Treatment with an endoglin-targeting antibody augmented VEGF expression in human umbilical vein endothelial cells (HUVECs). Therefore, approaches that inhibit both the androgen and VEGF pathways enhance the HUVECs cytotoxicity and reverse semaxanib resistance. The purpose of this study was to find natural-occurring compounds that inhibited the endoglin-targeting pathway. METHODS: Curcuminoids targeting endoglin were recognized from two thousand compounds in the Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan) using Discovery Studio 4.5. RESULTS: Our results, obtained using cytotoxicity, migration/invasion, and flow cytometry assays, showed that curcumin (Cur) and demethoxycurcumin (DMC) reduced angiogenesis. In addition, Cur and DMC downregulated endoglin/pSmad1 phosphorylation. CONCLUSIONS: The study first showed that Cur and DMC demonstrated antiangiogenic activity via the inhibition of endoglin/Smad1 signaling. Synergistic effects of curcuminoids (i.e., curcumin and DMC) and semaxanib on HUVECs were found. This might be attributed to endoglin/pSmad1 downregulation in HUVECs. Combination treatment with curcuminoids and a semaxanib is therefore expected to reverse semaxanib resistance.

Double attack strategy for leukemia using a pre-targeting bispecific antibody (CD20 Ab-mPEG scFv) and actively attracting PEGylated liposomal doxorubicin to enhance anti-tumor activity.

BACKGROUND: Tumor-targeted nanoparticles hold great promise as new tools for therapy of liquid cancers. Furthermore, the therapeutic efficacy of nanoparticles can be improved by enhancing the cancer cellular internalization. METHODS: In this study, we developed a humanized bispecific antibody (BsAbs: CD20 Ab-mPEG scFv) which retains the clinical anti-CD20 whole antibody (Ofatumumab) and is fused with an anti-mPEG single chain antibody (scFv) that can target the systemic liquid tumor cells. This combination achieves the therapeutic function and simultaneously "grabs" Lipo-Dox® (PEGylated liposomal doxorubicin, PLD) to enhance the cellular internalization and anticancer activity of PLD. RESULTS: We successfully constructed the CD20 Ab-mPEG scFv and proved that CD20 Ab-mPEG scFv can target CD20-expressing Raji cells and simultaneously grab PEGylated liposomal DiD increasing the internalization ability up to 60% in 24 h. We further showed that the combination of CD20 Ab-mPEG scFv and PLD successfully led to a ninefold increase in tumor cytotoxicity (LC50: 0.38 nM) compared to the CD20 Ab-DNS scFv and PLD (lC50: 3.45 nM) in vitro. Importantly, a combination of CD20 Ab-mPEG scFv and PLD had greater anti-liquid tumor efficacy (P = 0.0005) in Raji-bearing mice than CD20 Ab-DNS scFv and PLD. CONCLUSION: Our results indicate that this "double-attack" strategy using CD20 Ab-mPEG scFv and PLD can retain the tumor targeting (first attack) and confer PLD tumor-selectivity (second attack) to enhance PLD internalization and improve therapeutic efficacy in liquid tumors.

Humanized bispecific antibody (mPEG × HER2) rapidly confers PEGylated nanoparticles tumor specificity for multimodality imaging in breast cancer.

BACKGROUND: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG × HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. RESULT: We used a one-step formulation to rapidly modify the nanoprobes with mPEG × HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The αHER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2++) but not MCF7/neo1 cells (HER2+/-). The αHER2/Lipo-DiR and αHER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2++). In in vivo imaging, αHER2/Lipo-DiR and αHER2/SPIO increased the specific targeting and enhanced PEG-NPs accumulation at 175% and 187% on 24 h, respectively, in HER2-overexpressing tumors. CONCLUSION: mPEG × HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.

Development of a novel thermal-sensitive multifunctional liposome with antibody conjugation to target EGFR-expressing tumors.

A novel EGFR-targeting, thermal-sensitive multifunctional liposome (TSML) was developed based on manganese-doped magnetism-engineered iron oxide nanoparticles (MnMEIOs) and gold nanorods (AuNRs) for efficient photothermal therapy and magnetic resonance (MR) imaging. An Erbitux-conjugated TSML (Erb-TSML) was encapsulated with doxorubicin and gold nanorods conjugated with manganese-doped magnetism-engineered iron oxide nanoparticles, for theranostic applications of EGFR-positive tumors. The Erb-TSML selectively targeted EGFR-positive tumors and promoted tumor destruction by laser activation. Using confocal microscopy, MR and optical imaging, we demonstrated that Erb-TSML specifically bound to A431 tumor cells. No signs of major morphological damages to the normal tissues were observed in mice treated with Erb-TSML and laser, indicating this theranostic platform protected heart against doxorubicin-induced toxicity to normal tissues. These results indicate that the Erb-TSML may be a promising diagnostic and therapeutic platform for EGFR-overexpressing tumors.

Juveniles with a history of violent behavior show cognitive performance and electrophysiology consistent with inhibitory control and emotional feedback processing problems.

Inhibitory control and the effects of negative emotional feedback were investigated in adolescents with a history of violent behavior and normal adolescents using the Taylor Aggression Paradigm (TAP), a task simulating real situations of social interaction to elicit aggressive behavior and negative emotions, with concurrent event related potential recordings. The Reactive Proactive Aggression Questionnaire (RPAQ), the Barratt Impulsiveness Scale (BIS) and the Negative Mood Regulation (NMR) Scale were also presented. These showed that reactive scores, proactive scores, and BIS scores were all significantly higher for the violent offender group whereas scores from the NMR scale were significantly lower for this group. In the TAP, the violent offender group chose significantly higher levels of punishment, indicative of both higher proactive and higher reactive aggression, for their opponent than did the control group. The ERP data showed the N2 amplitude for the decision phase, indicative of inhibitory control, was lower for the violent offender group than for the control group, with mediation analysis showing that the N2 component was related to proactive aggression. The decision-related negativity and the feedback-related negativity in the result phase were also both lower for the violent offender group than for the control group. Adolescent violent offenders showed higher levels of aggressive behavior than normal adolescents. This is associated with both worse inhibitory control and worse negative emotion regulation. Investigation of common factors underlying these processes, in conjunction with possible ways in which they might be improved, should be a priority for future work.

In Vitro and in Vivo Imaging of Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish.

Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli's salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40⁻360 µM with a detection limit of 9.05 µM. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.

Suppression of IL-8-Src signalling axis by 17ß-estradiol inhibits human mesenchymal stem cells-mediated gastric cancer invasion.

Epidemiologic data show the incidence of gastric cancer in men is twofold higher than in women worldwide. Oestrogen is reported to have the capacity against gastric cancer development. Endogenous oestrogen reduces gastric cancer incidence in women. Cancer patients treated with oestrogens have a lower subsequent risk of gastric cancer. Accumulating studies report that bone marrow mesenchymal stem cells (BMMSCs) might contribute to the progression of gastric cancer through paracrine effect of soluble factors. Here, we further explore the effect of oestrogen on BMMSCs-mediated human gastric cancer invasive motility. We founded that HBMMSCs notably secrete interleukin-8 (IL-8) protein. Administration of IL-8 specific neutralizing antibody significantly inhibits HBMMSCs-mediated gastric cancer motility. Treatment of recombinant IL-8 soluble protein confirmed the role of IL-8 in mediating HBMMSCs-up-regulated cell motility. IL-8 up-regulates motility activity through Src signalling pathway in human gastric cancer. We further observed that 17ß -estradiol inhibit HBMMSCS-induced cell motility via suppressing activation of IL8-Src signalling in human gastric cancer cells. 17ß-estradiol inhibits IL8-up-regulated Src downstream target proteins including p-Cas, p-paxillin, p-ERK1/2, p-JNK1/2, MMP9, tPA and uPA. These results suggest that 17ß-estradiol significantly inhibits HBMMSCS-induced invasive motility through suppressing IL8-Src signalling axis in human gastric cancer cells.

Pleural Tags on CT Scans to Predict Visceral Pleural Invasion of Non-Small Cell Lung Cancer That Does Not Abut the Pleura.

PURPOSE: To evaluate the association of pleural tags with visceral pleural invasion of non-small cell lung cancer (NSCLC) that does not abut the pleural surface. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Informed consent was waived. The study of NSCLC that does not abut the pleura in 141 patients (44 patients [31.2%] with visceral pleural invasion proved by pathologic analysis and 97 patients [68.8%] without pleural invasion) was conducted at a single tertiary center. The pleural tags were classified into three types (type 1, one or more linear pleural tag; type 2, one or more linear pleural tag with soft tissue component at the pleural end; and type 3, one or more soft tissue cord-like pleural tag) and prioritized into types 3, 2, and 1 when more than one type was present. Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive likelihood ratio (LR) were calculated. RESULTS: In the absence of pleural tags, no pleural invasion was found. The presence of type 2 pleural tags was moderately associated with visceral pleural invasion with the following results: positive LR, 5.06; accuracy, 71%; sensitivity, 36.4%; specificity, 92.8%; PPV, 76.2%; and NPV, 69.6%. Type 1 pleural tags provided weak evidence to rule out visceral pleural invasion (positive LR, 0.38). Type 3 pleural tags indicated minimal increase in the likelihood of visceral pleural invasion (positive LR, 1.68). CONCLUSION: Type 2 pleural tags on conventional CT images can increase the accuracy of early diagnosis of visceral pleural invasion by NSCLC that does not abut the pleura.

Abnormal white matter integrity in rapists as indicated by diffusion tensor imaging.

BACKGROUND: Recent research has documented structural brain abnormalities in various criminal offenders. However, there have been few brain imaging studies of sex offenders, and none on white matter integrity. The current study tested the hypothesis that rapists, when compared to matched controls, would show abnormal cortical and subcortical white matter integrity. RESULTS: Rapists showed significantly increased fractional anisotropy in the internal capsul e in the thalamus, caudate, and globus pallidus, and also in white matter tracts near the angular gyrus, posterior cingulate, frontal pole, lateral occipital cortex, and genu compared to controls matched for age, gender, and educational status. Reduced fractional anisotropy was observed in rapists in the posterior cingulum and in the inferior fronto-occipital fasciculus. CONCLUSIONS: To our knowledge, this is the first study indicating white matter abnormalities in rapists. Findings indicate abnormalities in white matter connectivity in brain regions involved in reward/motivation and moral judgment, which may predispose rapists to be both over-responsive to sexual reward stimuli and also to make inappropriate moral decisions.

Diagnostic Performance of Split-Bolus Portal Venous Phase Dual-Energy CT Urography in Patients With Hematuria.

OBJECTIVE: The purpose of this study is to evaluate the diagnostic performance of split-bolus portal venous phase dual-energy CT (DECT) urography in patients with hematuria. MATERIALS AND METHODS: True unenhanced and split-bolus portal venous phase contrast-enhanced weighted-average images were obtained in 171 patients with hematuria. Virtual unenhanced and iodine-overlay images were reconstructed from contrast-enhanced 80-kVp and tin-filtered 140-kVp scans. Images were independently reviewed by two radiologists who were blinded to the final diagnoses in two separate reading sessions: virtual unenhanced and iodine-overlay images (single phase) in the first session and true unenhanced and contrast-enhanced weighted-average images (dual phase) in the second session (mean ± SD, 52 ± 8 days later). Sensitivity, specificity, and accuracy of mass detection were calculated from the data of both reading sessions. The number of calculi detected on virtual unenhanced images was compared with the number detected on true unenhanced images. The difference in radiation dose between the single- and dual-phase protocols was calculated. The statistical significance was determined by ANOVA. RESULTS: The sensitivity, specificity, and accuracy were 98.7%, 98.9%, and 98.8%, respectively, for the single-phase approach to malignant mass detection and 98.7%, 97.9%, and 98.3%, respectively, for the dual-phase approach (p > 0.05 for all comparisons). The overall sensitivity of stone detection was 86.7% (39/45) for virtual unenhanced images. Omitting the unenhanced scan reduced the mean radiation dose from 15.4 to 6.7 mSv. CONCLUSION: The diagnostic performance of both the single- and dual-phase approaches of portal venous phase split-bolus DECT urography is equally good in patients with hematuria, and single-phase acquisition has the added benefit of radiation reduction.

Altered Functional Connectivity of the Insula and Nucleus Accumbens in Internet Gaming Disorder: A Resting State fMRI Study.

AIMS: A possible addiction mechanism has been represented by altered functional connectivity (FC) in the resting state. The aim of this study was to evaluate the FCs of the insula and nucleus accumbens among subjects with Internet gaming disorder (IGD). METHODS: We recruited 30 males with IGD and 30 controls and evaluated their FC using functional magnetic imaging scanning under resting, a state with relaxation, closed eyes, with inducement to think of nothing systematically, become motionless, and instructed not to fall asleep. RESULTS: Subjects with IGD had a lower FC with the left insula over the left dorsolateral prefrontal cortex (DLPFC) and orbital frontal lobe and a higher FC with the insula with the contralateral insula than controls. The inter-hemispheric insula connectivity positively correlated with impulsivity. Further, they had lower FC with the left nucleus accumbens over the left DLPFC and with the right nucleus accumbens over the left DLPFC, and insula and a higher FC with that over the right precuneus. CONCLUSION: The elevated inter-hemispheric insula FC is found to be associated with impulsivity and might explain why it is involved in IGD. The attenuated frontostriatal suggests that the emotion-driven gaming urge through nucleus accumbens could not be well regulated by the frontal lobe of subjects with IGD.

Assessment of psychiatric disorders among sex offenders: Prevalence and associations with criminal history.

BACKGROUND: Much of the research on the prevalence of psychiatric disorders among sex offenders has been conducted in the USA or Europe. Less is known about it in other regions, particularly in Asia. AIMS: The objective of this study is to determine the prevalence of psychiatric disorders among sex offenders in Taiwan and their associations with offender characteristics and criminal history. METHODS: Participants were randomly selected from men serving sentences in Taiwan's prison for serious sex offenders. Consenting men were assessed using the structured clinical interviews for DSM-IV-TR Axis I and II disorders. Demographics and criminal history were also recorded. RESULTS: Over two-thirds of the 68 participants met criteria for one or more lifetime Axis I disorders, and nearly 60% met criteria for one or more Axis II disorder. The higher the number of Axis I and cluster B personality disorders, the higher was the total number of convictions. CONCLUSIONS: Our study adds to the literature that suggests that psychiatric assessment is likely to have an important role in the management and treatment of sex offenders. The finding that multiple disorders are common in this group and associated with more convictions for sex offences suggests that failure to include psychiatric assessment in planning the management of sex offenders may increase the risk of recidivism.

Split-Bolus Portal Venous Phase Dual-Energy CT Urography: Protocol Design, Image Quality, and Dose Reduction.

OBJECTIVE: The purpose of this study is to evaluate the image quality of split-bolus portal venous phase urography and the potential reduction of radiation dose by using a second-generation dual-source dual-energy CT (DECT) scanner. MATERIALS AND METHODS: DECT urography was performed in 84 patients. Unenhanced CT was performed 20 minutes after drinking 800 mL of water. The split-bolus protocol consisted of a sequence of injections, as follows: 200 mL of normal saline (2.0 mL/s), 50 mL of contrast medium (2.5 mL/s) at 0 second, 70 mL of contrast medium (2.5 mL/s) at 360 seconds, and a saline flush of 25 mL. The scan was started at 420 seconds. Virtual unenhanced images were reconstructed from contrast-enhanced images. The mean CT density and signal-to-noise ratio (SNR) of the renal parenchyma, vessels, upper urinary tract, normal reference tissues, and tumors were measured for image quantitative analysis. Image quality and opacification of the collecting systems were rated by two radiologists using 3- or 4-point scales. RESULTS: The SNR of all measured sites, except the renal pelvis, showed a statistically significant correlation (p < 0.001) between the true unenhanced and virtual unenhanced images. The overall sensitivity of stone detection was 87.5% (28/32) in virtual unenhanced images. Image quality of the renal parenchyma, arteries, and veins was excellent in 59.5%, 75.0%, and 97.6% of cases, respectively. Opacification of the intrarenal collecting systems, proximal, middle, and distal ureters, and bladder was complete in 92.9%, 83.9%, 78.6%, 77.4%, and 26.2% of patients, respectively. Omitting the unenhanced scan can reduce the mean radiation dose from 15.6 to 6.7 mSv. CONCLUSION: Portal venous phase split-bolus DECT urography provides sufficient image quality with potential to reduce radiation exposure.

Lowering radiation dose during dedicated colorectal cancer MDCT: comparison of low tube voltage and sinogram-affirmed iterative reconstruction at 80 kVp versus blended dual-energy images in a population of patients with low body mass index.

PURPOSE: To assess the diagnostic accuracy, cancer staging, image quality, and radiation dose of 80-kVp computed tomography (CT) images for patients with colorectal cancers (CRCs) using sinogram-affirmed iterative reconstruction (SAFIRE). METHODS: Sixty-four consecutive patients (mean weight 62.5  ±  11.3 kg, mean BMI 24.1  ±  3.3 kg/m(2)) with known CRC underwent dual-energy CT. Data were reconstructed as a weighted average (WA) 120-kVp dataset. Both filtered back projection (FBP) and SAFIRE were applied to reconstruct the WA 120-Kvp (Protocol A, B) and 80-kVp (Protocol C, D) image sets. The image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of the cancers, the normal reference tissues, and the effective dose for each protocol were assessed. The cancer detection, staging, and image quality were evaluated. Analysis of variance was used for statistical analysis. RESULTS: Compared with the FBP datasets at WA 120-kVp (Protocol A) and 80-kVp (Protocol C), the SAFIRE-reconstructed images (Protocols B, D) demonstrated significantly lower image noise (P  <  0.0083). Protocol D yielded significantly higher CNRs and SNRs for the CRCs and normal reference tissues than did Protocols A and C (P  <  0.0083). Protocol D also exhibited a significantly higher CNR for the CRC and some normal reference tissues than did Protocol B (P  <  0.0083). For hypovascular liver metastases (n  =  10), Protocol D yielded better SNRs and significantly higher CNRs than did Protocol A (P  <  0.0083). Overall, accuracy for tumor staging and liver metastasis was 95.3% (61/64) and 100%, respectively, in all of the 4 protocols. The mean effective dose decreased 41% from the WA 120-kVp to the 80-kVp protocols (6.23 vs. 3.68 mSv). CONCLUSIONS: The 80-kVp technique with SAFIRE provided high SNR, high CNR, and good accuracy for staging in nonobese patients with CRC. Our study results should be extrapolated to patient populations with a high BMI with caution. Further studies of high BMI patients are therefore warranted.

Brain correlates of response inhibition in Internet gaming disorder.

AIMS: The present study aimed to evaluate the brain correlates of response inhibition among subjects with Internet gaming disorder (IGD). METHODS: For this purpose, 15 men with IGD for at least 1 year, and 15 controls with no history of IGD were recruited to perform the Go/Nogo task under functional magnetic resonance imaging investigation. Prior to scanning, the subjects were assessed using the Chen Internet Addiction Scale and the Barrett Impulsivity Scale. RESULTS: The control group exhibited activation of the right supplement motor area (SMA), dorsolateral prefrontal cortex, and caudate for response inhibition. However, the IGD group had a higher impulsivity and lower activity of the right SMA/pre-SMA in comparison to the control group. CONCLUSIONS: The results obtained suggest that dysfunctional activation of the SMA for response inhibition is one of the candidate mechanisms of IGD.

Altered brain activation during response inhibition and error processing in subjects with Internet gaming disorder: a functional magnetic imaging study.

The aim of the present study was to evaluate the impulsivity and brain correlates of response inhibition and error processing among subjects with Internet gaming disorder (IGD). We evaluated the response inhibition and error processing by functional magnetic resonance imaging (fMRI) in subjects with IGD and controls. Twenty-six men with IGD for at least 2 years and 23 controls with no history of IGD were recruited as the IGD and control groups, respectively. All subjects performed the event-related designed Go/No-go task under fMRI and completed questionnaires related to Internet addiction and impulsivity. The IGD group exhibited a higher score for impulsivity than the control group. The IGD group also exhibited higher brain activation when processing response inhibition over the left orbital frontal lobe and bilateral caudate nucleus than controls. Both the IGD and control groups exhibited activation of the insula and anterior cingulate cortex during error processing. The activation over the right insula was lower in the subjects with IGD than the control group. Our results support the fact that the fronto-striatal network involved in response inhibition, and the salience network, anchored by the anterior cingulate and insula, contributes to error processing. Further, adults with IGD have impaired insular function in error processing and greater activation of the fronto-striatal network in order to maintain their response inhibition performance.

The potential of transcranial magnetic stimulation for population-based application: a region-based illustrated brief overview.

The awareness of the global trends in neuroscience study, especially in the cognitive neuroscience field, should be increased. One notable approach is the use of transcranial magnetic stimulation (TMS) not only as a research tool but also as a choice for treatment and rehabilitation in neurological disorders, such as post-stroke hemiplegia, visuospatial neglect syndrome, Alzheimer's disease (AD) and psychiatric conditions such as major depression and schizophrenia. All of these occur in significant numbers in highly populated regions. This paper briefly discusses the basic protocols and potential benefits of using TMS with the aim of providing insight that is useful in the design of future public health strategies in highly populated regions with a large neurocognitive burden of disease where this technique is currently underemployed.

Brain correlates of craving for online gaming under cue exposure in subjects with Internet gaming addiction and in remitted subjects.

This study aimed to evaluate brain correlates of cue-induced craving to play online games in subjects with Internet gaming addiction (IGA), subjects in remission from IGA and controls. The craving response was assessed by event-related design of functional magnetic resonance images (fMRIs). Fifteen subjects with IGA, 15 in remission from IGA and 15 controls were recruited in this study. The subjects were arranged to view the gaming screenshots and neutral images under investigation of fMRIs. The results showed that bilateral dorsolateral prefrontal cortex (DLPFC), precuneus, left parahippocampus, posterior cingulate and right anterior cingulate were activated in response to gaming cues in the IGA group and their activation was stronger in the IGA group than those in the control group. Their region-of-interest was also positively correlated with subjective gaming urge under cue exposure. These activated brain areas represent the brain circuit corresponding to the mechanism of substance use disorder. Thus, it would suggest that the mechanism of IGA is similar to substance use disorder. Furthermore, the IGA group had stronger activation over right DLPFC and left parahippocampus than did the remission group. The two areas would be candidate markers for current addiction to online gaming and should be investigated in future studies.

Use of the P300 event-related potential component to index transcranial direct current stimulation effects in drug users.

Drug use causes significant social and financial problems and these are exacerbated by difficulties in stopping use and subsequent maintenance of abstinence. There is also difficulty in identifying the beneficial treatment for an individual, made more problematic given the high drop-out rates in treatment programs. Here, the effects of transcranial direct current stimulation (tDCS) on the amplitude of the P300 event-related potential component, previously suggested to be indicative of successful remission, was measured in recently abstinent amphetamine users. This component was collected during a Posner cuing task which was presented to this group and to control (non-user) participants, using task cues of neutral and drug-related images. The abstinent drug users were divided into two groups, one of which received tDCS daily for five days, with the cathode over the left dorsolateral prefrontal cortex (DLPFC) and the anode over the right DLPFC, and one receiving sham stimulation over the same time period. Behavioral performance and P300 amplitudes were measured before and after the period of tDCS delivery. Control participants were tested with the same time-schedule of task presentation but without administration of tDCS. Drug users initially showed a larger cost of invalid cues on task performance compared to control (non-drug user) participants and this was reduced following delivery of tDCS. Additionally, tDCS resulted in increased amplitude of the P300 component, significantly so for neutral cues, with the resulting pattern being more similar to that of the non-users. This provides a good basis for further investigation of both the utility of tDCS in modulation of cognition in addict groups, and to investigate the effects of modulating the P300 component on remission rates, a relationship that seems to be the case for this measure without use of tDCS modulation. Importantly, this study also provides a further addiction group showing P300 amplitude modulation as a result of tDCS administration.

Identifying novel radioprotective drugs via salivary gland tissue chip screening.

During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (ß-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC 50 values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.