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 FDA 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. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except 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 exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent 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 non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.

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.

A phase Ib/II trial of PEP503 (NBTXR3, radioenhancer) with radiotherapy and chemotherapy in patients with rectal cancer.

Aims: To investigate the safety profile, dose-limiting toxicity and antitumor activity of PEP503 (NBTXR3) nanoparticles with radiotherapy and concurrent chemotherapy in patients with locally advanced or unresectable rectal cancer. Methods: Patients will receive a single intratumoral injection of the nanoparticles, followed by radiotherapy and intravenous infusion of fluorouracil or oral capecitabine concurrently. In phase Ib (escalation phase, 3 + 3 design), volume escalation is based on the tumor volume of 5, 10, 15 and 22% of total baseline tumor volume. In phase II (expansion phase), 18 additional patients will be enrolled. Discussion: This study will be the first prospective, open-label, single-arm, nonrandomized study to investigate the efficacy and safety profile of PEP503 (NBTXR3) nanoparticles with radiotherapy and chemotherapy in these patients. Trial registration number: NCT02465593 (ClinicalTrials.gov).

Preoperative concurrent chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer. PEP503 (NBTXR3) has radioenhancement properties. Therefore, the dose per fraction during radiotherapy could be reduced, and the same therapeutic efficacy could be retained when PEP503 (NBTXR3) nanoparticles are used during radiotherapy. This study reveals the protocol of a phase Ib/II study to investigate the safety profile, dose-limiting toxicity and antitumor activity of PEP503 (NBTXR3) nanoparticles with radiotherapy combined with concurrent chemotherapy in patients with locally advanced or unresectable rectal cancer.

Slow hydrogel matrix degradation enhances salivary gland mimetic phenotype.

We recently developed a salivary gland tissue mimetic (SGm), comprised of salivary gland cells encapsulated in matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) hydrogels within arrays of ∼320 µm diameter spherical cavities molded in PDMS. The SGm provides a functional and physiologically relevant platform well-suited to high-throughput drug screening for radioprotective compounds. However, the utility of the SGm would benefit from improved retention of acinar cell phenotype and function. We hypothesized that tuning biochemical cues presented within the PEG hydrogel matrix would improve maintenance of acinar cell phenotype and function by mimicking the natural extracellular matrix microenvironment of the intact gland. Hydrogels formed using slower-degrading MMP-sensitive peptide crosslinkers showed >2-fold increase in sphere number formed at 48 h, increased expression of acinar cell markers, and more robust response to calcium stimulation by the secretory agonist, carbachol, with reduced SGm tissue cluster disruption and outgrowth during prolonged culture. The incorporation of adhesive peptides containing RGD or IKVAV improved calcium flux response to secretory agonists at 14 days of culture. Tuning the hydrogel matrix improved cell aggregation, and promoted acinar cell phenotype, and stability of the SGm over 14 days of culture. Furthermore, combining this matrix with optimized media conditions synergistically prolonged the retention of the acinar cell phenotype in SGm. STATEMENT OF SIGNIFICANCE: Salivary gland (SG) dysfunction occurs due to off-target radiation due to head and neck cancer treatments. Progress in understanding gland dysfunction and developing therapeutic strategies for the SG are hampered by the lack of in vitro models, as salivary gland cells rapidly lose critical secretory function within 24 hours in vitro. Herein, we identify properties of poly(ethylene glycol) hydrogel matrices that enhance the secretory phenotype of SG tissue mimetics within the previously-described SG-microbubble tissue chip environment. Combining slow-degrading hydrogels with media conditions optimized for secretory marker expression further enhanced functional secretory response and secretory marker expression.

Development of NS2B-NS3 protease inhibitor that impairs Zika virus replication.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes severe neurological disorders, such as microcephaly in fetuses. Most recently, an outbreak of ZIKV started in Brazil in 2015. To date, no therapeutic agents have been approved to treat ZIKV infection in the clinic. Here, we screened a small molecule inhibitor that can inhibit the function of ZIKV non-structural protein 2B (NS2B)-NS3 protease (ZIKV NS2B-NS3 protease), thereby interfering with viral replication and spread. First, we identified the half maximal inhibitory concentration (IC50) of compound 3 (14.01 µM), 8 (6.85 µM), and 9 (14.2 µM) and confirmed that they are all non-competitive inhibitors. In addition, we have used the blind molecular docking method to simulate the inhibition area of three non-competitive inhibitors (compound 3, 8, and 9) with the ZIKV NS2B-NS3 protease. The results indicated that the four allosteric binding residues (Gln139, Trp148, Leu150, and Val220) could form hydrogen bonds or non-bonding interactions most frequently with the three compounds. The interaction might induce the reaction center conformation change of NS2B-NS3 protease to reduce catalyzed efficiency. The concentration of compounds required to reduce cell viability by 50% (CC50), and the concentration of compounds required to inhibit virus-induced cytopathic effect by 50% (EC50) of three potential compounds are >200 µM, 2.15 µM (compound 3), > 200 µM, 0.52 µM (compound 8) and 61.48 µM, 3.52 µM (compound 9), and Temoporfin are 61.05 µM, 2 µM, respectively. To select candidate compounds for further animal experiments, we analyzed the selectivity index (SI) of compound 3 (93.02), 8 (384.61), 9 (17.46), and Temoporfin (30.53, FDA-approved drug against cancer). Compound 8 has the highest SI value. Therefore, compound 8 was selected for verification in animal models. In vivo, compound 8 significantly delayed ZIKV-induced lethality and illness symptoms and decreased ZIKV-induced weight loss in a ZIKV-infected suckling mouse model. We conclude that compound 8 is worth further investigation for use as a potential future therapeutic agent against ZIKV infection.

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.

Elevated intramuscular adipose tissue content with a high Ishak fibrosis stage (>3) had a negative effect on liver regeneration in cirrhotic patients undergoing portal vein embolization.

This study investigated the relationship between body composition parameters and changes in future liver remnant volume (FLRV) in hepatocellular carcinoma (HCC) patients undergoing portal vein embolization (PVE) in preparation for right hepatectomy. This retrospective study enrolled 21 patients between May 2013 and October 2020. Body composition parameters, including skeletal muscle attenuation (SMA), skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR), were measured by computed tomography (CT) prior to PVE. Liver volumetry was measured before and at least 5 weeks after PVE. The mean interval between two CT volumetries was 9.1 ± 4.9 weeks, the mean value of increase in FLRV (ΔFLRV) was 236.0 ± 118.3 cm3 , the ratio of increased FLRV (ΔFLRV%) was 55.7 ± 29.4%, and the rate of increased FLRV was 31.0 ± 18.8 (cm3 /week). Subjects with high IMAC showed significantly lower (p = 0.044) ΔFLRV% than those with normal IMAC. Furthermore, ΔFLRV% was linearly reduced (p for trend = 0.043) among those with low Ishak fibrosis stage (<3) + normal IMAC (76.1 ± 36.8%), those with low Ishak fibrosis stage (<3) + high IMAC or high Ishak fibrosis stage (>3) + normal IMAC (54.0 ± 24.1%), and those with high Ishak fibrosis stage (>3) + low IMAC (28.7 ± 1.6%) (p for trend = 0.043). Our data indicated that high IMAC with a high Ishak fibrosis stage (>3) had a significant negative effect on ΔFLRV%.

Acute Exercise Improves Inhibitory Control but Not Error Detection in Male Violent Perpetrators: An ERPs Study With the Emotional Stop Signal Task.

Violence has been linked to the co-occurrence of cognitive dysfunction and altered activations in several brain regions. Empirical evidence demonstrated the benefits of acute exercise on motor inhibition and error detection and their neuronal processing. However, whether such effects also hold for the population with violent behaviors remains unknown. This study examined the effects of acute aerobic exercise on inhibitory control and error monitoring among violent offenders. Fifteen male violent offenders were counterbalanced into experimental protocols, which comprised a 30-min moderately aerobic exercise [60% heart rate (HR) reserve] and a 30-min reading control session. After each session, participants performed an emotional stop signal task while event-related potentials (ERPs) were recorded simultaneously. Results showed insignificant changes in ERPs components [i.e., N2, P3, error-related negativity (ERN), and error-positivity (Pe) amplitudes] and the behavioral performance in go condition, stop accuracy, and post-error adjustments by exercise. However, the current study demonstrated that the acute exercise facilitated stop signal reaction time (SSRT) when compared to the control session regardless of emotional conditions. This is the first research to exhibit the improvements in inhibitory performance by acute exercise for violent offenders. Most importantly, this effect was independent of affective settings, expanding the existing knowledge of the influences of acute exercise on cognition. Our findings implicate the perspective of acute exercise for clinical and correctional practices.

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.

The experience of use of percutaneous transhepatic biliary drainages for early biliary complications after liver transplantation.

This study aimed to describe our experience and discuss the results, controversies, and the use of percutaneous transhepatic biliary drainage (PTBD) in patients with biliary complications after liver transplantation (LT). Between November 2009 and August 2020, 76 consecutive patients who underwent 77 LTs (44 deceased donor LTs and 33 living donor LTs [LDLT]) were enrolled retrospectively. Endoscopic therapy as initial approach and PTBD as rescue therapy were used for patients with biliary complications. There were 31 patients (31/76, 40.8%) with biliary complications, and two of them died (2/31, 6.5%). Clinical success rate of endoscopic therapy alone was 71.0% (22/31). The remaining nine patients received salvage PTBD and their clinical results were observed according to whether their intrahepatic bile ducts (IHBDs) was dilated (group A, n = 5) or not (group B, n = 4). In group A, the technical and long-term clinical success rates of PTBD were 100% and 20%, respectively. These five patients received PTBD ranging from 75 to 732 days after their LTs, and no procedure-related complications were encountered. In group B, the technical and long-term clinical success rates of PTBD were 50% and 25%, respectively. Three group B patients (75%) underwent PTBD within 30 days after LDLT and had lethal complications. One patient had graft laceration and survived after receiving timely re-transplantation. The other two patients died of sepsis due to PTBD-related bilioportal fistula or multiple liver abscesses. Our experience showed salvage PTBD played a limited role in biliary complications without dilated IHBDs within 1 month after LT.

Thermosensitive Polyester Hydrogel for Application of Immunosuppressive Drug Delivery System in Skin Allograft.

Tacrolimus (FK506) is a common immunosuppressive drug that is capable of suppressing acute rejection reactions, and is used to treat patients after allotransplantation. A stable and suitable serum concentration of tacrolimus is desirable for better therapeutic effects. However, daily drug administration via oral or injection routes is quite inconvenient and may encounter drug overdose or low patient compliance problems. In this research, our objective was to develop an extended delivery system using a thermosensitive hydrogel of poly ethylene glycol, D,L-lactide (L), and ϵ-caprolactone (CL) block copolymer, mPEG-PLCL, as a drug depot. The formulation of mPEG-PLCL and 0.5% PVP-dissolved tacrolimus was studied and the optimal formulation was obtained. The in vivo data showed that in situ gelling is achieved, a stable and sustained release of the drug within 30 days can be maintained, and the hydrogel was majorly degraded in that period. Moreover, improved allograft survival was achieved. Together, these data imply the potential of the current formulation for immunosuppressive treatments.

The comparisons of inhibitory control and post-error behaviors between different types of athletes and physically inactive adults.

To properly behave and correct mistakes, individuals must inhibit inappropriate actions and detect errors for future behavioral adjustment. Increasing evidence has demonstrated that athletes are superior in cognitive functions and this benefit varied dependent on the types of sport that individuals involved in, but less is known on whether athletes have a different error-related behavioral pattern. The purpose of this study was to compare the behavioral performance of inhibition and error monitoring between individuals who participated in an open-skill sport (n = 12), a closed-skill sport (n = 12), and a sedentary lifestyle (n = 16). A combined flanker/stop signal task was presented and the derived stop signal reaction time (SSRT), post-correct accuracy and reaction time (RT), as well as post-error accuracy and RT were compared across groups. Our findings indicated there was no difference in SSRT between groups. Surprisingly, significant post-error slowing (PES) was observed only in controls but not in sport groups, the controls also exhibited significantly longer post-error RT compared with the open-skill group. However, there was no difference in the post-error accuracy between groups, indicating a higher efficiency in the post-error processing among open- and closed-skill groups by requiring comparatively less time for behavioral adjustments. The present study is the first to disclose the discrepancies in PES between different types of athletes and controls. The findings suggest that sport training along with higher amounts of physical activity is associated with a more efficient behavioral pattern for error processing especially when the sport requires open skills in nature.

Migration and invasion of NSCLC suppressed by the downregulation of Src/focal adhesion kinase using single, double and tetra domain anti- CEACAM6 antibodies.

Carcinoembryonic antigen-related cell adhesion molecules 6 (CEACAM6) is a cell adhesion receptor. Expression of CEACAM6 in non-small cell lung cancer (NSCLC) associated with tumor progression and metastatic condition via Src/FAK signaling pathway. We established three anti-CEACAM6 antibodies with valences, which were designed to be monomeric sdAb, bivalent sdAb (2Ab), and tetravalent sdAb (4Ab). The anti-CEACAM6 antibodies can be used to target CEACAM6 overexpressing NSCLC. Anti-CEACAM6 antibodies, sdAb, 2Ab and 4Ab, were modified with different valency via protein engineering. sdAb and multivalent sdAbs (2Ab & 4Ab) were expressed and purified from E.coli and CHO cells, respectively. We compared the effect of anti-CEACAM6 antibodies with doxorubicin in NSCLC cell line both in vitro and in vivo. The 4Ab showed significant effect on cell viability. In addition, A549 cells treated with 2Ab and 4Ab inhibited the invasion and migration. In western blot, the 2Ab and 4Ab showed significant inhibition of phospho FAK domain Ty397 that is essential for activation of Src kinase family. Meanwhile, overall protein analysis revealed that 2Ab and 4Ab potently inhibited the phosphorylation of pSRC, pERK, pFAK, pAKT, MMP-2, MMP-9 and N-cadherin. Anti-tumor effect was observed in an A549 NSCLC xenograft model treated with 2Ab or 4Ab compared with doxorubicin. Confocal analysis showed higher targeting ability of 4Ab than that of 2Ab at 4 h incubation. Our data suggests that 2Ab and 4Ab inhibits EMT-mediated migration and invasion via suppression of Src/FAK signaling, which exhibits therapeutic efficiency for NSCLC treatment.

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.

Utilization of silicon nanowire field-effect transistors for the detection of a cardiac biomarker, cardiac troponin I and their applications involving animal models.

This study develops an ultrasensitive electrical device, the silicon nanowire-field effect transistor (SiNW-FET) for detection of cardiac troponin I (cTnI) in obesity induced myocardial injury. The biosensor device utilizes metal-oxide-semiconductor (MOS) compatible top-down methodology for the fabrication process. After fabrication, the surface of the SiNW is modified with the cTnI monoclonal antibody (Mab-cTnI) upon covalent immobilization to capture cTnI antigen. The sensitivity of the device is also examined using cTnI at different concentrations with the lowest detection limit of 0.016 ng/mL. The electrocardiogram (ECG), magnetic resonance imaging (MRI), and superior vena cave (SVC) provide more information about cardiac responses in a mouse model of acute myocardial infarction (AMI). Further, magnetic resonance imaging helps to evaluate the cardiac output of an obesity induced myocardial injury mouse model. These methods play an essential role in monitoring the obesity based cardiac injury and hence, these studies were carried out. This is the first report to use the ECG, MRI, and SVC sampling methods to study the obesity based cardiac injury involving Syrian hamsters as animal models. The proposed SiNW-FET in this study shows greater sensitivity than the previously developed devices and demonstrates great potential for future applications in point-of-care (POC) diagnosis.

Electrophysiological investigation of the effects of Tai Chi on inhibitory control in older individuals.

The possibility that improved inhibitory control in older adults is associated with engagement in non-contact sporting activity, Tai Chi, was investigated. Three groups of participants were compared; a group who regularly took part in Tai Chi (TC), a regularly exercising (RE) group, and a sedentary group (SG). Concurrent electroencephalographic recordings were obtained while a stop-signal inhibitory control task, where speeded responses are needed for most trials, but these must occasionally be withheld when a 'stop signal' is displayed, was performed. The electrophysiological components P3, broadly related to decision making, and Pe, related to error monitoring, were analyzed. Both exercise groups performed better on the stop-signal task for the measure indicative of inhibitory control, as well as being generally better for other indices of performance. No significant effects were seen for post-error slowing. Electrophysiological differences were seen for the TC group, with a significantly larger P3 component related to the stop-signal and a larger Pe component when errors were made. This indicated that the TC group seemed to show better decision making and have better awareness of errors. Future work should investigate whether such effects are seen when this type of exercise is applied as an 'intervention' in non-exercising individuals.

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.

Epigallocatechin-3-gallate inhibits tumor angiogenesis: involvement of endoglin/Smad1 signaling in human umbilical vein endothelium cells.

Strategies targeting endoglin are currently being investigated in clinical trials as an anti-angiogenic therapy. The redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis was verified. Increased endoglin signaling after an anti-VEGF treatment was observed in patients. Treatment with an endoglin-neutralizing antibody increased VEGF signaling in endothelial cells. Therefore, strategies targeting both the endoglin and VEGF pathways were applied to determine whether the anti-angiogenic effects were increased in vitro. Five possible hits for endoglin were identified from 2000 compounds in the Traditional Chinese Medicine Database using Discovery Studio 4.5 Epigallocatechin-3-gallate (EGCG) attenuates angiogenesis by downregulating VEGF; however, researchers have not determined whether its anti-angiogenic effects are mediated by endoglin/Smad1 signaling. A major contribution of this study is that EGCG significantly inhibited the upregulation of endoglin in semaxanib-treated human umbilical vein endothelial cell. Thus, a combination treatment with EGCG and a VEGF tyrosine kinase inhibitor would be appropriate to reverse drug resistance. EGCG alone significantly decreased endoglin/pSmad1 levels in HUVECs. In the angiogenesis assay, the migration, invasion, and tube formation of HUVECs were markedly suppressed by higher concentrations of EGCG. A combination treatment with EGCG and semaxanib further produced increased anti-angiogenic effects. The main contribution of the study indicated that EGCG significantly decreased the semaxanib-induced overexpression of endoglin. Therefore, a combination treatment including EGCG will probably solve the drug resistance to anti-VEGF treatments.

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.

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.