Tz Groups Research Articles

Gallic acid counteracts tartrazine-induced testicular dysfunction in rats: biochemical, histopathological and ultrastructural evidences

BackgroundTartrazine (Tz) is one of the most commonly used colorants incorporated in the food manufacturing. Its toxicity is derived from metabolic byproducts representing health hazards to consumers. Gallic acid (GA) is known for its redox stabilizing, anti-apoptotic, and cytoprotective characteristics. Therefore, the aim of this study is to explore the possible defensive effect of GA against Tz-induced testicular dysfunction. To achieve this objective, 18 male Wistar adult rats were randomly and equally categorized into three groups for 30 days. The control group received no treatment. Tz at a dose of 30 mg/kg BW was administered to the Tz group. The Tz + GA group received GA at a dose of 200 mg/kg BW in concurrent with the previously described Tz dosage. Both Tz and GA were supplemented orally once daily by a stomach tube.ResultsThe marked decline in luteinizing hormone, follicle stimulating hormone, testosterone, and estradiol 17beta confirmed deviation in pituitary–gonadal axis of Tz-exposed rats. Imbalances in plasma redox equilibrium were evident, characterized by a notable increase in malondialdehyde and nitric oxide levels, along with a decrease in reduced glutathione and total antioxidant capacity. Deteriorations in histopathological features, fibrosis in testicular tissue, abnormalities in Sertoli cell, and up-regulation in caspase-3 were observed. Conversely, GA administration successfully reversed these issues.ConclusionThe ability of GA to counteract toxicological molecular targets in Tz-exposed testes is believed to be achieved through the restoration of oxidant/antioxidant balance and the prevention of the apoptotic cascade.

Transzonular moxifloxacin and dexamethasone delivery in phacoemulsification: A novel dropless regimen.

To assess the safety and efficacy of transzonular moxifloxacin and dexamethasone versus standard postoperative topical drug regimen in phacoemulsification. Nonrandomized prospective study. The study included 100 eyes of 100 age and gender-matched individuals with senile cataract undergoing routine phacoemulsification. The patients were consecutively divided into transzonular (TZ = 50) and topical (TP = 50) groups. Both the groups were followed up for 4 weeks and assessed for intraocular inflammation, visual acuity, changes in intraocular pressure (IOP), and any adverse events. The grades of inflammation were significantly lower in TZ as compared to the TP group ( P < 0.001). The IOP remained normal and comparable in both the groups. Most of the patients in the two groups attained a visual acuity of 0.2 or better at the end of the follow-up. No adverse effects and increased rate of endophthalmitis were noted in TZ group. A one-time peroperative TZ moxifloxacin and dexamethasone combination is a safe and effective method to control postoperative inflammation after cataract surgery. A word of caution though, due precautions to be exercised to prevent the risk of inflammation and endophthalmitis.

Fracture strength of implant-supported hybrid abutment crowns in premolar region fabricated using different restorative CAD/CAM materials.

The present study investigated the fracture strength of hybrid abutment crowns (HACs) in the premolar region that were fabricated with different restorative computer-aided design/computer-aided manufacturing (CAD/CAM) materials. The abutment-implant structures were randomly assigned into four groups (n=11 per group): bi-layered zirconia restorations (BL), translucent zirconia (4Y-PSZ) restorations (TZ), lithium disilicate ceramic restorations (LD), and dispersed nanoparticle-filled composite resin restorations (CM). All restorations were adhesively bonded to the titanium abutments. After the restoration-abutment complex was tightened onto the implant, the fracture strength was measured. The TZ (2.06 kN) and LD (1.87 kN) groups had significantly higher median fracture strengths than the BL (1.12 kN) and CM (1.10 kN) groups. In terms of fracture resistance, the 4Y-PSZ and lithium disilicate ceramic monolithic restorations would be superior to bi-layered 3Y-TZP and composite resin monolithic restorations for HACs in the premolar region.

Cytokines, Chemokines, Insulin and Haematological Indices in Type 2 Diabetic Male Sprague Dawley Rats Infected with Trichinella zimbabwensis

Diabetes mellitus is a chronic metabolic disease induced by the inability to control high blood glucose level. Helminth-induced immunomodulation has been reported to prevent or delay the onset of type 2 diabetes mellitus (T2DM), which, in turn, ameliorates insulin sensitivity. Therefore, there is a need to understand the underlying mechanisms utilized by helminths in metabolism and the induction of immuno-inflammatory responses during helminthic infection and T2DM comorbidity. This study aimed at using a laboratory animal model to determine the cytokines, chemokines and haematological indices in diabetic (T2DM) male Sprague Dawley (SD) rats infected with Trichinella zimbabwensis. One hundred and two male SD rats (160–180 g) were randomly selected into three experimental groups (i. T2DM-induced group (D) ii. T. zimbabwensis infected + T2DM group (TzD) and iii. T. zimbabwensis-infected group (Tz)). Rats selected for the D group and TzD group were injected with 40 mg/kg live weight of streptozotocin (STZ) intraperitoneally to induce T2DM, while animals in the Tz and TzD group were infected with T. zimbabwensis. Results showed that adult T. zimbabwensis worm loads and mean T. zimbabwensis larvae per gram (lpg) of rat muscle were significantly higher (p &lt; 0.001) in the Tz group when compared to the TzD group. Blood glucose levels in the D group were significantly higher (p &lt; 0.001) compared to the TzD group. An increase in insulin concentration was observed among the TzD group when compared to the D group. Liver and muscle glycogen decreased in the D when compared to the TzD group. A significant increase (p &lt; 0.05) in red blood cells (RBCs) was observed in the D group when compared to the TzD and Tz groups. An increase in haematocrit, haemoglobin, white blood cells (WBCs), platelet, neutrophils and monocyte were observed in the D group when compared to the TzD group. TNF-α, IFN-γ, IL-4, IL-10 and IL-13 concentrations were elevated in the TzD group when compared to the D and Tz groups, while IL-6 concentration showed a significant reduction in the Tz when compared to the D and the TzD groups. A significant increase in CCL5 in the D and TzD groups was observed in comparison to the Tz group. CXCL10 and CCL11 concentration also showed an increase in the TzD group in comparison to the Tz and the D groups. Overall, our results confirm that T. zimbabwensis, a parasite which produces tissue-dwelling larvae in the host, regulates T2DM driven inflammation to mediate a positive protective effect against T2DM outcomes.

Cardiotoxicity of adjuvant chemotherapy with trastuzumab: a Japanese claim-based data analysis

ObjectiveAdjuvant chemotherapy with trastuzumab improves the postoperative life expectancy of women with early-stage breast cancer. Although trastuzumab is reportedly cardiotoxic, quantification based on real-world evidence is lacking. Therefore, in this...

Blood glucose, insulin and glycogen profiles in Sprague-Dawley rats co-infected with Plasmodium berghei ANKA and Trichinella zimbabwensis.

BackgroundPlasmodium falciparum and tissue dwelling helminth parasites are endemic in sub-Saharan Africa (SSA). The geographical overlap in co-infection is a common phenomenon. However, there is continued paucity of information on how the co-infection influence the blood glucose and insulin profiles in the infected host. Animal models are ideal to elucidate effects of co-infection on disease outcomes and hence, blood glucose, insulin and glycogen profiles were assessed in Sprague-Dawley rats co-infected with P. berghei ANKA (Pb) and Trichinella zimbabwensis (Tz), a tissue-dwelling nematode.MethodsOne-hundred-and-sixty-eight male Sprague-Dawley rats (weight range 90–150 g) were randomly divided into four separate experimental groups: Control (n = 42), Pb-infected (n = 42), Tz-infected (n = 42) and Pb- + Tz-infected group (n = 42). Measurement of Pb parasitaemia was done daily throughout the experimental study period for the Pb and the Pb + Tz group. Blood glucose was recorded every third day in all experimental groups throughout the experimental study period. Liver and skeletal muscle samples were harvested, snap frozen for determination of glycogen concentration.ResultsResults showed that Tz mono-infection and Tz + Pb co-infection did not have blood glucose lowering effect in the host as expected. This points to other possible mechanisms through which tissue-dwelling parasites up-regulate the glucose store without decreasing the blood glucose concentration as exhibited by the absence of hypoglycaemia in Tz + Pb co-infection group. Hypoinsulinemia and an increase in liver glycogen content was observed in Tz mono-infection and Tz + Pb co-infection groups of which the triggering mechanism remains unclear.ConclusionsTo get more insights into how glucose, insulin and glycogen profiles are affected during plasmodium-helminths co-infections, further studies are recommended where other tissue-dwelling helminths such as Taenia taeniformis which has strobilocercus as the metacestode in the liver to mimic infections such as hydatid disease in humans are used.

Association of prostate zonal volume with location and aggressiveness of clinically significant prostate cancer: A multiparametric MRI study according to PI-RADS version 2.1

BackgroundThe relationship between prostate cancer (PCa) and benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether prostate zonal volume was associated with the location and aggressiveness of PCa. Methods412 PCa patients were retrospectively enrolled. The volumes of the whole prostate (V) and transition zone (Vtz) were calculated by the prolate ellipsoid formula, and volume of the peripheral zone (Vpz) was calculated by their subtraction. Locations of PCa were divided into three categories, including peripheral zone (PZ), transition zone (Vtz) and mixed zone group. The mixed zone group was further divided into PZ-dominated, TZ-dominated and equally distributed subgroups. ResultsThe Vtz of Gleason score (GS) 3 + 4 group was the largest, while the Vpz of GS 9 group was the largest. Tumor diameters of the PZ and TZ groups were weakly correlated with their corresponding zonal volume (r = 0.261, p < 0.001; r = 0.311, p = 0.009, respectively). There was no significant difference in the zonal volumes and GS distribution among the location groups. The proportion of tumors with high-grade GS of 8 and 9 was higher in the PZ than that in the TZ group (38.5 vs 24.3%, p = 0.041). For tumors located in the TZ, the V and Vpz of tumors with high-grade GS were larger than those in the low-grade GS of 7 group (p = 0.033 and 0.039, respectively). Among the subgroups of mixed zone group, the Vtz of the TZ-dominated group was larger than those of PZ-dominated and equally distributed groups (p = 0.016 and 0.001, respectively). ConclusionPCa with high-grade GS is more likely to have a relatively larger Vpz and involve PZ, while PCa with a larger Vtz is more likely to be with low-grade GS, which support the theoretical model that pressure exerted by increasing prostate size/mechanical deformation may inhibit PCa growth from the clinical point. However, the increase in zonal volume might not be the direct cause of tumorigenesis and aggressiveness.

Highly porous and injectable hydrogels derived from cartilage acellularized matrix exhibit reduction and NIR light dual-responsive drug release properties for application in antitumor therapy

In this work, we developed novel stimuli-responsive injectable hydrogels composed of a highly biocompatible cartilage acellularized matrix (CAM) and a water-soluble cross-linker containing a diselenide bridge by using ultrafast norbornene (Nb)-tetrazine (Tz) click chemistry. The cross-linking reaction between the Nb groups of the CAM and Tz groups of the cross-linker evolved nitrogen gas and resulted in injectable hydrogels with highly porous structures. The synthesized hydrogels demonstrated high drug loading efficiencies (up to 93%), good swelling ratios, and useful mechanical properties. The doxorubicin (DOX)-loaded hydrogels released minimal amounts of DOX in the simulated physiological medium; however, sustained release of DOX was detected under reducing conditions, revealing more than 90% DOX release after 96 h. Interestingly, the indocyanine green (ICG)-incorporated hydrogels produced reactive oxygen species upon exposure to NIR light and exhibited burst release (>50% DOX release) of DOX during the first 4 h, followed by a sustained release phase. In vitro cytocompatibility tests showed that the synthesized CAM-Nb and hydrogels are essentially nontoxic to HFF-1 fibroblast cells and human colorectal adenocarcinoma cells (HT-29), indicating their excellent bioorthogonality and biocompatibility. Furthermore, DOX-loaded and DOX + ICG-loaded hydrogels inhibited the metabolic activities of HT-29 cells after GSH or NIR exposure and induced antitumor effects similar to those of free DOX. Therefore, these biocompatible and reduction-responsive injectable hydrogels, which exhibited on-demand drug release after NIR exposure, could be promising candidates for minimally invasive local delivery of cancer therapeutics.

Benzalkonium Chloride Resistance in Staphylococcus epidermidis on the Ocular Surface of Glaucoma Patients Under Long-Term Administration of Eye Drops.

PurposeWe previously reported the presence of multidrug-resistant staphylococci on the ocular surface of glaucoma patients using prostaglandin analog drops for more than 1 year. Here, we investigated the effect of benzalkonium chloride (BAC) on these multidrug-resistant staphylococci.Methods Staphylococcus epidermidis was isolated from the conjunctival sacs of 32 eyes of 32 patients comprised of 13 eyes treated with 0.005% latanoprost (Xalatan; Xa group) and 19 eyes treated with 0.004% travoprost (Travatan Z; Tz group). The minimum inhibitory concentrations (MICs) of prostaglandin analogs and BAC were measured. The presence of efflux pump genes was analyzed using polymerase chain reaction.ResultsNo difference was found in the MIC values of prostaglandin analogs. In contrast, the MIC values of BAC were significantly higher for the isolates from the Xa group than for those from the Tz group (2.02 vs. 1.02 µg/mL; P = 0.001). One proton-motive efflux gene, qacC/smr, was detected more frequently in the Xa isolates than in the Tz isolates (P < 0.001). The prevalence of methicillin resistance was correlated with the presence of qacC/smr (P = 0.010), and the MIC of BAC was significantly correlated with the detection of qacA/B and qacC/smr sequences (P = 0.03 and P < 0.001, respectively).ConclusionsThe long-term use of eye drops containing BAC might select BAC-resistant S. epidermidis harboring qacC/smr.Translational RelevanceThese findings suggest that the long-term use of eye drops containing BAC might be inappropriate in terms of avoiding antimicrobial resistance.

Metabolism of a Bioorthogonal PET Tracer Candidate [19F/18F]SiFA-Tetrazine in Mouse Liver Microsomes: Biotransformation Pathways and Defluorination Investigated by UHPLC-HRMS.

Organofluorosilicon based 18F-radiolabeling is an efficient method for incorporating fluorine-18 into 18F-radiopharmaceuticals for positron emission tomography (PET) by 19F/18F isotopic exchange (IE). The first PET radiopharmaceutical, 18F-SiFAlin-TATE, radiolabeled with a silicon-based [18F]fluoride acceptor (SiFA), namely, a para-substituted di-tert-butyl[18F]fluorosilylbenzene, has entered clinical trials, and is paving the way for other potential [18F]SiFA-labeled radiopharmaceuticals for diagnostic use. In this study, we report the in vitro metabolism of an oxime-linked SiFA tetrazine (SiFA–Tz), a new PET-radiotracer candidate, recently evaluated for pretargeted PET imaging and macromolecule labeling. Metabolism of SiFA–Tz was studied in mouse liver microsomes (MLM) for elucidating its major biotransformation pathways. Nontargeted screening by ultrahigh performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS) was utilized for detection of unknown metabolites. The oxime bond between the SiFA and Tz groups forms two geometric (E/Z) isomers, which underwent the same biotransformations, but unexpectedly with different kinetics. In total, nine proposed metabolites of SiFA–Tz from phase I and II reactions were detected, five of which were defluorinated in MLMs, elucidating the metabolic pathway leading to previously reported defluorination of [18F]SiFA–Tz in vivo. Based on the HRMS studies a biotransformation pathway is proposed: hydroxylation (+O) to tert-butyl group adjacent to the silicon, followed by oxidative defluorination (+OH/-F) cleaving the fluorine off the silicon. Interestingly, eight proposed metabolites of a reduced dihydrotetrazine analogue, SiFA–H2Tz, from phase I and II reactions were additionally detected. To the best of our knowledge, this is the first reported comprehensive investigation of enzyme mediated metabolic pathway of tetrazines and para-substituted di-tert-butylfluorosilylbenzene fluoride acceptors, providing novel structural information on the biotransformation and fragmentation patterns of radiotracers bearing these structural motifs. By investigating the metabolism preceding defluorination, structurally optimized new SiFA compounds can be designed for expanding the portfolio of efficient 19F/18F isotopic exchange labeling probes for PET imaging.

Plasma and Nail Zinc Concentrations, But Not Hair Zinc, Respond Positively to Two Different Forms of Preventive Zinc Supplementation in Young Laotian Children: a Randomized Controlled Trial

Plasma zinc concentrations (PZC) have been shown to significantly increase during zinc supplementation. This study investigated the effects of daily preventive zinc supplementation on hair and nail zinc concentrations compared with a control group. In a randomized controlled trial, 6- to 23-month-old children (n = 3407) in Lao PDR were randomly assigned to one of four groups and followed for ~ 36 weeks: daily preventive zinc dispersible tablet (7 mg/d; PZ), daily micronutrient powder (10 mg zinc/d; MNP), therapeutic zinc supplements for diarrhea treatment (20 mg/d for 10 days; TZ), or daily placebo powder (Control). Plasma, hair, and nail zinc concentrations were assessed in a sub-sample of participants (n = 457) at baseline and endline. At baseline, 75% of children had low PZC (< 65 μg/dL). At endline, geometric mean (95% CI) PZC were greater in the PZ and MNP groups compared with the TZ and control groups (P < 0.01), but hair zinc concentrations did not differ among groups (P = 0.99). Nail zinc concentrations were marginally higher in the PZ (115.8 (111.6, 119.9) μg/g) and the MNP (117.8 (113.3, 122.3) μg/g) groups than in the TZ group (110.4 (106.0, 114.8) μg/g; P = 0.055) at endline. This study does not support the use of hair zinc as a biomarker of zinc exposure in young children. However, it provides some evidence that zinc concentrations in nails may respond to supplemental zinc interventions and supports the need for collecting additional data on this emerging biomarker.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial

Background and purposeTianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT).MethodsA 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician’s Interview-based Impression of Change-plus caregiver information (CIBIC-plus).ResultsA total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found.ConclusionsTZ and donepezil could bring symptomatic benefit for mild to moderate VaD.Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1

The ameliorative effect of curcumin extract on the morphological and skeletal abnormalities induced by sunset yellow and tartrazine in the developing chick embryo Gallus domesticus

Previous studies have suggested that food dyes are responsible for causing number of health problems. The study under consideration aims to show the possible morphological and skeletal malformation induced due to in ovo administration of sunset yellow (SY) and tartrazine (Tz) with or without curcumin (Cur) during organogenesis of developing chick embryo at doses 1.575mg/egg, 0.375mg/egg and 3mg/kg eggs for SY, Tz and Cur comparing with control. The investigation revealed evident reduction in the weight and length of embryos as well as malformations in feather, head, and limbs. Most of the congenital malformations were seen in SY and Tz injected groups such as short beak, excencephaly, kniked tail and pygostyle, curved scapula and retardation in the degree of ossification were the most evident in endoskeleton malformation. In addition, the length of ossified long bones in SY and Tz groups was affected. Co-administration of Cur with SY and Tz ameliorate the reversed effect of SY and Tz on the shape, length, body weight and skeleton of embryos.

Effect of Zinc Supplementation on Innate and Adaptive Immunity in Lao Children at Risk of Zinc Deficiency (P19-013-19)

ObjectivesDetermine if children (6 to 23 mo) who received daily preventive zinc (PZ; 7 mg/d), daily high-zinc, low-iron micronutrient powder (MNP; 10 mg/d zinc, 6 mg/d iron) or therapeutic zinc during episodes of diarrhea (TZ; 20 mg/d for 10 d per episode) have improved markers of innate and adaptive immune function, compared to placebo (PL). MethodsRural Laotian children were recruited into a double-blind, randomized, controlled intervention trial for 9 mo. Venous blood was collected at baseline (BL) and endline (EL) for analysis. Primary outcomes included T-cell subsets (naïve and memory CD4, CD8, Tregs) measured by flow cytometry and production of T-cell cytokines (IL-2, IL-10, IL-13, IL-17A, INF-γ) and LPS-induced cytokines (IL-1β, IL-6, IL-10, TNF-α by whole blood cultures. Blood leukocytes (including lymphocytes, neutrophils, monocytes and eosinophils) were measured as secondary outcome variables. Group means at EL were compared by analysis of covariance (controlling for BL values of the outcome, sex, child age, district, month of enrollment and plasma zinc concentration). If an interaction with BL plasma zinc (above/below median) was observed, group means were compared separately in children above and below the median. ResultsMean BL plasma zinc in all children (N = 574) was 0.55 ± 0.12 mg/L. No significant group differences were seen at EL in the primary outcomes. For secondary outcomes, the counts (^103/μL) of lymphocytes from the PZ group (5.02 ± 0.16) were significantly lower than the PL group (5.64 ± 0.16; P = 0.032). The EL counts (^103/μL) of from the PZ group (0.144 ± 0.026) were significantly lower than in the PL (0.279 ± 0.048; P = 0.036) and TZ (0.285 ± 0.047; P = 0.025) groups among children with baseline zinc below the median. ConclusionsPrimary outcomes (T-cell subsets, and cytokine production) were not affected by the zinc intervention. Lymphocyte and eosinophil concentrations may be affected by zinc treatment but this result requires confirmation. Funding SourcesARS Project 2032-53000-001-00-D, Mathile Institute for the Advancement of Human Nutrition.

Pretargeted radioimmunotherapy and SPECT imaging of peritoneal carcinomatosis using bioorthogonal click chemistry: probe selection and first proof-of-concept.

Rationale: Pretargeted radioimmunotherapy (PRIT) based upon bioorthogonal click chemistry has been investigated for the first time in the context of peritoneal carcinomatosis using a CEA-targeting 35A7 mAb bearing trans-cyclooctene (TCO) moieties and several 177Lu-labeled tetrazine (Tz) radioligands. Starting from three Tz probes containing PEG linkers of varying lengths between the DOTA and Tz groups (i.e. PEGn = 3, 7, or 11, respectively, for Tz-1, Tz-2, and Tz-3), we selected [177Lu]Lu-Tz-2 as the most appropriate for pretargeted SPECT imaging and demonstrated its efficacy in tumor growth control. Methods: An orthotopic model of peritoneal carcinomatosis (PC) was obtained following the intraperitoneal (i.p.) injection of A431-CEA-Luc cells in nude mice. Tumor growth was assessed using bioluminescence imaging. Anti-CEA 35A7 mAb was grafted with 2-3 TCO per immunoglobulin. Pretargeted SPECT imaging and biodistribution experiments were performed to quantify the activity concentrations of [177Lu]Lu-Tz-1-3 in tumors and non-target organs to determine the optimal Tz probe for the PRIT of PC. Results: The pharmacokinetic profiles of [177Lu]Lu-Tz-1-3 alone were determined using both SPECT imaging and biodistribution experiments. These data revealed that [177Lu]Lu-Tz-1 was cleared via both the renal and hepatic systems, while [177Lu]Lu-Tz-2 and [177Lu]Lu-Tz-3 were predominantly excreted via the renal system. In addition, these results illuminated that the longer the PEG linker, the more rapidly the Tz radioligand was cleared from the peritoneal cavity. The absorbed radiation dose corresponding to pretargeting with 35A7-TCO followed 24 h later by [177Lu]Lu-Tz-1-4 was higher for tumors following the administration of [177Lu]Lu-Tz-2 (i.e. 0.59 Gy/MBq) compared to either [177Lu]Lu-Tz-1 (i.e. 0.25 Gy/MBq) and [177Lu]Lu-Tz-3 (i.e. 0.18 Gy/MBq). In a longitudinal PRIT study, we showed that the i.p. injection of 40 MBq of [177Lu]Lu-Tz-2 24 hours after the systemic administration of 35A7-TCO significantly slowed tumor growth compared to control mice receiving only saline or 40 MBq of [177Lu]Lu-Tz-2 alone. Ex vivo measurement of the peritoneal carcinomatosis index (PCI) confirmed that PRIT significantly reduced tumor growth (PCI = 15.5 ± 2.3 after PRIT vs 30.0 ± 2.3 and 30.8 ± 1.4 for the NaCl and [177Lu]Lu-Tz-2 alone groups, respectively). Conclusion: Our results clearly demonstrate the impact of the length of PEG linkers upon the biodistribution profiles of 177Lu-labeled Tz radioligands. Furthermore, we demonstrated for the first time the possibility of using bioorthogonal chemistry for both the pretargeted SPECT and PRIT of peritoneal carcinomatosis.

Effects of Different Types of Oral Glucose-Lowering Drugs on Hepatic Fat Accumulation and Liver Function in Japanese Subjects with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease—A Randomized, Open-Label, 3-Arm Active-Control Study

Objective: In this study, we compared the effects of different types of oral hypoglycemic agents on NAFLD in subjects with T2DM. Methods: We conducted a randomized, open-label, 3-arm active-control trial in subjects with T2DM and NAFLD. A total of 98 subjects were randomly allocated either to dapagliflozin (SG, n=32), pioglitazone (TZ, n=33) or glimepiride (SU, n=33) group, and the subjects took these drugs for 28 weeks. The primary endpoint was a change of liver-to-spleen (L/S) ratio on CT. Results: Baseline characteristics in the three groups were similar in various clinical parameters. SG, TZ and SU ameliorated glycemic control similarly. Body weight and visceral fat area (VFA) were significantly decreased only in SG group. Serum adiponectin level was increased in TZ group compared to other two groups. SG and TZ, but not SU, significantly increased L/S ratio and decreased ALT level, and the effects of SG and TZ on those parameters were comparable. In simple correlation analysis with all subjects, change of L/S ratio was negatively correlated with alteration of BMI, VFA, HbA1c and serum insulin, and positively associated with change of adiponectin level. Multiple linear regression analysis revealed that the decrease in VFA and the increase in adiponectin level contributed to improve NAFLD in subjects with T2DM. In addition, the common factor which improved NAFLD in all groups was reduced VFA. On the other hand, there were also some differences among three groups about which factors were correlated with the change of L/S ratio. Conclusions: The present study showed the decreased VFA and increased adiponectin independently contributed to improve NAFLD in patients with T2DM. Furthermore, dapagliflozin and pioglitazone, exerted equivalent beneficial effects on NAFLD in subjects with T2DM, although the two drugs have different mechanism of action. Disclosure T. Kinoshita: None. M. Shimoda: Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Taisho Pharmaceutical Co., Ltd. S. Nakanishi: Speaker's Bureau; Self; Sanofi. T. Mune: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Kaneto: Research Support; Self; Sanofi, Novo Nordisk Inc., Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Takeda Pharmaceuticals U.S.A., Inc., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Astellas Pharma US, Inc..

Conjunctival Bacteria Flora of Glaucoma Patients During Long-Term Administration of Prostaglandin Analog Drops

To investigate the effects of the long-term use of prostaglandin analogs for glaucoma treatment on the indigenous flora of the conjunctiva. Bacterial isolates were collected from the conjunctival sacs of 68 patients at Miyata Eye Hospital from February to September 2014, who had been receiving continuous monotherapy with prostaglandin analogs for glaucoma for at least 1 year. Minimum inhibitory concentrations of levofloxacin, gatifloxacin, moxifloxacin, cefmenoxime, tobramycin, chloramphenicol, and erythromycin against the isolates were measured to determine susceptibility. The positive culture rate in all cases was 90.5% (57/63 eyes), and a total of 79 bacterial strains were isolated. The isolated bacteria included aerobic gram-positive cocci (8% Staphylococcus aureus and 41% Staphylococcus epidermidis), coagulase-negative staphylococci (5%), Streptococcus spp. (1%), Corynebacterium spp. (4%), gram-negative bacteria (4%), and the facultative anaerobe Propionibacterium acnes (33%). The positive culture rates for patients using 0.005% latanoprost (Xa group) and 0.004% travoprost (Tz group) were 88.9% and 92.6%, respectively, with no statistically significant difference in the composition of isolated bacteria between groups. Methicillin-resistant S. epidermidis (MRSE) was significantly more frequently isolated in the Xa group. The antimicrobial susceptibility rates of S. epidermidis were significantly lower in the Xa group for levofloxacin, gatifloxacin, moxifloxacin, and tobramycin. The indigenous flora may be affected by the long-term use of prostaglandin analogs. The higher incidence of MRSE in the Xa group should be considered during the long-term, continuous administration of eye drops, such as in glaucoma treatment.

Synthesis by Direct Arylation of Thiazole–Derivatives: Regioisomer Configurations–Optical Properties Relationship Investigation

The synthesis of thiazole(Tz)-based regioisomer materials using selective direct arylation to avoid any protection steps has been developed. A series of trimers in which the Tz groups sandwich either an electron-rich or an electron-deficient unit, with a regioselective orientation of the respective Tz unit, has therefore been synthesized. This chemical strategy has also been followed to synthesize a second series of pentamers in which the Tz group is used as a π-conjugated bridge between an electron-rich central unit and electron-deficient end-capping groups and vice versa. On both trimers and pentamers, the effect of Tz orientation on the conjugation properties of the synthesized materials was investigated by a combination of experimental measurements and density functional theory calculations. This study highlights that control of the orientation of the Tz unit leads to the synthesis of the most conjugated regioisomer derivative. The present work gives chemical synthesis tools for the synthesis of selectively oriented Tz-based materials as well as a general guideline for the design of Tz-based materials with the highest conjugation length, including the Tz-orientation effect.

Characterization of Patients With Heterozygous Cystinuria

To characterize a contemporary cohort of patients with heterozygous (TZ) cystinuria and compare them with a concurrent cohort of patients with homozygous (MZ) cystinuria. A retrospective review of prospectively collected data was performed for 42 consecutive patients presenting with a positive cyanide-nitroprusside test from September 2009 to September 2011. Clinical data were collected, including the findings from a detailed metabolic stone workup that included two 24-hour urine collections with quantitative cystine. The patients were divided into 2 groups: those with TZ (30-400 mg/d) and those with MZ (>400 mg/d) cystinuria. One patient was excluded because the cystine excretion was within the normal range (<30 mg/d), 35 (83.3%) and 6 (14.3%) had TZ and MZ cystinuria, respectively. Compared with those with TZ cystinuria, those with MZ cystinuria were significantly younger at the first stone episode (median 48 years, range 14-67, vs 17, range 6-44, P = .002), more were female (20% vs 66.7%; P = .03), and more patients had bilateral stones (8.6% vs 50%; P = .03). Finally, the patients with MZ cystinuria had more stone episodes than those with TZ cystinuria (3 vs 1; P = .04). From the detailed metabolic stone evaluation, the incidence of hyperuricemia was significantly greater in the MZ patients (17.1% vs 66.7%; P = .02). Although all the MZ patients developed pure cystine stones, 18 (51.4%), 7 (20.0%), and 3 (8.6%) of the TZ patients developed calcium oxalate, uric acid, and cystine stones, respectively (P < .001). In the TZ group, 11 patients (31.4%) had false-negative results on subsequent cyanide-nitroprusside testing. Significant differences were found between the patients with TZ and MZ cystinuria in terms of age at the first stone episode, male/female ratio, incidence of hyperuricemia, and stone composition. The clinical significance remains to be elucidated.

Abstract P2-20-03: Combination Immunotherapy for Breast Cancer Patients: Safety and Immunologic Data from a Phase II Trial Administering a HER2/neu-Derived Peptide vaccine (AE37+GM-CSF) Sequentially or Concurrently with Trastuzumab in the Adjuvant Setting

Abstract Background. AE37 is a HER2-derived peptide (AA:776-790) modified to enhance antigen-specific stimulation of CD4+ T cells. A phase I trial has shown that AE37 mixed with GM-CSF (GM) is safe and effective in raising HER2-specific immunity. Our group is conducting a prospective, randomized, single-blinded phase II clinical trial of AE37+GM vs GM alone. The goal of the current study is to determine the effects on cardiac safety and immunologic response of vaccinating sequentially or concurrently with administration of trastuzumab (Tz). Methods. The trial is enrolling high-risk breast cancer patients with tumors having any degree of HER2 expression (IHC 1-3+). At the time of enrollment, all patients are disease-free having completed surgery, chemotherapy and when indicated, XRT. Patients receiving Tz as part of their standard therapy were administered the vaccine sequentially after completion of Tz or concurrently with Tz. Cardiac toxicity was assessed by determining ejection fraction (EF). Immunologic response was monitored by delayed-type hypersensitivity (DTH) responses and [3H]thymidine proliferative assays for the hybrid AE37 and native AE36 (unmodified AA:776-790) peptides. Results. To date the trial has enrolled 102 patients at our international site, including 51 receiving Tz as part of standard therapy. Of these, 30 were randomized to receive AE37+GM; 13 sequentially after Tz (group 1) and 17 concurrently (group 2). 21 patients were randomized to receive GM alone. There was no change in EF pre-and post completion of vaccination series for patients in group 1 (mean 63±1.7% vs 65±2.9%, p=.32) or group 2 (mean 68±3.7% vs 63±%, p=.14). There was a statistically significant difference in DTH response pre-vs post-vaccination with AE37+GM in both group 1 (mean 1 mm vs 20 mm, p&amp;lt;.001) and group 2 (2 mm vs 29 mm, p&amp;lt;.001); however, there was no significant difference in the post-vaccination DTH response when comparing group 1 to group 2 (p=.16). There was no significant difference in the DTH response pre vs post inoculation for patients receiving GM alone. There was a significant proliferative response to AE36 and AE37 in both group 1 and 2 with the response greater in group 2. There was no proliferative response in patients receiving GM alone. Conclusions. Administration of the AE37+GM peptide vaccine with Tz administered either concurrently or sequentially is safe without any increase in the incidence of cardiotoxicity. Vaccination with AE37+GM concurrently with Tz results in enhanced proliferation suggesting that there may be clinical benefit to such a combination immunotherapy strategy. Patients will continue to be followed to determine the effects of vaccination with sequential vs concurrent Tz administration on clinical outcome. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-20-03.