Lifetime toxicity/carcinogenicity studies of FD & C Blue No. 1 (brilliant blue FCF) in rats and mice

FD & C Blue No. 1 was fed to Charles River CD rats and CD-1 mice as a dietary admixture in lifetime toxicity/carcinogenicity studies. The rat study was conducted with an in utero phase in which the compound was administered to the F0 generation rats (60/sex/group) at dietary concentrations of 0.0%, 0.0%, 0.1%, 1.0% or 2.0%. After randomly selecting the F1 animals, the lifetime phase was initiated at the same levels with 70 rats/sex/group, including two control groups. The maximum exposure times were 116 and 111 wk for males and females, respectively. The no-observed-adverse-effect levels are dietary concentrations of 2.0% for males (1072 mg/kg body weight/day), and 1.0% for females (631 mg/kg/day) based on a 15.0% decrease in terminal body weight and decreased survival in the high-dose females compared with the combined control groups. Charles River CD-1 mice (60/sex/group) were fed FD & C Blue No. 1 as a dietary admixture at levels of 0.0%, 0.0%, 0.5%, 1.5% or 5.0% in a lifetime toxicity/carcinogenicity study. The maximum exposure time was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse-effect level established in this study is a dietary concentration of 5.0% (7354 mg/kg/day and 8966 mg/kg/day for male and female mice, respectively.     

Deficits in spatial coding and feature binding following damage to spatiotopic maps in the human pulvinar.

We report a patient with unilateral damage to the rostral part of the pulvinar who was impaired in localizing stimuli in the inferior visual field contralateral to the lesion and who made errors in the binding of shape and color in that quadrant. The findings demonstrate the importance of the pulvinar in spatial coding and provide support for the function of the thalamus in binding of features. They also provide evidence for a homology between the visual field maps of the inferior and lateral subdivisions of the pulvinar in monkeys and in humans, such that the inferior visual field is represented in the rostral part of the nucleus.     

Ipsilesional line bisection bias in patients with chronic parietal lesions

The current study investigated whether an ipsilesional bias in line bisection, a conventional measure for diagnosing hemispatial neglect, persists even in the absence of this syndrome in patients with chronic lesions restricted to posterior association cortex or dorsolateral prefrontal cortex. Both left and right hemisphere parietal lesions produced ipsilesional bisection errors, and to a comparable degree. Patients with lesions in frontal cortex, on the other hand, did not show a consistent bias. We conclude that chronic parietal lesions produce an ipsilesional bias in line bisection, even in the absence of other clinical signs of neglect, and that left hemisphere lesions can affect line bisection to the same degree as right hemisphere lesions.     

Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2'-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice.

PURPOSE: Recent findings indicating that many genes related to cancer development are silenced by an aberrant DNA methylation suggest that inhibitors of this process may be effective cancer therapeutics. In this study we investigated the efficacy of low-dose 5-aza-2'-deoxycitydine (DAC), a methylation inhibitor, with interleukin (IL) 12, one of the most potent cytokines with antitumor activity. Experimental Design: Mice inoculated with L1210 leukemia cells or with B16F10 melanoma cells were treated with 7 daily injections of low-dose DAC (0.2 mg/kg) and/or 7 daily doses of IL-12 (100 ng/dose). Scid/scid mice as well as monoclonal antibodies against CD4, CD8, and NK1.1 were used to investigate the mechanisms of the antitumor effects of the combination treatment. The activity of murine lymphocytes was measured with enzyme-linked immunospot and (51)Cr release assays. RESULTS: Treatment with DAC or IL-12 given alone produced moderate antitumor effects. In both tumor models combined treatment resulted in potentiated antitumor effects and produced 70% long-term survivors among mice inoculated with L1210 cells. The antitumor efficacy of combined treatment was abrogated in scid/scid mice, and after depletion of CD4(+) and CD8(+) T cells. Mice inoculated with B16F10 melanoma cells had significantly delayed tumor growth after combined treatment with DAC and IL-12. Strong antitumor effect correlated with a significant activation of lymph node-derived CD8(+) and CD4(+) cells. Transient neutropenia was observed in mice under treatment of DAC alone, but remarkably this effect was not potentiated by IL-12. CONCLUSIONS: This study provides the first evidence that antitumor effects of DAC can be strongly potentiated by IL-12 and could be beneficial in an effective low-dose-based antitumor therapy.     

Radiolabeled small-molecule ligands for prostate-specific membrane antigen: in vivo imaging in experimental models of prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a cell surface protein that is overexpressed in prostate cancer, including hormone-refractory and metastatic disease. Our goal in this study was to develop a series of PSMA-based imaging agents for clinical use. EXPERIMENTAL DESIGN: We have synthesized and evaluated the in vivo biodistribution of two radiolabeled urea derivatives that have high affinity for PSMA in severe combined immunodeficient mice harboring MCF-7 (breast, PSMA-negative), PC-3 (prostate, PSMA-negative), and LNCaP (prostate, PSMA-positive) xenografts. Radiopharmaceutical binding selectivity and tumor uptake were also evaluated in vivo using dedicated small animal positron emission tomography, single photon emission computed tomography, and gamma scintigraphic imaging devices. N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[(11)C]methyl-L-cysteine ([(11)C]DCMC K(i), 3.1 nmol/L) and N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[(125)I]iodo-L-tyrosine ([(125)C]DCIT K(i), 1.5 nmol/L) were synthesized using [(11)C]CH(3)I and with [(125)I]NaI/Iodogen, respectively.RESULTS: At 30 minutes postinjection, [(11)C]DCMC and [(125)I]DCIT showed tumor/muscle ratios of 10.8 and 4.7, respectively, with clear delineation of LNCaP-derived tumors on imaging. MCF-7- and PC-3-derived tumors showed significantly less uptake of [(11)C]DCMC or [(125)I]DCIT. CONCLUSION: These results show the feasibility of imaging PSMA-positive prostate cancer using low molecular weight agents.     

Predictors of all‐cause mortality among patients hospitalized with influenza,respiratory syncytial virus,or SARS‐CoV‐2

BackgroundShared and divergent predictors of clinical severity across respiratory viruses may support clinical and community responses in the context of a novel respiratory pathogen.MethodsWe conducted a retrospective cohort study to identify predictors of 30‐day all‐cause mortality following hospitalization with influenza (N = 45,749; 2010‐09 to 2019‐05), respiratory syncytial virus (RSV; N = 24 345; 2010‐09 to 2019‐04), or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2; N = 8988; 2020‐03 to 2020‐12; pre‐vaccine) using population‐based health administrative data from Ontario, Canada. Multivariable modified Poisson regression was used to assess associations between potential predictors and mortality. We compared the direction, magnitude, and confidence intervals of risk ratios to identify shared and divergent predictors of mortality.ResultsA total of 3186 (7.0%), 697 (2.9%), and 1880 (20.9%) patients died within 30 days of hospital admission with influenza, RSV, and SARS‐CoV‐2, respectively. Shared predictors of increased mortality included older age, male sex, residence in a long‐term care home, and chronic kidney disease. Positive associations between age and mortality were largest for patients with SARS‐CoV‐2. Few comorbidities were associated with mortality among patients with SARS‐CoV‐2 as compared with those with influenza or RSV.ConclusionsOur findings may help identify patients at greatest risk of illness secondary to a respiratory virus, anticipate hospital resource needs, and prioritize local prevention and therapeutic strategies to communities with higher prevalence of risk factors.     

Virome of Ixodes ricinus,Dermacentor reticulatus,and Haemaphysalis concinna Ticks from Croatia

Tick-borne diseases are a serious threat to both public and veterinary health. In this study, we used high-throughput sequencing to characterize the virome of three tick species implicated in the spread of vector-borne disease throughout Croatia. Ten viruses were identified, including seven potential novel species within the viral families Flaviviridae, Nyamiviridae, Rhabdoviridae, Peribunyaviridae, Phenuiviridae, and Nairoviridae.     

Gallic Acid-Functionalized,TiO2-Based Nanomaterial—Preparation,Physicochemical and Biological Properties

Wound healing and skin tissue regeneration remain the most critical challenges faced by medical professionals. Titanium(IV) oxide-based materials were proposed as components of pharmaceutical formulations for the treatment of difficult-to-heal wounds and unsightly scarring. A gallic acid-functionalized TiO₂ nanomaterial (TiO₂-GA) was obtained using the self-assembly technique and characterized using the following methods: scanning electron microscopy (SEM), transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy and thermogravimetry (TG). Additionally, physicochemical and biological tests (DPPH assay, Microtox^® acute toxicity test, MTT assay) were performed to assess antioxidant properties as well as to determine the cytotoxicity of the novel material against eukaryotic (MRC-5 pd19 fibroblasts) and prokaryotic (Staphylococcus aureus, Escherichia coli, Candida albicans, Aliivibrio fischeri) cells. To determine the photocytotoxicity of the material, specific tests were carried out with and without exposure to visible light lamps (425 nm). Following the results, the TiO₂-GA material could be considered an additive to dressings and rinsing suspensions for the treatment of difficult-to-heal wounds that are at risk of bacterial infections.