scholarly journals A 3D RANGE MODULATOR FOR ULTRA-SHORT PROTON FLASH IRRADIATION

2021 ◽  
Author(s):  
Georgios Kourkafas ◽  
Juergen Bundesmann ◽  
Andrea Denker ◽  
Timo Fanselow ◽  
Jörg Röhrich ◽  
...  
Keyword(s):  
Dose Distribution ◽  
Dose Range ◽  
Ccd Camera ◽  
Uniform Field ◽  
Depth Dose ◽  
Flat Dose ◽  
Short Beam ◽  
Beam Delivery

Background and aims In the pursuit of optimal parameters for FLASH irradiation, all components involved in the beam delivery should be compatible with requirements spread in an extreme and wide unexplored regime. Aiming for minimal total irradiation times with modulated proton beams, which deliver a flat depth-dose distribution along tumors, a static range modulator has been developed to accommodate ultra-short beam durations regardless of their time structure. The design goals were set to match the functionality of the rotating wheel used for in-vivo and in-vitro FLASH investigations at HZB. Methods Having the form of a ridge filter extended to an additional dimension, a hexagonal-pyramid pattern was configured to an incoming beam of 23 MeV energy with > 1 mm radius, in order to create a 6 mm uniform field with a flat dose range of 5 mm at the target. The manufacturing was done with a 3D printer using VeroWhite, a material similar to PMMA. The lateral and distal dose distribution of both modulators were measured using a Markus Chamber (PTW-Freiburg, Germany) in a water phantom and a radioluminescent screen mounted in front of CCD camera, respectively. Results The developed modulator created very flat dose distributions as designed, with negligible differences to the reference rotating wheel. The positioning tolerances were evaluated as relatively relaxed, with offsets of 2 cm and an angle of 5 degrees not compromising the desired performance. Conclusions The developed static modulator allows systematic proton FLASH studies on small organs using a broad range of timing schemes, disentangled from temporal and spatial incoherencies.

Multi-mode light microscopy of microtubule assembly dynamics and chromosome movement in vivo and In vitro

1996 ◽  
Vol 54 ◽  
pp. 730-731
Author(s):  
E. D. Salmon ◽  
J. C. Waters ◽  
C. Waterman-Storer
Keyword(s):  
Imaging System ◽  
Ccd Camera ◽  
Transmitted Light ◽  
Microtubule Assembly ◽  
Live Cells ◽  
Optical Efficiency ◽  
Multiple Band ◽  
Multi Mode

We have developed a multi-mode digital imaging system which acquires images with a cooled CCD camera (Figure 1). A multiple band pass dichromatic mirror and robotically controlled filter wheels provide wavelength selection for epi-fluorescence. Shutters select illumination either by epi-fluorescence or by transmitted light for phase contrast or DIC. Many of our experiments involve investigations of spindle assembly dynamics and chromosome movements in live cells or unfixed reconstituted preparations in vitro in which photodamage and phototoxicity are major concerns. As a consequence, a major factor in the design was optical efficiency: achieving the highest image quality with the least number of illumination photons. This principle applies to both epi-fluorescence and transmitted light imaging modes. In living cells and extracts, microtubules are visualized using X-rhodamine labeled tubulin. Photoactivation of C2CF-fluorescein labeled tubulin is used to locally mark microtubules in studies of microtubule dynamics and translocation. Chromosomes are labeled with DAPI or Hoechst DNA intercalating dyes.

scholarly journals Low-Molecular Weight BDNF Mimetic, Dimeric Dipeptide GSB-106, Reverses Depressive Symptoms in Mouse Chronic Social Defeat Stress

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 252
Author(s):  
Tatiana A. Gudasheva ◽  
Anna V. Tallerova ◽  
Armen G. Mezhlumyan ◽  
Tatyana A. Antipova ◽  
Ilya O. Logvinov ◽  
...  
Keyword(s):  
Dose Range ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
In Vivo Experiments ◽  
Trk Receptor ◽  
Chronic Social Defeat Stress ◽  
Swimming Test ◽  
Scientific Group

A mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, named GSB-106, was designed and synthesized in our scientific group. The compound activated TrkB, MAPK/ERK, PI3K/AKT, and PLCγ in in vitro experiments. In vivo experiments with rodents revealed its antidepressant-like activity in the forced swim and the tail suspension tests at the dose range of 0.1–5.0 mg/kg (i.p., p.o.). However, GSB-106 was not studied in depression models modulating major depression in humans. In the present study, the GSB-106 antidepressant-like activity was revealed in mice at the depression model induced by 28-day social defeat stress with 21-days oral administration (0.1 mg/kg) after stress. At the same time, GSB-106 restored reduced locomotor activity and completely eliminated the anhedonia manifestations. The compound also restored reduced levels of synaptophysin and CREB in the hippocampus. In addition, the Trk receptor antagonist K252A, and the PLC inhibitor U73122, were found to completely block the antidepressant-like activity of GSB-106 in the forced swimming test in mice. Thus, the present results demonstrate the dipeptide BDNF mimetic GSB-106 reversed depressive-like behavior and restored hippocampal neuroplasticity in a rodent depression model. These effects of GSB-106 are probably regulated by TrkB signaling.

Measurement of the Optical Properties of Muscle Tissue In Vivo

2000 ◽  
Author(s):  
P. L. Kopsombut ◽  
D. Willis ◽  
A. E. Schen ◽  
L. X. Xu ◽  
X. Xu
Keyword(s):  
Optical Properties ◽  
Transport Theory ◽  
Rapid Development ◽  
Ccd Camera ◽  
High Sensitivity ◽  
Biological Tissues ◽  
In Vivo Measurement ◽  
Living Tissues

Abstract Along with rapid development of diagnostic and therapeutic applications of lasers in medicine, optical properties of various biological tissues have been extensively studied [1]. Most of the studies were performed in vitro owing to the complexity involved in in vivo measurement. To date, it is well understood that living tissue is an absorbing and scattering heterogeneous medium because of its complex structures including blood network. The transport theory cannot be readily used due to the heterogeneity and the absence of the optical properties of living tissues [2]. In this research, we have developed a procedure for measuring the total attenuation coefficient (μ1) of the exteriorized rat 2-D spinotrapezius muscle in the wavelength ranged from 480–560 nm using the collimated light from a Nitrogen-pumped dye laser and a high-sensitivity CCD camera.

scholarly journals Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis

2008 ◽  
Vol 52 (8) ◽  
pp. 2831-2835 ◽  
Author(s):  
R. Rustomjee ◽  
A. H. Diacon ◽  
J. Allen ◽  
A. Venter ◽  
C. Reddy ◽  
...  
Keyword(s):  
Pulmonary Tuberculosis ◽  
Bactericidal Activity ◽  
Dose Range ◽  
Study Drug ◽  
First Line ◽  
Serious Adverse Events ◽  
Once Daily ◽  
Smear Positive Pulmonary Tuberculosis

ABSTRACT Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log10 decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log10 CFU counts (± standard deviation) from baseline to day 7 were 0.04 ± 0.46 for 25 mg TMC207 (n = 14), 0.26 ± 0.64 for 100 mg TMC207 (n = 14), 0.77 ± 0.58 for 400 mg TMC207 (n = 14), 1.88 ± 0.74 for INH (n = 11), and 1.70 ± 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.

Comparison of Vibrio and Firefly Luciferases as Reporter Gene Systems for Use in Bacteria and Plants

1996 ◽  
Vol 23 (1) ◽  
pp. 75 ◽  
Author(s):  
SR Mudge ◽  
WR Lewis-Henderson ◽  
RG Birch
Keyword(s):  
Gene Expression ◽  
Reporter Gene ◽  
Ccd Camera ◽  
Reporter Gene Expression ◽  
In Vitro Assays ◽  
E Coli ◽  
Cell Extracts ◽  
Cooled Ccd

Luciferase genes from Vibrio harveyi (luxAB) and firefly (luc) were introduced into E. coli, Agrobacteriurn, Arabidopsis and tobacco. Transformed bacteria and plants were quantitatively assayed for luciferase activity using a range of in vitro and in vivo assay conditions. Both lux and luc proved efficient reporter genes in bacteria, although it is important to be aware that the sensitive assays may detect expression due to readthrough from distant promoters. LUX activity was undetectable by liquid nitrogen-cooled CCD camera assays on intact tissues of plants which showed strong luxAB expression by in vitro assays. The decanal substrate for the lux assay was toxic to many plant tissues, and caused chemiluminescence in untransformed Arabidopsis leaves. These are serious limitations to application of the lux system for sensitive, non-toxic assays of reporter gene expression in plants. In contrast, LUC activity was readily detectable in intact tissues of all plants with luc expression detectable by luminometer assays on cell extracts. Image intensities of luc-expressing leaves were commonly two to four orders of magnitude above controls under the CCD camera. Provided adequate penetration of the substrate luciferin is obtained, luc is suitable for applications requiring sensitive, non-toxic assays of reporter gene expression in plants.

scholarly journals Genotoxic and cytotoxic potential of methacrylate-based orthodontic adhesives

2020 ◽  
Author(s):  
Andreas Taubmann ◽  
Ines Willershausen ◽  
Christian Walter ◽  
Sarah Al-Maawi ◽  
Bernd Kaina ◽  
...  
Keyword(s):  
Incubation Period ◽  
Dose Range ◽  
Test Group ◽  
Universal Adhesive ◽  
Xtt Assay ◽  
Genotoxic Potential ◽  
Γh2ax Foci ◽  
Orthodontic Adhesives

Abstract Objectives The biocompatibility of methacrylate-based adhesives is a topic that is intensively discussed in dentistry. Since only limited evidence concerning the cyto- and genotoxicity of orthodontic adhesives is available, the aim of this study was to measure the genotoxic potential of seven orthodontic methacrylate-based adhesives. Materials and methods The XTT assay was utilized to determine the cytotoxicity of Assure Plus, Assure Bonding Resin, ExciTE F, OptiBond Solo Plus, Scotchbond Universal Adhesive, Transbond MIP, and Transbond XT after an incubation period of 24 h on human gingival fibroblasts. We also performed the γH2AX assay to explore the genotoxic potential of the adhesives within cytotoxic dose ranges after an incubation period of 6 h. Results The XTT assay showed a concentration-dependent reduction in cell viability. The decrease in cellular viability was in the same dose range most significant for Assure Plus, rendering it the adhesive material with the highest cytotoxicity. Employing the γH2AX assay, a concentration-dependent increase in H2AX phosphorylation was detected, indicating induction of DNA damage. Conclusions For most products, a linear correlation between the material concentration and γH2AX foci was observed. The most severe effect on γH2AX focus induction was found for Transbond MIP, which was the only adhesive in the test group containing the co-initiator diphenyliodonium hexafluorophosphate (DPIHP). Clinical relevance The data indicate that orthodontic adhesives, notably Transbond MIP, bear a genotoxic potential. Since the study was performed with in vitro cultivated cells, a direct translation of the findings to in vivo exposure conditions should be considered with great diligence.

IMAGE, a randomized phase Ib/II study of elisidepsin (E) as a single agent in pretreated advanced gastroesophageal (GE) cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 92-92 ◽  
Author(s):  
Ramon Salazar ◽  
Jean Philippe Metges ◽  
David Alan Anthoney ◽  
Gianluca Laus ◽  
Maria Alsina Maqueda ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Single Agent ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Primary Objective ◽  
Phase Ib ◽  
Flat Dose

92 Background: E is a new marine compound with broad in vitro/in vivo antitumor activity. Low μM concentrations lead to cell-death through membrane permeabilization. E has shown evidence of activity in pre-treated GE patients (pts) in phase I trials. Methods: The primary objective was to determine the tolerability and efficacy of E in pts with GE cancer after 1-2 prior chemotherapy (CT) lines. Initially, dose was optimized (Phase Ib) in two different schedules: a fixed flat dose (FD) of intravenous (i.v) E (8 and 10 mg), in 24h, biweekly (Arm A) and i.v E (3.0 and 3.75mg), in 3h, weekly (Arm B). After dose optimization patients were included and stratified by histology to each optimal dose (Phase II) to determine the rate of progression-free survival at week 16 ± 1 (PFS4) in an intention to treat analysis. If at least two out of 15 pts reached PFS4, recruitment would continue to a maximum of 40 pts per arm. Results: A total of 45 pts were recruited, 12 pts into Phase Ib (Arm A/B: 6/6 pts) and 33 pts into Phase II (Arm A/B: 15/18 pts). Median age was 60 years (35–81 years), 39 were males and ECOG PS was 1 in 75% of pts. Tumour sites were gastric (32% pts), esophageal (39% pts) and esophago-gastric junction (30% pts). Ninety percent of pts had metastatic disease, 31.8% of which had liver metastasis; 55% of pts had two prior lines of CT . No DLTs occurred during the first cycle in the Phase Ib. The optimal dose for Arm A was 10 mg FD, 24h, biweekly; the optimal dose for Arm B was 3.75mg FD, 3h, weekly. Two patients reached PFS4 in Phase Ib (Arm A). Only one patient reached PFS4 in Phase II (Arm A). No objective responses were observed. Therefore, protocol criteria for further recruitment were not met. The safety profile showed grade 1-2 toxicity pruritus (29.5%), nausea (15.9%), vomiting (6.8%) and fatigue (25%). Grade 3-4 toxicity consisted of asymptomatic reversible liver enzyme increases in 20.5% of patients. Conclusions: E is a very tolerable drug with a unique mechanism of action. In the current setting of non-stratified advanced GE patients, E has insufficient antitumor activity to warrant further investigation. Clinical trial information: 2010-020325-40.

scholarly journals In Vitro and In Vivo Activities of Gatifloxacin against Mycobacterium tuberculosis

2002 ◽  
Vol 46 (4) ◽  
pp. 1022-1025 ◽  
Author(s):  
Enrique J. Alvirez-Freites ◽  
Janna L. Carter ◽  
Michael H. Cynamon
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Dose Range ◽  
Tuberculosis Model ◽  
Range Study

ABSTRACT Gatifloxacin (GAT) and moxifloxacin (MXF) were evaluated in vitro to determine their activities against Mycobacterium tuberculosis. GAT was subsequently compared in a dose range study to isoniazid (INH) in a murine tuberculosis model. GAT was somewhat less active than INH. GAT and MXF were evaluated in mice infected with M. tuberculosis and were found to have similar activities. GAT was studied alone and in combination with ethambutol, ethionamide (ETA), and pyrazinamide (PZA) and compared to INH and rifampin (RIF). GAT appears to have sufficient activity alone and in combination with ETA with or without PZA to merit evaluation for treatment of tuberculosis.

Pharmacokinetics and pharmacodynamics of recombinant and urinary human FSH in the male monkey (Macaca fascicularis)

1994 ◽  
Vol 141 (1) ◽  
pp. 113-121 ◽  
Author(s):  
G F Weinbauer ◽  
M Simoni ◽  
J S Hutchison ◽  
E Nieschlag
Keyword(s):  
Macaca Fascicularis ◽  
Statistical Significance ◽  
Dose Range ◽  
Dose Finding ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Serum Samples ◽  
Maximum Serum ◽  
Fsh Bioactivity

Abstract A dose-finding study was performed in adult male monkeys (Macaca fascicularis) to evaluate the pharmacokinetics and pharmacodynamics of a recombinant human FSH preparation (rhFSH). Groups of five monkeys were randomly assigned to receive single i.m. injections of 0·9% (w/v) NaCl (diluent), 6, 12 or 24 IU rhFSH/kg or 24 IU urinary human FSH/kg (uhFSH). The doses were based on an in vivo ovarian weight gain assay. Blood samples were collected 24 h before and immediately prior to injections, and 4, 8, 12, 24, 72 and 96 h after injections for determination of serum levels of immunoactive FSH by fluoroimmunoassay, bioactive FSH by an in vitro Sertoli cell assay, and inhibin and testosterone by radioimmunoassay. Inhibin was chosen as a marker for in vivo hFSH activity, since the secretion of inhibin in male monkeys is under the control of FSH. Administration of hFSH resulted in dose-related increases in serum hFSH concentrations. rhFSH and uhFSH exhibited similar pharmacokinetics. Comparable findings were obtained when serum samples were analysed for in vitro FSH bioactivity. Maximum serum hFSH levels were obtained 4–6 h after administration and the elimination half-life of hFSH was on average 18–22 h. The serum pharmacokinetics of rhFSH were linear within the dose range explored. Baseline inhibin concentrations varied significantly between groups. However, when the changes in inhibin concentrations were normalized to the baseline values (per cent change, area under curve and maximum inhibin level), a dose-dependent stimulatory effect of rhFSH on serum inhibin was evident. This effect attained statistical significance with doses of 24 IU rhFSH/kg and 24 IU uhFSH/kg, and the serum inhibin responses to rhFSH and uhFSH were not significantly different. No significant differences were observed with regard to the serum concentrations of testosterone between the diluentand hFSH-treated groups. It was concluded that rhFSH is bioactive in terms of stimulating testicular inhibin production in the male monkey and that the pharmacokinetic properties of rhFSH and uhFSH are similar. Journal of Endocrinology (1994) 141, 113–121

Effect of in vivo Administration of FeibaR on Clotting Tests: Dose-Response Relationship

1979 ◽  
Author(s):  
Chr. Nowotny ◽  
K. Lechner ◽  
H. Niessner ◽  
E. Thaler
Keyword(s):  
Dose Response ◽  
Dose Range ◽  
Inverse Correlation ◽  
In Vitro Test ◽  
Clotting Time ◽  
Vitro Test ◽  
R Value ◽  
Dose Dependent

FEIBA causes in vitro a concentration-dependent shortening of APTT of hemophilic plasma containing antibody to factor VIII. Since the potency of preparation is based on this in vitro test, it was of interest to examine whether a dose-dependent shortening of APTT and clotting time is also observed under in vivo conditions, APTT, whole blood glass clotting time and reaction time (=R value of thrombelastogramm) were determined before and 30 to 60 min. after 91 infusions of FE IBA (dose range 6 - 100 U/kg) to 10 hemophiliacs with antibody. Although there was a considerable scatter, a significant inverse correlation between the dose of FE IBA and postinfusion APTT and R-value was observedThe dose response curve was, however, rather flat. No significant correlation existed between FE IBA dose and glass clotting time. The effect of FE IBA on the APTT was not dependent on the antibody level, both, in vitro and in vivo. There was only a slight variant ot the effect among different patients, but a marked variation among different lots ot tne preparation, FE IBA seems to have a weak clinical hemostatic effect. A clear relationship between dose and clinical effect could not be established but it appears that doses higher than 50 U/kg are not more effective than smaller doses.

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