Objectives To investigate .sup.68 Ga-TRAP-(RGD).sub.3 hybrid imaging for the in vivo monitoring of alpha.sub.v ß.sub.3 -integrin expression as biomarker of anti-angiogenic therapy effects in ...experimental breast cancer. Materials and Methods Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq .sup.68 Ga-TRAP-(RGD).sub.3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImax.sub.tumor /VOImean.sub.muscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (alpha.sub.v ß.sub.3 -integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). Results .sup.68 Ga-TRAP-(RGD).sub.3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (DELTATBR.sub.follow-up/baseline : therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (DELTAvolume.sub.therapy 134±77 muL, DELTAvolume.sub.control 132±56 muL, p = 1.000). Immunohistochemistry revealed a significant reduction of alpha.sub.v ß.sub.3 -integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group. Conclusions .sup.68 Ga-TRAP-(RGD).sub.3 hybrid imaging allows for the in vivo assessment of alpha.sub.v ß.sub.3 -integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
sup.68Ga-TRAP Kazmierczak, Philipp M; Todica, Andrei; Gildehaus, Franz-Josef ...
PloS one,
12/2016, Volume:
11, Issue:
12
Journal Article
Peer reviewed
To investigate .sup.68 Ga-TRAP-(RGD).sub.3 hybrid imaging for the in vivo monitoring of alpha.sub.v ß.sub.3 -integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast ...cancer. Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq .sup.68 Ga-TRAP-(RGD).sub.3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImax.sub.tumor /VOImean.sub.muscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (alpha.sub.v ß.sub.3 -integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). .sup.68 Ga-TRAP-(RGD).sub.3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (DELTATBR.sub.follow-up/baseline : therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (DELTAvolume.sub.therapy 134±77 muL, DELTAvolume.sub.control 132±56 muL, p = 1.000). Immunohistochemistry revealed a significant reduction of alpha.sub.v ß.sub.3 -integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group. .sup.68 Ga-TRAP-(RGD).sub.3 hybrid imaging allows for the in vivo assessment of alpha.sub.v ß.sub.3 -integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
This prospective study was designed to demonstrate root level recovery of sensation in the zone of partial preservation in patients with C4 through C8, Frankel A spinal cord injuries. Subjects were ...evaluated for pin (n = 18) and light touch (n = 17) sensation. All subjects had normal sensation at the level of injury, and decreased or absent sensation at all levels caudal to that level within the zone of partial preservation; they had absent sensation at all levels below the zone of partial preservation. After the initial examination, patients were evaluated weekly for four weeks, and then at 2, 3, 6, 12, 18, and 24 months postinjury. Six of 18 patients recovered pin sensation and five of 17 recovered light touch within three months of injury. Most subjects who recovered had injuries from C5 through C8. Eleven of 12 C4 patients did not recover pin sensation, and 11 of 11 failed to recover light touch. However, five of six C5 to C8 patients recovered both pin and light touch. The p values (Fisher-Exact tests) for the C4 vs C5 to C8 groups were .004 and .001 for pin and light touch, respectively. In conclusion, approximately 30% of the total population improved one sensory root level, with the C5 to C8 injured patients comprising the majority of this improvement.
To investigate a multimodal, multiparametric perfusion MRI / .sup.18 F-fluoro-deoxyglucose-(.sup.18 F-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal ...adenocarcinomas in rats with immunohistochemical validation. Human colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 17 (n = 10 therapy group; n = 7 control group) female athymic nude rats (Hsd:RH-Foxn1.sup.rnu). Animals were imaged at baseline and after a one-week daily treatment protocol with regorafenib (10 mg/kg bodyweight) using a multimodal, multiparametric perfusion MRI/.sup.18 F-FDG-PET imaging protocol. In perfusion MRI, quantitative parameters of plasma flow (PF, mL/100 mL/min), plasma volume (PV, %) and endothelial permeability-surface area product (PS, mL/100 mL/min) were calculated. In .sup.18 F-FDG-PET, tumor-to-background-ratio (TTB) was calculated. Perfusion MRI parameters were correlated with TTB and immunohistochemical assessments of tumor microvascular density (CD-31) and cell proliferation (Ki-67). Regorafenib significantly (p<0.01) suppressed PF (81.1±7.5 to 50.6±16.0 mL/100mL/min), PV (12.1±3.6 to 7.5±1.6%) and PS (13.6±3.2 to 7.9±2.3 mL/100mL/min) as well as TTB (3.4±0.6 to 1.9±1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0±2.4 vs. 16.1±5.9) and tumor cell proliferation (Ki-67, 434.0 ± 62.9 vs. 663.0 ± 98.3) in the therapy group. Perfusion MRI parameters DELTAPF, DELTAPV and DELTAPS showed strong and significant (r = 0.67-0.78; p<0.01) correlations to the PET parameter DELTATTB and significant correlations (r = 0.57-0.67; p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55; p<0.05). A multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and .sup.18 F-FDG-PET validated by immunohistochemistry.
The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by
F-FDG-PET/CT and ...diffusion-weighted MRI (DW-MRI).
Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by
F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq
F-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density - CD31; tumor cell proliferation - Ki-67).
Tumor glucose uptake was significantly suppressed under therapy (∆TTL
- 1.00 ± 0.53 vs. ∆TTL
0.85 ± 1.21; p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (∆ADC
0.12 ± 0.14 × 10
mm
/s; ∆ADC
- 0.12 ± 0.06 × 10
mm
/s; p < 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 ± 48 vs. 287 ± 92; p = 0.001) and proliferation (Ki-67, 3718 ± 998 vs. 5389 ± 1332; p = 0.007) in the therapy compared to the control group.
A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by
F-FDG-PET/CT and DW-MRI.
Objectives To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of alpha vs3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. ...Materials and Methods Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (alpha vs3-integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). Results 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (deltaTBRfollow-up/baseline: therapy -1.07 plus or minus 0.83, control +0.32 plus or minus 1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (deltavolumetherapy 134 plus or minus 77 ML, deltavolumecontrol 132 plus or minus 56 ML, p = 1.000). Immunohistochemistry revealed a significant reduction of alpha vs3-integrin expression (308 plus or minus 135 vs. 635 plus or minus 325, p = 0.03), microvascular density (CD31, 168 plus or minus 108 vs. 432 plus or minus 70, p = 0.002), proliferation (Ki-67, 5,195 plus or minus 1,002 vs. 7,574 plus or minus 418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432 plus or minus 1,974 vs. 3,776 plus or minus 1,378, p = 0.002) in the therapy compared to the control group. Conclusions 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of alpha vs3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
FlashCam is a camera proposed for the medium-sized telescopes of the Cherenkov Telescope Array (CTA). We compare camera trigger rates obtained from measurements with the camera prototype in the ...laboratory and Monte-Carlo simulations, when scanning the parameter space of the fully-digital trigger logic and the intensity of a continuous light source mimicking the night sky background (NSB) during on-site operation. The comparisons of the measured data results to the Monte-Carlo simulations are used to verify the FlashCam trigger logic and the expected trigger performance.
Cryptomonads are unicellular algae with chloroplasts surrounded by four membranes. Between the inner and the outer pairs of membranes is a narrow plasmatic compartment which contains a nucleus-like ...organelle called the nucleomorph. Using pulsed field gel electrophoresis it is shown that the nucleomorph of the cryptomonad Pyrenomonas salina contains three linear chromosomes of 195 kb, 225 kb and 240 kb all of which encode rRNAs. Thus, this vestigial nucleus has a haploid genome size of 660 kb, harboring the smallest eukaryotic genome known so far. From the cell nucleus of P. salina at least 20 chromosomes ranging from 230 kb to 3.000 kb were fractionated. Here, the rDNA was detected on a single chromosome of about 2.500 kb.
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