| 1. |
- Bragina, Olga, et al.
(författare)
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Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first in-human study was to evaluate biodistribution, dosimetry, and safety of HER2-specific 99mTc-ADAPT6.METHODS. Twenty-two patients with HER2-positive (n=11) or HER2-negative (n=11) primary breast cancer were intravenously injected with 385125 MBq. The injected amount of protein was either 500 μg (n=11) or 1000 μg (n=11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort received a dose of 250 μg, and the planar scintigraphy followed by SPECT imaging was performed after 2 h only.RESULTS. Injection of 99mTc-ADAPT6 was well tolerated for all doses evaluated in the study, and was not associated with any adverse effects. 99mTc-ADAPT6 cleared rapidly from the blood and the majority of tissues. The normal organs with the highest accumulation were kidney, liver and lung. The effective doses were determined to 0.0090.002 and 0.0100.003 mSv/MBq when injecting protein amounts of 500 and 1000 μg, respectively. Injection of 500 μg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 3719 vs 52, p < 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p < 0.5) higher for the injected mass of 500 μg than for both 250 and 1000 μg. In one patient, the imaging using 99mTc-ADAPT6 revealed three bone metastases, which were not found at the time of diagnosis by CT or 99mTcpyrophosphate bone scan. MRI imaging confirmed this finding.CONCLUSION. Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 μg is preferable for discrimination between tumors with high and low expression of HER2. 99mTc-ADAPT6 is a promising imaging probe for the stratification of patients for HER2-targeting therapy.
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| 2. |
- Bragina, Olga, et al.
(författare)
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Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
- 2021
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 62:4, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first-in-human study was to evaluate biodistribution, dosimetry, and safety of the HER2-specific 99mTc-ADAPT6.METHODS: Twenty-nine patients with primary breast cancerwere included. In 22 patients with HER2-positive (n = 11) or HER2-negative (n = 11) histopathology an intravenous injection with 385±125 MBq 99mTc-ADAPT6 was performed, randomized to an injected protein mass of either 500 µg (n = 11) or 1000 µg (n = 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort (n = 7) was injected with 165±29 MBq (injected protein mass 250 µg) and imaging was performed after 2 h only.RESULTS: Injections of 99mTc-ADAPT6 at all injected mass levels were well tolerated and not associated with adverse effects. 99mTc-ADAPT6 cleared rapidly from blood and most other tissues. The normal organs with the highest accumulation were kidney, liver and lung. Effective doses were 0.009±0.002 and 0.010±0.003 mSv/MBq for injected protein masses of 500 and 1000 µg, respectively. Injection of 500 µg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 37±19 vs 5±2, p<0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p<0.05) higher for injected mass of 500 µg than for both 250 and 1000 µg.CONCLUSION: Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. Protein dose of 500 µg is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate if 99mTc-ADAPT6 can be used as an imaging probe for stratification of patients for HER2-targeting therapy in the areas where PET imaging is not readily available.
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| 3. |
- Bragina, Olga, et al.
(författare)
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Phase I Trial of 99mTc-(HE)3-G3, a DARPin-Based Probe for Imaging of HER2 Expression in Breast Cancer
- 2022
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 63:4, s. 528-535
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Tidskriftsartikel (refereegranskat)abstract
- Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may enable a noninvasive discrimination between HER2-positive and HER2-negative breast cancers for stratification of patients for HER2-targeted treatments. DARPin (designed ankyrin repeat proteins) G3 is a small (molecular weight, 14 kDa) scaffold protein with picomolar affinity to HER2. The aim of this first-in-humans study was to evaluate the safety, biodistribution, and dosimetry of 99mTc-(HE)3-G3.Methods: Three cohorts of patients with primary breast cancer (each including at least 4 patients with HER2-negative and 5 patients with HER2-positive tumors) were injected with 1,000, 2,000, or 3,000 μg of 99mTc-(HE)3-G3 (287 ± 170 MBq). Whole-body planar imaging followed by SPECT was performed at 2, 4, 6, and 24 h after injection. Vital signs and possible side effects were monitored during imaging and up to 7 d after injection.Results: All injections were well tolerated. No side effects were observed. The results of blood and urine analyses did not differ before and after studies. 99mTc-(HE)3-G3 cleared rapidly from the blood. The highest uptake was detected in the kidneys and liver followed by the lungs, breasts, and small intestinal content. The hepatic uptake after injection of 2,000 or 3,000 μg was significantly (P < 0.05) lower than the uptake after injection of 1,000 μg. Effective doses did not differ significantly between cohorts (average, 0.011 ± 0.004 mSv/MBq). Tumor–to–contralateral site ratios for HER-positive tumors were significantly (P < 0.05) higher than for HER2-negative at 2 and 4 h after injection.Conclusion: Imaging of HER2 expression using 99mTc-(HE)3-G3 is safe and well tolerated and provides a low absorbed dose burden on patients. This imaging enables discernment of HER2-positive and HER2-negative breast cancer. Phase I study data justify further clinical development of 99mTc-(HE)3-G3.
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| 4. |
- Chernov, Vladimir, et al.
(författare)
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Phase I Trial of [Tc-99m]Tc-maSSS-PEG(2)-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [Tc-99m]Tc-maSSS-PEG(2)-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 mu g of [Tc-99m]Tc-maSSS-PEG(2)-RM26 (600-700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 +/- 0.0007 for male patients and 0.008 +/- 0.003 mSv/MBq for female patients. The accumulation of [Tc-99m]Tc-maSSS-PEG(2)-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was safe and well tolerated. [Tc-99m]Tc-maSSS-PEG(2)-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.
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| 5. |
- Xie, Meng, et al.
(författare)
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Secondary ossification center induces and protects growth plate structure
- 2020
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Ingår i: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Growth plate and articular cartilage constitute a single anatomical entity early in development but later separate into two distinct structures by the secondary ossification center (SOC). The reason for such separation remains unknown. We found that evolutionarily SOC appears in animals conquering the land - amniotes. Analysis of the ossification pattern in mammals with specialized extremities (whales, bats, jerboa) revealed that SOC development correlates with the extent of mechanical loads. Mathematical modeling revealed that SOC reduces mechanical stress within the growth plate. Functional experiments revealed the high vulnerability of hypertrophic chondrocytes to mechanical stress and showed that SOC protects these cells from apoptosis caused by extensive loading. Atomic force microscopy showed that hypertrophic chondrocytes are the least mechanically stiff cells within the growth plate. Altogether, these findings suggest that SOC has evolved to protect the hypertrophic chondrocytes from the high mechanical stress encountered in the terrestrial environment.
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| 6. |
- Anantha, Krishnan Hariramabadran, et al.
(författare)
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Correlative Microstructure Analysis and In Situ Corrosion Study of AISI 420 Martensitic Stainless Steel for Plastic Molding Applications
- 2017
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Ingår i: Journal of the Electrochemical Society. - : Electrochemical Society. - 0013-4651 .- 1945-7111. ; 164:4, s. C85-C93
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Tidskriftsartikel (refereegranskat)abstract
- In this work, the corrosion behavior of tempered AISI 420 martensitic stainless steel (MSS) was studied by in-situ atomic force microscopy (AFM) in 0.1M NaCl and correlated with the microstructure. Thermocalc simulation, dilatometry, and X-ray diffraction (XRD) were performed to investigate phase transformation which showed the formation of M3C, M7C3, and M23C6 type of carbides and also retained austenite. Optical microscopy, scanning electron microscopy (SEM), and AFM characterization revealed undissolved carbides and tempering carbides in the martensitic matrix. Volta potential mapping measured by scanning Kelvin probe force microscopy (SKPFM) indicated higher electrochemical (practical) nobility of the carbides with respect to the martensitic matrix whereas regions adjacent to carbides showed lower nobilities due to chromium depletion. Open circuit potential and cyclic potentiodynamic polarization measurements showed metastable corrosion activities associated with a weak passive behavior and a risk for localized corrosion along certain carbide boundaries. In-situ AFM measurements revealed selective dissolution of certain carbide interphases and martensitic inter-lath regions indicating higher propensity to localized corrosion.
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| 7. |
- Anantha, Krishnan Hariramabadran, et al.
(författare)
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Experimental and modelling study of the effect of tempering on the susceptibility to environment-assisted cracking of AISI 420 martensitic stainless steel
- 2019
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Ingår i: Corrosion Science. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0010-938X .- 1879-0496. ; 148, s. 83-93
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Tidskriftsartikel (refereegranskat)abstract
- The resistance to environment-assisted cracking (EAC) of AISI 420 martensitic stainless steel (MSS) was investigated in 0.3 M NaCl solution (room temperature) at constant loads for 30 days. The steel tempered at 250 degrees C was superior to the 500 degrees C-temper, which showed corrosion pits favouring cracking. The fracture surface showed faceted grains, cleavage, striations, and inter- and transgranular cracks, suggesting a mixed stress corrosion cracking (SCC) and hydrogen embrittlement (HE) mechanism as the cause for EAC. Finite element modelling (FEM) indicated strain/stress localization at the mouth of deep pits and at the wall of shallow pits, displaying the favoured locations for pit-to-crack transition.
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| 8. |
- Chernov, Vladimir, et al.
(författare)
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Phase I Clinical Trial Using [Tc-99m]Tc-1-thio-D-glucose for Diagnosis of Lymphoma Patients
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923 .- 1999-4923. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- Similar to [F-18]-FDG, [Tc-99m]Tc-1-thio-D-glucose ([Tc-99m]Tc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of [Tc-99m]Tc-TG. Twelve lymphoma patients were injected with 729 +/- 102 MBq [Tc-99m]Tc-TG. Whole-body planar imaging was performed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients, SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. [Tc-99m]Tc-TG injections were well-tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone marrow, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. [Tc-99m]Tc-TG SPECT/CT revealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal lesions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using [Tc-99m]Tc-TG. Potentially, [Tc-99m]Tc-TG can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.
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