Tumor hypoxia as a mechanism of resistance to bevacizumab in a murine model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13111-e13111 ◽  
Author(s):  
Linda Heijmen ◽  
Otto C. Boerman ◽  
Cornelis J. A. Punt ◽  
E. Ter Voert ◽  
Wim J.G. Oyen ◽  
...  
Keyword(s):  
Imaging Techniques ◽  
Tumor Hypoxia ◽  
Therapy Resistance ◽  
Control Group ◽  
Vascular Density ◽  
Hypoxic Fraction ◽  
Induced Changes ◽  
T2 Mri ◽  
Over Time

e13111 Background: Despite the promise of preclinical and early phase clinical studies, the efficacy of bevacizumab in solid tumors is more limited than expected. One of the presumed reasons is the induction of tumor hypoxia by the anti-angiogenic effects of bevacizumab, leading to therapy resistance. The aim of this study was to assess the effect of bevacizumab on tumor hypoxia in vivo in a colorectal cancer model, using functional imaging techniques. Methods: Nude mice with s.c. LS174T colon carcinoma xenografts (0.05 - 0.3 cm3) were treated with bevacizumab (5 mg/kg; 2/wk, i.p.) or saline as a control. To assess tumor hypoxia in vivo 18F-MISO-PET microPET or T2*-MRI images were acquired of separate groups of mice (n=5) before treatment and at day 2, 6 and 10 days after start of treatment. Tumors were harvested directly after imaging to microscopically assess the hypoxic fraction (pimonidazole staining) and vascular density (9F1 staining). Results: Linear regression analyses showed that FMISO uptake increased significantly more over time in the control group than in the bevacizumab group (beta -0.44, p=0.02), indicating that bevacizumab reduced the inherent increase in tumor hypoxia over time. T2* time increased significantly less in the bevacizumab group (beta -0.45, p=0.01), indicating a higher deoxyhemoglobine concentration, which might indicate a higher perfusion of the tumor and thus less hypoxia. The hypoxic fraction did not change over time and no difference was observed between the tumors in the treated and the control group. Vessel density significantly decreased over time in the bevacizumab group (beta -0.25, p=0.05), while the hypoxic fraction remained unchanged in the control group. Conclusions: The bevacizumab-induced changes in the tumor were most prominent at 10 days after treatment initiation, implying a build-up effect of repeated bevacizumab administration. The treatment induced changes could be detected with both T2*-MRI as well as with FMISO microPET. Bevacizumab did not induce tumor hypoxia, despite the observed decrease in vascular density. Therefore, induction of tumor hypoxia as a resistance mechanism to bevacizumab treatment seems unlikely.

scholarly journals Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI, EPRI, and PET

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1614
Author(s):  
Ken-ichiro Matsumoto ◽  
James B. Mitchell ◽  
Murali C. Krishna
Keyword(s):  
Radiation Therapy ◽  
Functional Imaging ◽  
Imaging Techniques ◽  
Biological Effects ◽  
Tumor Hypoxia ◽  
Redox Status ◽  
Blood Oxygen Level Dependent ◽  
Oxygen Level ◽  
Cancer Tumor

Radiation therapy is one of the main modalities to treat cancer/tumor. The response to radiation therapy, however, can be influenced by physiological and/or pathological conditions in the target tissues, especially by the low partial oxygen pressure and altered redox status in cancer/tumor tissues. Visualizing such cancer/tumor patho-physiological microenvironment would be a useful not only for planning radiotherapy but also to detect cancer/tumor in an earlier stage. Tumor hypoxia could be sensed by positron emission tomography (PET), electron paramagnetic resonance (EPR) oxygen mapping, and in vivo dynamic nuclear polarization (DNP) MRI. Tissue oxygenation could be visualized on a real-time basis by blood oxygen level dependent (BOLD) and/or tissue oxygen level dependent (TOLD) MRI signal. EPR imaging (EPRI) and/or T1-weighted MRI techniques can visualize tissue redox status non-invasively based on paramagnetic and diamagnetic conversions of nitroxyl radical contrast agent. 13C-DNP MRI can visualize glycometabolism of tumor/cancer tissues. Accurate co-registration of those multimodal images could make mechanisms of drug and/or relation of resulted biological effects clear. A multimodal instrument, such as PET-MRI, may have another possibility to link multiple functions. Functional imaging techniques individually developed to date have been converged on the concept of theranostics.

scholarly journals Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhi-hang Zhou ◽  
Si-yuan Liang ◽  
Tong-chao Zhao ◽  
Xu-zhuo Chen ◽  
Xian-kun Cao ◽  
...  
Keyword(s):  
Controlled Release ◽  
Therapeutic Effect ◽  
Cell Apoptosis ◽  
Metastatic Cancer ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Control Group ◽  
Hypoxia Inducible Factor 1Α

Abstract Background Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO2 nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. Result Here, intelligent “theranostic” platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. Conclusion In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions. Graphic abstract

scholarly journals Osseointegration of Zirconia Implants after UV-Light or Cold Atmospheric Plasma Surface Treatment In Vivo

Materials ◽  
2022 ◽  
Vol 15 (2) ◽  
pp. 496
Author(s):  
Lisa Krautwald ◽  
Ralf Smeets ◽  
Carolin Stolzer ◽  
Rico Rutkowski ◽  
Linna Guo ◽  
...  
Keyword(s):  
Uv Light ◽  
Atmospheric Plasma ◽  
Control Group ◽  
Plasma Surface Treatment ◽  
Bone To Implant Contact ◽  
Parietal Bones ◽  
Zirconia Implants ◽  
Over Time

The influence of UV light and non-thermal plasma on the osseointegration of yttria-stabilized zirconia implants (Y-TZP) comparing the two methods is unclear. The aim of this study was to show the influence of these methods on the osseointegration of dental zirconia implants in an animal model. A total of 54 implants were either untreated, treated with UV light (UV), or non-thermal oxygen plasma for 12 min and inserted into the parietal bones of six domestic pigs. The animals were sacrificed after a healing interval of two, four, and nine weeks. The degree of osseointegration was determined using histomorphometric determination of bone-to-implant contact values (BIC) and the bone-to-implant contact values within the retentive parts of the implants (BAFO). BIC values decreased in all groups after four weeks of healing and re-increased after nine weeks in all groups. BAFO increased significantly over time in all groups. However, there were no statistically significant differences in BIC and BAFO values between the control group and the test groups and over time. Clinical studies may follow to confirm the influence of cold plasma and UV light on the healing and survival of zirconia implants.

3D microscopic analysis of molecular distributions in vivo: Modulation of hexokinase localization

1991 ◽  
Vol 49 ◽  
pp. 394-395
Author(s):  
R.M. Lynch ◽  
W. Carrington ◽  
K.E. Fogarty ◽  
F.S. Fay
Keyword(s):  
Turnover Rate ◽  
Imaging Techniques ◽  
Cell Metabolism ◽  
Microscopic Analysis ◽  
Living Cells ◽  
Mitochondrial Outer Membrane ◽  
Quantitative Image ◽  
Metabolic Conditions ◽  
Over Time

Several enzymes involved in cell metabolism appear to associate with subcellular structures in a dynamic fashion; i.e., their binding is modulated during changes in metabolic rate. Our current focus of investigation is on the modulation of binding of hexokinase isozyme I (HKI) to mitochondria in vivo. Binding of HKI to the mitochondrial outer membrane is proposed to provide kinetic advantages to the enzyme, thereby elevating turnover rate. Moreover, binding of the enzyme may be modulated, and therefore, is suggested to be involved in regulating glycolysis. Recently, we have used quantitative confocal microscopy to demonstrate that HKI is localized to mitochondria in astrocytes even though fractionation studies of these cells indicate that most HKI is not bound. In order to understand the dynamics of association of HKI with mitochondria under different metabolic conditions, we have used 3D microscopic imaging techniques to acquire information regarding the distribution of fluorophore labeled HKI and quantitative image analysis to monitor changes in this distribution over time in living cells.

scholarly journals Longitudinal in vivo Imaging Reveals Balanced and Branch-Specific Remodeling of Mature Cortical Pyramidal Dendritic Arbors after Stroke

2009 ◽  
Vol 30 (4) ◽  
pp. 783-791 ◽  
Author(s):  
Craig E Brown ◽  
Jamie D Boyd ◽  
Timothy H Murphy
Keyword(s):  
Adult Mouse ◽  
Pyramidal Neurons ◽  
Receptive Fields ◽  
Two Photon ◽  
Cortical Pyramidal Neurons ◽  
Dendritic Arbors ◽  
Cortical Receptive Fields ◽  
Induced Changes ◽  
Over Time

The manner in which fully mature peri-infarct cortical dendritic arbors remodel after stroke, and thus may possibly contribute to stroke-induced changes in cortical receptive fields, is unknown. In this study, we used longitudinal in vivo two-photon imaging to investigate the extent to which brain ischemia can trigger dendritic remodeling of pyramidal neurons in the adult mouse somatosensory cortex, and to determine the nature by which remodeling proceeds over time and space. Before the induction of stroke, dendritic arbors were relatively stable over several weeks. However, after stroke, apical dendritic arbor remodeling increased significantly (dendritic tip growth and retraction), particularly within the first 2 weeks after stroke. Despite a threefold increase in structural remodeling, the net length of arbors did not change significantly over time because dendrite extensions away from the stroke were balanced by the shortening of tips near the infarct. Therefore, fully mature cortical pyramidal neurons retain the capacity for extensive structural plasticity and remodel in a balanced and branch-specific manner.

Facilitated migration of cells from a transected peripheral nerve over collagen fibers: in vivo observations

1989 ◽  
Vol 47 ◽  
pp. 888-889
Author(s):  
Arthur J. Wasserman ◽  
Azam Rizvi ◽  
George Zazanis ◽  
Frederick H. Silver
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Collagen Gel ◽  
Collagen Fibers ◽  
Control Group ◽  
Guide Tube ◽  
Sprague Dawley ◽  
Silicone Tube ◽  
Thin Sections

In cases of peripheral nerve damage the gap between proximal and distal stumps can be closed by suturing the ends together, using a nerve graft, or by nerve tubulization. Suturing allows regeneration but does not prevent formation of painful neuromas which adhere to adjacent tissues. Autografts are not reported to be as good as tubulization and require a second surgical site with additional risks and complications. Tubulization involves implanting a nerve guide tube that will provide a stable environment for axon proliferation while simultaneously preventing formation of fibrous scar tissue. Supplementing tubes with a collagen gel or collagen plus extracellular matrix factors is reported to increase axon proliferation when compared to controls. But there is no information regarding the use of collagen fibers to guide nerve cell migration through a tube. This communication reports ultrastructural observations on rat sciatic nerve regeneration through a silicone nerve stent containing crosslinked collagen fibers.Collagen fibers were prepared as described previously. The fibers were threaded through a silicone tube to form a central plug. One cm segments of sciatic nerve were excised from Sprague Dawley rats. A control group of rats received a silicone tube implant without collagen while an experimental group received the silicone tube containing a collagen fiber plug. At 4 and 6 weeks postoperatively, the implants were removed and fixed in 2.5% glutaraldehyde buffered by 0.1 M cacodylate containing 1.5 mM CaCl2 and balanced by 0.1 M sucrose. The explants were post-fixed in 1% OSO4, block stained in 1% uranyl acetate, dehydrated and embedded in Epon. Axons were counted on montages prepared at a total magnification of 1700x. Montages were viewed through a dissecting microscope. Thin sections were sampled from the proximal, middle and distal regions of regenerating sciatic plugs.

EEG Measurement of Emotion Processing in Children with Daytime Urinary Incontinence

2018 ◽  
Vol 46 (4) ◽  
pp. 336-341
Author(s):  
Justine Niemczyk ◽  
Monika Equit ◽  
Katja Rieck ◽  
Mathias Rubly ◽  
Catharina Wagner ◽  
...  
Keyword(s):  
Urinary Incontinence ◽  
Patient Group ◽  
Imaging Techniques ◽  
Emotion Processing ◽  
Event Related Potentials ◽  
Oddball Paradigm ◽  
Control Group ◽  
Central Processing ◽  
Daytime Urinary Incontinence ◽  
Related Potentials

Abstract. Objective: Daytime urinary incontinence (DUI) is common in childhood. The aim of the study was to neurophysiologically analyse the central emotion processing in children with DUI. Method: In 20 children with DUI (mean age 8.1 years, 55 % male) and 20 controls (mean age 9.1 years, 75 % male) visual event-related potentials (ERPs) were recorded after presenting emotionally valent (80 neutral, 40 positive, and 40 negative) pictures from the International Affective Picture System (IAPS) as an oddball-paradigm. All children received a full organic and psychiatric assessment. Results: Children with DUI did not differ significantly from controls regarding responses to emotional pictures in the frontal, central, and parietal regions and in the time intervals 250–450 ms, 450–650 ms, and 650–850 ms after stimulus onset. The patient group had more psychological symptoms and psychiatric comorbidities than the control group. Conclusions: EEG responses to emotional stimuli are not altered in children with DUI. Central emotion processing does not play a major role in DUI. Further research, including a larger sample size, a more homogeneous patient group (regarding subtype of DUI) or brain imaging techniques, could reveal more about the central processing in DUI.

In-vitro- und In-vivo-Wirkung von Schilddrüsenhormon auf das Wachstum von Neuroblastomzellen

1990 ◽  
Vol 29 (03) ◽  
pp. 120-124
Author(s):  
R. P. Baum ◽  
E. Rohrbach ◽  
G. Hör ◽  
B. Kornhuber ◽  
E. Busse
Keyword(s):  
Cell Differentiation ◽  
Neuroblastoma Cells ◽  
Control Group ◽  
Initial Value ◽  
Initial Rise ◽  
Biphasic Effect ◽  
Contrast Microscopy ◽  
Morphological Sign

The effect of triiodothyronine (T3) on the differentiation of cultured neuroblastoma (NB) cells was studied after 9 days of treatment with a dose of 10-4 M/106 cells per day. Using phase contrast microscopy, 30-50% of NB cells showed formation of neurites as a morphological sign of cellular differentiation. The initial rise of the mitosis rate was followed by a plateau. Changes in cyclic nucleotide content, in the triphosphates and in the activity of the enzyme ornithine decarboxylase (ODC) were assessed in 2 human and 2 murine cell lines to serve as biochemical parameters of the cell differentiation induced by T3. Whereas the cAMP level increased significantly (3 to 7 fold compared with its initial value), the cGMP value dropped to 30 to 50% of that of the control group. ATP and GTP increased about 200%, the ODC showed a decrease of about 50%. The present studies show a biphasic effect of T3 on neuroblastoma cells: the initial rise of mitotic activity is followed by increased cell differentiation starting from day 4 of the treatment.

Platelet Aggregation in Diabetes Mellitus and the Effect of Insulin in Vivo on Aggregation

1972 ◽  
Vol 27 (01) ◽  
pp. 114-120 ◽  
Author(s):  
A. A Hassanein ◽  
Th. A El-Garf ◽  
Z El-Baz
Keyword(s):  
Platelet Aggregation ◽  
Rapid Onset ◽  
Control Group ◽  
Diabetic Patients ◽  
Fasting State ◽  
Clotting Time ◽  
Cholesterol Levels ◽  
Platelet Disaggregation ◽  
Aggregation And Disaggregation

SummaryADP-induced platelet aggregation and calcium-induced platelet aggregation tests were studied in 14 diabetic patients in the fasting state and half an hour after an intravenous injection of 0.1 unit insulin/kg body weight. Platelet disaggregation was significantly diminished as compared to a normal control group, and their results were negatively correlated with the corresponding serum cholesterol levels. Insulin caused significant diminution in the ADP-induced platelet aggregation as a result of rapid onset of aggregation and disaggregation. There was also a significant increase in platelet disaggregation. In the calcium-induced platelet aggregation test, there was a significant shortening of the aggregation time, its duration, and the clotting time. The optical density fall due to platelet aggregation showed a significant increase. Insulin may have a role in correcting platelet disaggregation possibly through improvement in the intracellular enzymatic activity.

The Development of Homologous (Canine/Anti-Canine) Antibodies in Dogs with Haemophilia A (Factor VIII Deficiency): A Ten-Year Longitudinal Study

1993 ◽  
Vol 69 (01) ◽  
pp. 021-024 ◽  
Author(s):  
Shawn Tinlin ◽  
Sandra Webster ◽  
Alan R Giles
Keyword(s):  
Factor Viii ◽  
Canine Model ◽  
Significant Inhibition ◽  
Human Condition ◽  
Haemophilia A ◽  
Variable Expression ◽  
The Family ◽  
Over Time

SummaryThe development of inhibitors to factor VIII in patients with haemophilia A remains as a serious complication of replacement therapy. An apparently analogous condition has been described in a canine model of haemophilia A (Giles et al., Blood 1984; 63:451). These animals and their relatives have now been followed for 10 years. The observation that the propensity for inhibitor development was not related to the ancestral factor VIII gene has been confirmed by the demonstration of vertical transmission through three generations of the segment of the family related to a normal (non-carrier) female that was introduced for breeding purposes. Haemophilic animals unrelated to this animal have not developed functionally significant factor VIII inhibitors despite intensive factor VIII replacement. Two animals have shown occasional laboratory evidence of factor VIII inhibition but this has not been translated into clinical significant inhibition in vivo as assessed by clinical response and F.VIII recovery and survival characteristics. Substantial heterogeneity of inhibitor expression both in vitro and in vivo has been observed between animals and in individual animals over time. Spontaneous loss of inhibitors has been observed without any therapies designed to induce tolerance, etc., being instituted. There is also phenotypic evidence of polyclonality of the immune response with variable expression over time in a given animal. These observations may have relevance to the human condition both in determining the pathogenetic factors involved in this condition and in highlighting the heterogeneity of its expression which suggests the need for caution in the interpretation of the outcome of interventions designed to modulate inhibitor activity.

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