Radionuclide Imaging of Apoptosis in Malignancies: Promise and Pitfalls of 99mTc-Hynic-rh-Annexin V Imaging

Radionuclide detection of apoptosis with of 99mTc-Hynic-rh-Annexin V scintigraphy is an effective tool for in vivo visualisation and monitoring of apoptosis in various malignant tumour. Early therapy-induced increase of the tumour tracer uptake correlates with favourable outcome, whereas stable or decreased uptake correlates with stable disease or tumour progression. Therefore sequential 99mTc-Hynic-rh-Annexin V scintigraphy could be used to predict therapy outcome on a patient-to-patient basis within 48 hours after the start of treatment. However, moderate tumour-to-background ratio and therapy-induced changes in normal tissues could confound image analysis. To assure accurate interpretation of Annexin V scans, the awareness of the biophysiological and biochemical properties contributing to the tracer distribution is essential. In with manuscript we discuss the patterns of Annexin V tumour uptake and illustrate the most frequent pitfalls associated with Annexin V imaging in correlation with CT and MRI imaging.

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Abstract 3195: Quantification of Endothelial Cell Apoptosis in Pulmonary Arterial Hypertension Using Tc99m-Annexin V

Circulation ◽

10.1161/circ.116.suppl_16.ii_718-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Eileen M Rattigan ◽

Marija Sedlar ◽

Elizabeth DelGiacco ◽

Kazue Okajima ◽

John Hoppin ◽

...

Keyword(s):

Endothelial Cell ◽

Region Of Interest ◽

Annexin V ◽

Inflammatory Cells ◽

Pulmonary Artery Hypertension ◽

Tracer Uptake ◽

Early Event ◽

Sprague Dawley ◽

Pulmonary Uptake

Background - Pulmonary artery hypertension (PAH) is usually detected late in its course. Early detection may allow for the earlier initiation of disease-modifying therapies. Endothelial cell (EC) apoptosis is an early event that leads to unrestrained EC growth and subsequent smooth muscle cell proliferation. We tested the hypothesis that these early apoptotic changes may be detected non-invasively using Tc99m-labeled Annexin V (Tc99m-ANX) in the monocrotaline (MCT)-induced PAH rat model. Methods - To document disease course, 54 MCT treated Sprague Dawley rats (60mg/kg) were compared to 18 controls; 5– 6 treated rats and 3 controls were sacrificed weekly over 6 weeks for gross pathology and histopathologic sectioning. PA pressures were estimated by echocardiography. EC apoptosis was detected by caspase staining in arterioles smaller than 50 microns and quantified by random sampling. A second group of 16 rats were treated with MCT and underwent serial non-invasive SPECT imaging. They were injected with 55.5 MBq of Tc99m-ANX and imaged by HiSPECT at baseline (before MCT) and weekly for 6 weeks. Quantification of Tc99m-ANX uptake was assessed by biodistribution and by region of interest (ROI) analyses of SPECT images using MIP Tool. Results - See table below. Quantitative pulmonary tracer uptake peaked at day 14, correlated with peak positive caspase staining and preceded hemodynamic changes and RVH. Tc99m-ANX pulmonary uptake seen at later time points corresponded to caspase positive inflammatory cells in a dense intra-alveolar infiltrate. Conclusions - EC apoptosis can be detected in vivo with Tc99m-ANX during the early development of PAH in MCT treated rats before the onset of any detectable changes in pulmonary pressures or changes in RV architecture. Data Summary

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Surface Ultrastructure of Human Ectocervix in Certain Pathological Conditions

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100119636 ◽

1985 ◽

Vol 43 ◽

pp. 570-571

Author(s):

S. Mukherjee ◽

T. Guha ◽

B. Chakrabarti ◽

P. Chakrabarti

Keyword(s):

Epithelial Cells ◽

Marked Reduction ◽

Squamous Epithelium ◽

Malignant Tumour ◽

Surface Ultrastructure ◽

Normal Tissues ◽

Pathological Conditions ◽

Hexagonal Shape ◽

Columnar Cells ◽

Scanning Electron

The cervix is an important organ in reproduction. Its malfunction is frequently a factor for infertility. Ectocervix region does not appear to have received much attention although many studies have been reported on the endocervix. We report here our SEM observations on ectocervix in certain pathological conditions compared to normal ectocervix.Ectocervix specimens from human females with specific pathological disorders were processed for Scanning Electron Microscopy by conventional method and they were examined in a Philips SEM.The normal ectocervix is lined by flat layer of squamous epithelial cells with microridges (Fig. 1). These cells are known to be formed from columnar cells through metaplastic transformation. The cells of carcinoma-bearing ectocervix show a disorganised appearance (Fig. 2). In non-malignant tumour surface some cuboidal and few columnar cells were seen (Fig. 3). A cyst appears like an overgrowth on the surface of the squamous epithelium (Fig. 4). In ulcerated ectocervix a marked reduction of epithelial cells are observed (Fig. 5); the cells are devoid of microridges and, the large polygonal cells, as observed in normal tissues, have somehow acquired comparatively small hexagonal shape

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Clinical Evaluation of Radio-Labelled Bleomycin for Tumor Detection

Nuklearmedizin ◽

10.1055/s-0037-1620700 ◽

1978 ◽

Vol 17 (06) ◽

pp. 238-248

Author(s):

H. Beekhuis ◽

M.A.P.C. van de Poll ◽

A. Versluis ◽

H. Jurjens ◽

M.G. Woldring ◽

...

Keyword(s):

Clinical Evaluation ◽

Acidic Solution ◽

Tumor Detection ◽

Neutral Solution ◽

Normal Tissues ◽

Patients With Cancer ◽

Tumor Bearing

Investigations with bleomycin labelled with radionuclides other than 57Co in patients with cancer and in tumor-bearing animals are described. In patients 57Co-bleo appears to be a better tumor-seeking radiopharmaceutical than 111In-bleo, 99mTc-bleo or 197Hg-bleo. This can be explained by a higher stability in vivo and a better tumor-seeking property of 57Co-bleo and less disturbing activity in the cardiac pool and in bone and other normal tissues when assessing the scintigram.Results with 111In-bleo labelled in acidic solution are not essentially different from those with 111In-bleo labelled in neutral solution.Results of 197Hg-bleo are almost identical with those of 197HgCl2 regarding the tumor-seeking effect as well as the distribution in normal tissues and organs. Probably the complex of 197Hg to bleomycin is not stable in vivo. The superiority of 57Co-bleo over 99mTc-bleo, 197Hg-bleo and also over 67Cu-bleo is confirmed by experiments on tumor bearing animals.We may conclude that the indication for use of bleomycin as a tumor-seeking pharmaceutical labelled with 111In, 99mTc, 197Hg or 67Cu seems to be very limited.

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The Effects of Heparin and Annexin V on Fibrin Accretion after Injury in the Jugular Veins of Rabbits

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651585 ◽

1993 ◽

Vol 69 (03) ◽

pp. 227-230 ◽

Cited By ~ 28

Author(s):

J Van Ryn-McKenna ◽

H Merk ◽

T H Müller ◽

M R Buchanan ◽

W G Eisert

Keyword(s):

Vessel Wall ◽

Thrombin Generation ◽

Antithrombin Iii ◽

Specific Effect ◽

Annexin V ◽

Inhibitory Effect ◽

Jugular Veins ◽

Prothrombinase Complex ◽

Wall Injury

SummaryWe compared the relative abilities of unfractionated heparin and annexin V to prevent fibrin accretion onto injured jugular veins in vivo. Heparin was used to accelerate the inhibition of thrombin by antithrombin III, and annexin V was used to inhibit the assembly of the prothrombinase complex on phospholipid surfaces, thereby blocking thrombin generation. Rabbit jugular veins were isolated in situ, a 2 cm segment was injured by perfusing it with air, and then blood flow was re-established. Five minutes later, each rabbit was injected with heparin (20 U/kg) or annexin V (0.3 mg/kg) and then with 125I-fibrinogen. The amount of 125I-fibrin accumulation onto each injured vessel wall segment was measured 4 h later. Each injured vessel was completely deendothelialized as a result of the air perfusion as demonstrated by electron microscopy. 125I-fibrin accretion onto the injured jugular veins was enhanced 2.4-fold as compared to the uninjured veins in sham-operated animals. Heparin treatment did not reduce fibrin accretion, whereas, annexin V treatment decreased fibrin accretion by 60%, p <0.05. This latter effect was achieved without sustained circulating anticoagulation. Additional experiments confirmed that the inhibitory effect of annexin V on fibrin accretion was associated with a surface specific effect, since more annexin V bound to the injured jugular vein segments as compared to the non-injured jugular veins. We conclude that, i) mild vessel wall injury (selective de-endothelialization) in veins results in a thrombogenic vessel wall; ii) the thrombogenecity of which is not inhibited by prophylactic doses of heparin; but iii) is inhibited by annexin V, which binds to injured vessel wall surface, and inhibits thrombin generation independently of antithrombin III.

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Absolute SPECT/CT quantification of cerebral uptake of 99mTc-HMPAO for patients with neurocognitive disorders

Nuklearmedizin ◽

10.3413/nukmed-0765-15-09 ◽

2016 ◽

Vol 55 (04) ◽

pp. 158-165 ◽

Cited By ~ 3

Author(s):

Friedrich Welz ◽

James Sanders ◽

Torsten Kuwert ◽

Juan Maler ◽

Johannes Kornhuber ◽

...

Keyword(s):

Tissue Concentration ◽

Tracer Uptake ◽

Planar Imaging ◽

Quantitative Spect ◽

Dementia Patients ◽

Hmpao Spect ◽

Patient Groups ◽

The Absolute ◽

99Mtc Hmpao

SummaryIt was reported from planar imaging studies that the cerebral uptake of injected 99mTc-HMPAO activity is about 4–7% in humans. Recent work has shown that modern SPECT/ CT devices are able to quantify the tissue concentration of radioactivity in vivo in absolute units (Bq/ml), while avoiding the limitations of planar techniques. The aims of this study were (a) to determine the cerebral uptake of 99mTc-HMPAO in absolute units in SPECT/CT, (b) to investigate potential differences in absolute tracer uptake for patients suspected of dementia. Patients, methods: We performed 99mTc-HMPAO SPECT/CT in 65 patients with suspected dementia. 99mTc-HMPAO uptake was determined using a previously published quantitative SPECT/CT protocol. The absolute HMPAO uptake and the results of a regionalized analysis were compared for MMSE and NINCDS-ADRDA based patient groups. Results: The mean absolute uptake of 99mTc-HMPAO for our patient population was 4.3 ± 0.8% of the injected dose. The uptake, as well as the regionalized analysis yielded significantly different results for low ( 23) and high (>23) MMSE groups and also for some of the NINCDS-ADRDA groups. Conclusion: Our results show that the absolute cerebral uptake of 99mTc-HMPAO is in the range of previously reported results, obtained by planar techniques. Absolute uptake is significantly different between the patient groups.

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Derivatives of Deoxypodophyllotoxin Induce Apoptosis Through Bcl-2/Bax Proteins Expression

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620999200730160952 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ya-Nan Li ◽

Ni Ning ◽

Lei Song ◽

Yun Geng ◽

Jun-Ting Fan ◽

...

Keyword(s):

Annexin V ◽

Mtt Method ◽

Anthriscus Sylvestris ◽

Anti Tumor Activity ◽

Derivatives Of ◽

Toxicity In Vitro ◽

Ht 29 ◽

Mcf 7

Background: Deoxypodophyllotoxin, isolated from theTraditional Chinese Medicine Anthriscus sylvestris, is well-known because of its significant antitumor activity with strong toxicity in vitro and in vivo. Objective: In this article, we synthesized a series of deoxypodophyllotoxin derivatives, and evaluated their antitumor effectiveness.Methods:The anti tumor activity of deoxypodophyllotoxin derivatives was investigated by the MTT method. Apoptosis percentage was measured by flow cytometer analysis using Annexin-V-FITC. Results: The derivatives revealed obvious cytotoxicity in the MTT assay by decreasing the number of late cancer cells. The decrease of Bcl-2/Bax could be observed in MCF-7, HepG2, HT-29 andMG-63 using Annexin V-FITC. The ratio of Bcl-2/Bax in the administration group was decreased, which was determined by the ELISA kit. Conclusion: The derivatives of deoxypodophyllotoxin could induce apoptosis in tumor cell lines by influencing Bcl-2/Bax.

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PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

Cell Death and Disease ◽

10.1038/s41419-021-04013-y ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Dawei Chen ◽

Zhenguo Zhao ◽

Lu Chen ◽

Qinghua Li ◽

Jixue Zou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Alternative Splicing ◽

Protein Function ◽

Vital Role ◽

Normal Tissues ◽

Mechanistic Analysis ◽

Highly Correlated ◽

Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

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Activation of MAT2A-RIP1 signaling axis reprograms monocytes in gastric cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001364 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001364

Author(s):

Yan Zhang ◽

Hui Yang ◽

Jun Zhao ◽

Ping Wan ◽

Ye Hu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Metabolism ◽

Vital Role ◽

Methionine Metabolism ◽

Promoter Regions ◽

Normal Tissues ◽

Methionine Cycle

BackgroundThe activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored.MethodsMonocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed.ResultsTAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions.ConclusionsOur data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.

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LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-01808-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bo Jia ◽

Junfeng Dao ◽

Jiusong Han ◽

Zhijie Huang ◽

Xiang Sun ◽

...

Keyword(s):

Noncoding Rna ◽

Xenograft Model ◽

Tumor Xenograft ◽

Luciferase Reporter ◽

Cell Cycle Regulators ◽

Normal Tissues ◽

Stat3 Signaling ◽

Long Intergenic Noncoding Rna

Abstract Background Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2′-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Conclusions Our findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

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Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy

Scientific Reports ◽

10.1038/s41598-021-84538-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alejandro Schcolnik-Cabrera ◽

Alma Chavez-Blanco ◽

Guadalupe Dominguez-Gomez ◽

Mandy Juarez ◽

Ariana Vargas-Castillo ◽

...

Keyword(s):

Cancer Cells ◽

Drug Combination ◽

Cell Cycle Progression ◽

De Novo ◽

In Vivo Evaluation ◽

Fat Loss ◽

Normal Tissues ◽

Animal Metabolism ◽

Energetic Expenditure

AbstractThe malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.

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