Date: October 9, 2003
by Chaya Venkat
Roughly 2.5 million tons of dried tea is produced each year, and about 20% of it is "green tea", which is made by steaming the fresh tea leaves lightly, and drying them quickly. The rest of it is called "black tea", and it involves fermentation of the fresh tea leaves. For medicinal purposes, green tea is considered superior to regular black tea, since it has as much as five times more of the polyphenols that are of interest to us as potent anti-oxidants and cancer preventives.
The composition of the green tea varies with the geography, climate, seasonal fluctuations and the methods used in growing it. When tea is harvested, they are supposed to take only the leaf bud and the two adjacent young leaves. Older leaves are considered inferior, and they have much less of the medicinal polyphenols. Usually, a good quality green tea has about 10% by weight of polyphenols.
There are several individual compounds in this group:
Of this lot, epigallocatechin gallate (EGCG) is the most important since it has significantly higher potency than the rest. Fortunately, it is also the most abundant component, if the green tea was grown and harvested properly and processed right afterwards. As you can see, there can be many a slip between cup and lip and there is no way of guessing whether your favorite brand is high or low in EGCG, not without a certified analysis that states the EGCG content. Many health food stores also sell "green tea extracts" as capsules. Once again, it is hard to judge the relative quality of these products. Also, beware of taking large doses of green tea either as a regular brew or as extract capsules and overdosing on the caffeine. You might want to explore decaffeinated versions to avoid this problem.
Tea polyphenols, especially EGCG, were shown to exert cancer-protective activity by a number of mechanisms, some of which are listed below.
We are still trying to unravel all the different mechanisms by which EGCG exerts its potent cancer preventive effects. In this article we will focus only on its effects as they pertain to CLL. You will have to learn a few bits of jargon along the way, but I hope you continue to read. There are some interesting action items that you can consider to help yourself, and the decisions will be smarter if you understand some of the facts behind the hype you have read about green tea.
Angiogenesis refers to the creation of new blood vessels and capillaries. Think of these as the highways and byways of your body, necessary for the vital transport of food (glucose), other nutrients and oxygen to each and every cell in your body. They are also necessary to carry away the waste products of cells, such as carbon dioxide and cellular debris. If the circulatory system breaks down, such as when a person has a heart attack and the heart is no longer pumping blood, the effect is that of complete traffic gridlock. Such a traffic jam, if it is allowed to persist more than for a few very short minutes, causes death of the individual cells of the body, soon to be followed by the death of the individual. Whether it be a normal cell or a cancer cell, no cell can survive long unless it has access to the transportation system of our blood vessels.
By the time we are adults, our circulatory system is pretty much built and fully functional. There is not much need for further building of super highways or byways, except under special circumstances. Pregnancy is one such exception, a developing child in a mother’s womb must create the vast network of arteries, veins, and capillaries that eventually become newborn child’s circulatory system. Angiogenesis is active a few days each month in women as new blood vessels form in the lining of the uterus during the menstrual cycle. Another important time for angiogenesis to kick in is when it is necessary to repair damaged tissue during wound healing. With the exceptions listed here, there are few occasions when healthy adult bodies need to invoke angiogenesis. By and large, this transportation system is well laid out and sturdy, and sufficient to carry the traffic for the long haul of the individual's life.
The story is very different in cancer patients. When solid tumors grow, unless the growing bulk of the tumor can be supplied with nutrients and oxygen, and waste products are removed as they are formed, the tumor cells will starve to death and choke to death on their own garbage. Angiogenesis driven by cancer starts with cancer cells releasing molecules that send signals to surrounding normal host tissue. When the signal molecules mate with their appropriate receptors, the cells of the surrounding tissue is activated to multiply grow into new blood vessels. Often, these new blood vessels are a jury-rigged mishmash, leaky and convoluted. They do not serve the purposes of the body, their only reason to exist is to feed the cancer.
One of the most important signal molecules are VEGF (Vascular Endothelial Growth Factor; 'vascular' refers to blood vessels, 'endothelial' refers to the particular type of cells that line blood vessels, so 'VEGF' refers to signaling molecules that encourage the growth of the cells lining blood vessels. Acronyms are not so hard, if you take the time to figure them out!) The second one is called bFGF (basic fibroblast growth factor; basic fibroblasts are another kind of structural cells, think of them as the bricks and mortar that are needed to build the infrastructure of your body). VEGF and bFGF are produced in small amounts by normal cells, but many kinds of cancer cells produce large quantities of them. In the absence of VEGF and bFGF signal molecules, endothelial and basic fibroblast cells rarely divide, sometimes only about once in every couple of years. If you would like to know more about this very important function of the body, here is a website that explains it in very easy language, nice pictures to make it easier to understand. This website is sponsored by the National Institute of Health.
It came as no surprise when it was discovered that bone marrow and lymph nodes in CLL patients with advanced disease had a lot more twisted and convoluted maze of blood vessels and capillaries, classic pattern of blood supply mandated by cancer cells. As these solid organs fill up with CLL cells, the need for new blood vessels to service the CLL cells increases, and angiogenesis kicks in.
Blood. 2000 Nov 1;96(9):3181-7.
In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells.
Chen H, Treweeke AT, West DC, Till KJ, Cawley JC, Zuzel M, Toh CH.
Departments of Haematology and Immunology, University of Liverpool, Liverpool, United Kingdom.
Expansion of primary solid tumors and their malignant dissemination are angiogenesis-dependent. Vascular endothelial growth factor (VEGF) is the key factor playing a pivotal role in solid tumor-induced angiogenesis. Recent studies indicate that angiogenesis may also be involved in the pathogenesis of certain hemic malignancies, including B-cell chronic lymphocytic leukemia (B-CLL). Mechanisms underlying angiogenesis in B-CLL and the role of VEGF in this process are incompletely understood. In this study, it was examined whether angiogenically functional VEGF is produced by B-CLL cells. Immunohistochemical staining with antibodies against VEGF and CD34, an endothelial cell marker, demonstrated the presence of VEGF protein and abundant blood vessels in infiltrated lymphoreticular tissues. Low levels of VEGF were detected by ELISA in the culture media of unstimulated cells; this was enhanced up to 7-fold by hypoxic stimulation. SDS-PAGE and Western blot analysis of the concentrated culture media showed 2 isoforms of VEGF protein with molecular weights of 28 and 42 kd, respectively. RNA hybridization showed that these cells expressed VEGF mRNA. Reverse transcription-polymerase chain reaction, combined with nucleotide sequence analysis, revealed that the predominantly expressed isoforms were VEGF121 and VEGF165. Moreover, (3)H-thymidine incorporation and an in vivo angiogenic assay demonstrated that the VEGF produced by CLL cells can induce angiogenesis by stimulating endothelial cell proliferation. In conclusion, this study shows that B-CLL cells produce VEGF and demonstrates the angiogenic effects of this growth factor, which may be relevant for the tissue phase of the disease.
The real surprise came when researchers looked at individual CLL cells, floating free in the blood. Here were cells that were surrounded and bathed by rich blood plasma, food and air was all around them. Why would such cancer cells have any need for angiogenesis? This is where the story got interesting. It turns out that CLL cells have a huge surplus of the receptors of VEGF. Compared to normal B-cells, CLL cells had as much as 60% higher expression of the receptors for VEGF. In fact, patients whose CLL cells expressed higher levels of this receptor had poorer prognosis, their died a lot sooner than patients whose CLL cells did not have as high a level of this receptor.
Clin Cancer Res. 2001 Apr;7(4):795-9.
High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia.
Ferrajoli A, Manshouri T, Estrov Z, Keating MJ, O'Brien S, Lerner S, Beran M, Kantarjian HM, Freireich EJ, Albitar M.
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Vascular endothelial growth factor receptor-2 (VEGFR-2), also termed KDR, is a high-affinity vascular endothelial growth factor (VEGF) receptor. VEGFR-2 plays a role in de novo blood vessel formation and hematopoietic cell development. Recently, we found that chronic lymphocytic leukemia (CLL) cells express high levels of VEGF. Therefore, we sought to investigate the role of VEGFR-2 in CLL. Using Western blot analysis, we first determined that VEGFR-2 is present in peripheral blood CLL cells. We then quantified the cellular levels of VEGFR-2 protein using a solid-phase radioimmunoanalysis in peripheral blood cells from 216 patients with CLL. As control, we used peripheral blood mononuclear cells (PBMNCs) from 31 hematologically normal individuals. The median of VEGFR-2 levels detected in the control samples was assigned a value of 1.0, and VEGFR-2 protein levels were normalized to the control median value. The median level of VEGFR-2 in CLL cells was 1.57. Patients with VEGFR-2 levels higher than 1.57 had elevated lymphocyte counts, severe anemia, elevated beta(2)-microglobulin and advanced-stage disease. Elevated VEGFR-2 levels were also associated with statistically significantly shorter survival (35.4 versus 60.1 months; P < 0.01). Our data indicate that cellular VEGFR-2 levels may serve as a prognostic factor in CLL. Further studies should investigate the biological implications of these findings and the effect of the interaction between VEGF and VEGFR-2 on CLL cell proliferation.
It turns out that VEGF and its receptors (called appropriately enough, 'VEGFR") are not just for passing messages about angiogenesis, they are good for just plain communication of all sorts. It is now recognized that this pair, the VEGF molecule and its receptor, play an important role in the chitchat and communication systems of CLL cells. Some of you may remember that when CLL cells are taken away from their local microhabitats, and they are quick to die. But in their own neighborhood, they are very hard to kill. Without the ability to communicate with each other, and the other normal cells in their neighborhood, CLL cells are much more vulnerable. Cancer cells live by spreading mis-information, making sure that the performance of the rest of the immune system is confused and ineffective. Take away their communication system, and they become vulnerable to attack, they can no longer reassure and protect each other from death.
Light bulb goes off, what happens if we gum up the works? What happens if we block the access port of the VEGF receptor so that the VEGF molecule can no longer mate with it? Does this make the CLL cell go mute, and unable to communicate with its fellow cancer cells or its neighbors, does it get lonely and die? YES!!! (Abstract 3) This reminds me of the time when our daughter was a teenager. The worst thing we could do to her was to take away her phone privileges. Being plugged in with her peer group was as important for her as food and sleep. Where adults can survive loss of phone service for a couple of days, heck actually welcome the respite from constant telemarketers and so on, for a teenage girl it was worse than starvation. Same case here. Normal cells do fine under circumstances of restricted communications, but CLL cells cannot bear the same level of isolation. (I will have to apologize to my daughter later on, for comparing her to a cancer cell!)
Leuk Res. 2001 Apr;25(4):279-85.
Clinical relevance of Flt1 and Tie1 angiogenesis receptors expression in B-cell chronic lymphocytic leukemia (CLL).
Aguayo A, Manshouri T, O'Brien S, Keating M, Beran M, Koller C, Kantarjian H, Rogers A, Albitar M.
Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 72, Houston, TX.
Angiogenesis, a complex process tightly controlled by several molecules including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) along with their receptors, plays a major role in the growth and metastasis of solid tumors. The expression and production of VEGF and bFGF have been documented in numerous solid tumors and hematopoietic neoplasms. Having recently shown increased expression of cellular VEGF in the leukemic cells of patients with chronic lymphocytic leukemia (CLL) we decided to investigate the expression of angiogenic receptors Flt1 and Tie1. Levels of Tie1 and Flt1 proteins were measured in leukemic cells from 231 patients with B-cell CLL using Western blot analysis and solid-phase radioimmunoassay (RIA). A strong correlation was found between Flt1 and Tie1 levels and white blood cell count (WBC) and absolute lymphocyte counts. Levels of Flt1 but not Tie1 correlated with levels of cellular VEGF. Interestingly, Tie1 correlated well with Rai stage (P=0.04). Flt1 and Tie1 did not correlate with survival, although when we evaluated the patients with early disease (Rai stage 0-II), higher levels of Tie1 but not of Flt1 correlated with worse survival. These data suggest that Tie1 plays a role in the early stages of B-cell CLL and as the disease progresses, the tumor cells become independent from the effects of Tie1. Further studies are now needed to dissect the mechanisms responsible for this phenomenon.
Now we know what to look for. We want some way of blocking the VEGF receptor on CLL cells. This is not a heavy handed way of killing cancer cells, as is done in many chemotherapy drugs, but a subtle "mental game" that makes them unable to resist the signals to commit suicide. Turns out that some of the polyphenols in green tea are just the right size and shape to plug the VGEF receptor, and our favorite, EGCG, is better than the rest at doing this. As you indulge in this popular beverage, the EGCG molecules get into your blood stream, and little by little, they lock on to the VEGF receptors. Since there are many more of these receptors on CLL cells than normal B-cells, the cancer cells get attacked more often. And the effect of the garbled up communications is much more serious to the cancer cells.
Cancer Res. 2002 Jan 15;62(2):381-5.
Green tea catechins inhibit vascular endothelial growth factor receptor phosphorylation.
Lamy S, Gingras D, Beliveau R.
Laboratoire de Medecine Moleculaire, Centre de Cancerologie Charles-Bruneau, Hopital Ste-Justine et Universite du Quebec a Montreal, Montreal, Quebec H3C 3P8, Canada.
Vascular endothelial growth factor (VEGF) receptors (VEGFR) play a major role in tumor angiogenesis and, thus, represent attractive targets for the development of novel anticancer therapeutics. In this work, we report that green tea catechins are novel inhibitors of VEGFR-2 activity. Physiological concentrations (0.01-1 microM) of epigallocatechin-3 gallate, catechin-3 gallate, and, to a lesser extent, epicatechin-3 gallate induce a rapid and potent inhibition of VEGF-dependent tyrosine phosphorylation of VEGFR-2. The inhibition of VEGFR-2 by epigallocatechin-3 gallate was similar to that induced by Semaxanib (SU5416), a specific VEGFR-2 inhibitor. The inhibition of VEGFR-2 activity by the catechins displayed positive correlation with the suppression of in vitro angiogenesis. These observations suggest that the anticancer properties of green tea extracts may be related to their inhibition of VEGF-dependent angiogenesis.
Leukemia. 2002 May;16(5):911-9.
B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules.
Kay NE, Bone ND, Tschumper RC, Howell KH, Geyer SM, Dewald GW, Hanson CA, Jelinek DF.
Department of Medicine, Division of Hematology, Mayo Graduate and Medical Schools, Mayo Clinic, 200 First Street SW, Rochester, MN.
Initial work has shown that clonal B cells from B-chronic lymphocytic leukemia (B-CLL) are able to synthesize pro-angiogenic molecules. In this study, our goal was to study the spectrum of angiogenic factors and receptors expressed in the CLL B cell. We used ELISA assays to determine the levels of basic fibroblast growth factors (bFGF), vascular endothelial growth factor (VEGF), endostatin, interferon-alpha (IFN-alpha) and thrombospondin-1 (TSP-1) secreted into culture medium by purified CLL B cells. These data demonstrated that CLL B cells spontaneously secrete a variety of pro- and anti-angiogenic factors, including bFGF (23.9 pg/ml +/- 7.9; mean +/- s.e.m.), VEGF (12.5 pg/ml +/- 2.3) and TSP-1 (1.9 ng/ml +/- 0.3). Out of these three factors, CLL B cells consistently secreted bFGF and TSP-1, while VEGF was expressed in approximately two-thirds of CLL patients. Of interest, hypoxic conditions dramatically upregulated VEGF expression at both the mRNA and protein levels. We also employed ribonuclease protection assays to assay CLL B cell expression of a variety of other angiogenesis-related molecules. These analyses revealed that CLL B cells consistently express mRNA for VEGF receptor 1 (VEGFR1), thrombin receptor, endoglin, and angiopoietin. Further analysis of VEGFR expression by RT-PCR revealed that CLL B cells expressed both VEGFR1 mRNA and VEGFR2 mRNA. In summary, these data collectively indicate that CLL B cells express both pro- and anti-angiogenic molecules and several vascular factor receptors. Because of the co-expression of angiogenic molecules and receptors for some of these molecules, these data suggest that the biology of the leukemic cells may also be directly impacted by angiogenic factors as a result of autocrine pathways of stimulation.
If you type EGCG or green tea extracts into PubMed or even Google search, you will be amazed at the number of hits you will get. This subject is very "hot" right now, and generating a great deal of serious scientific interest. Even discounting the hype on the tabloids, green tea extracts (polyphenols, catechins, EGCG) seem to be very potent in this cancer prevention role, and they are also blessed with extraordinarily low toxicity (Abstract 6). Healthy human volunteers have been fed copious quantities of green tea and its extracts, well above the amounts needed to show cancer preventive effects, and there has been no side effects worth mentioning. Of course, the frequent pit-stops necessary to unload after so many cups of tea is not really a side effect. The caffeine in the many cups of green tea can be quite substantial and can get you that jittery feeling, so you might want to consider the decaffeinated variety.
Clin Cancer Res. 2003 Aug 15;9(9):3312-9.
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals.
Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS.
Arizona Cancer Center, The University of Arizona, Tucson, AZ
PURPOSE: Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response. EXPERIMENTAL DESIGN: Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment. RESULTS: Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of epigallocatechin and epicatechin were not affected by repeated green tea polyphenol treatment. Four weeks of green tea polyphenol treatment at the selected dose and dosing schedule did not provide protection against UV-induced erythema. CONCLUSIONS: We conclude that it is safe for healthy individuals to take green tea polyphenol products in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day or in divided doses twice a day for 4 weeks. There is a >60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (800 mg EGCG or Polyphenon E once daily).
As we pointed out above, EGCG and other green tea polyphenols and catechins do a lot more besides gum up the VEGF receptor. Turns out they are also pretty good at inhibiting the NF-kB pathway, just like aspirin and the other NSAID drugs we considered in previous articles (Abstract 7). They also do one more thing, they change the expression of some of the adhesion molecules on CLL cells (Abstract 8). Adhesion molecules are the sticky Velcro like stuff on cells that allows to stick to the surface of blood vessels and the like, or even stick to each other. The different types and levels of adhesion molecules control the way CLL cells behave, their homing patterns, their preference for lymph nodes versus peripheral blood and so on. All of these are very crucial and substantial functions of the cancer cells, and EGCG puts a spoke in the wheel on all these counts.
Arch Biochem Biophys. 2000 Apr 15;376(2):338-46.
Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells.
Ahmad N, Gupta S, Mukhtar H.
Department of Dermatology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH
Green tea has shown remarkable anti-inflammatory and cancer chemopreventive effects in many animal tumor bioassays, cell culture systems, and epidemiological studies. Many of these biological effects of green tea are mediated by epigallocatechin 3-gallate (EGCG), the major polyphenol present therein. We have earlier shown that EGCG treatment results in apoptosis of several cancer cells, but not of normal cells (J. Natl. Cancer Inst. 89, 1881-1886 (1997)). The mechanism of this differential response of EGCG is not known. In this study, we investigated the involvement of NF-kappaB during these differential responses of EGCG. EGCG treatment resulted in a dose-dependent (i) inhibition of cell growth, (ii) G0/G1-phase arrest of the cell cycle, and (iii) induction of apoptosis in human epidermoid carcinoma (A431) cells, but not in normal human epidermal keratinocytes (NHEK). Electromobility shift assay revealed that EGCG (10-80 microM) treatment results in lowering of NF-kappaB levels in both the cytoplasm and nucleus in a dose-dependent manner in both A431 cells and NHEK, albeit at different concentrations. EGCG treatment was found to result in a dose-based differential inhibition of TNF-alpha- and LPS-mediated activation of NF-kappaB in these cells. The inhibition of NF-kappaB constitutive expression and activation in NHEK was observed only at high concentrations. The immunoblot analysis also demonstrated a similar pattern of inhibition of the constitutive expression as well as activation of NF-kappaB/p65 nuclear protein. This inhibition of TNF-alpha-caused NF-kappaB activation was mediated via the phosphorylative degradation of its inhibitory protein IkappaBalpha. Taken together, EGCG was found to impart differential dose-based NF-kappaB inhibitory response in cancer cells vs normal cells; i.e., EGCG-mediated inhibition of NF-kappaB constitutive expression and activation was found to occur at much higher dose of EGCG in NHEK as compared to A431 cells. This study suggests that EGCG-caused cell cycle deregulation and apoptosis of cancer cells may be mediated through NF-kappaB inhibition. Copyright 2000 Academic Press.
Int J Cancer. 2003 Oct 10;106(6):871-8.
Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of VE-cadherin phosphorylation and inactivation of Akt molecule.
Tang FY, Nguyen N, Meydani M.
Vascular Biology Laboratory, JM USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA
Studies have indicated that the consumption of green tea is associated with a reduced risk of developing certain forms of cancer and angiogenesis. The mechanism of inhibition of angiogenesis by green tea or its catechins, however, has not been well-established. Vascular endothelial (VE)-cadherin, an adhesive molecule located at the site of intercellular contact, is involved in cell-cell recognition during vascular morphogenesis. The extracellular domain of VE-cadherin mediates initial cell adhesion, whereas the cytosolic tail binding with beta-catenin is required for interaction with the cytoskeleton and junctional strength. Therefore, the cadherin-catenin adhesion system is implicated in cell recognition, differentiation, growth and migration of capillary endothelium. Using tube formation of human microvascular endothelial cells (HMVEC) in culture as an in vitro model of angiogenesis, we reported that vascular endothelial growth factor (VEGF)-induced tube formation is inhibited by anti-VE-cadherin antibody and dose-dependently by green tea catechins. We also demonstrated here that inhibition of tube formation by epigallocatechin gallate (EGCG), one of the green tea catechins, is in part mediated through suppression of VE-cadherin tyrosine phosphorylation and inhibition of Akt activation during VEGF-induced tube formation. These findings indicate that VE-cadherin and Akt, known downstream proteins in VEGFR-2-mediated cascade, are the new-targeted proteins by which green tea catechins inhibit angiogenesis. Copyright 2003 Wiley-Liss, Inc.
Now that we have understood some of the science and logic behind how green tea extracts, and especially EGCG work, it is important to also consider the pitfalls.
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