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Phytoestrogens & Cancer

Do phytoestrogens prevent cancer?  The evidence to support the industry claim is scant and recent work indicates that phytoestrogens may actually increase the risk of breast cancer.  And HOT OFF THE PRESS are two articles that propose a link between bioflavonoids and soy and infantile leukemia.

(Read the British Food Standards Agencies Committee on Toxicity Report Here)

Soy phytoestrogens causing cancer?  Hold on a minute, what about all the latest research that tells us that soy prevents cancer?!  The key arguments in the case for soy as an anti-cancer foodstuff appear based on:

• Crude epidemiology.  Mortality rates of certain types of hormone dependent cancers (such as breast and prostate) are lower in Asians.  Asians eat lots o soy.  Wow, if we eat lots of soy we will reduce our risk of cancer too!
• Evidence that the soy isoflavone genistein displays anti-cancer properties in vitro.  Wow, genistein inhibits the growth of, and kills, cancer cells; let's eat more today!

But long before these anti-cancer claims became common, researchers had noted that phytoestrogens such as genistein could greatly enhance the proliferation of cancer cells.

 

Confused? Well there's no need to be. it is not uncommon for hormonally active agents, such as the soy phytoestrogens, to act as both estrogens and anti-estrogens. In simple terms this means that they can act to stimulate or inhibit the growth of certain types of cells, such as those found in the human breast.

How do we know whether a compound will have a tendency to stimulate or inhibit cell growth?  Well both natural hormones and hormonally active agents can work quite differently in people according primarily to dose and life stage.  Contrast adults with children; premenopausal women with menopausal or post-menopausal women; women with breast cancer with women with no abnormal breast tissue growth.

 

Hence, although you may have heard lots about studies showing the anti-cancer effects of soy you may not have read about the following work:

 

• Phytoestrogen concentration determines effects on DNA synthesis in  Human breast cancer cells .

• Effects of dietary menhaden oil, soy and cyclooxygenase inhibitor on human breast cancer cell growth
• Short-term soy feeding increases breast cancer cell proliferation in pre-menopausal women with a history of benign or malignant breast disease.

Newbold et al. found that at 18 months in mice, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation (e.g. the foetus).  The authors also recommended that the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined

Postmenopausal women consuming soy isoflavones as a natural HRT may place themselves at greater risk of breast cancer. In 1996 Dr Nicholas Petrakis, University of California, San Francisco, reported that 'Prolonged consumption of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterised by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells and elevated levels of estradiol. These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein contained in soy protein isolate'

In support of a precautionary approach to consuming soy to prevent breast cancer is Dr Bill Helferich of the University of Illinios. He has recently stated that 'there is potential for dietary genistein to stimulate the growth of estrogen-dependent tumors in humans with low circulating endogenous estrogen levels, such as those found in postmenopausal women'.

Dr Craig Dees of Oak Ridge National Laboratory has also found that soy isoflavones cause breast cancer cells to grow. He reported that 'low concentrations of genistein may stimulate MC-7 cells to enter the cell cycle'. Dees concluded that ' women should not consume particular foods (eg. soy-derived products) to prevent breast cancer'.  The safety issues of phytoestrogens in breast cancer patients have also been raised in correspondence to the Journal of Clinical Oncology.

Dees has also found that xenoestrogens, such as genistein, significantly enhance risk for breast cancer during growth and adolescence.  Now there's a good reason to keep your teenage daughter off soy.

 

Recommended reading:

	CANCER patients are being warned to avoid foods rich in soy because they can accelerate the growth of tumours.
The Cancer Council NSW will issue guidelines today, warning about the dangers of high-soy diets and soy supplements for cancer patients and those people in remission from cancer. "The Cancer Council does not support the use of health claims on food labels that suggest soy foods or phyto-oestrogens protect against the development of cancer.'' Read the article here!

 

Meta-analysis of soy intake and breast cancer risk
Trock BJ, Hilakivi-Clarke L, Clarke R. Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. btrock@jhmi.edu
BACKGROUND: High intake of soy foods has been proposed to contribute to the low breast cancer risk in Asian countries. However, results of epidemiologic studies of this association are highly variable, and experimental data suggest that soy constituents can be estrogenic and potentially risk enhancing. Thus, rigorous evaluation of available epidemiologic data is necessary before appropriate recommendations can be made, especially for women at high risk of breast cancer or those who have survived the disease.
METHODS: We performed a meta-analysis of 18 epidemiologic studies (12 case-control and six cohort or nested case-control) published from 1978 through 2004 that examined soy exposure and breast cancer risk. Pooled relative risk estimates were based on either the original soy exposure measure defined in each study or on an estimate of daily soy protein intake.
RESULTS: Risk estimates, levels and measures of soy exposure, and control for confounding factors varied considerably across studies. In a pooled analysis, among all women, high soy intake was modestly associated with reduced breast cancer risk (odds ratio [OR] = 0.86, 95% confidence interval [CI] = 0.75 to 0.99); the association was not statistically significant among women in Asian countries (OR = 0.89, 95% CI = 0.71 to 1.12). Among the 10 studies that stratified by menopausal status the inverse association between soy exposure and breast cancer risk was somewhat stronger in premenopausal women (OR = 0.70, 95% CI = 0.58 to 0.85) than in postmenopausal women (OR = 0.77, 95% CI = 0.60 to 0.98); however, eight studies did not provide menopause-specific results, six of which did not support an association. When exposure was analyzed by soy protein intake in grams per day, a statistically significant association with breast cancer risk was seen only among premenopausal women (OR = 0.94, 95% CI = 0.92 to 0.97).
CONCLUSIONS: Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassification, confounding, and lack of a dose response. Given these caveats and results of some experimental studies that suggest adverse effects from soy constituents, recommendations for high-dose isoflavone supplementation to prevent breast cancer or prevent its recurrence are premature.

Work by Manfred Metzler has shown that genistein is clastogenic!  A clastogen is any substance which causes chromosomal breaks.

Vegetable oils are again linked to a significant occurrence of lung cancers in Chinese women who cook in open utensils such as woks. This study reinforces similar results in an earlier Korean study. Do not believe the soy promoters when they tell you that "Asians" are marvellously healthy. For instance, a New York Times article on June 6 1996 cited 100 million cases of goiters at present in China.

And what about the risk of leukemia in infants?

Cancer rates are up, particularly for cancers that affect the young.  Could soy consumption be playing a role?

More on the link between soy and infant leukemia:

Soy Products and Infant Leukemia

Further Cancer/Leukemia Reading

Duffy C, Perez K, Partridge A., CA Cancer J Clin. 2007 Sep-Oct;57(5):260-77.

Genistein can act as an oestrogen agonist resulting in proliferation of E-dependent human breast cancer tumours in vivo and its activity can be modulated by the presence of other bioactive components in complex soy foods. Additionally, dietary genistein can negate the inhibitory effects of Tamoxifen on E-stimulated growth of MCF-7 cell tumours.

Full Abstract Here

Helferich WG, Andrade JE, Hoagland MS., Inflammopharmacology. 2008 Oct;16(5):219-26.

In several placebo-controlled randomized trials among breast cancer survivors, soy has not been found to decrease menopausal symptoms. There is very little human data on the role of phytoestrogens in preventing breast cancer recurrence, but the few studies conducted do not support a protective role. There is in vivo animal data suggesting the phytoestrogen genistein may interfere with the inhibitive effects of tamoxifen on breast cancer cell growth.

Full Abstract Here

Jiang X, Patterson NM, Ling Y, Xie J, Helferich WG, Shapiro DJ., Endocrinology. 2008 Nov;149(11):5366-73.

A significant population consumes levels of genistein in soy products that may be high enough to induce Protein Inhibitor 9, perhaps potentiating the survival of some preexisting breast cancers by enabling them to evade immunosurveillance.

Full Abstract Here

Dietary soy protein and isoflavones have no significant effect on bone and a potentially negative effect on the uterus of sexually mature intact Sprague-Dawley female rats.

Nakai M, Cook, L, Pyter, LM, Black M, Sibona, J, Turner RT, Jeffery EH, Bahr JM., Menopause. 2005 May-Jun;12(3):291-8.

Histologically, uteri and vaginae were normal in all groups except that 1 of 10 rats in the high-soy group and 2 of 10 rats in the high-extract group showed extensive squamous metaplasia in the uterine gland. CONCLUSION: These results suggest that dietary isolated soy protein and isoflavones have no effect on bone and the vagina during premenopausal period, but may have an adverse effect on the uterus.

Full Abstract Here

Mammary gland morphology in Sprague-Dawley rats following treatment with an organochlorine mixture in utero and neonatal genistein.

Foster WG, Younglai EV, Boutross-Tadross O, Hughes CL, Wade MG., Toxicol Sci. 2004 Jan;77(1):91-100

Collectively, our results reveal that postnatal exposure to pharmacological levels of genistein induces profound morphological changes in the mammary glands of adult female rats, and that high levels of phytoestrogens possess the potential to modulate the toxicological effects of toxicant mixtures.

Full Abstract Here

Effects of Soy-Derived Isoflavones and a High-Fat Diet on Spontaneous Mammary Tumor Development in Tg.NK (MMTV/c-neu) Mice.

Luijten M, Thomsen AR, van den Berg JA, Wester PW, Verhoef A, Nagelkerke NJ, Adlercreutz H, van Kranen HJ, Piersma AH, Sorensen IK, Rao GN, van Kreijl CF.  Nutr Cancer. 2004;50(1):46-54.

Comparison of both exposure scenarios revealed a strongly accelerated onset of tumor growth after perinatal high-fat diet exposure compared with the low-fat diet.

Full Abstract Here

Dietary soy and increased risk of bladder cancer: A prospective cohort study of men in Shanghai, China.

Sun CL, Yuan JM, Wang XL, Gao YT, Ross RK, Yu MC.; Int J Cancer. 2004 Nov 1;112(2):319-23.

Compared to men consuming soy less than once a week, the RR (95% CI) for those who consumed soy 1-<3 times per week, 3-<7 times a week and daily were 2.05 (0.80-5.29), 2.45 (0.89-6.76) and 4.61 (1.57-13.51), respectively (p for trend = 0.004), after adjustment for age, cigarette smoking and level of education.

Full Abstract Here

More from the Weston A. Price Foundation Here

Estrogen Linked to Insulin Resistance

In addition to estrogen increasing the risk of breast cancer, the study shows it increases insulin levels. Read More Here.

Estrogen found in soy stimulates human breast-cancer cells in mice. 

The increasingly consumed isoflavone genistein – a plant estrogen linked to the health benefits of soy – has been shown in a series of University of Illinois studies to stimulate the growth of estrogen-dependent human breast-cancer cells implanted into laboratory mice. Read More Here.

Genotoxicity of the isoflavones genistein, daidzein and equol in V79 cells.

Di Virgilio AL, Iwami K, Watjen W, Kahl R, Degen GH.

Toxicol Lett. 2004 Jun 15;151(1):151-62.

Full Abstract Here

Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice.

Ju YH, Allred CD, Allred KF, Karko KL, Doerge DR, Helferich WG.

J Nutr. 2001 Nov;131(11):2957-62.

Previously our laboratory has shown that the soy isoflavone, genistein, stimulates growth of human breast cancer (MCF-7) cells in vivo and in vitro.

Dietary genistein (> or = 250 microg/g) increased tumor size in a dose-dependent manner

The percentage of proliferating cells was significantly increased by genistein at and above 250 microg/g

Expression of pS2 mRNA was also significantly increased with increasing dietary genistein levels

In conclusion, dietary treatment with genistein at physiological concentrations produces blood levels of genistein sufficient to stimulate estrogenic effects, such as breast tumor growth, cellular proliferation and pS2 expression in athymic mice in a dose-responsive manner similar to that seen in vitro.

Full Abstract Here

Cell-transforming activity and mutagenicity of 5 phytoestrogens in cultured mammalian cells.

Tsutsui T, Tamura Y, Yagi E, Someya H, Hori I, Metzler M, Barrett JC.

Int J Cancer 2003 Jun 20;105(3):312-20

Morphological transformation in SHE cells was elicited by all phytoestrogens, except, prunetin. The transforming activities were ranked as follows: genistein > coumestrol > daidzein > biochanin A. Somatic mutations in SHE cells at the Na(+)/K(+) ATPase and hprt loci were induced only by genistein, coumestrol, or daidzein. Chromosome aberrations were induced by genistein or coumestrol, and aneuploidy in the near diploid range was occurred by genistein or biochanin A. Genistein, biochanin A or daidzein induced DNA adduct formation in SHE cells with the abilities: genistein > biochanin A > daidzein. Prunetin was negative for any of these genetic endpoints. Our results provide evidence that genistein, coumestrol, daidzein and biochanin A induce cell transformation in SHE cells and that the transforming activities of these phytoestrogens correspond to at least 2 of the mutagenic effects by each phytoestrogen, i.e., gene mutations, chromosome aberrations, aneuploidy or DNA adduct formation, suggesting the possible involvement of mutagenicity in the initiation of phytoestrogen-induced carcinogenesis.

Full Abstract Here

The phytoestrogens coumoestrol and genistein induce structural chromosomal aberrations in cultured human peripheral blood lymphocytes.

Kulling SE, Rosenberg B, Jacobs E, Metzler M.

Arch Toxicol. 1999 Feb;73(1):50-4.

These results, together with previously published reports on the induction of micronuclei and DNA strand breaks in cultured Chinese hamster V79 cells by COUM and GEN, but not DAI, suggest that some but not all phytoestrogens have the potential for genetic toxicity.

Full Abstract Here

Maternal exposure to potential inhibitors of DNA topoisomerase II and infant leukemia (United States): a report from the Children's Cancer Group.

Ross JA, Potter JD, Reaman GH, Pendergrass TW, Robison LL.

Cancer Causes Control. 1996 Nov;7(6):581-90.

It has been hypothesized that de novo infant leukemias may occur as a result of maternal exposure to agents in diet and medications that inhibit DNA topoisomerase II.

However, within the AML stratum, there was a statistically significant positive association (P trend = 0.04) with increasing consumption of DNA topoisomerase II-inhibitor containing foods (odds ratio [OR] = 9.8, 95 percent confidence interval [CI] = 1.1-84.8; OR = 10.2, CI = 1.1-96.4; for medium and high consumption, respectively).

Full Abstract Here

Dietary topoisomerase II-poisons: contribution of soy products to infant leukemia?

Jan G. Hengstler, Carolin K. Heimerdinger1, Ilka B. Schiffer1, Susanne Gebhard1, Jens Sagemüller1, Berno Tanner2, Hermann M. Bolt3, Franz Oesch1

EXCLI Journal 2002;1:8-14

Recently, some alarming studies have been published, suggesting that maternal exposure to low doses of dietary topoisomerase II poisons, including bioflavonoids such as genistein or quercetin, may contribute to the development of infant leukemia:

These observations are relevant, since many foods contain topoisomerase IIpoisons, predominantly soy and soy products, but also coffee, wine, tea, cocoa, as well as some fruits and vegetables.

If the causal relationship between dietary exposure to topoisomerase IIpoisons and infant leukemia will be confirmed, care should be taken to reduce exposure to critical foods during pregnancy.

Full Abstract Here, Full Paper Available Here

Dietary soy and increased risk of bladder cancer: the Singapore Chinese Health Study.

Sun CL, Yuan JM, Arakawa K, Low SH, Lee HP, Yu MC.

Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1674-7.

High intake of soyfood was statistically significantly related to an elevated risk of bladder cancer.

The soyfood-bladder cancer risk association did not differ significantly between men and women and was not explained by other dietary factors. The soy-cancer relationship became stronger when the analysis was restricted to subjects with longer (> or =3 years) duration of follow-up.

Full Abstract Here

Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice.

Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG.

Cancer Res 2002 May 1;62(9):2474-7

The use of dietary isoflavone supplements by postmenopausal women with breast cancer is increasing.

Dietary genistein negated/overwhelmed the inhibitory effect of TAM on MCF-7 tumor growth, lowered E2 level in plasma, and increased expression of E-responsive genes (e.g., pS2, PR, and cyclin D1). Therefore, caution is warranted for postmenopausal women consuming dietary genistein while on TAM therapy for E-responsive breast cancer.

Full Abstract Here

Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice.

Ju YH, Allred CD, Allred KF, Karko KL, Doerge DR, Helferich WG.

J Nutr 2001 Nov;131(11):2957-62

Previously our laboratory has shown that the soy isoflavone, genistein, stimulates growth of human breast cancer (MCF-7) cells in vivo and in vitro.

Dietary genistein (> or = 250 microg/g) increased tumor size in a dose-dependent manner

The percentage of proliferating cells was significantly increased by genistein at and above 250 microg/g

In conclusion, dietary treatment with genistein at physiological concentrations produces blood levels of genistein sufficient to stimulate estrogenic effects, such as breast tumor growth, cellular proliferation and pS2 expression in athymic mice in a dose-responsive manner similar to that seen in vitro.

Full Abstract Here

Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein.

Allred CD, Ju YH, Allred KF, Chang J, Helferich WG.

Carcinogenesis 2001 Oct;22(10):1667-73

The estrogenic soy isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo.

Dietary genistin resulted in increased tumor growth, pS2 expression and cellular proliferation similar to that observed with genistein.

When mice were placed on isoflavone free diets, tumors regressed over a span of 9 weeks.

In summary, the glycoside genistin, like the aglycone genistein, can stimulate estrogen-dependent breast cancer cell growth in vivo. Removal of genistin or genistein from the diet caused tumors to regress.

Full Abstract Here

Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner.

Allred CD, Allred KF, Ju YH, Virant SM, Helferich WG.

Cancer Res 2001 Jul 1;61(13):5045-50

We have demonstrated that the isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo

Soy protein diets containing varying amounts of genistein increased estrogen-dependent tumor growth in a dose-dependent manner. Cell proliferation was greatest in tumors of animals given estrogen or dietary genistein (150 and 300 ppm).

Here we present new information that soy protein isolates containing increasing concentrations of genistein stimulate the growth of estrogen-dependent breast cancer cells in vivo in a dose-dependent manner.

Full Abstract here

Effects of the dietary phytoestrogens daidzein and genistein on the incidence of vulvar carcinomas in 129/J mice.

Thigpen JE, Locklear J, Haseman JK, Saunders H, Grant MF, Forsythe DB.

Cancer Detect Prev 2001;25(6):527-32

Within one month, the incidence of vulvar carcinomas in mice fed the AIN-76A modified soy protein diet was significantly (P < .05) increased over those of mice fed the AIN-76A modified casein diet, the #5K96, or the # 5058 diet. At three months, the incidence of vulvar carcinomas in mice fed the soy protein diet was significantly (P < .05) increased over those of mice fed the NIH-31 diet or the PMI #5K96 diet.

We concluded that dietary levels of daidzein and genistein were associated with an increase in the incidence of vulvar carcinomas in mice

Full Abstract Here

Effects of soy phytoestrogens genistein and daidzein on breast cancer growth.

de Lemos ML

Ann Pharmacother 2001 Sep;35(9):1118-21.

CONCLUSIONS: Genistein and daidzein may stimulate existing breast tumor growth and antagonize the effects of tamoxifen. Women with current or past breast cancer should be aware of the risks of potential tumor growth when taking soy products.

Full Abstract Here

Uterine adenocarcinoma in mice treated neonatally with genistein.

Newbold, RR, EP Banks, B Bullock, and WN Jefferson

Cancer Research 61: 4325-4328 2001.

The developing fetus is uniquely sensitive to perturbation with estrogenic chemicals.

At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation. Thus, the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined

Original Abstract Here

For further commentary, follow the link below

http://www.ourstolenfuture.org/NewScience/phytoestrogens/2001newboldetal.htm

Influence of perinatal genistein exposure on the development of MNU-induced mammary carcinoma in female Sprague-Dawley rats.

Yang J, Nakagawa H, Tsuta K, Tsubura A. Cancer Lett 2000 Feb 28;149(1-2):171-9

Genistein treatment during the perinatal period resulted in lower body weight and lower relative uterine-ovarian weight at 35 days, and a prolonged estrus cycle with a long estrus phase at 12-16 weeks.

Thus, perinatal genistein is an endocrine disrupter and increases the multiplicity of MNU-induced mammary carcinoma in rats.   

Full Abstract Here

Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring.

Hilakivi-Clarke L, Cho E, Onojafe I, Raygada M, Clarke R. Oncol Rep 1999 Sep-Oct;6(5):1089-95

A high estrogenic environment in utero may increase subsequent breast cancer risk.

Our results suggest that a maternal exposure to subcutaneous administration of genistein can increase mammary tumorigenesis in the offspring, mimicking the effects of in utero estrogenic exposures. Further, increased ER protein levels and reduced PKC activity in the mammary gland may be involved in increasing susceptibility to carcinogen-induced mammary tumorigenesis in rats exposed to genistein in utero.

Full Abstract Here

Enhancement of experimental colon cancer by genistein.

Rao CV, Wang CX, Simi B, Lubet R, Kelloff G, Steele V, Reddy BS. Cancer Res 1997 Sep 1;57(17):3717-22

Administration of genistein significantly increased noninvasive and total adenocarcinoma multiplicity (P < 0.01) in the colon...

...observed colon tumor enhancement...

Full Abstract Here

p53, mutations, and apoptosis in genistein-exposed human lymphoblastoid cells.

Morris SM, Chen JJ, Domon OE, McGarrity LJ, Bishop ME, Manjanatha MG, Casciano DA.Mutat Res 1998 Aug 31;405(1):41-56

Our results may be interpreted that genistein is a chromosomal mutagen

Full Abstract Here

Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring.

Hilakivi-Clarke L, Cho E, Onojafe I, Raygada M, Clarke R.  Oncol Rep 1999 Sep-Oct;6(5):1089-95

The results indicate that in utero exposure to genistein, but not to zearalenone, dose-dependently increased the incidence of DMBA-induced mammary tumors, when compared with the controls.

Our results suggest that a maternal exposure to subcutaneous administration of genistein can increase mammary tumorigenesis in the offspring, mimicking the effects of in utero estrogenic exposures. Further, increased ER protein levels and reduced PKC activity in the mammary gland may be involved in increasing susceptibility to carcinogen-induced mammary tumorigenesis in rats exposed to genistein in utero.

Full Abstract Here

Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States). 

Hatch EE.  Herbst AL.  Hoover RN.  Noller KL.  Adam E.  Kaufman RH. Palmer JR.  Titus-Ernstoff L.  Hyer M.  Hartge P.  Robboy SJ.  Cancer Causes & Control. 12(9):837-845, 2001 Nov.

Women exposed prenatally to diethylstibestrol (DES) have an excess risk of clear-cell adenocarcinoma of the vagina and cervix

The findings support an association between in-utero DES exposure and high-grade squamous neoplasia

Full abstract Here