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Cancer protection of soy resembles cancer protection during pregnancy

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Abstract

It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.

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To test whether accelerated sarcopenia in older persons with high interleukin (IL)-6 serum levels plays a role in the prospective association between inflammation and disability found in many studies. Cohort study of older women with moderate to severe disability. Six hundred twenty older women from the Women's Health and Aging Study in whom information on baseline IL-6 serum level was available. Self-report of functional status, objective measures of walking performance, and knee extensor strength were assessed at baseline and over six semiannual follow-up visits. Potential confounders were baseline age, race, body mass index, smoking, depression, and medical conditions. At baseline, women with high IL-6 were more often disabled and had lower walking speed. After adjusting for confounders, women in the highest IL-6 tertile (IL-6>3.10 pg/mL) were at higher risk of developing incident mobility disability (risk ratio (RR) = 1.50, 95% confidence interval (CI) = 1.01-2.27), disability in activities of daily living (RR = 1.41, 95% CI = 1.01-1.98), and severe limitation in walking (RR = 1.61, 95% CI = 1.09-2.38) and experienced steeper declines in walking speed (P <.001) than women in the lowest IL-6 tertile (IL-6 < or =1.78 pg/mL). Decline in knee extensor strength was also steeper, but differences across IL-6 tertiles were not significant. After adjusting for change over time in knee extensor strength, the association between high IL-6 and accelerated decline of physical function was no longer statistically significant. Older women with high IL-6 serum levels have a higher risk of developing physical disability and experience a steeper decline in walking ability than those with lower levels, which are partially explained by a parallel decline in muscle strength.
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Background Cancer cachexia is a debilitating, wasting condition that affects many cancer patients, including those with head and neck cancer. The overall incidence of cancer cachexia is quite high for some types of cancer, and cachexia will be the main cause of death for more than 20% of all cancer patients. This syndrome uniquely challenges patients with head and neck cancer. This article outlines the diagnosis of cancer cachexia, reviews its impact on patient quality of life (QOL) and survival, and updates the reader on potential therapies that may suppress it.MethodsA comprehensive literature search was performed using PubMed of the National Library of Medicine, which includes more than 15 million citations back to the 1950s. The Cochrane Library and Google search engine were used as well.ResultsThis syndrome differs significantly from starvation, and thus accurate and timely diagnosis is essential. Nutritional therapy alone is insufficient. Current management strategies include corticosteroids and megesterol acetate, in conjunction with nutritional therapy. Future strategies may include nutraceuticals, omega-3 fatty acids, inflammatory antagonists, and other targeted treatments.Conclusions Because cancer cachexia differs significantly from starvation, nutritional supplementation must be used in conjunction with other anti-cachexia agents to reverse the chronic systemic inflammatory state and the effects of circulating tumor-derived factors seen in cachexia. Careful identification of patients at risk and those suffering from this syndrome will lead to better outcomes and treatments. Ultimately, more research is needed to better treat this devastating condition. © 2007 Wiley Periodicals, Inc. Head Neck, 2007
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The prognosis of prostate cancer is mainly determined by thepresence or absence of metastases. Nevertheless, the metastasic pathways in prostate cancer are not entirely understood. Among 19,316 routine autopsies performed from 1967 to 1995 on men older than 40 years of age, the reports from those 1,589 (8.2%) with prostate cancer were analyzed. Hematogeneous metastases were present in 35% of 1,589 patients with prostate cancer, with most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and adrenals (13%). Several lines of evidence suggested the existence of a backward metastasic pathway through veins from the prostate to the spine in addition to classical hematogeneous tumor spread via the vena cava. First, there was an inverse relationship between spine and lung metastases, suggesting that metastasis to the spine is independent of lung metastasis. Second, the maximum frequency of spine involvement occurred in smaller tumors (4 to 6 cm) as compared with the maximum spread to lung (6 to 8 cm) and liver (> 8 cm), suggesting that spine metastases precede lung and liver metastases in many prostate cancers. Third, there was a gradual decrease in spine involvement from the lumbar to the cervical level (97% v 38%), which is consistent with a subsequent upward metastasic spread along spinal veins after initial lumbar metastasis. The results of this study show that bone, lung, and liver are the most frequent sites of distant prostate cancer metastases. Besides the cava-type of metastasis through lung passage, there are strong arguments for the existence and clinical significance of a backward venous spread to the spine, which is likely to occur early in the metastatic process.
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The precise cell types that give rise to tumors and mechanisms that underpin tumor heterogeneity are poorly understood. There is increasing evidence to suggest that diverse solid tumors are hierarchically organized and may be sustained by a distinct subpopulation of cancer stem cells (CSCs). The CSC hypothesis provides an attractive cellular mechanism that can account for the therapeutic refractoriness and dormant behavior exhibited by many tumor types. Breast cancer was the first solid malignancy from which CSCs were identified and isolated. Direct evidence for the CSC hypothesis has also recently emerged from mouse models of mammary tumorigenesis, although alternative models to explain heterogeneity also seem to apply. Our group has found that the luminal epithelial progenitor marker CD61/beta3 integrin identified a CSC population in mammary tumors from MMTV-wnt-1 mice. However, no CSCs could be identified in the more homogeneous MMTV-neu/erbB2 model, suggesting an alternate (clonal evolution or stochastic) model of tumorigenesis. It seems likely that both paradigms of tumor propagation exist in human cancer. From a clinical perspective, the CSC concept has significant implications. Quiescent CSCs are thought to be more resistant to chemotherapy and targeted therapy. Enrichment of putative CSCs has been noted in studies of chemotherapy-treated patients, lending support to the CSC hypothesis and their potential role in chemoresistance. Although many unresolved questions on CSCs remain, ongoing efforts to identify and characterize CSCs continue to be an important area of investigation, with the potential to identify novel tumor targeting strategies.
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There is increasing evidence that many cancers, including breast cancer, contain populations of cells that display stem-cell properties. These breast cancer stem cells, by virtue of their relative resistance to radiation and cytotoxic chemotherapy, may contribute to treatment resistance and relapse. The elucidation of pathways that regulate these cells has led to the identification of potential therapeutic targets. A number of agents capable of targeting breast cancer stem cells in preclinical models are currently entering clinical trials. Assessment of the efficacy of the agents will require development of innovative clinical trial designs with appropriate biologic and clinical end points. The effective targeting of breast cancer stem cells has the potential to significantly improve outcome for women with both early-stage and advanced breast cancer.
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Although all cells within a colon cancer may harbour adenomatous polyposis coli (APC) or beta-catenin mutations, activation of Wnt signalling is limited to a subpopulation of cells that display cancer stem cell properties. This activation requires a co-stimulatory signal mediated by hepatocyte growth factor, which is produced by tumour-associated myofibroblasts.
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There is a large variation in breast cancer incidence and mortality rates worldwide. Migration studies have indicated that this variation is primarily the result of lifestyle influences. Although there has been much research conducted, definitively identifying dietary factors that impact breast cancer risk has proven difficult. In part this may be because most clinical and epidemiologic studies have focused on adult dietary exposure. However, evidence suggests that childhood and/or adolescence is the period of life when the breast is most sensitive to dietary influences. Further, the available epidemiologic and animal data suggest that early soy intake reduces breast cancer risk. Soy foods are unique dietary sources of isoflavones, diphenolic compounds that exert estrogen-like effects under certain experimental conditions. The protection effects of soy may result from the soybean isoflavones stimulating differentiation of the breast in much the same way that the elevated estrogen levels do during pregnancy. More specifically, in rats, the primary isoflavone genistein reduces mammary tumorigenesis and increases mammary tissue differentiation by leading to a reduction in the number of terminal end buds (TEB) and an increase in the number of differentiated lobules. There is need and justification for continued investigation of the early soy intake hypothesis, particularly to determine the cellular targets of soy action and to identify the signaling pathways mediating the effects on mammary gland morphology and susceptibility to breast cancer.
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Melanoma is an uncommon tumour in childhood. Only isolated cases in pregnant patients younger than 18 years old have been previously described, therefore the biological behaviour of cutaneous melanoma in this group of age remains largely unknown. We report a single-institution experience with three patients who developed cutaneous melanoma before the age of 18 years and became pregnant concomitantly or during the course of the disease. High tumour thickness was attributed to later diagnosis and could be responsible for the aggressive biological behaviour in these patients. This delay was in part due to patients considering changes in nevi to be normal during pregnancy. The effect of pregnancy on the prognosis of patients with melanoma, particularly the role of hormonal and immunological factors on clinical outcome, survival and risk of developing metastases, as well as the differences between adolescent and adult populations are still controversial. Since there are no specific treatment strategies for this group of patients, treatment recommendations should be established according to adult experience.
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2-methoxyestradiol (2ME2) is a potent antiangiogenic molecule that inhibits the expression of hypoxia-inducible factor (HIF)-1alpha and, consequently, of VEGF and other HIF-1alpha target genes. Although 2ME2 is elevated during pregnancy in maternal serum, its presence in fetal fluids and its impact in neonatal health are unknown. In this study, we 1) described normal levels of 2ME2 in maternal blood, cord blood, breast milk, and amniotic fluid, and 2) compared a composite measure of perinatal outcome between infants born with high and low levels of 2ME2. We found that 2ME2 was significantly decreased in all fluids compared with prepartum maternal serum. After stratifying babies by 2ME2 exposure levels, we observed no differences in the vulnerability to impaired lung development or to complications involving aberrant angiogenesis or vascular leak, such as necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), posthemorrhagic hydrocephalus (PHH), and retinopathy of prematurity (ROP). In summary, fetal 2ME2 concentrations do not appear to affect neonatal outcome.
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The soybean-derived serine protease inhibitor, Bowman-Birk inhibitor (BBI), has been reported as a potent chemoprevention agent against several types of tumors. The present study was undertaken to evaluate the effects of BBI on androgen-sensitive/dependent prostate cancers using a human prostate cancer cell (LNCaP) and the transgenic rats developing adenocarcinoma of the prostate (TRAP) model. Treatment of LNCaP prostate cancer cells with 500 microg/mL BBI resulted in inhibition of viability measured on WST-1 assays, with induction of connexin 43 (Cx43) and cleaved caspase-3 protein expression. Feeding of 3% roughly prepared BBI (BBIC) to TRAP from the age 3 weeks to 13 weeks resulted in significant reduction of the relative epithelial areas within the acinus and multiplicity of the adenocarcinomas in the lateral prostate lobes. Cx43- and terminal deoxynucleotidyl transferase mediated dUTP-biotin end labeling of fragmented DNA (TUNEL)-positive apoptotic cancer cells were more frequently observed in the lateral prostates treated with BBIC than in the controls. These in vivo and in vitro results suggest that BBI possesses chemopreventive activity associated with induction of Cx43 expression and apoptosis.
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The association between soy food consumption and breast cancer risk has been inconsistent. A hospital-based case-control study was conducted to assess the relationship between soy food intake and breast cancer risk according to the estrogen receptor (ER) and/or progesterone receptor (PR) status of breast cancer in Chinese women residing in Guangdong province from June 2007 to August 2008. A total of 438 consecutively recruited cases with primary breast cancer were frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). Dietary intake was assessed by face-to-face interviews using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were obtained by using multiple unconditional logistic regression adjusted for the potential confounders. We observed a statistically significant inverse association between soy isoflavone and soy protein intake with breast cancer risk. The multivariate ORs (95% CIs) of breast cancer risk for the highest quartile compared with the lowest quartile were 0.54 (0.34-0.84) for soy isoflavone and 0.62 (0.40-0.96) for soy protein, respectively. A preventive effect of soy food was found for all subtypes of ER and/or PR status of breast cancer. The inverse association was more evident among premenopausal women. This study suggests that consumption of soy food, soy isoflavone, is inversely associated with the risk of breast cancer. The protective effects of soy did not seem to differ by ER and PR breast cancer status.
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Metastases do not result from random survival of cells released from the primary tumour but from the selective growth of specialised subpopulations of highly metastatic cells endowed with specific properties that befit them to complete each step of the metastatic process.
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To study the clinical effects of Prescription Zhuyun-III (ZYIII) on early pregnant women diagnosed as threatened abortion, and its mechanism in immunity and endocrine by determining serum Th1- and Th2-type cytokines, progesterone, and beta-human chorionic gonadotropin (beta-HCG). The treatment group comprised 30 early pregnant women diagnosed as threatened abortion of deficiency syndrome of Pi, Shen, or both. The control group consisted of 20 normal early pregnant women of similar gestational age. Patients in the treatment group were administered with ZYIII for 4 weeks. Peripheral blood samples were collected pre- and post-treatment from both the treatment and the control groups. Serum Th1-type cytokine [interleukin-2 (IL-2)] and Th2-type cytokine [interleukin-10 (IL-10)] were determined by flow cytometry, and serum progesterone and beta-HCG were determined by ELISA. (1) The treatment was effective in 26 and ineffective in 4 patients of the treatment group. Therefore, the cure percentage was 86.67%. (2) In the treatment group before the treatment, IL-2 was significantly higher, IL-10 tended to be less, and the Th1/Th2 balance shifted toward Th1 compared with those in the control group. (3) After the treatment, IL-2 was decreased, IL-10 was increased, and IL-2/IL-10 was decreased. Both progesterone and beta-HCG were increased. Changes of progesterone were positively correlated with changes of IL-10, whereas changes of beta-HCG were negatively correlated with changes of IL-2. Our study suggests that ZYIII has an evident function of protecting the fetus, and one of its mechanisms is inhibiting the secretion of Th1 cytokines, promoting the secretion of Th2 cytokines, and recovering the pathological shift of the Th1/Th2 balance. The other possible mechanism is increasing serum progesterone and beta-HCG concentrations. Moreover, there are some correlations between the above two effects.
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The neonate is born with a distinct immune system that is biased against the production of T-helper cell 1 (Th1) cytokines. Birth imposes a great challenge on the neonatal immune system, which is confronted with an outside world rich in foreign antigens. Exposure to these antigens shapes the developing neonatal immune system. Inducing Th-1 or Th-2 polarized responses that may extend beyond the neonatal age and counteract or promote allergic sensitization. This review describes how engagement of the innate immune system might contribute to the development of allergy in children. The exact role of innate immune stimulation in the development of allergies is a controversial area. Epidemiological literature suggests that microbial exposure in early childhood protects against the development of allergies, whereas a large amount of experimental data demonstrates that innate immune stimulation enhances Th2 responses upon primary and secondary antigen exposure. Dose, site and timing of allergen exposure are likely to modulate the innate immune response, polarizing the maturing neonatal immune system towards Th1 or Th2-type responses, thereby protecting from or predisposing to asthma and allergies. Modulation of neonatal innate immune responses may be a novel approach to prevent asthma and allergies.
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The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk. Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done. Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (P(heterogeneity) = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER(+) OR, 0.74; 95% CI, 0.62-0.89; ER- OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor. Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor-mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis).
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2-Methoxyestradiol (Panzem, 2ME2) is an endogenous metabolite of estradiol that destabilizes microtubules and exerts anti-angiogenic properties. This study was conducted to determine the activity and safety of 2ME2 administered as a NanoCrystal dispersion (NCD) formulation in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). Eligible patients had relapsed, platinum-resistant or refractory EOC with measurable or detectable disease. There was no limit on the number of prior treatment regimens. 2ME2 NCD 1000 mg orally four times daily (q.i.d.) was administered continuously during 4 week cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were assessment of toxicity, rate of clinical benefit defined as the number of patients experiencing an objective response, a CA125 response or stable disease (SD) >3 months, mean change in CA-125, progression-free survival (PFS), and pharmacokinetic analyses of 2ME2. Eighteen patients were enrolled. Median age was 65.5 (range 40-73). Patients had received a median of five prior treatments. The most common adverse events were fatigue (78%), nausea (78%), diarrhea (39%), neuropathy (50%), edema (39%), and dyspnea (44%), the majority being grade 1-2. There were no objective responses, but seven patients had SD as best response. Of those, two patients had SD for greater than 12 months. The rate of clinical benefit was 31.3%. Fairly stable plasma levels of 2ME2 ranging within the predicted therapeutic window were observed. The NCD formulation of 2ME2 is well tolerated in patients with heavily pretreated EOC. Few of these heavily pretreated patients had sustained stable disease.
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Endometriosis affects 5-15% of women in the general population and 40% of women seeking infertility evaluation. Its etiology and pathogenesis is controversial. Abnormalities of genes involved in the regulation of apoptosis have been thought to play a role in origin. Hence, we investigated the expression of pro-apoptotic and anti-apoptotic genes in eutopic endometrium from women with endometriosis and healthy controls in relation to disease occurrence and severity. A prospective study in women undergoing laparoscopic surgery for pelvic pain was conducted. In total, 45 women (30 healthy controls and 15 patients) matched inclusion criteria. The mRNA expression of apoptotic genes (p53, Bcl-x(L,S) and Bax) from eutopic endometrium was detected by RT-PCR. A significant increase in expression of mRNA p53 (1.42 versus 1.02; p<0.05), and Bcl-x(S) (0.41 versus 0.19; p=0.0006) was found in women with endometriosis compared to healthy controls. Insignificantly increased expression was found for Bax (1.22 versus 1.15). The expression of anti-apoptotic Bcl-x(L) was unchanged (1.08 versus 1.07). The Bcl-x(L)/Bcl-x(S) ratio was twofold higher (5.63 versus 2.63) in controls. By stratifying patients by disease stage we have revealed an increased mRNA expression of apoptotic genes in patients with grades III-IV endometriosis compared to those with grades I-II. However, the difference was significant only for Bcl-x(S) expression (p<0.05). Results suggest that an increased transcription of pro-apoptotic genes (p53 and Bcl-x(S)) in eutopic endometrium is significantly associated with endometriosis, which indicates dysregulation of apoptotic gene transcription associated with disease.
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Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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The trophoblastic theory of cancer, proposed in the early 1900s by Dr John Beard, may not initially seem relevant to current cancer models and treatments. However, the underpinnings of this theory are remarkably similar to those of the cancer stem cell (CSC) theory. Beard noticed that a significant fraction of germ cells never reach their final destination as they migrate during embryonic development from the hindgut to the germinal ridge. In certain situations, upon aberrant stimulation, these vagrant germ cells are able to generate tumors. Simplistically, the CSC theory surmises that a small population of tumorigenic cells exists, which initiate and maintain tumors, and these cells have a likely origin in normal stem cells. Both these theories are based on the potential of a single primitive cell to form a tumor. This has a major implication for cancer therapy, in that only a small percentage of cells need to be targeted to ablate a tumor.
Article
The British developmental biologist John Beard, DSc (1858-1924) is little remembered today. Yet, he made outstanding contributions to the life sciences. Beard deserves to be included among the leading biologists of the late 19th and early 20th century. He has been hailed as a forerunner of the present-day theory of the cancer stem cell (CSC). He was the first to point to the parallels between cancer and the trophoblastic cells that envelop and nourish the embryo, characterizing cancer as "irresponsible trophoblast." He pointed out that the initiation of fetal pancreatic function coincided with a reduction in the invasiveness of trophoblast, which otherwise might progress to clinical cancer (ie, choriocarcinoma). Based on the above propositions, he recommended the therapeutic use of pancreatic enzymes in treating cancer and other diseases. This therapy created a worldwide controversy, and although rejected in his day, persists in the world of complementary and alternative medicine (CAM) today.
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Breast cancer is a major health problem and concern of women religious in the USA. Although they have been identified as a high-risk population, only a limited number of breast health studies have been conducted. The purpose of this study was to explore breast-related health practices (breast self-examination [BSE], clinical breast examination [CBE], and mammography) of women religious residing in the United States. A survey design was used to collect a national sample. The probability sample consisted of 1,615 women religious between the ages of 24 and 99 (mean age = 64.5). Nearly 71% of the respondents reported performing BSE; 22.7% monthly. Sixty-nine percent of participants reported having a mammogram within the past year. Nearly 70% of the respondents reported having had a CBE within the past year. Several factors for not performing BSE or having mammogram are described by this population. Findings suggest a need for increase engagement by women religious in breast-related health practices.
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During the physiological process of adrenarche, the adrenal glands of healthy children secrete increasing amounts of weak androgenic steroids partly metabolized to potent sex steroids. The aim of the study was to examine whether adrenal androgen metabolite excretion rates before the onset of puberty may be prospectively associated with late-pubertal diaphyseal bone strength. We conducted the study in an auxological and metabolic child nutrition research facility. STUDY POPULATION AND DESIGN: The sample included 45 healthy adolescents who underwent proximal forearm bone and muscle area measurements by peripheral quantitative computed tomography at the age of 16 yr (SD 1.5) and who had collected a 24-h urine sample 8 yr earlier, allowing to quantify the prepubertal urine metabolome. Prepubertal hormonal predictors quantified by gas chromatography-mass spectrometry were: dehydroepiandrosterone, its 16-hydroxylated downstream metabolites, 5-androstene-3beta,17beta-diol (androstenediol), sums of total androgen and glucocorticoid metabolites, cortisol, and 6beta-hydroxycortisol. Proximal forearm radius was measured. Of all prepubertal hormones analyzed, only sex- and age-specific androstenediol levels significantly predicted pubertal stage-, height-, and muscularity-adjusted diaphyseal bone modeling (periosteal circumference, beta = 0.67, P = 0.002; cortical area, beta = 2.15, P = 0.02), bone mineral content (beta = 2.2; P = 0.04), and polar strength strain index (beta = 12.2; P = 0.002). Androstenediol explained 5-10% of the late-pubertal diaphyseal radius variability. Our prospective profiling of urinary steroid metabolites in 24-h urine samples collected before puberty suggests that androstenediol is an early predictor of the diaphyseal bone strength in late puberty. This predominantly peripheral conversion product of adrenarchal dehydroepiandrosterone by 17beta-hydroxysteroid dehydrogenase may hence be involved in a sustained improvement of radial bone accretion during growth.
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Genistein is an isoflavone with oestrogenic activity that is present in a variety of soy products as a constituent of complex mixtures of bioactive compounds, whose matrix profiles play an important role in determining the overall oestrogenic bioactivity of genistein. We review data on how the profile of soy bioactive compounds can modulate genistein-stimulated oestrogen-dependent tumour growth. Our research has focused on the effects of dietary genistein on the growth of oestrogen (E)-dependent mammary tumours both in vitro and in vivo. Genistein enhances the proliferation of E-dependent human breast cancer tumour growth. In a similar manner, dietary genistein stimulates tumour growth in the chemically-induced (NMU) mammary cancer rodent model. Genistin, the glycoside of genistein, simulates growth similar to that of genistein and withdrawal of either genistein or genistin results in tumour regression. The extent of soy processing modulates the effects of dietary genistein in vivo as soy protein isolate, a highly purified and widely used source of protein that is processed to contain low, medium, and high amounts of isoflavones, stimulate the growth of the E-dependent mammary tumours in a dose dependent manner. In contrast to the more purified diets, studies with soy flour of equivalent genistein levels did not stimulate the growth of E-dependent breast cancer tumours in vivo. However, the size of these tumours also did not regress as is observed in control groups in which oestrogen and genistein have been withdrawn. The expression of the oestrogen-target genes of pS2, progesterone receptor, and cyclin D1 correlates with the growth of E-dependent tumours and has been consistently observed to be induced in response to treatment with dietary genistein. To evaluate whether dietary genistein interacts with current anti-oestrogen breast cancer therapies such as tamoxifen (TAM), we implanted E-dependent tumours into ovariectomized athymic mice and administered oestradiol, oestradiol plus TAM, or oestradiol, TAM, and dietary genistein. In these studies dietary genistein was able to negate the inhibitory effect of TAM on E-stimulated tumour growth. In summary, 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 TAM on E-stimulated growth of MCF-7 cell tumours implanted into ovariectomized athymic mice.
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Specific receptor binding of estradiol (E-2) and dihydrotestosterone (DHT) was studied in human myometrial tissue and in human mammary cancer tissue. The inhibition of binding for E-2 and DHT by E-2, testosterone (T), DHT, dehydroepiandosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), androstendione (A) and 5-androstene-3beta, 17beta-diol (Adiol) was tested with the use of dextran-coated charcoal separation of bound and free E-2, respectively, and DHT. The percentage of binding inhibition was calculated with reference to the inhibition obtained with nafoxidine in a molar concentration ratio of 1,000 for E-2 binding, respectively, with cyproterone acetate in a molar concentration ratio of 10,000 for DHT binding. In 15 samples of myometrium tested, receptors were found for both E-2 and DHT. From 19 samples of mammary carcinoma tissue one showed no binding activity, three samples did bind E-2 only, five samples DHT only, and ten samples showed binding of both steroids. A 50% inhibition of E-2 binding, in myometrial as well as in tumor tissue, required a molar concentration ratio of 40 for Adiol, of more than 2,000 for DHEA. No significant inhibiting activity could be found for A up to a molar concentration ratio of 10,000 and for DHEA-S up to 40,000. With regard to DHT binding, Adiol is more active than E-2 and less active than T. Of the substances tested Adiol is therefore the only one which exerts a significant inhibiting influence at a molar ratio not far beyond the physiological range. This signifies that Adiol might interfere at the receptor level in the estrogenic stimulation of mammary cancer cells.
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Various numbers of spleen cells from specifically immunized mice were mixed with constant numbers of target tumor cells, and were inoculated subcutaneously into thymectomized, x-irradiated recipients. Small numbers of admixed immune spleen cells produced a statistically significant, and reproducible, acceleration of tumor growth in the inoculum as compared with controls of either nonimmune spleen cells or spleen cells from animals immune to a different, non-cross-reacting, tumor. Larger. numbers of specifically immune spleen cells, however, produced inhibition of tumor growth. These data imply that the normal immune reaction may have a dual function in relation to neoplasia: (i) stimulation of tumor growth, early in the course of the disease, or whenever the immune reaction is minimal; (ii) inhibition of tumor growth at other times.