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The resurgence of estrogens in the treatment of castration-resistant prostate cancer
H Krishna Moorthy1, GG Laxman Prabhu2, P Venugopal2
1 Department of Urology, Lourdes Hospital, Kochi, Kerala, India
2 Department of Urology, Kasturba Medical College (A Unit of Manipal Academy of Higher Education), Mangalore, Karnataka, India
Date of Submission 17-Feb-2019
Date of Acceptance 26-May-2019
Date of Web Publication 2-Jul-2019
P Venugopal
Department of Urology, Kasturba Medical College (A Unit of Manipal Academy of Higher Education), Mangalore, Karnataka
DOI: 10.4103/iju.IJU_56_19
Use of exogenous estrogens in manipulating the androgenestrogen equilibrium was one of the earliest therapeutic strategies developed to treat prostate cancer which followed close on heels the discovery of hormone dependence of this tumor. Despite its well-documented benefit, estrogen therapy fell out of favor with the advent of other forms of androgen deprivation therapy (ADT) as the former registered a higher incidence of cardiovascular complications and poorer overall survival. Clearer understanding of the mechanism of action of estrogen coupled with the adoption of alternative routes of administration has triggered a renewed interest in estrogen therapy. Since then, many studies have not only proved the therapeutic benefit of estrogens but also explored the ways and means of minimizing the dreaded side effects deterring its use. Further, the fact that estrogen therapy offered a clear advantage of reduced cost of treatment over other treatments has led many countries to readopt it in the treatment of advanced prostatic cancer. We reviewed the published data on the use of estrogens in CRPC, which may affect its revival as an efficacious treatment option having minimal side effects, with modified dosage and route of administration. Estrogen therapy would be a less expensive option having equivalent or even better therapeutic effect than ADT in advanced carcinoma of prostate.
Moorthy H K, Laxman Prabhu G G, Venugopal P. The resurgence of estrogens in the treatment of castration-resistant prostate cancer. Indian J Urol 2019;35:189-96
Moorthy H K, Laxman Prabhu G G, Venugopal P. The resurgence of estrogens in the treatment of castration-resistant prostate cancer. Indian J Urol [serial online] 2019 [cited 2023 Jan 28];35:189-96. Available from: https://www.indianjurol.com/text.asp?2019/35/3/189/261936
Testosterone and 5 α dihydrotestosterone stimulate the growth of prostate cells, though they do not induce prostate cancer per se. Prostate cancer metastases in men with progressive castration-resistant prostate cancer (CRPC) have been found to contain higher levels of testosterone receptors than those in prostate cancer tissue from eugonadal men which clearly underscores the testosterone dependency of this disease. Endogenous estrogens work in synergy with androgens for the malignant transformation of prostate epithelial cells through a complex mechanism.[1],[2]
Androgen deprivation therapy (ADT) has long been recognized as the corner stone for the treatment of locally advanced and metastatic carcinoma of prostate. However, ADT is associated with major side effects such as skeletal-related events (osteopenia, osteoporosis, and fracture of bones), increased risk of cardiovascular diseases, weight gain, metabolic syndrome, reduced quality of life (due to hot flushes, sexual dysfunction, fatigue, and mental depression), and cognitive decline.[3] These side effects are due to the reduction in testosterone levels which in turn result in reduced peripheral conversion of testosterone to estrogen. The reduction in testosterone level in ADT is up to 95% with a concurrent reduction in endogenous estrogen by about 80%.
Usefulness of exogenous estrogen therapy in the management of advanced and CRPC has been known for several decades. It is possible that exogenous estrogen suppresses pituitary luteinizing hormone (LH) production via negative feedback thereby reducing systemic testosterone production. Concurrently, the exogenous estrogens replace the lost endogenous estrogens so that the overall estrogen levels remain high, thus avoiding the undesired side effects of estrogen reduction seen with ADT. The role of estrogen in the coagulation cascade which is also the pharmacologic basis of its adverse events is depicted in [Figure 1].
Figure 1: The role of estrogens in coagulation cascade which is the pharmacologic basis of adverse events
Despite its well-documented benefit, estrogen therapy fell out of favor with the advent of other forms of ADT as the former had a higher incidence of cardiovascular complications and poorer overall survival. Most of the toxicity caused by exogenous estrogen therapy is a consequence of the first pass portal circulation which facilitates the hepatic metabolism of hormones, lipids, and coagulation proteins. Administration of estrogen by routes which bypass the hepatic enzyme induction can significantly reduce its side effects. Clearer understanding of the mechanism of action of estrogen coupled with the adoption of alternative routes of administration has triggered a renewed interest in estrogen therapy, particularly in CRPC. We reviewed the published articles on treatment of CRPC with exogenous estrogens by searching the Medline PubMed databases from 2000 to 2018.
Role of Endogenous Estrogens in Prostate Cancer
While some studies have shown that elevated plasma estrogens increase the risk of prostate cancer,[4],[5] certain others have observed contradictory findings.[6] Estrogen mediates its biological effects in prostate tissue by binding to the intracellular estrogen receptor (ER) β, with minor effects on ER α.[7],[8] The principal ERs, namely ER α and ER β are expressed by prostate in health and disease. They exhibit functional specificity, and any imbalance in their expression can significantly alter the estrogenic effect on target cells in the prostate. Loss of expression of ER β has been reported to be associated with development of prostate cancer.[9]
There is growing evidence to believe that endogenous estrogens exert their effect on carcinogenesis through a genotoxic mechanism that protects against catechol estrogen and redox cycle.[10],[11] In contrast, the natural estrogens from plants products (phytoestrogens, like soy isoflavones such as genistein) and dietary estrogen analogs have been proposed to retard prostate cancer development and therefore have the potential for use as anticancer agents.[12]
Historical Perspective of Exogenous Estrogen Therapy
The first description of the role of exogenous estrogen therapy in advanced prostate cancer was given by Huggins and Hodges in 1942.[13],[14] Subsequently, over the next four decades, estrogens and orchiectomy became the standard of care for the treatment of all patients with advanced carcinoma of prostate. However, the Veterans Administration Cooperative Urological Research Group (VACURG) study published their results in late 1960s which showed significant discrepancy between cancer specific survival and overall survival of cancer prostate patients with exogenous estrogens.[15],[16],[17] These studies also revealed significantly increased risk of cardiovascular mortality in 36% of patients and thromboembolism in up to 15% of patients receiving diethylstilboestrol (DES) at a dosage of 5 mg daily. These alarming results combined with development of luteinizing hormone-releasing hormone (LHRH) agonists (LHRHa) and nonsteroidal antiandrogens with equivalent oncological effects and lower cardiovascular toxicity pushed estrogens to the back seat in therapeutics of advanced carcinoma of prostate.
Interestingly, the subsequent VACURG studies using DES at lower doses and studies using transdermal estradiol (E2) reported significant therapeutic response in selected patients with CRPC associated with lesser cardiovascular side effects and delayed mortality. Other studies have also reported significant effect of 17 β E2 in suppressing CRPC growth and delayed mortality.[18] These studies have rekindled a new interest in exploring the potential for safer use of estrogens in the management of advanced carcinoma of the prostate.
Mechanism of Action of Exogenous Estrogens
The various mechanisms that are postulated for the beneficial effects of exogenous estrogen in patients with carcinoma of prostate are as follows:[19],[20],[21]
Suppression of circulating androgens
Inhibition of LHRH from hypothalamus with subsequent suppression of LH and testicular production of testosterone
Strong binding activity to the androgen receptors
Suppression of androgens (dehydroepiandrosterone sulfate and androstenedione) from extra gonadal sources
Nonhormonal pathways.
Effects on cell cycle/intracellular apparatus
Inhibition of growth of primary cultures of benign prostatic hyperplasia and carcinoma of prostate cell lines
Interaction with cellular and mitochondrial ATP synthase
Interaction with cellular microtubules
Promotion of cell cycle arrest and apoptosis through a non-ER mechanism
Alteration in levels and stability of tubulin (mitotic apparatus component)
Induction of cell cycle arrest G2-M phase by microtubule polymerization
Downregulation of genes involved in tumorigenesis and upregulation of insulin-like growth factor binding protein 6 gene expression and protein levels
Effects of telomerase activity and gene expression
Antiangiogenic effects by inhibiting the growth and migration of vascular smooth muscle cells
Inhibition of enzymes of androgen steroidogenesis in tissues to suppress local androgen levels
Direct cytotoxic effects on prostate cells
Induction of immune surveillance
Metabolism of 17 β E2 to cytotoxic estrogens such as 2-methoxyestradiol which has significant antiangiogenic and proapoptotic effects
Direct suppression of Leydig cell function and androgen steroidogenesis
Antiandrogen action in prostate cancer cell lines with a mutated androgen receptors.
Mechanism of Estrogenic Side Effects
These are various mechanisms by which exogenous estrogens exert their side effects in the body.[19]
Induction of hypercoagulability by increasing synthesis of coagulation factors I, II, VII, IX, X
Increasing the serum level of factor VII
Reduction in plasminogen activation levels, thereby reducing fibrinolysis
Reduction in antithrombin III
Alteration in platelet function
Alteration in serum lipid profile.
Low-Dose Diethylstilboestrol in the Treatment of Crpc
There are several studies which have proved that low-dose DES would be beneficial in the treatment of CRPC. The phase II trial with 1 mg of oral DES in 21 patients showed a prostate-specific antigen (PSA) response in 43% patients with confirmed adenocarcinoma of prostate and distant metastasis refractory to first-line androgen deprivation.[22] These authors reported only 5% of patients developing deep vein thrombosis (DVT), 14% developing gynecomastia though 90% of patients had minimal nipple hypersensitivity. Baseline PSA, hemoglobin, lactate dehydrogenase, alkaline phosphate, and length of time on first hormonal treatment did not correlate with the response. The estimated survival at 2 years of treatment was 63%.
In a review article, Malkowicz has reported that 0.1 mg of DES/day was quite effective as much as 3 mg/day as an anticancer agent with lesser side effects, although subsequently, 1 mg of DES three times a daily evolved as the standard form of treatment.[23]
Wilkins et al. in 2012 reported a PSA response rate of 28.9%, median time to PSA progression of 4.6 months, improvement in European Organization for the Research and Treatment of Cancer pain score in 18% and thromboembolic complication in 9.9% of patients in their study involving 231 patients with CRPC using DES.[24] The patients received initial daily dose of 1 mg of DES with titration up to 3 mg. 75 mg of aspirin was also given to all patients with the exception of those who were already on Warfarin. Single fraction of 8 cGY external radiation was given to the breast buds before starting DES to prevent painful breast enlargement. Similar beneficial effects of low dose DES have also been reported by other authors using the drug in the treatment of CRPC before initiating chemotherapy.[25]
In a retrospective single center study on 43 CRPC patients with oral DES in a daily dose of 1–4 mg/day, there was >50% decline in serum PSA levels with durable responses (>1 year) in 31% of patients. Only 9% of patients in this study developed thromboembolic complications when thromboprophylaxis was given along with the treatment.[26]
The review article by Turo et al. also highlighted the usefulness of low-dose DES in many clinical trials for the treatment of CRPC with minimal side effect profiles.[19] These authors also proposed a synergistic effect of DES on tumor cells when used in conjunction with the newer therapies for cancer of prostate.
Aggarwal et al. reported that there was a significant reduction in serum testosterone levels in 12 weeks of treatment with DES at 3 mg/day or a herbal supplement (PC-SPES 960 mg TID) in patients with CRPC.[27] The patients in this study also received Warfarin 2 mg/day continuously as thromboembolism prophylaxis.
There are reports that 1 mg DES combined with dexamethasone resulted in more than 50% PSA decline in 64%–68% patients, although venothromboembolism occurred in 22% of patients.[28] These authors reported that DES would be an alternative in patients with failed abiraterone treatment in patients with CRPC.
Shamash et al. in their multicenter randomized phase III trial compared the use of dexamethasone (2 mg/day), aspirin (75 mg/day), and ranitidine (150 mg twice a day) along with immediate addition of DES (1 mg/day) or deferred (until disease progression) addition of DES in CRPC.[29] They concluded that immediate or deferred use of DES in the management of CRPC did differ neither in terms of PSA response nor in terms of progression free survival. Therefore, deferring DES until failure of dexamethasone would be the preferred strategy when using these agents in CRPC to reduce the toxicity of DES.
Oral ethinyl E2 at 1 mg/day along with aspirin (100 mg/day) was found to be effective in 116 CRPC patients in a single center prospective analysis done by Sciarra et al.[30] They confirmed PSA response in 70.5% of patients and a median time to PSA progression of 15.1 months. About 23.2% of patients required treatment cessation due to toxicity at a median time of 16 months mainly due to thromboembolism.
Parenteral Estrogens in the Treatment of CRPC
To mitigate the cardiovascular complications of oral estrogen by avoiding first-pass hepatic metabolism and avoid the complications caused by estrogen deprivation, an alternate approach using parenteral estrogens has been proposed. The Scandinavian Prostate Cancer Group-5 trial study evaluated the results of intramuscular injections of 240 mg polyestradiol phosphate (PEP) every 2nd week for the first 8 weeks followed by a maintenance dose of 240 mg monthly in 915 patients with advanced prostate carcinoma. It was concluded that parenteral estrogen regimen had comparable efficacy and cardiovascular safety to medical or surgical orchiectomy in patients with advanced cancer of prostate with lesser skeletal side effects, although the nonfatal complications such as gynecomastia were more pronounced in the PEP group.[31]
Norman et al. in their systematic review[32] and Phillips et al.[33] in their study on use of parenteral estrogen in the treatment of cancer of prostate reported the efficacy of this form of drug regimen in advanced prostate cancer compared to LHRH analog with the added advantage of lower cost of treatment.
Transdermal Estrogens in the Treatment of CRPC
It is recognized that transdermal application of estrogens can eliminate cardiovascular and thromboembolic complications resulting from first-pass effect in the liver with production of prothrombotic proteins.
Langley et al. assessed the hormonal effects of Fem 7 (100 mg transdermal estrogen patches) on men undergoing first-line ADT for advanced prostate cancer.[34] They found that the estrogen patches produced castrate levels of testosterone with concomitant PSA reduction at 12 weeks of therapy, with lesser side effects. The testosterone levels in eight of the 13 patients studied were <1.7 nmol/l, two were 1.7–2 nmol/l, and three were more than 2 nmol/l. All patients had a PSA response, with eight having a PSA level <4 ng/ml. Therefore, early evidence from these studies supports estrogen patches as viable alternatives to LHRH.
Stein et al. also proved in their study involving 22 patients, who had advanced, heavily pretreated castrate and chemotherapy refractory cancers that transdermal E2 patches (0.4 mg/24 h total) applied at weekly intervals to be effective with significant PSA responses.[35] In another study, an average of two patches per day (0.6 mg/24 h of 17 β E2) for 8 weeks was found to be sufficient to maintain androgen ablation in 20 men with locally advanced or metastatic prostate cancer.[36] Ockrim et al. in their study observed that transdermal E2 therapy resulted in increase in mean and peak systolic velocities and photoplethysmography in arterial blood flow at 6 months of treatment.[37] Arterial compliances initially decreased but got normalized after 12 months. However, the venous variables were unaffected by therapy. This study probably pointed to the cause for increase in cardiovascular toxicity in early phase of estrogen patch therapy and the cardioprotective effect that accrued thereafter.
The PATCH trial (NCT00303784) is currently being under taken to compare the efficacy and safety of transdermal E2 agonists versus gonadotropin-releasing hormone analogs in men with locally advanced and metastatic prostate cancer with reduced cardiovascular side effects.[38] Transdermal E2 has also been found to be beneficial in improving bone mineral density.[39] This form of therapy has been reported to produce more favorable metabolic profiles with better quality of life although there has been increased chance of gynecomastia.[40] The STAMPEDE trial (NCT00268476) is also currently recruiting patients to compare transdermal E2 with standard ADT as a compliment to the PATCH trial.[41]
These studies strongly support the use of transdermal E2 as a potential alternative to LHRH analog for the suppression of androgens in the treatment of locally advanced and metastatic prostate cancer. This form of treatment is probably less thrombogenic as it avoids hepatic first-pass mechanism which increases the synthesis of thrombophilic coagulation factors. The treatment is also significantly cost-effective in comparison to LHRHa.
Other Forms of Estrogen Therapy
Estramustine phosphate, a nitrogen mustard derivative of E2-17 β-phosphate, has been found to have antitumor properties. Ravery et al. reviewed the studies on combination therapy with estramustine and docetaxel in the treatment of advanced prostate cancer.[42] The studies revealed that use of estramustine with adjunctive low molecular weight heparin could be used as an effective second-line treatment strategy in hormone refractory prostate cancer.
Fosfestrol, a DES prodrug developed to achieve higher water solubility and lower toxicity, was found to produce higher intracellular levels of DES with significant anti-tumor activity.[43] Fosfestrol 100 mg thrice a day was given orally in a continuous schedule until the appearance of progressive disease or excess toxicity. In 38 patients with hormone refractory prostate cancer, the median time to progression with oral fosfestrol was 7 months; in 34% of patients, pain remained stable, and in another 53%, there was improvement in pain score. Toxicities such as worsening of gynecomastia, peripheral edema, and DVT were observed in 8% of patients. There was no treatment-related deaths reported in the trial. The authors proposed concomitant prophylaxis with anticoagulants in patients with predisposing factors during the therapy.
Toremifene, as a second generation of selective ER modulators, was reported to have lesser cardiovascular side effects compared to ADT when administered at 80 mg dose.[44]
The analogue of 2-Methoxyoestradiol named as ENMD-1198 was found to be beneficial in patients with advanced prostate cancer.[45]
The agonist of ER α, Tx 758 was also found to decrease the estrogen deficiency side effects during ADT though it increased the risk of venous thromboembolic complication.[46]
Estrogen in the Management of Hot Flushes in Men Receiving Androgen-Deprivation Therapy
Hot flushes are characterized by a subjective sensation of rise in cutaneous temperature due to vasodilation predominantly in the face; throat and extremities usually followed by perfuse sweating. Following the administration of ADT, there is steep decline in serum LH and follicle-stimulating hormone resulting in the release of hypothalamic catecholamines, particularly that of norepinephrine. This affects the thermoregulatory center in upper hypothalamus resulting in abnormal peripheral vasodilatation. About 80% of patients on ADT will experience hot flushes, of which 27% is likely to have persistent troublesome effects.
There are many drugs including cyproterone acetate, gabapentin, clonidine, selective serotonin reuptake inhibitors, and various herbal products containing phytoestrogens recommended for the treatment of hot flushes. Megestrol acetate 20 mg twice a day has been reported to produce complete resolution of symptoms in 70% of men on ADT and reduction in the severity of symptom in another 20%.[47]
Oral DES in the dose of 0.25–0.5 mg/day was found to be effective in reducing hot flushes though gynecomastia remained a notable side effect.[48] Transdermal DES in the dose of 0.1 mg/h was also found to reduce the number and severity of hot flushes significantly.[49]
In a Japanese study conducted in 2004, it was observed that estramustine phosphate also reduced the hot flush score significantly in patients undergoing ADT.[50]
Cost of Therapy
The cost of treatment at this advanced stage of the disease is yet another limiting factor. Treating prostate cancer and treatment-associated toxicities has been reported to cost the UK over £100 million per annum with a total global health bill estimated at more than £2 billion. Abiraterone was estimated to cost around £50, 000 per quality adjusted life years, when it extended the median survival by a mere 3–5 months.[51]
The cost-effectiveness of ADT in advanced prostate cancer has been analyzed by Bayoumi et al. which is shown in [Table 1].[52] These authors questioned the cost-effectiveness of wide spread use of expensive androgen suppression strategies based solely on biochemical evidence of disease progression in men with advanced prostate cancer. ADT was found to be the least economically attractive option yielding small health benefits at relatively higher cost.
Table 1: Cost-effectiveness estimates in carcinoma of prostate Bayoumi et al.[52]
The selection of treatment options for CRPC is often linked to poor prognosis prediction since the reduction in PSA level observed in these patients need not necessarily correlate with the outcome of treatment, especially in the first 3 months of treatment. Shamash et al. reported a validated prognostic index predicting the response of dexamethasone and DES in the treatment of CRPC which could have some clinical relevance.[53] However, the distressing side effects of currently used ADT still continue to cast doubts on the therapeutic judgment of treating physician in advanced carcinoma of prostate.
It is well known that with the advent of LHRH analogues, estrogen therapy which was far more cost effective receded from the therapeutic armamentarium for a while. However, since 2010, there has been a renewed interest in revisiting this mode of therapy as an alternative to ADT or even as an option before chemotherapy in CRPC. Hongo et al. in 2014 reported complete response to ethinyl E2 administered for almost 2 years in patients with CRPC.[54] There is an interesting article on a urologist's personal experience with multiple surgical, hormonal, and radio/immunotherapeutic options for the treatment of advanced prostate cancer and thoughts on the role of old and new therapies.[55] The author narrated that in 2008, he was advised transdermal E2 patch which he began and continued to the present. E2 slowed his PSA doubling time but of equal importance, improved his sense of well-being. The author finally concluded that estrogen was barely mentioned in the guidelines of the major oncology societies and was being essentially overlooked and very much underappreciated.
For patients with metastatic castration-resistant prostate cancer on androgen receptor signaling inhibitors and standard chemotherapy, it is now reported that those who harbored circulating tumor cells that had AR-V7 protein in the cellular nuclei were very likely to survive longer on taxane-based chemotherapy.[56] There are also reports that detection of AR-V7 in circulating tumor cells from patients with CRPC has been reported to be associated with resistance to enzalutamide and abiraterone.[57] Estrogens would be a good alternative in these situations, if AR-V7 proteins could be detected before the administration of the newer forms of ADT.
Recent study by Pramesh et al. highlighted that delivery of affordable and equitable cancer care as one of India's greatest public health challenges.[58] These authors calculated that the public expenditure on cancer in India as below $ 10 per person (compared with more than $100 per person in high-income countries), with overall public expenditure on health care being only slightly above 1% of gross domestic product. Interestingly, out-of-pocket payments, which accounted for more than three-quarters of cancer expenditures in India, was regarded as one of the greatest threats to patients and families. A cancer diagnosis was increasingly responsible for catastrophic expenditures that negatively affected not only the patient but also the welfare and education of several generations of their family. Yet another interesting study by Haddad et al. highlighted that there existed a social gradient in community as far as healthcare delivery was concerned in India, which was not solely explained by differences in material deprivation, but was dependent on other factors, such as social exclusion and caste discrimination.[59] Therefore, we believe that effective treatment with low cost using estrogens in advanced cancer prostate in a country like India with wide social, economic, developmental and cultural stratifications, and ramifications would be a boon to the families to avert the economic drain on them caused by the disease and its treatment.
It is now well recognized that oral estrogens, due to the first pass though the liver, has been responsible for the alarming cardiovascular and thromboembolic setbacks of estrogen. Low dose estrogen, especially given parenterally or transdermally appears to be well tolerated with minimal side effects and highly cost-effective. Estrogens in low doses may not cause osteoporosis and has beneficial effect in patients with CRPC compared to ADT. Estrogen and their analogs could also be used to alleviate the distressing side effect of hot flushes in patients on ADT.
There is currently enough evidence to support the efficacy of estrogen therapy in the management of CRPC. The resurgence of estrogen therapy would be a less expensive option having equivalent or even better therapeutic effects than ADT in this disease scenario.
Financial support and sponsorship: Nil.
Conflicts of interest: There are no conflicts of interest.
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Orlando M, Chacón M, Salum G, Chacón DR. Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory' prostate cancer. Ann Oncol 2000;11:177-81.
Smith MR, Malkowicz SB, Brawer MK, Hancock ML, Morton RA, Steiner MS. Toremifene decreases vertebral fractures in men younger than 80 years receiving androgen deprivation therapy for prostate cancer. J Urol 2011;186:2239-44.
Zhou Q, Gustafson D, Nallapareddy S, Diab S, Leong S, Lewis K, et al. Aphase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer. Invest New Drugs 2011;29:340-6.
Yun H, Xie J, Olumi AF, Ghosh R, Kumar AP. Activation of AKR1C1/ERβ induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity. Oncotarget 2015;6:11600-13.
Khan A, Lewis R, Huger S. Managing hot flush in men receiving androgen deprivation therapy for prostate cancer. Trends Urol Mens Health 2014;5:31.
Smith JA Jr. A prospective comparison of treatments for symptomatic hot flushes following endocrine therapy for carcinoma of the prostate. J Urol 1994;152:132-4.
Gerber GS, Zagaja GP, Ray PS, Rukstalis DB. Transdermal estrogen in the treatment of hot flushes in men with prostate cancer. Urology 2000;55:97-101.
Fukuhara S, Yokoyama S, Tsutahara K, Mori N, Hara T, Yamaguchi S. A clinical study of estramustine phosphate sodium for the treatment of hot flushes in men with prostate cancer. Nihon Hinyokika Gakkai Zasshi 2004;95:761-5.
Wilson HC, Sahah SI, Price P, Abel PD. Re-state of the art treatment in castration-resistant prostate cancer-forward to the past-again. EMJ 2014;2:100-5.
Bayoumi AM, Brown AD, Garber AM. Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst 2000;92:1731-9.
Shamash J, Stebbing J, Sweeney C, Sonpavde G, Harland S, Dawkins G, et al. Avalidated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate-resistant prostate cancer. Cancer 2010;116:3595-602.
Hongo H, Kosaka T, Oya M. Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer. Can Urol Assoc J 2014;8:E921-3.
Schellhammer PF. A urologist's personal view of prostate cancer. Turk J Urol 2016;42:121-6.
Scher HI, Graf RP, Schreiber NA, McLaughlin B, Lu D, Louw J, et al. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol 2017;71:874-82.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Rosser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028-38.
Pramesh CS, Badwe RA, Borthakur BB, Chandra M, Raj EH, Kannan T, et al. Delivery of affordable and equitable cancer care in India. Lancet Oncol 2014;15:e223-33.
Haddad S, Mohindra KS, Siekmans K, Màk G, Narayana D. "Health divide" between indigenous and non-indigenous populations in Kerala, India: Population based study. BMC Public Health 2012;12:390.
1 Resveratrol inhibits TRAF6/PTCH/SMO signal and regulates prostate cancer progression
Jianping Li, Ziming Wang, Hecheng Li, Jun Cao, Ning Nan, Xiaoqiang Zhai, Ying Liu, Tie Chong
Cytotechnology. 2022;
2 Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review
Herjan J T Coelingh Bennink, Jan Krijgh, Jan F M Egberts, Maria Slootweg, Harm H E van Melick, Erik P M Roos, Diederik M Somford, Yvette Zimmerman, Iman J Schultz, Noel W Clarke, R Jeroen A van Moorselaar, Frans M J Debruyne
Endocrine Connections. 2022; 11(12)
3 The androgen receptor inhibits transcription of GPER1 by preventing Sp1 and Sp3 from binding to the promoters in prostate cancer cells
Austin McDermott, KyoungHyun Kim, Susan Kasper, Shuk-Mei Ho, Yuet-Kin Leung
Oncotarget. 2022;
4 Phytoestrogens as Potential Antiandrogenic Agents Against Prostate Cancer: An In Silico Analysis
Neetu Agrawal, Somdutt Mujwar, Ahsas Goyal, Jeetendra Kumar Gupta
Letters in Drug Design & Discovery. 2022; 19(1): 69
5 miRNAs and androgen deprivation therapy for prostate cancer
Maria Yu Konoshenko, Olga E. Bryzgunova, Pavel P. Laktionov
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2021; 1876(2): 188625
6 Bioelectrochemical systems for environmental remediation of estrogens: A review and way forward
Zainab Syed, Monika Sogani, Aman Dongre, Anu Kumar, Kumar Sonu, Gopesh Sharma, Akhilendra Bhushan Gupta
Science of The Total Environment. 2021; 780: 146544
Moorthy H K
Laxman Prabhu G G
Venugopal P
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Other Forms of E...
Estrogen in the ...
© 2006 - Indian Journal of Urology | Published by Wolters Kluwer - Medknow
Online since 1st January, 2006


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Campaign 2016 updates: Donald Trump touts school choice as a 'new civil rights issue' of our time
Sep. 24, 2016, 5:33 p.m.
Donald Trump calls school choice 'new civil rights issue' of our time
(Steve Helber / Associated Press)
Donald Trump had nothing to say at his rally Saturday about the recent police shootings of black men that have mobilized civil rights activists across the country -- but he did talk talk about what he sees as the "new civil rights issue of our time."
In Trump's view, it is school choice.
"Too many African Americans have been left behind and trapped in poverty," Trump said in Roanoke, Va., stressing that he, not Democratic nominee Hillary Clinton, will foster better schools and create more jobs for African Americans.
Watch: Donald Trump rallies supporters in Roanoke, Va., ahead of debate
Sep. 24, 2016, 11:33 a.m.
By Melanie Mason
Sep 24, 2016 | 11:33 AM
In Twitter spat with Mark Cuban, Trump jabs at Bill Clinton sex scandal
It's supposed to be a relatively slow weekend on the campaign front, with both nominees devoting most of their days to prepping for the first presidential debate on Monday.
But so long as Donald Trump is tweeting, it's never truly quiet. On Saturday, he took this shot at Dallas Mavericks owner Mark Cuban:
If dopey Mark Cuban of failed Benefactor fame wants to sit in the front row, perhaps I will put Gennifer Flowers right alongside of him!
Trump appears to be responding to Cuban's announcement earlier this week that the "Shark Tank" star scored prime seats to watch Monday's debate in person.
New York Times editorial board sides with Hillary Clinton
Breaking News: The Times editorial board has endorsed Hillary Clinton for president. Here's why.https://t.co/6iNnG00V7R
— The New York Times (@nytimes) September 24, 2016
Hillary Clinton is way ahead with Latinos -- but should she be doing better?
(Eric Gay/AP)
Democrats be warned: Don't take the support of Latinos for granted.
It's a message, to the surprise of some, coming from Latino elected officials upset over the party's outreach to that crucial voting bloc in races up and down the ballot.
"I am disappointed to this day with the Democratic Party, with the Democratic Congressional Campaign Committee, the Democratic National Committee, and I would like to see Hillary Clinton's campaign hire more consultants who are of the communities," Rep. Tony Cárdenas (D-Los Angeles) chairman of the Congressional Hispanic Caucus' fundraising arm, Bold PAC, told The Hill this week.
Sep. 24, 2016, 8:49 a.m.
By Stephen Battaglio
Presidential debate expected to set audience record
(Los Angeles Times)
If NBC News anchor Lester Holt is nervous about moderating the first presidential debate, he wasn't showing it earlier this week as he rocked his electric bass on the rooftop lounge overlooking the Hudson River.
Playing with a rock band made up of cohorts from the network's news magazine show "Dateline," Holt ably soloed on the Alabama Shakes song "Always Alright" in front of a throng of cheering colleagues. It was a break from his intensive preparation for Monday's showdown between Hillary Clinton and her Republican opponent, Donald Trump.
Holt's homework sessions kept him away from his anchor duties on "NBC Nightly News" in the days before the live telecast from Hofstra University in Hempstead, N.Y. Airing across the major broadcast networks, Spanish-language channels and cable services, the anticipated match-up is expected to top the previous debate audience record of 80.6 million TV viewers set in 1980 for the single meeting between Ronald Reagan and Jimmy Carter.
By David Horsey
Opinion: Nobody expects the Spanish Inquisition -- or President Trump
(David Horsey/Los Angeles Times)

redpajama_set_name: RedPajamaCommonCrawl


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Please consider making a donation to the IM SAFE CAC today!
The CAC welcomes the donations we have listed. These products help us on a daily basis and are greatly appreciated. Please feel free to drop off items at our office 10260 S Sheridan Rd. Fenwick, MI 48834.
Washable markers, acrylic paints, small art canvases, paint brushes, tempera paint scrapbooking materials, Hobby Lobby and Michael's gift cards. Moldable clay (non-bake variety). Stickers: bees, bugs, hearts, dots, smiling faces, band-aids, Glitter glue, Glue dots, journals, and thin and regular Sharpies.
Individually wrapped snacks, juice boxes, bottled water, Sam's Club and Meijer's gift cards.
Copy paper, postage stamps, DVD-R blank discs, manilla file folders (1/3 cut), office supply store gift cards.
Sanitizing wipes, tissues, paper towel rolls, hand soap, gift cards, gas cards and fast food restaurant cards for court days.
Donated breakfast and lunches for center tours, Multidisciplinary Team case and peer review meetings as well as advertising space in print and broadcast media.


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The Gold Coast Training Academy (GCTA) was established in 1986 as one of Australia's first registered beauty academies.
After almost a quarter of a century building an impressive reputation for the quality of its graduates, The Academy is now one of the largest beauty training organisations in Australia, educating over 500 therapists each year, many of whom secure jobs before they graduate. Its long history and rich traditions have steered The Academy's growth through the building of a state-of-the-art campus at Robina and our rebirth as The French Beauty Academy.
Throughout its history, The Academy is proud to have been involved in the revolution of education in beauty therapies, having played a key role in the development of the first-ever training package for the Diploma of Beauty Therapy in Australia, now formally adopted by the Federal Government and providing the foundation for courses taught nationwide.
Our commitment to our students is to groom them as individuals, recognise their personal potential and give them the very best life and learning experiences. Likewise, we are fully committed to listening to the needs of industry, to help refine our program to meet industry needs. As a result of listening to the needs of industry, our graduates have the opportunity to transition seamlessly through to university and complete a Business degree after the completion of their Diploma – fulfilling a major gap in spa and wellness management employment needs.
The French Beauty Academy and Southern Cross University (SCU) have developed an exciting, industry-first arrangement where students will be able to complete a Bachelor of Business, furthering management aspirations for graduates in the spa and wellness industry. For those students interested in this unique pathway, please contact the Future Students Team
Our current arrangement with the University, provides credit for the Diploma of Beauty Therapy (one semester), towards a Bachelor of Business. Students will also have the exciting opportunity to do an international exchange in their second year of study with one of SCU's international exchange partners. SCU also supports our students in securing internships during term breaks at hotel, spa and resort chains, which can also be credited towards their business degree.
For students who have already completed a Diploma of Beauty, an undergraduate degree at an approved institution, or have extensive work experience, SCU offers entry into a Graduate Certificate in Tourism and Hotel Management.
For further information on the pathway arrangement with Southern Cross University – please visit this on AQF Vocational Qualification Linkages approved by SCU
The Academy has also developed an articulation agreements with Victoria University, which allow Academy graduates to credit their Diploma studies towards a degree in dermal therapies.
We continue to be at the forefront of beauty education and trends, working with government and business leaders to develop advanced training programs that meet the changing needs of industry. And we continue to establish partnerships with a network of premium global brands to further The French Beauty Academy as the industry's leading education provider.
The School of Tourism and Hospitality Management at Southern Cross University is delighted to create an articulation pathway with The French Beauty Academy into our degree programs. We are proud to work with them to develop pathways for those who wish to continue on to university. Our business degrees provide students the opportunity to develop their business, technical, management and interpersonal skills. The global demand for tourism, spa and wellness managers continues to grow, and graduates from this program will have the highly sought after combination of technical knowledge and practice and business acumen required by leading hotels and spas around the world.
Professor Elizabeth Roberts – Southern Cross University
Read about our service excellence


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Ford launches 'Auto Remedio' campaign
April 8, 20130460
Ford's exclusive technologies include the hands-free liftgate, which opens the back end by simply activating a motion sensor.
The effort highlights Ford's leadership in smart technology by demonstrating the advantages of features as "Active Park Assist," "EcoBoost" and the automatic rear liftgate in scenarios familiar to Puerto Rican consumers.
Automaker Ford will kick off a new, multi-channel marketing campaign dubbed "Auto Remedio" today, through which it seeks to shows how brand-exclusive technologies featured across its vehicle lineup make life easier for drivers.
The effort highlights Ford's leadership in smart technology by demonstrating the advantages of features such as "Active Park Assist," "EcoBoost" and the automatic rear liftgate in scenarios familiar to Puerto Rican consumers.
"Ford technologies exceed the limits of what vehicles are able to do," said Mark Buzzell, managing director for Ford's Caribbean and Central America region. "The thrill consumers experience when they interact with these technologies is something that we have captured in these ads; the confidence of driving a vehicle that can practically park itself, the ease of opening a liftgate with a swift leg motion, and the peace of mind of fewer trips to the gas pump are some of the 'Auto Remedios' featured in this exciting new campaign."
"We're certain it will change perceptions about our brand and continue solidifying our technology leadership," added Buzzell.
Three television spots, filmed entirely on location in Puerto Rico, are the centerpiece of the campaign, which also includes print and outdoor executions during its first phase. Ford's global advertising team in collaboration with the local JWT office developed the concept for the campaign that will begin airing on local television starting today, with print and outdoor executions to soon follow.
"Puerto Rico is such an important market for Ford," said Buzzell. "We value our local customers and realize that in customizing Ford's global message to suit local tastes, we bring consumers even closer to our brand."
"Along with proof of the superior Ford driving experience, our local consumers will be delighted to see Ford vehicles in such familiar settings as Old San Juan and Ocean Park beach in this campaign," he added.
A second phase of the campaign will bring local consumers closer to Ford technologies, as they will be called upon to nominate themselves, family members, friends or anyone they know who may need an "Auto Remedio" from the automaker.
At the end of 2012, Ford reported a 25 percent increase in the minivan segment — which includes the Transit Connect work van — and a 15 percent increase in the F-150 and Super Duty truck segment. Ford sold a total of 11,017 units last year, representing a 6.6 percent increase over 2011, securing a second place position in the Puerto Rico auto sales market.
Related tags : advertisingcampaignFord
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Hey Buddy!, I found this information for you: "Ford launches 'Auto Remedio' campaign". Here is the website link: https://newsismybusiness.com/ford-launches-auto-remedio-campaign/. Thank you.


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NicaNotes
NicaNotes: Nicaragua Celebrates the 19th of July; Solidarity Releases New Book!
The 41st anniversary of the Sandinista Revolution was celebrated in Nicaragua in a mainly virtual fashion with broadcasts on television, Facebook, and YouTube in the days running up to the holiday. Film strips from the 1979 insurrection, greetings from foreign dignitaries and solidarity groups along with instructions on fighting the corona virus could be viewed throughout the day on the 19th. In the evening, President Daniel Ortega, Vice-President Rosario Murillo, and other government officials gathered in the Plaza of the Revolution with several hundred young people to hear the President speak about recent advances in social and health policies. Dignitaries and youth were all seated in a socially distant fashion with their masks on. (Read more about Daniel Ortega's speech below.)
For this 19th of July, international solidarity has announced a brand new book. The free digital book The Revolution Won't Be Stopped is a publication by a group of international activists in solidarity with the Sandinista Revolution. The work has been coordinated by the Alliance for Global Justice (based in the US) together with the UK-based Nicaragua Solidarity Campaign Action Group. The book is edited by Nan McCurdy and written by a collective of historians, researchers and activists committed to finding and sharing the truth about US intervention in Nicaragua.
The new book, The Revolution Won't Be Stopped: Nicaragua Advances Despite US Unconventional Warfare describes the country progressing in every aspect of national life up to and including the arrival of the global pandemic in early 2020. All the work and progress described took place despite a cruel unconventional war that is explained in four chapters. The writers are a collective of researchers, historians, analysts and journalists the majority of whom are women; six Nicaraguans, five residents, one author who lived here for years and experienced the final offensive of the Sandinista push to oust the dictatorship and two more deeply connected with Nicaragua for more than thirty years. You can download the book in English or Spanish here.
The chapter titled Economic and Social Progress Continues compiles an exceptional group of articles and news briefs that highlight the many aspects of that progress. Louise Richards states that the government has emphasized "policies which benefit the poorest and most vulnerable in society." As an example, she notes spending on health care has tripled since 2006 and the maternal mortality rate has declined from 97 to 37 for every 100,000 live births. Writing on the anniversary of the death of Carlos Fonseca Amador, Nan McCurdy highlights achievements that would have made the FSLN founder proud including reducing the poverty rate from 48.3% to 24.5% and extreme poverty to 6.9%. She states that, in carrying out internationally financed projects in roads, hospitals, electrification, water and sanitation projects, Nicaragua "has a perfect execution rate of its project portfolio and serves as an example for other Central American countries," according to the Central American Bank for Economic Integration. In the first of two articles, Jorge Capelán highlights the recovery of the Nicaraguan economy after the 2018 coup attempt including an increase in agricultural production, food price stability, and the construction of affordable housing. In his second article, Capelán writes about infrastructure improvements, quoting Minister of Transportation Oscar Mojica who stated that, according to the World Economic Forum Ranking, Nicaragua has the best roads in Central America. Then, David Archuleta describes what he learned about food sovereignty as part of a delegation of visitors to projects of the Rural Workers Association (ATC). News briefs from the publication NicaNotes covering economic and social development issues month by month complete the chapter.
Polls and Surveys provides authoritative data confirming the results of elections, the popularity of the Sandinista government and miniscule support for the US-funded opposition. Multiple polls confirm that all but a small fraction of Nicaraguan voters oppose opposition violence, trust the police and military, and would re-elect the current government in a landslide that would be envied by other elected leaders. Independent poll data provides no support for opposition claims of dictatorship, police brutality, or any of the other Big Lies that the US and its internal agents hope to make true by constant repetition.
The Amnesty describes the historic process that led the Sandinista government to an audacious decision to pass a simple law that would free criminals from the 2018 coup attempt convicted of murder, kidnapping, torture, extortion, arson and more, and even extend it to those for whom the justice system had ample evidence to capture, process and try who were in other countries, so that they could return and enjoy complete freedom and a clean slate. The victims of the criminals' horrendous acts as well as the family members of those killed, kidnapped, tortured, burned and most of the population traumatized by the unbelievably brutal state of terror created by the opposition from April to July 2018, understandably were resistant to letting them out of jail. Nevertheless, President Daniel Ortega, Vice President Rosario Murillo, Sandinista leaders and analysts and journalists like William Grigsby helped the people recall that forgiveness is a revolutionary trait. Only with forgiveness and devotion to reconciliation will the country arrive at a real peace that will allow prosperity and wellbeing for all.
The chapter on Peace and Reconciliation first describes the history of the Sandinista Front for National Liberation's long commitment to seeking reconciliation and peace, as
in the examples of Sandino, Miguel d'Escoto, the peace accords of Esquipulas and Sapoa, Tomas Borge, etc. Then it explains how the Peace and Reconciliation Commissions were formed immediately after the attempted coup of April-July 2018
to facilitate reconciliation between neighbors on a community level all over Nicaragua. After the cruel Somoza dictatorship and the US war on the new revolution in the 80s came 17 years of three neoliberal governments that caused the death of hundreds of thousands of people from illnesses related to poverty, unemployment and almost a total lack of heath care for anyone who couldn't pay. The Sandinista government has always been deeply committed to bringing about peace so that the people can enjoy wellbeing.
Physically uniting the Caribbean and the Pacific of Nicaragua had been on the international agenda, especially that of Spain, England and the United States, for centuries. But it took a Revolution to really take on that challenge and succeed. Even more important is the ongoing work to unite a country´s people from different cultural heritages, and to facilitate their socio-economic development with programs which bring education, health, electricity, water and sanitation, communication infrastructure and other programs to stimulate food security and economic development on the Caribbean Coast. A person in the US recently told a story of her experience with a local group in a city in the southwest of the United States that wanted to come to Nicaragua to build wells. She told them to just look down the road from where they lived and they would find Native Americans living in shacks, no electricity, water or sanitation so why travel so far to help? US Native community members were the last on the list to receive their one-time financial support. Their people, along with non-white communities, are the hardest hit from the pandemic in the US. That harsh reality is becoming more and more evident now in the US, to those who want to see the truth. And the truth about what is happening in the Caribbean Coast of Nicaragua presented in this chapter tells a story of processes which could be replicated in other countries, north and south.
The chapter on Nicaragua's environmental policy gives a broad overview of the many elements that make up Nicaragua's incredibly diverse range of marine, forest, fresh water, land, mineral and wild life resources. It covers how the country is addressing the diverse challenges of conserving the country's natural resources and adapting to the effects of climate change at a national and regional level. But it also covers the leading role Nicaragua has played in the UN system of international conferences addressing climate change, insisting on the issue of climate justice. Nicaragua's environmental policy has been an integral part of the country's economic democratization via the development of the popular economy which has also accompanied defense of the wellbeing and rights of the country's many ethnic groups, especially on the Caribbean Coast. Among the most important achievements in defending the environment has been the decisive shift to the use of renewable energy resources for electricity generation. The chapter on the environment is an important resource explaining how government policy has managed the complex dilemma of promoting economic development while protecting and conserving natural resources on which that economic development depends.
The World Economic Forum ranks Nicaragua 5th in the world in its 2020 Global Gender Gap Report, behind only the Nordic countries, and by far the leading country in the Americas for gender equality. Women have advanced because of the astounding halving of poverty, free education and health care, amazing reduction in maternal mortality and great availability of child development centers where their children are cared for, fed and taught, and maternity wait homes where women from the countryside can live for the last weeks of pregnancy to insure professional attention to their births. Nicaragua has relaunched women's police stations all around the country as part of an all-out push to lower violence against women. Nicaragua has the lowest rate of femicides in the region. Women have benefitted from the government's conscious promotion of every kind of small business through training and loans for nearly a million women since 2007. Some 300,000 rural women who are organized cooperatively have benefitted from government programs as you will read in numerous interviews with women in the countryside who describe the concrete changes in their lives.
As 2020 approaches, the Sandinista-led people of Nicaragua continue to challenge conventional models of thought and action, fighting creatively and heroically for social justice while facing imperialist economic sanctions and a media manipulation campaign against them. In this journey, the popular economy has been a key factor in guaranteeing the resistance of a people who are clinging to their freedom and dignity. The chapter on the popular economy shares the progress made by the people of Nicaragua in consolidating the popular and solidarity economy as an economic and social alternative for the majority of Nicaraguans. It describes the historical genesis, characteristics, values that underpin it and the public policies that the Sandinista government has promoted from 2007 to the present day, to favor and dignify it, as part of an integrating and revolutionary project that seeks, from its own realities and cultural roots, an alternative path of democratization of wealth, social justice and political sovereignty in the face of financial, impoverishing and imperialist capitalism.
While the major Western international news media continue to peddle fake news about a "dictatorship", a "regime" and a "crisis of democracy" in Nicaragua, they ignore one of the most important threats that the Sandinista government poses not only for Nicaragua, but also the world. The Nicaraguan government, and specifically the Sandinista movement, is a threat to one of the most important ideological babies of the West: Development. Since coming back to the presidency in 2007, the Sandinista government has continued to grapple with the contradictions of breaking with the conventional development. Recognizing the limits of development – while facing global and internal contradictions, such as a capitalist money system, unequal wealth and land distribution and a globalized monoculture encouraging world economy – the Nicaraguan government has attempted to re-embed the economy in the biosphere as well as within Nicaraguan culture(s). And it is within government tourism policy that one can effectively observe how the break from Development is taking place.
How Nicaragua is presented in the national and international media is crucial, both for its effect on Nicaraguan people and for its effect on opinion abroad, from intentional bodies like the United Nations, to governments especially in the US and Europe, to left-leaning opinion and solidarity networks. Tackling a false image of present-day Nicaragua has been a big part of the media battle. Another has been to continue to ascertain the truth of what happened in 2018 and present the evidence, to the Nicaraguan people and also abroad. In this, official bodies, government supporters and independent investigators have been very active, uncovering the real stories behind some of the worst violence. The opposition-supporting media – and the mainstream international press – have ignored such investigations, sticking to the versions of events that were concocted immediately after they took place in 2018. Many well-known examples of opposition violence, ones whose responsibility cannot be disputed, are still treated as if they didn't happen. This chapter tells the media story, with many examples, through 2019 and into the first part of 2020. We can be sure that the media battle will only intensify as the 2021 elections approach.
The Nicaraguan Opposition chapter is a damning portrayal of groups opposing the current FSLN government, and of their US and EU benefactors. It shines light on a web of lies, such as the creation of false media events – actors tearfully pretending to be under gunfire, bidding farewell to their loved ones, while passersby are continuing life as usual. Opposition claims of being peaceful are also laid bare, not only by the witnesses and victims of their crimes, but by their own proud admissions, in a leaked video, of murder and other violent acts. Their alleged desire for democracy and freedom from "dictatorship" is also belied by examining their bedfellows – like the murderous coup mongers in Bolivia and the most right-wing politicians in the United States. All this and more is covered by solid evidence and incisive analysis.
The chapter on human rights organizations exposes the complicity of such bodies, including some of the most prestigious in the world, with the campaigns to overthrow the government of Nicaragua by the United States. Readers will be able to understand how the main international human rights organizations, operating in coordination with their equally corrupt local counterparts, have worked on behalf of their financier, the United States government, to destabilize Nicaragua and ultimately attempt to overthrow its president, Comandante Daniel Ortega Saavedra. The selection of articles paints a clear and discouraging picture of how said organizations, as international institutions, lack objectivity and rigor, and play the role of a for-profit industry that serves the interests of the world's premier neoliberal powers. The chapter ends with a selection of article summaries that covers a series of measures that the Sandinista government has taken to fight for its sovereignty and protect the human rights of all its citizens.
The history of US obsession with control of the Nicaraguan people and their resources is long. US military intervention in Nicaragua began in the 1850s when the US destroyed Greytown as punishment for thwarting US interests there. Until the successful Sandinista Revolution on July 19, 1979, the Nicaraguan people suffered under a series of US-puppet regimes assuring US investors a field day. After waging a vicious war against the Sandinista-led revolutionary government, the US in 1990 forced them out of power expending nearly $50,000,000 on its chosen candidate, along with a promise to continue the brutal war if the US candidate lost. When the Sandinistas won the elections in 2006, the US angrily began plans for a US-"approved democracy." It has committed at least $300,000,000 to oust the Sandinistas in their re-elections, one way or another, including its 2018 dirty coup attempt. It continues to wage an ugly corporate and social media campaign against Nicaragua based on incredible lies. The US has never forgiven the Sandinistas for overthrowing its all-time favorite dictator, Somoza. But, the one force obstructing the US will is the democratic will of the Nicaraguan people to preserve their political economy.
The new book The Revolution Won't Be Stopped: Nicaragua Advances Despite US Unconventional Warfare brings all these efforts forward while giving valuable background on recent and past events.
The Revolution Won't Be Stopped: Nicaragua Advances Despite US Unconventional Warfare
La Revolucion No Se Detendra
The Revolution Won't be Stopped Ebook
The Revolution Won't Be Stopped .Mobi
By Nan McCurdy
President Ortega Emphasizes Commitment to Good Health Care for All
On the 41st anniversary of the Sandinista Revolution, July 19th, President Daniel Ortega said "Our commitment is to the peace, unity and stability of the Nicaraguan people. Today we bear witness that which we said and swore in this square 41 years ago. We said it with the certainty that we were carrying the red and black flag, the dignity of General Sandino." Ortega stressed that they were celebrating the anniversary of the Sandinista Revolution in the midst of the precautionary measures for the COVID-19 virus but added: "The worst epidemic is the hunger caused by savage capitalism, which was shaken by this pandemic." He added that the impacts of the coronavirus stripped capitalism bare, adding "it has to do with the economic model that has been installed in the world and that has been considered perfect. Perfect as long as it does not touch the pockets of big capital."
The President emphasized that investment in health during the last 14 years has allowed the country to confront the COVID-19 virus with forcefulness. "In Nicaragua, medicine is for the poor, the humble, the workers and the people." He stressed that the country's health model focuses on disease prevention, "a total of 1,394,168 children have been assessed in the recent food census" and 2,370,000 doses of vaccines have been applied up to June 30 to protect children and adults from 16 diseases. "In this year 2020 we feel proud to say, in front of those who destroy hospitals, that we have 332 dialysis machines attending 2,270 patients…more than 28,000 health fairs were held, more than 1 million houses were fumigated, 19 hospitals were built, 16 of them primary hospitals, 18 health centers, 188 natural medicine centers and centers for complementary therapies," he noted. "Seven new hospitals are being built and there are funds for seven more hospitals after those, and a regional epidemiological laboratory," said the President.
The leader also highlighted the commitment of the institutions of the Government of Reconciliation and National Unity to accompany peasant farming families so that they can improve their production capacity. Nueva Radio Ya, 19 July 2019
Nearly 30,000 Jobs Created in First Half of 2020
Vice President Rosario Murillo reported that so far in 2020, new businesses have created 28,600 new jobs. Among food enterprises are dining rooms, tortilla shops, bakeries, production of buttermilk, fried food stands, fruit and vegetable sales, and butchers, among others. In addition, 40 workshops were opened in cabinetmaking, carpentry, construction, automotive mechanics, refrigeration, welding, and others. Radiolaprimerisima, 16 July 2020
Foreign Investment to Continue Despite Pandemic
Nicaragua confirmed on July 21st that it will continue to execute foreign investment mega-projects like building a natural gas electricity plant with an investment of US$400 million despite the global pandemic. Wes Edens, Executive Director of New Fortress, the US company that will build the plant said the project will start in 2021 with a total investment of US$700 million. "In Nicaragua, opening a company takes 14 days, the shortest time in the region, according to World Bank statistics, and the shortest time in Central America," said Jalima Gómez of the ProNicaragua Agency, who also explained that in this country investors pay the lowest tariffs for exports. Another of Nicaragua's investment attractions is its global commercial relationship, since the country has agreements with at least 45 nations, which allowed the value of exports last year to exceed US$5.6 billion dollars. Nicaragua has an excellent road network that exceeds 24 thousand kilometers and 70 percent of its population is young people under 40 years of age. Radio La Primerisima, 21 July 2019
Health Ministry Report July 21 on Covid
The Health Ministry reported that in the week from July 14 to 20 there were 292 new cases of corona virus reported, 210 newly recovered and 9 deaths with Covid-19. To date there have been a total of 2,892 Covid cases reported and 2,492 have recovered. Total deaths to date are 108. Radio La Primerisima, 21 July 2020
Army General Emphasizes Rejection of Interference
Nicaraguan Army head General Julio César Avilés stated July 16 that the members of the military are capable of giving their lives for the interests of the nation. The Military Council of the Nicaraguan Army, the highest consultative body of the High Command, "unanimously and cohesively, expresses the feelings of Army: We reject and do not accept acts of interference, attacks and slanderous accusations, and we reject the disinformation that is carried out at the national and international level against our institution and our Commander-in-Chief Army General Julio César Avilés Castillo." "The Army continues to be attacked and slandered by those who simply do absolutely nothing. With all the moral authority of our soldiers, sergeants, officers, we tell you that our dedication to the fulfillment of our missions and tasks is not determined by the salaries we earn," said Avilés. The general invited all those who criticize to join the work that the Army does to guard the borders, provide humanitarian aid to the population, put out fires, among other duties. Radio La Primerisima, 16 July 2020
Nicaragua: Leader in Stopping Drugs to the United States
Some 700 tons of drugs per year no longer pass through Nicaragua thanks to the hard work that the army does through the "retaining wall against drug trafficking and organized crime," reported General Julio Cesar Aviles July 16 on presenting results of the Army's work to guarantee security. According to General Avilés, South America produces an estimated 3,000 tons of drugs per year, 80% of which are intended to transit Central America and reach the US. Several international agencies have recognized Nicaragua's work to maintain this retaining wall and that this is why at least 700 tons of drugs have been prevented from passing through. "We try to stop the greatest possible amount of drugs from entering our territory; the success is not in the amount captured but in the capacity to stop and divert the drugs so that they do not enter our territory," Avilés said. Radio La Primerisima, 16 July 2019
Rafael Valdez, Christian Revolutionary, Dies on 41st Anniversary of the Revolution
Rafael Valdez Rodríguez, a Sandinista and one of the founders of the first Christian Base Communities in 1966, that of the San Pablo Apostle Church in Managua, died at 12:20 a.m. July 19, 2020. During the Somoza dictatorship he was known for leading struggles against the rise in the cost of milk and transportation. He was an FSLN collaborator and his home was used as a safe house for combatants. During the first stage of the Revolution, Valdez held the post of director of the postal service in the National Telecommunications Company. From the 1990s onwards, he worked at the Antonio Valdivieso Ecumenical Center under the direction of Father Uriel Molina and later was director for more than 20 years. His brother Tomás Valdez, also a Christian leader, said "a committed Christian and revolutionary for social causes and the gospel of Jesus has died." Rafael and Tomas led the effort to write a letter to the pope requesting that Bishop Silvio Baez be removed from Nicaragua and nearly 600,000 Catholics signed the letter. Baez worked closely with the US in directing the opposition to mount the 2018 coup attempt and was taped talking about his desire to put President Ortega in front of a firing squad. Radio La Primerisima, 19 July 2010
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We have had some pretty decent movie licensed games releasing recently, which makes you wonder if times are finally changing.
This trailer for Terminator: Salvation is specifically geared to give us a peak at ground enemies, but also shows off quite a lot of the gameplay and visuals. The graphics are looking pretty decent to be honest, but it's the gameplay that is the most important, now isn't it?
It looks as though they are pushing for a semi Gears of War clone, with cover systems and all the rest and doesn't actually look too bad to be honest. We will have to wait until we can see more of it before jumping to any conclusions, but so far it looks like it has potential.
The game will be releasing this month on the 19th for Xbox 360, PC and PS3.
So what's the verdict from our readers so far? Hot or not?
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text:
J.S. Frankel
The Undernet
Author: J.S. Frankel
Word Count: 68764
Series: The Undernet #0
Categories: Mystery, Suspense, Action , New Adult
Log onto the Undernet. Don't think about logging out.
Milton (Milt) Edwards, eighteen, high school graduate and gamer supreme, lives for the next game to be played on the internet. His friend, Simon Smith, is no different, and together they rule the world of war simulations and zombie invasions.
When Simon tells Milt about the newest site he's heard of—the Undernet—Milt is intrigued. However, when Simon turns up dead shortly after telling him, Milt is determined to find out why. Was it the Undernet, a shadowy cyber world, or simply a maniac with a vendetta? He is soon recruited by Ramon, a former prisoner turned FBI hacker, and Larry Caldwell, an FBI agent. Ramon introduces Milt to the Darknet, and soon the clues fall into place, or at least Milt thinks they do.
Against the counsel of his girlfriend, Roberta Jones, Milt goes deeper and deeper into the netherworld known as the Undernet, finding out that reality isn't what he thinks it is. More deaths happen, and when Milt discovers the truth behind who killed Simon—and others—it may be too late. Log onto the Undernet. Don't think about logging out.
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