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The Holocaust, whose memory usually serves as an honored shared point for the Jewish community, sometimes is a point of contention for haredi Jews, who say they feel excluded from mainstream histories of the period. Those histories, and exhibits in Yad Vashem, emphasize the exploits of secular partisans and pay less attention to religious Jews who resisted the Nazis by studying Torah in ghettoes and keeping the commandments in death camps. For many Orthodox Jews, the day of mourning for Holocaust victims is Tisha b'Av, which commemorates the destruction of the Temples in Jerusalem and other Jewish tragedies, not Yom HaShoah.
Dr. Meir Wikler, a psychotherapist who lives in Brooklyn's Borough Park, has met with Yad Vashem officials for several years in an effort to sensitize them to the concerns of fervently Orthodox Jews. He discussed the topic with The Jewish Week.
Q: Why do haredi Jews object to Yad Vashem's presentation of the Holocaust's history? Because of what's there or what's not there?
A: There are videotaped testimonies of only two haredi survivors in the New Wing of the museum. Compared with the 50 or 60 testimonies of non-haredi survivors, it gives the mistaken impression that hardly any haredi Jews survived, and by extension, that haredi Judaism did not survive the Holocaust. And the truth is that at least half, if not more, of all survivors were haredi. And there are only scant illustrations of the countless examples of spiritual heroism, relegating that key aspect of Holocaust history to barely footnote status. The description of Harav [Rabbi] Michoel Dov Weissmandel, of blessed memory, [who led an effort to save Jews from the Holocaust] depicts him as having been naïve and duped by the Nazis. The truth is just the opposite. He was a brilliant rabbinic leader who outwitted the Nazis at every turn.
Is it just Yad Vashem, or do you take issue with the way the Orthodox experience during the Shoah is presented by most historians?
Other Holocaust museums are guilty of similar omissions and commissions. Yad Vashem, however, is the only major Holocaust museum under Jewish auspices. In addition, Yad Vashem has the documentation, artifacts and taped testimonies in their archives that could correct these distortions.
Unofficially representing the haredi population, what proposals have you made to Yad Vashem, or to other Holocaust historians? Are you satisfied with the changes that were made?
I and others have made concrete proposals to Yad Vashem; some changes have been made — some of the immodest photos that were on display when the New Wing opened six years ago have been removed. Furthermore, when the New Wing opened, there were no videotaped testimonies of haredi survivors at all. Today there are two.
There is a perception that remembering the Holocaust is not an important part of haredi life — many haredi Jews don't observe Yom HaShoah. How does your community honor the memory of the Shoah and its victims?
If Yom HaShoah observance is the only criterion used to measure Holocaust remembrance, then it is understandable why some would conclude that remembering the Holocaust is not an important part of haredi life. Haredi Jews do not observe Yom HaShoah because it was never accepted or sanctioned by haredi rabbinic leaders. Yom HaShoah is completely antithetical to the religious significance of Nisan, the Hebrew month chosen for its observance by the Knesset, even though Nisan is the month of Passover and, thus, of celebration. And the establishment of Yom HaShoah denigrates the significance of Tisha b'Av, the traditional commemoration of Jewish suffering throughout the ages.
Haredi Jews, however, choose to express their remembrance of the Holocaust in ways more meaningful to them: observing the yahrtzeits of martyrs, dedicating sifrei Torah [Torah scrolls] in honor of martyrs, donating tzedakah in the memory of martyrs, reciting Tehillim [Psalms] and studying Mishnayos [sections of Mishna] for the merit of martyrs, naming their children after martyrs, sending their children to yeshivos and Bais Yaakovs [girls schools] that include Holocaust history in the curriculum, telling and retelling their children and grandchildren inspirational stories of spiritual heroism and personal miracles experienced during the Holocaust.
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What does the egg on the Sedar Plate remind use all of ??? Life and death.
Those Korbans of the war might have given use a new leaf on life, with the rebirth of a new nation for the Jewa. Some say it is before our timeother say not. The only thing I know is the ashes of my parents family where the building blocks for our future in this modern world .......
My father, A"H survived Auschwitz along with other camps. We lost an unbelievable and larger than life man a year and a half ago. My mother survived Mathausen, along with her parents and 7 siblings. We are slowly losing all of our survivors. At this point, does it really matter that "Yom Hashoah was never accepted or sanctioned by haredi rabbinic leaders"? To say that "Yom HaShoah is completely antithetical to the religious significance of Nisan" might be true to some but again, I have to ask, does it really matter anymore, at a time when we are slowly losing the last of our survivors? Is Yom Hashoah in competition with "Tisha b'Av, the traditional commemoration of Jewish suffering throughout the ages"? The point is that we must be unified in our mourning and in our celebrations. At the very least, let us not criticize our fellow Jews for how and when they choose to commemorate and celebrate.
Remembering is very important. How each person remembers is his own personal choice. For many like my relatives who are Charedei and who lost parents and siblings, the production of Yom Hashoua in any Shule is too impersonal and too staged. To them it is an ongoing conversation trying to understand and make peace with G-d and accept his will. To them, Torah study, prayer and good deeds is how a Jew commemorates significant events. Saying "AL - Eleh ani bochiya" (for these I cry) on Tisha B'av is how they are most comfortable in dealing with their grief and the commemoration. Frankly, watching my relatives say Kaddish for their slaughtered love ones is more powerful to me than any Yom Hashoua commemoration.
This is just one more issue in which the cultural disconnect between Charedeim and the rest of the population in Israel manifests. There is nothing nefarious about what the Charedeim are doing.
Nevertheless, I would like to point out that the Halachic point about not having mourning during the joyous month of Nissan is not correct. the Omer period of Nissan has since the time of Rabbi Akiva turned into a period of mourning and the Talmud recounts days of mourning and minor holidays that were instituted and then abolished over the years. Yom Hashoua is not acceptable because the "Gedolim" do not accept it. Given the climate of separatism that permeates the Charedei world, particularly in Israel, it doesn't seem like this will soon change. At the end, Hitler's henchmen made no distinction between Charedei, Reform, Zionist or Secular. A lesson for us all!
According to Wikipedia, Yom Hashoah is a national holiday of the State of Israel, established in 1953. How that obligates Jews all over the world to observe it is unclear.
Moreover, its official name is "Yom hazikaron lashoah velagevura," "memorial day for the Holocaust and heroism." The founders of the modern State of Israel were unable to come to terms with the fact that the Jewish people had been decimated, and decided that the only good Jew was a strong one who fought for the Zionist cause (think gun-toting tractor-riding kibbutznik singing as he works with hair blowing in the wind), not the old religious European Jew of the shtetl. The purpose of this day, and even its very name, reflect that mindset.
So you can see how it might rub people the wrong way.
Speaking as a child of holocaust survivors who ended up in California, the amount of charedim in the 2 biggest communities (los angelos and san francisco) was less than 5%. I would add that maybe 50% attending an orthodox shul, and then add that about 95% of the shul goers went to work after services on shabbat.
I see this article an a way for charedim to find a legitimate excuse for not celebrating Yom HaShoah. If Yad VeShem had 50% of the testimonials from charedim, it wouldn't change anything in the charedi world.
The reason that the secular Jews can be hypocrites is because charedim see themselves as having taken the high road, the spiritual path, the path of God.
So it always saddens me that charedim have found so many ways to disconnect with the rest of Am Yisrael. Yom HaShoah, Yom Ha'Atzmaut to name just 2.
"And the truth is that at least half, if not more, of all survivors were haredi." Where and how could you come up with such a statistic? Also, who says that the "Holocaust education" in the Yeshivos and Bais Yaacov's aren't guilty of this type of one-sided education either?
"Hasidic Tales of the Holocaust" by Yaffa Eliach is filled with stories of Jewish courage and spirirtual survival under Nazi oppression.
I thought Charedim commemorate the Shoah on Asara b'Teves?
Designating Asara BeTevet, an already sad day on the Jewish calendar, as Yom hakadish, to mourn for the dead of the Shoah PRECEDED the Knesset establishment of Yom hashoah. But Israelis, defending a new country, had a hard time understanding Spiritual resistance, and how so many Jews could have gone 'like sheep to the slaughter' and it was a raging debate at the time. They identified better with the brave (but hopeless) revolt of the Warsaw Ghetto which took place at Pesach time. For them that was a natural Jewish rallying point and overrode the tradition of No Hespaidim(Eulogies) in Nissan, not even for your own parents! and it came one week before Yom ha'atzma'ut so was a natural segue - Jewish might and resistance leads to Jewish Independence! No suprise that hareidim don't identify with the mentality, but DO identify with the event.
to #1. What you choose to believe is your choice obviously. I am interested in where he got those statistics from and will keep an open mind until I am presented with the data.
#2. This article is explaining why the chareidim are not participating and what steps need to be taken so that there is some participation. Additionally, if what he claims is true, the Yad Vashem's displays are misrepresenting history. Again, I am interested in where he got those numbers from.


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The worlds(s) of Planescape When any piece of fantasy fiction is compared to Dungeons & Dragons, it's rarely a positive thing.... 2016-02-23T20:57:06+01:00 Planescape: Torment - Retrospective Review https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=34550 Phantomatica has reviewed the old classic Planescape: Torment: Torment Revisited If you're anything like me, the Early Access release of Torment: Tides of Numenera got your blood boiling, and the game's full release can't come quickly enough.... 2016-02-19T22:48:39+01:00 Original Sin - Dunamis Mod @ RPGCodex https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=33439 A new mod called Dunamis has been released for Divinity: Original Sin by SniperHF: Dunamis Features: 12 Quests with 21 total solutions and 28 total results. Varied endings based on player directed outcomes. Dense map design. 19 specifically crafted combats featuring custom stats and scripting; all designed for challenge and not filler.... 2015-10-22T22:43:34+01:00 Original Sin - The Road to Original Sin https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=33152 Eye noticed that TechRaptor created an editorial about Larian Studios' road towards Divinity: Original Sin. Beyond Divinity, a sequel set 20 years after the last game, changed things up. The roleplaying makes a return, but with a twist as you now have an inseparable companion to control and manage.... 2015-09-30T22:33:57+01:00 Larian Studios - Swen In Search of Women https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=32875 On his blog, Swen Vincke mentioned he discovered that the statistics from Kickstarter and Facebook show that only a very small portion of their visitors are women, which doesn't compute with his own experience. That experience is derived from his home situation and the women he meets on gameshows, which made him feel that at least a quarter or a third of the players are female.... 2015-09-07T22:44:06+01:00 Larian Studios - Kirill Pokrovsky RIP https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31994 The latest Original Sin Kickstarter update brings us the sad news that Kirill Pokrovsky, the composer for all Divinity games up to now has passed away yesterday. A great man, a fantastic composer and a good friend passed away yesterday. Rest in peace Kirill Pokrovsky – we will miss you.... 2015-06-02T15:48:00+01:00 Larian Studios - Interview with Swen https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31981 9Lives talk to SwenVincke about Larian Studios, that they risked the entire company during the development of Divinity Original Sin, which they also did during the development of Divinity 2 and about the plans to release a major RPG every year. The interview is in Dutch, which isn't a problem for me, but for those who don't master this language, there is always Google Translate.... 2015-06-01T12:38:21+01:00 Larian Studios - The why of Our Third Secret Project https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31820 Larian Studios' Swen Vincke also updated his blog with some background information regarding Divinity Original Sin: Enhanced Edition and why they choose Focus as a publisher. Finally, the last big reason I didn't mention yet about the why of the Enhanced Edition is the strategic one.... 2015-05-15T13:00:28+01:00 Original Sin - Something Coming Our Way https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31699 Larian Studios is now on Instagram and in their first post their they mention something is coming our way, with the following teaser: Dragon's scale and witch's hair,Take a peek soon, if you dare.Tooth of wolf and impish blood,Something wicked this way comes.... 2015-05-04T16:09:46+01:00 Larian Studios - Interview @ GamesIndustry.biz https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31393 GamesIndustry.biz published a candid interview with Swen Vincke from GDC 2015 who reflects on the success of Divinity: Original Sin, his mistakes, and Kickstarter backers. Not everyone has fun at GDC. With so many of the industry's key players concentrated in one relatively small area, there is no better time to forge alliances and seek out new opportunities.... 2015-04-10T05:51:37+01:00 Larian Studios - Making Time to Develop https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31340 Swen Vincke released a new post on his blog about finding time to develop games. In-case you missed his GDC Postmortem video this week here is the link again. I have to fight to find time to breathe these days. Things are moving so fast now and we're doing so many things simultaneously that my previous concerns over our growth scaring the hell out of me can now be considered to be a big understatement.... 2015-04-05T06:41:26+01:00 Larian Studios - GDC Postmortem Panel https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31304 Another video was released on the GDC Vault today. This time we have Swen Vincke of Larian Studios giving a Postmortem Panel about the lessons he has learned. In this talk Swen will focus on Larian's experience of successfully turning into independent and self-publishing company after 15 years of working with different publishers.... 2015-04-02T01:34:31+01:00 Black Isle - The Cancelled Planescape Game https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31259 Eurogamer has another article style interview this week with Colin McComb about the story behind Black Isle's cancelled PlayStation Planescape game. The Souls effect will reach fever pitch this week with the release of Bloodborne, and very important gaming people at lunch around the world will wonder how they can copy it.... 2015-03-29T05:49:27+01:00 Original Sin - Interview @ One Angry Gamer https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31243 One Angry Gamer interviewed Thierry Van Gyseghem who was the animator & artist for Divinity: Original Sin about Boob-Plates, Sexism And Moral Outrage. Billy: One of the things I was curious about was when the controversy broke out over the boob-plate armor, was it actually Kickstarter backers sending most of the criticisms or was it relegated to the gaming media and pockets of social media sub-communities? Thierry: The original cover art had been used for nearly a year at that point, we even had a booth on E3 2012, without a complaint.... 2015-03-28T04:56:49+01:00 Original Sin - Now Available in Italian https://www.rpgwatch.com/show/newsbit?rwsiteid=4&newsbit=31146 Larian Studios released a new video update for Divinity: Original Sin with information the game is now available to play in Italian. Thank you for the link MadGamer. loading... Divinity Original Sin is live on Steam in Italian! Made possible by fans from RPGItalia.... 2015-03-20T04:16:01+01:00


text: public policy State Supreme Court Extends Federal Ruling About Juvenile Sentencing By Wilson Sayre • Mar 20, 2015 Creative Commons via Flickr / Boston Public Library (https://flic.kr/p/dm18Ao) The Florida Supreme Court has reached a groundbreaking decision about inmates who were sentenced to mandatory life in prison without parole for crimes they committed while they were still kids. The decision makes 2012's Miller v. Alabama apply retroactively. It was a U.S. Supreme Court decision that ruled mandatory life sentences without the opportunity for release were cruel and unusual. For the past three years, 201 Florida inmates have been in a kind of limbo. They're inmates who were sentenced to life in prison without parole as juveniles before the Miller ruling. Florida Food Stamps Receive Cuts By Wilson Sayre • Nov 1, 2013 Cuts to food stamps for over 3.5 million Floridians went into effect Friday, Nov. 1. And more could be coming through the pipeline soon. Increases in food stamps, which are part of the Supplemental Nutrition Assistance Program (SNAP), were approved as part of the 2009 Recovery Act's temporary boost to the economy. And those increases have run out. For a family of four, the cuts translate to $36 per month or a total loss of $396 per year. Cuts to benefits in Florida are the third largest.


text:
Most Cited The Journal of Steroid Biochemistry and Molecular Biology Articles
The most cited articles published since 2011, extracted from Scopus.
Bisphenol A: An endocrine disruptor with widespread exposure and multiple effectsBeverly S. Rubin
Volume 127, Issues 1-2, October 2011, Pages 27-34
Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. This compound is a building block of polycarbonate plastics often used for food and beverage storage, and BPA is also a component of epoxy resins that are used to line food and beverage containers. Studies have shown that BPA can leach from these and other products in contact with food and drink, and as a result, routine ingestion of BPA is presumed. This compound is also found in an enormous number of other products that we come into contact with daily, and therefore it is not surprising that it has been detected in the majority of individuals examined. BPA is a known endocrine disruptor. Although initially considered to be a weak environmental estrogen, more recent studies have demonstrated that BPA may be similar in potency to estradiol in stimulating some cellular responses. Moreover, emerging evidence suggests that BPA may influence multiple endocrine-related pathways. Studies in rodents have identified adverse effects of BPA at levels at or below the current acceptable daily intake level for this compound. The various reported adverse effects of BPA are reviewed, and potential mechanisms of BPA action are discussed. Much more investigation is needed to understand the potential adverse health effects of BPA exposure in humans and to understand the multiple pathways through which it may act. Although many questions remain to be answered, it is becoming increasingly apparent that exposure to BPA is ubiquitous and that the effects of this endocrine disruptor are complex and wide-ranging. © 2011 Elsevier Ltd. All rights reserved.
Endocrine disrupting chemicals and disease susceptibilityThaddeus T. Schug | Amanda Janesick | Bruce Blumberg | Jerrold J. Heindel
Volume 127, Issues 3-5, November 2011, Pages 204-215
Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products - including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption. © 2010 Elsevier Ltd. All rights reserved.
Steroidogenesis in the skin: Implications for local immune functionsAndrzej Slominski | Blazej Zbytek | Georgios Nikolakis | Pulak R. Manna | Cezary Skobowiat | Michal Zmijewski | Wei Li | Zorica Janjetovic | Arnold Postlethwaite | Christos C. Zouboulis | Robert C. Tuckey
Volume 137, Issue , March 2013, Pages 107-123
The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Δ-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'. © 2013 Elsevier Ltd. All rights reserved.
Endocrine disrupting properties of perfluorooctanoic acidSally S. White | Suzanne E. Fenton | Erin P. Hines
Volume 127, Issues 1-2, October 2011, Pages 16-26
Perfluoroalkyl acids (PFAAs) have attracted attention in recent years for their environmental ubiquity, as well as their toxicity. Several PFAAs are found in human tissues globally, as humans are exposed on a daily basis through intake of contaminated food, water, and air, irrespective of proximity to industry. Perfluorooctanoic acid (PFOA) is a PFAA shown to be developmentally toxic in mice, with broad and varied health consequences that may include long-lasting effects in reproductive tissues and metabolic reprogramming. To date, the only demonstrated mode of action by which the health effects of PFOA are mediated is via the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The endogenous roles for this receptor, as well as the adverse outcomes of activation by exogenous agents during development, are currently under investigation. Recent studies suggest that PFOA may alter steroid hormone production or act indirectly, via ovarian effects, as a novel means of endocrine disruption. Here we review the existing literature on the known health effects of PFOA in animal models, focusing on sensitive developmental periods. To complement this, we also present epidemiologic health data, with the caveat that these studies largely address only associations between adult exposures and outcomes, rarely focusing on endocrine-specific endpoints, susceptible subpopulations, or windows of sensitivity. Further research in these areas is needed. © 2011 Elsevier Ltd. All rights reserved.
Aromatase, aromatase inhibitors, and breast cancerSaranya Chumsri | Timothy Howes | Ting Bao | Gauri Sabnis | Angela Brodie
Volume 125, Issues 1-2, May 2011, Pages 13-22
Estrogens are known to be important in the growth of breast cancers in both pre and postmenopausal women. As the number of breast cancer patients increases with age, the majority of breast cancer patients are postmenopausal women. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors (AIs) are now FDA approved and have been shown to be more effective than the antiestrogen tamoxifen and are well tolerated. AIs are now a standard treatment for postmenopausal patients. AIs are effective in adjuvant and first-line metastatic setting. This review describes the development of AIs and their current use in breast cancer. Recent research focuses on elucidating mechanisms of acquired resistance that may develop in some patients with long term AI treatment and also in innate resistance. Preclinical data in resistance models demonstrated that the crosstalk between ER and other signaling pathways particularly MAPK and PI3K/Akt is an important resistant mechanism. Blockade of these other signaling pathways is an attractive strategy to circumvent the resistance to AI therapy in breast cancer. Several clinical trials are ongoing to evaluate the role of these novel targeted therapies to reverse resistance to AIs. Article from the special issue on 'Targeted Inhibitors'. © 2011 Elsevier Ltd. All rights reserved.
Standardized LC-MS/MS based steroid hormone profile-analysisTherese Koal | Diane Schmiederer | Hai Pham-Tuan | Cornelia Röhring | Manfred Rauh
Volume 129, Issues 3-5, April 2012, Pages 129-138
In order to overcome many limitations of immunoassays, high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has the potential to find its place in the clinical laboratory medicine for quantification of steroid hormones. A prerequisite for the application of a new analytical procedure in clinical diagnostics is standardization to minimize analytical intra- and interlaboratory variability and inaccuracy. We evaluate a newly standardized HPLC-MS/MS assay in kit-format, developed for routine determination of 16 steroid hormones in human serum samples. Fifteen metabolites can be measured quantitatively, which include aldosterone, androstenedione, androsterone, corticosterone, cortisol, cortisone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17β-estradiol (E2), estrone (E1), etiocholanolone, 17α- hydroxyprogesterone (17OHP), progesterone, and testosterone. 11-Deoxycorticosterone is the only compound rated as semi-quantitative in this kit. The sample preparation is performed by solid phase extraction (SPE) on a 96-well plate. The standardized assay has been validated for human serum in terms of lower and upper limit of quantification (LLOQ 0.01-32 ng/mL, ULOQ 5-8000 ng/mL), linear correlation coefficient of calibration (R 2 > 0.9966), intra- and inter-day precision (intra-day 1.1-8.8%, inter-day 5.2-14.8% and 8.2-18.6% for 11-deoxycorticosterone), accuracy (intra-day 88.3-115.5% and 109.3-128.2% for 11-deoxycorticosterone, inter-day 91.4-117.2% and 102.3-137.1% for 11-deoxycorticosterone), analytical total error (3.6-17.8%), proficiency test accuracy (85.4-113.4%), recovery (68-99%), and metabolite stability (freeze/thaw stability 95.5-108.1%, short term stability 86.9-107.2%). Inter-assay comparison with a routine reference HPLC-MS/MS assay and seven immunoassays demonstrates the outstanding high performance of this HPLC-MS/MS based kit by improvements in accuracy for progesterone, androstenedione, and 17OHP. Finally, results of two metyrapone tests demonstrate the potential of the standardized HPLC-MS/MS assay for the analysis of a comprehensive steroid hormone profile in clinical diagnostics. © 2011 Elsevier Ltd.
Disruption of androgen receptor signaling in males by environmental chemicalsDoug C. Luccio-Camelo | Gail S. Prins
Volume 127, Issues 1-2, October 2011, Pages 74-82
Androgen-disruptors are environmental chemicals in that interfere with the biosynthesis, metabolism or action of endogenous androgens resulting in a deflection from normal male developmental programming and reproductive tract growth and function. Since male sexual differentiation is entirely androgen-dependent, it is highly susceptible to androgen-disruptors. Animal models and epidemiological evidence link exposure to androgen disrupting chemicals with reduced sperm counts, increased infertility, testicular dysgenesis syndrome, and testicular and prostate cancers. Further, there appears to be increased sensitivity to these agents during critical developmental windows when male differentiation is at its peak. A variety of in vitro and in silico approaches have been used to identify broad classes of androgen disrupting molecules that include organochlorinated pesticides, industrial chemicals, and plasticizers with capacity to ligand the androgen receptor. The vast majority of these synthetic molecules act as anti-androgens. This review will highlight the evidence for androgen disrupting chemicals that act through interference with the androgen receptor, discussing specific compounds for which there is documented in vivo evidence for male reproductive tract perturbations. This article is part of a Special Issue entitled 'Endocrine disruptors'. © 2011 Elsevier Ltd. All rights reserved.
Demasculinization and feminization of male gonads by atrazine: Consistent effects across vertebrate classesTyrone B. Hayes | Lloyd L. Anderson | Val R. Beasley | Shane R. De Solla | Taisen Iguchi | Holly Ingraham | Patrick Kestemont | Jasna Kniewald | Zlatko Kniewald | Valerie S. Langlois | Enrique H. Luque | Krista A. McCoy | Mónica Muñoz-De-Toro | Tomohiro Oka | Cleida A. Oliveira | Frances Orton | Sylvia Ruby | Miyuki Suzawa | Luz E. Tavera-Mendoza | Vance L. Trudeau | Anna Bolivar Victor-Costa | Emily Willingham
Volume 127, Issues 1-2, October 2011, Pages 64-73
Atrazine is the most commonly detected pesticide contaminant of ground water, surface water, and precipitation. Atrazine is also an endocrine disruptor that, among other effects, alters male reproductive tissues when animals are exposed during development. Here, we apply the nine so-called "Hill criteria" (Strength, Consistency, Specificity, Temporality, Biological Gradient, Plausibility, Coherence, Experiment, and Analogy) for establishing cause-effect relationships to examine the evidence for atrazine as an endocrine disruptor that demasculinizes and feminizes the gonads of male vertebrates. We present experimental evidence that the effects of atrazine on male development are consistent across all vertebrate classes examined and we present a state of the art summary of the mechanisms by which atrazine acts as an endocrine disruptor to produce these effects. Atrazine demasculinizes male gonads producing testicular lesions associated with reduced germ cell numbers in teleost fish, amphibians, reptiles, and mammals, and induces partial and/or complete feminization in fish, amphibians, and reptiles. These effects are strong (statistically significant), consistent across vertebrate classes, and specific. Reductions in androgen levels and the induction of estrogen synthesis - demonstrated in fish, amphibians, reptiles, and mammals - represent plausible and coherent mechanisms that explain these effects. Biological gradients are observed in several of the cited studies, although threshold doses and patterns vary among species. Given that the effects on the male gonads described in all of these experimental studies occurred only after atrazine exposure, temporality is also met here. Thus the case for atrazine as an endocrine disruptor that demasculinizes and feminizes male vertebrates meets all nine of the "Hill criteria". © 2011 Elsevier Ltd. All rights reserved.
Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cellsYa Xie | Yan Ling Wang | Li Yu | Qian Hu | Lei Ji | Yan Zhang | Qin Ping Liao
Volume 126, Issues 3-5, September 2011, Pages 113-120
Progesterone has been used in the hormonal treatment of endometrial cancer (EC) for many years, but the response rates are unsatisfying. The down-regulated progesterone receptor (PR) is the main reason for treatment failure. The insulin-like growth factor (IGF) system is related to EC risk, and IGF-I can inhibit PR transcription in breast cancer. Recent evidence suggests that metformin-combined oral contraceptives may reverse progesterone-resistant atypical endometrial hyperplasia, but the mechanism is unclear. We attempt to investigate the interaction of metformin, PR and IGF-II expression, and identify whether metformin can enhance the antitumor effect of medroxyprogesterone acetate (MPA) using Ishikawa and HEC-1B EC cell lines. We found that both IGF-I and IGF-II inhibit PR A/B mRNA and protein expression, whereas metformin markedly promotes PR expression. In parallel, IGF-II increases phosphorylation of AKT and p70S6K, while metformin increases AMPK phosphorylation and decreases p70S6K phosphorylation. The effects of metformin on PR A/B and p70S6K are partially reversed by an AMPK inhibitor. Furthermore, metformin synergistically antiproliferates MPA in two cell lines, with the peak synergy occurring with 10 μM metformin combined with 1 μM MPA (CI = 0.20448 for Ishikawa, CI = 0.12801 for HEC-1B). Our results demonstrate that metformin promotes PR expression, which can be inhibited by overexpressed IGF-II in EC. This effect is partially mediated through activating AMPK followed by inhibiting the overactivated mTOR pathway. © 2011 Elsevier Ltd. All rights reserved.
The ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 is predictive of 25-hydroxyvitamin D3 response to vitamin D3 supplementationDennis Wagner | Heather E. Hanwell | Kareena Schnabl | Mehrdad Yazdanpanah | Samantha Kimball | Lei Fu | Gloria Sidhom | Dérick Rousseau | David E C Cole | Reinhold Vieth
Volume 126, Issues 3-5, September 2011, Pages 72-77
24,25-Dihydroxyvitamin D (24,25VD) is a major catabolite of 25-hydroxyvitamin D (25VD) metabolism, and may be physiologically active. Our objectives were to: (1) characterize the response of serum 24,25VD3 to vitamin D3 (VD3) supplementation; (2) test the hypothesis that a higher 24,25VD3 to 25VD3 ratio (24,25:25VD3) predicts 25VD3 response. Serum samples (n = 160) from wk 2 and wk 6 of a placebo-controlled, randomized clinical trial of VD3 (28,000 IU/wk) were analyzed for serum 24,25VD3 and 25VD3 by mass spectrometry. Serum 24,25VD3 was highly correlated with 25VD3 in placebo- and VD3-treated subjects at each time point (p < 0.0001). At wk 2, the 24,25:25VD3 ratio was lower with VD3 than with placebo (p = 0.035). From wk 2 to wk 6, the 24,25:25VD3 ratio increased with the VD3 supplement (p < 0.001) but not with placebo, such that at wk 6 this ratio did not significantly differ between groups. After correcting for potential confounders, we found that 24,25:25VD3 at wk 2 was inversely correlated to the 25VD3 increment by wk 6 in the supplemented group (r = -0.32, p = 0.02) but not the controls. There is a strong correlation between 24,25VD 3 and 25VD3 that is only modestly affected by VD 3 supplementation. This indicates that the catabolism of 25VD 3 to 24,25VD3 rises with increasing 25VD3. Furthermore, the initial ratio of serum 24,25VD3 to 25VD3 predicted the increase in 25VD3. The 24,25:25VD3 ratio may therefore have clinical utility as a marker for VD3 catabolism and a predictor of serum 25VD3 response to VD3 supplementation. © 2011 Elsevier Ltd. All rights reserved.
FXR and PXR: Potential therapeutic targets in cholestasisJohan W. Jonker | Christopher Liddle | Michael Downes
Volume 130, Issues 3-5, July 2012, Pages 147-158
Cholestatic liver disorders encompass hepatobiliary diseases of diverse etiologies characterized by the accumulation of bile acids, bilirubin and cholesterol as the result of impaired secretion of bile. Members of the nuclear receptor (NR) family of ligand-modulated transcription factors are implicated in the adaptive response to cholestasis. NRs coordinately regulate bile acid and phospholipid transporter genes required for hepatobiliary transport, as well as the phases I and II metabolizing enzymes involved in processing of their substrates. In this review we will focus on FXR and PXR, two members of the NR family whose activities are regulated by bile acids. In addition, we also discuss the potential of pharmacological modulators of these receptors as novel therapies for cholestatic disorders. © 2011 Elsevier Ltd. All rights reserved.
Is vitamin D deficiency a major global public health problem?Cristina Palacios | Lilliana Gonzalez
Volume 144, Issue PART A, January 2014, Pages 138-145
Vitamin D deficiency is a major public health problem worldwide in all age groups, even in those residing in countries with low latitude, where it was generally assumed that UV radiation was adequate enough to prevent this deficiency, and in industrialized countries, where vitamin D fortification has been implemented now for years. However, most countries are still lacking data, particularly population representative data, with very limited information in infants, children, adolescents and pregnant women. Since the number of recent publications is escalating, with a broadening of the geographic diversity, the objective of the present report was to conduct a more recent systematic review of global vitamin D status, with particular emphasis in at risk groups. A systematic review was conducted in PubMed/Medline in April-June 2013 to identify articles on vitamin D status worldwide published in the last 10 years in apparently healthy individuals. Only studies with vitamin D status prevalence were included. If available, the first source selected was population-based or representative samples studies. Clinical trials, case-control studies, case reports or series, reviews, validation studies, letters, editorials, or qualitative studies were excluded. A total of 103 articles were eligible and included in the present report. Maps were created for each age group, providing an updated overview of global vitamin D status. In areas with available data, the prevalence of low vitamin D status is a global problem in all age groups, in particular in girls and women from the Middle East. These maps also evidenced the regions with missing data for each specific population groups. There is striking lack of data in infants, children and adolescents worldwide, and in most countries of South America and Africa. In conclusion, vitamin D deficiency is a global public health problem in all age groups, particularly in those from the Middle East. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. © 2013 Elsevier Ltd.
Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivityMegan K. Dennis | Angela S. Field | Ritwik Burai | Chinnasamy Ramesh | Whitney K. Petrie | Cristian G. Bologa | Tudor I. Oprea | Yuri Yamaguchi | Shin Ichi Hayashi | Larry A. Sklar | Helen J. Hathaway | Jeffrey B. Arterburn | Eric R. Prossnitz
Volume 127, Issues 3-5, November 2011, Pages 358-366
GPER/GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates many aspects of mammalian biology and physiology. We have previously described both a GPER-selective agonist G-1 and antagonist G15 based on a tetrahydro-3H-cyclopenta[c]quinoline scaffold. The antagonist lacks an ethanone moiety that likely forms important hydrogen bonds involved in receptor activation. Computational docking studies suggested that the lack of the ethanone substituent in G15 could minimize key steric conflicts, present in G-1, that limit binding within the ERα ligand binding pocket. In this report, we identify low-affinity cross-reactivity of the GPER antagonist G15 to the classical estrogen receptor ERα. To generate an antagonist with enhanced selectivity, we therefore synthesized an isosteric G-1 derivative, G36, containing an isopropyl moiety in place of the ethanone moiety. We demonstrate that G36 shows decreased binding and activation of ERα, while maintaining its antagonist profile towards GPER. G36 selectively inhibits estrogen-mediated activation of PI3K by GPER but not ERα. It also inhibits estrogen- and G-1-mediated calcium mobilization as well as ERK1/2 activation, with no effect on EGF-mediated ERK1/2 activation. Similar to G15, G36 inhibits estrogen- and G-1-stimulated proliferation of uterine epithelial cells in vivo. The identification of G36 as a GPER antagonist with improved ER counterselectivity represents a significant step towards the development of new highly selective therapeutics for cancer and other diseases. © 2010 Elsevier Ltd. All rights reserved.
17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: Protein structures, functions, and recent progress in inhibitor developmentSandrine Marchais-Oberwinkler | Claudia Henn | Gabriele Möller | Tobias Klein | Matthias Negri | Alexander Oster | Alessandro Spadaro | Ruth Werth | Marie Wetzel | Kuiying Xu | Martin Frotscher | Rolf W. Hartmann | Jerzy Adamski
Volume 125, Issues 1-2, May 2011, Pages 66-82
17β-Hydroxysteroid dehydrogenases (17β-HSDs) are oxidoreductases, which play a key role in estrogen and androgen steroid metabolism by catalyzing final steps of the steroid biosynthesis. Up to now, 14 different subtypes have been identified in mammals, which catalyze NAD(P)H or NAD(P)+ dependent reductions/oxidations at the 17-position of the steroid. Depending on their reductive or oxidative activities, they modulate the intracellular concentration of inactive and active steroids. As the genomic mechanism of steroid action involves binding to a steroid nuclear receptor, 17β-HSDs act like pre-receptor molecular switches. 17β-HSDs are thus key enzymes implicated in the different functions of the reproductive tissues in both males and females. The crucial role of estrogens and androgens in the genesis and development of hormone dependent diseases is well recognized. Considering the pivotal role of 17β-HSDs in steroid hormone modulation and their substrate specificity, these proteins are promising therapeutic targets for diseases like breast cancer, endometriosis, osteoporosis, and prostate cancer. The selective inhibition of the concerned enzymes might provide an effective treatment and a good alternative to the existing endocrine therapies. Herein, we give an overview of functional and structural aspects for the different 17β-HSDs. We focus on steroidal and non-steroidal inhibitors recently published for each subtype and report on existing animal models for the different 17β-HSDs and the respective diseases. Article from the Special issue on Targeted Inhibitors. © 2011 Elsevier Ltd. All rights reserved.
Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgenYuuki Ooishi | Suguru Kawato | Yasushi Hojo | Yusuke Hatanaka | Shimpei Higo | Gen Murakami | Yoshimasa Komatsuzaki | Mari Ogiue-Ikeda | Tetsuya Kimoto | Hideo Mukai
Volume 131, Issues 1-2, August 2012, Pages 37-51
The hippocampus synthesizes estrogen and androgen in addition to the circulating sex steroids. Synaptic modulation by hippocampus-derived estrogen or androgen is essential to maintain healthy memory processes. Rapid actions (1-2 h) of 17β-estradiol (17β-E2) occur via synapse-localized receptors (ERα or ERβ), while slow genomic E2 actions (6-48 h) occur via classical nuclear receptors (ERα or ERβ). The long-term potentiation (LTP), induced by strong tetanus or theta-burst stimulation, is not further enhanced by E2 perfusion in adult rats. Interestingly, E2 perfusion can rescue corticosterone (stress hormone)-induced suppression of LTP. The long-term depression is modulated rapidly by E2 perfusion. Elevation of the E2 concentration changes rapidly the density and head structure of spines in neurons. ERα, but not ERβ, drives this enhancement of spinogenesis. Kinase networks are involved downstream of ERα. Testosterone (T) or dihydrotestosterone (DHT) also rapidly modulates spinogenesis. Newly developed Spiso-3D mathematical analysis is used to distinguish these complex effects by sex steroids and kinases. It has been doubted that the level of hippocampus-derived estrogen and androgen may not be high enough to modulate synaptic plasticity. Determination of the accurate concentration of E2, T or DHT in the hippocampus is enabled by mass-spectrometric analysis in combination with new steroid-derivatization methods. The E2 level in the hippocampus is approximately 8 nM for the male and 0.5-2 nM for the female, which is much higher than that in circulation. The level of T and DHT is also higher than that in circulation. Taken together, hippocampus-derived E2, T, and DHT play a major role in modulation of synaptic plasticity. © 2011 Elsevier Ltd. All rights reserved.
Endocrine disrupting chemicals and other substances of concern in food contact materials: An updated review of exposure, effect and risk assessmentJane Muncke
Volume 127, Issues 1-2, October 2011, Pages 118-127
Food contact materials (FCM) are an underestimated source of chemical food contaminants and a potentially relevant route of human exposure to endocrine disrupting chemicals (EDCs). Quantifying the exposure of the general population to substances from FCM relies on estimates of food consumption and leaching into food. Recent studies using polycarbonate plastics show that food simulants do not always predict worst-case leaching of bisphenol A, a common FCM substance. Also, exposure of children to FCM substances is not always realistically predicted using the common conventions and thus possibly misjudged. Further, the exposure of the whole population to substances leaching into dry foods is underestimated. Consumers are exposed to low levels of substances from FCM across their entire lives. Effects of these compounds currently are assessed with a focus on mutagenicity and genotoxicity. This approach however neglects integrating recent new toxicological findings, like endocrine disruption, mixture toxicity, and developmental toxicity. According to these new toxicology paradigms women of childbearing age and during pregnancy are a new sensitive population group requiring more attention. Furthermore, in overweight and obese persons a change in the metabolism of xenobiotics is observed, possibly implying that this group of consumers is insufficiently protected by current risk assessment practice. Innovations in FCM risk assessment should therefore include routine testing for EDCs and an assessment of the whole migrate toxicity of a food packaging, taking into account all sensitive population groups. In this article I focus on recent issues of interest concerning either exposure to or effects of FCM-related substances. Further, I review the use of benzophenones and organotins, two groups of known or suspected EDCs, in FCM authorized in the US and EU. © 2010 Elsevier Ltd. All rights reserved.
An overview of current and emerging SERMsBarry S. Komm | Sebastian Mirkin
Volume 143, Issue , January 2014, Pages 207-222
Selective estrogen receptor modulators (SERMs) are compounds that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity, and are used for various indications, including treatment of breast cancer, osteoporosis, and menopausal symptoms. Endometrial safety has been a key differentiator between SERMs in clinical practice. For example, tamoxifen exhibits ER agonist activity in the uterus, resulting in an increased risk of endometrial hyperplasia and malignancy, whereas raloxifene and bazedoxifene have neutral effects on the uterus. Based on their efficacy and long-term safety, SERMs are increasingly being prescribed for women who cannot tolerate other treatment options and for younger women at an increased risk of fracture who may remain on therapy for long periods of time. Continuing advances in the understanding of SERM mechanisms of action and structural interactions with the ER may lead to the development of new agents and combinations of agents to provide optimal treatments to meet the varying needs of postmenopausal women. One such example is the tissue selective estrogen complex, which partners a SERM with 1 or more estrogens, with the aim of blending the desired estrogen-receptor agonist activities of estrogens on vasomotor symptoms, vulvar-vaginal atrophy, and loss of bone mass with the tissue selectivity of a SERM. © 2014 Elsevier Ltd.
CYP17 inhibitors for prostate cancer therapyTadas S. Vasaitis | Robert D. Bruno | Vincent C O Njar
Volume 125, Issues 1-2, May 2011, Pages 23-31
Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17, 20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors. © 2010 Elsevier Ltd. All rights reserved.
The effects of vitamin D on skeletal muscle function and cellular signalingAmie J. Dirks-Naylor | Shannon Lennon-Edwards
Volume 125, Issues 3-5, July 2011, Pages 159-168
It is thought that every cell in the body expresses the vitamin D receptor, and therefore vitamin D may play a role in health and homeostasis of every organ system, including skeletal muscle. Human, animal, and cell culture studies have collectively shown that vitamin D affects muscle strength and function. Vitamin D functions in a plethora of cellular processes in skeletal muscle including calcium homeostasis, cell proliferation, cell differentiation, fiber size, prevention of fatty degeneration, protection against insulin resistance and arachidonic acid mobilization. These processes appear to be mediated by several signaling pathways affected by vitamin D. This review aims to explore the effects of vitamin D on skeletal muscle in each model system and to delineate potential cell signaling pathways affected by vitamin D. © 2011 Elsevier Ltd. All rights reserved.
Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndromeAnnamaria Morelli | Paolo Comeglio | Sandra Filippi | Erica Sarchielli | Ilaria Cellai | Linda Vignozzi | Ravit Yehiely-Cohen | Elena Maneschi | Mauro Gacci | Marco Carini | Luciano Adorini | Gabriella B. Vannelli | Mario Maggi
Volume 132, Issues 1-2, October 2012, Pages 80-92
In the male, metabolic syndrome (MetS) is associated to an increased risk of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). A recently established rabbit model of high fat diet (HFD)-induced MetS showed hypogonadism and the presence of prostate gland alterations, including inflammation, hypoxia and fibrosis. The present study investigated whether HFD-induced MetS might also alter bladder structure and function. Testosterone and the farnesoid X receptor (FXR) agonist INT-747, were evaluated for possible effects on HFD bladder. MetS rabbits develop bladder alterations, including fibrosis (reduced muscle/fiber ratio), hypoxia [2-fold increase as compared to regular diet (RD) group], low-grade inflammation (increased leukocyte infiltration and inflammatory markers) and RhoA/ROCK hyperactivity. Bladder strips from HFD rabbits, pre-contracted with carbachol, showed an overactive response to the selective ROCK inhibitor Y-27632. All these HFD-induced bladder alterations were partially blunted by testosterone and almost completely reverted by INT-747. Both treatments prevented some MetS features (glucose intolerance and visceral fat increase), thus suggesting that their effects on bladder could be ascribed to an improvement of the metabolic and/or hypogonadal state. However, a pathogenetic role for hypogonadism has been ruled out as GnRH analog-induced hypogonadal rabbits, fed a regular diet, did not show any detectable bladder alterations. In addition, INT-747 did not revert the MetS-induced hypogonadal state. FXR mRNA was highly expressed in rabbit bladder and positively associated with visceral fat increase. A direct effect of INT-747 on bladder smooth muscle was further suggested by inhibition of RhoA/ROCK-mediated activity by in vitro experiments on isolated cells. In conclusion, HFD-related MetS features are associated to bladder derangements, which are ameliorated by testosterone or INT-747 administration. INT-747 showed the most marked effects in counteracting MetS-related RhoA/ROCK overactivity, thus opening novel therapeutic opportunities for this drug. © 2012 Elsevier Ltd. All rights reserved.
Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancerErcole L. Cavalieri | Eleanor G. Rogan
Volume 125, Issues 3-5, July 2011, Pages 169-180
Among the numerous small molecules in the body, the very few aromatic ones include the estrogens and dopamine. In relation to cancer initiation, the estrogens should be considered as chemicals, not as hormones. Metabolism of estrogens is characterized by two major pathways. One is hydroxylation to form the 2- and 4-catechol estrogens, and the second is hydroxylation at the 16α position. In the catechol pathway, the metabolism involves further oxidation to semiquinones and quinones, including formation of the catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. These electrophilic compounds react with DNA to form the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E 2)-1-N7Gua. The apurinic sites obtained by this reaction generate the mutations that may lead to the initiation of cancer. Oxidation of catechol estrogens to their quinones is normally in homeostasis, which minimizes formation of the quinones and their reaction with DNA. When the homeostasis is disrupted, excessive amounts of catechol estrogen quinones are formed and the resulting increase in depurinating DNA adducts can lead to initiation of cancer. Substantial evidence demonstrates the mutagenicity of the estrogen metabolites and their ability to induce transformation of mouse and human breast epithelial cells, and tumors in laboratory animals. Furthermore, women at high risk for breast cancer or diagnosed with the disease, men with prostate cancer, and men with non-Hodgkin lymphoma all have relatively high levels of estrogen-DNA adducts, compared to matched control subjects. Specific antioxidants, such as N-acetylcysteine and resveratrol, can block the oxidation of catechol estrogens to their quinones and their reaction with DNA. As a result, the initiation of cancer can be prevented. © 2011 Elsevier Ltd. All rights reserved.
Minireview: PPARγ as the target of obesogensAmanda Janesick | Bruce Blumberg
Volume 127, Issues 1-2, October 2011, Pages 4-8
The peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipogenesis and is medically important for its connections to obesity and the treatment of type II diabetes. Activation of this receptor by certain natural or xenobiotic compounds has been shown to stimulate adipogenesis in vitro and in vivo. Obesogens are chemicals that ultimately increase obesity through a variety of potential mechanisms, including activation of PPARγ. The first obesogen for which a definitive mechanism of action has been elucidated is the PPARγ and RXR activator tributyltin; however, not all chemicals that activate PPARγ are adipogenic or correlated with obesity in humans. There are multiple mechanisms through which obesogens can target PPARγ that may not involve direct activation of the receptor. Ligand-independent mechanisms could act through obesogen-mediated post-translational modification of PPARγ which cause receptor de-repression or activation. PPARγ is active in multipotent stem cells committing to the adipocyte fate during fat cell development. By modifying chromatin structure early in development, obesogens have the opportunity to influence the promoter activity of PPARγ, or the ability of PPARγ to bind to its target genes, ultimately biasing the progenitor pool towards the fat lineage. Obesogens that act by directly or indirectly activating PPARγ, by increasing the levels of PPARγ protein, or enhancing its recruitment to promoters of key genes in the adipogenic pathway may ultimately play an important role in adipogenesis and obesity. © 2011 Elsevier Ltd. All rights reserved.
Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: Effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeysMasuo Yamaoka | Takahito Hara | Takenori Hitaka | Tomohiro Kaku | Toshiyuki Takeuchi | Junzo Takahashi | Satoru Asahi | Hiroshi Miki | Akihiro Tasaka | Masami Kusaka
Volume 129, Issues 3-5, April 2012, Pages 115-128
Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC 50 value of orteronel for cortisol was ∼3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC. © 2012 Elsevier Ltd.
Androgen receptor in triple negative breast cancerK. M. McNamara | T. Yoda | K. Takagi | Y. Miki | T. Suzuki | H. Sasano
Volume 133, Issue 1, January 2013, Pages 66-76
The clinical management of triple negative breast cancer (TNBC) is challenging due to the relatively aggressive biological behaviour and paucity of specific targeted therapy. A subset of TNBC patients has been reported to express androgen receptor (AR) in carcinoma cells and the manipulation of androgen signalling or AR targeted therapies have been proposed. However, the biological significance of AR in TNBC has remained relatively unknown. Therefore, this review aims to summarise the reported studies assessing the rates of AR positivity in TNBC patients and androgenic effects in TNBC cell lines. The rates of AR positivity among TNBC cases varied depending on the study population (0-53% of all TNBC patients). This difference among the reported studies may be largely due to the methodological differences of analysing AR. While the majority of cell line studies suggest that androgen increase proliferation and preliminary clinical studies suggest that AR antagonists improve the prognosis of AR positive TNBC patients, cell line transfection experiments and survival analyses of histological samples suggest that the presence of AR in tumour is either benign or predicts better survival. Therefore further translational investigations regarding the mechanisms of androgen action in TNBC are required to explain this discrepancy between clinical and basic studies. © 2012 Elsevier Ltd. All rights reserved.
Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studiesDavid A. Jolliffe | Christopher J. Griffiths | Adrian R. Martineau
Volume 136, Issue 1, January 2013, Pages 321-329
Vitamin D metabolites enhance immunity to a wide range of respiratory pathogens in vitro. Numerous observational studies have investigated whether vitamin D deficiency is a risk factor for acute respiratory infection, and a number of clinical trials of vitamin D supplementation for the prevention of acute respiratory infection have recently been conducted. Syntheses of this literature are lacking. We therefore conducted a systematic review of clinical studies investigating the association between vitamin D deficiency and susceptibility to acute respiratory infection in humans. A total of 39 studies (4 cross-sectional studies, 8 case-control studies, 13 cohort studies and 14 clinical trials) satisfying review eligibility criteria were identified. Observational studies predominantly reported statistically significant associations between low vitamin D status and increased risk of both upper and lower respiratory tract infections. Results from randomised controlled trials were conflicting however, reflecting heterogeneity in dosing regimens and baseline vitamin D status in study populations. Further trials of vitamin D supplementation for the prevention of acute respiratory infection should be conducted in populations with a high prevalence of vitamin D deficiency at baseline, using doses sufficient to induce sustained elevation of serum 25-hydroxyvitamin D concentrations, and powered to detect clinically important sub-group effects. This article is part of a Special Issue entitled 'Vitamin D Workshop'. © 2012 Elsevier Ltd. All rights reserved.


text: Explore France Fact file Where to go When to go Getting there Getting around Accommodation Food and drink The media Festivals Sports Shopping Travel essentials Outdoor activities Share Prices Hotels in the budget and mid-range category are less expensive than those in many other European capitals.By contrast, the city's four- and five-star hotels are among Europe's most expensive. Smaller two-star hotels typically charge between €75 and €150 for a double room, though for something with a bit of style you'll probably have to pay in the region of €120–240. Bargains exist in the 10e, especially around place de la République, and you can also get good deals in quieter areas further out, in the 13e and 14e, south of Montparnasse. Reservations If you want to secure a really good room it's worth booking a couple of months or more ahead, as even the nicer hotels often leave their pokiest rooms at the back for last-minute reservations, and the best places will sell out well in advance in all but the coldest months. If you find yourself stuck on arrival, the main tourist office will help you find a room in a hotel or hostel free of charge. The tourist office also offers a free online reservation service (Wparis-info.com), with discounts on some hotels. Hostels Most hostels take advance bookings, including the hostel groups: FUAJ (wfuaj.fr), which is part of Hostelling International, and MIJE (wmije.com), which runs three excellent hostels in historic buildings in the Marais. (There is a third big hostel group, UCRIF, but it caters largely to groups; full details can be found online at wucrif.asso.fr.) Read More


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23 Halloween Crafts for Kids: Homemade Halloween Costume Ideas and Spooky Dcor
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Super Fun Superhero Capes
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It's so easy to become your favorite superhero all you need is a cape and an imagination. Your wildest dreams will come true when you put on these Super Fun Superhero Capes. If you're looking for some awesome craft ideas for boys, this one is a total blast. You'll be zooming around and diving to save citizens in trouble when you wear these superhero capes. These step-by-step instructions will teach you how to make a superhero cape for each and every member of the family.
Materials: Fabric Crafts, Mixed Media/Miscellaneous
Age Group: Toddlers, Preschool & Kindergarten
Time to complete: In an evening
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http://TheMMAdigest.com watch video >>
Megan Olivi talks to Dana White about everything related to UFC 133: Rashad Evans, Tito Ortiz, Vitor Belfort and more. Dana also talks about Brittney Palmer's situation with the UFC in this HeavyMMA. watch video >>
In this Gracie Breakdown Ryron and Rener analyze all the critical moments from UFC 133 - from Brian Ebersole's back mount defense to Costa Philippou's failed Omoplata attempt to Tito Ortiz's rolling watch video >>
Follow Rashad Evans as he embarks on fight week and prepares to face Tito Ortiz at UFC 133 on Saturday night. watch video >>
Rashad Evans talks with Megan Olivi about UFC 133 and facing Tito Ortiz for the second time. watch video >>
Dana White UFC 133 video blog day 3. BTS of UFC 133 press conference and UFC 133 weigh-ins. watch video >>
Tito Ortiz stepped up on just over 2 weeks notice to take the fight with Rashad Evans at UFC 133, and had a performance that earned him 'Fight of the Night' honors. Despite the effort however, Ortiz watch video >>


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Ai Wei WeiStudents discover how art can tell stories about different people, times, and places, and learn how the basic elements of art create a visual language. Art Tells a Tale encourages observation skills while enhancing vocabulary and oral-presentation skills. This tour is aligned with state content standards for history/social science for grades 2 and 4 and language arts for grades 2.
See It First
Members see it first! View select exhibitions before they open to the public during Member Previews. Upcoming Member Previews include:
L.A. Exuberance: New Gifts by Artists
October 27-28
John McLaughlin Paintings: Total Abstraction
November 10–12
Renaisaance and Reformation: German Art in the Age of Dürer and Cranach
November 17–19
Members at the Individual level and above may purchase up to two discounted General Admission guest tickets every time they visit LACMA.
LACMA Membership | 323 857-6151
Members Only
Guillermo del Toro: Members and donors may reserve free tickets for this specially ticketed exhibition. Reserve Tickets.
Read Connect, the member newsletter. (PDF 455 KB)


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HGTV is showing you low-cost DIY ideas for headboards using doors, wood, pillows, drop cloth and other items.
Add colorful charm to a kid's room or nursery with this simple, colorful mobile.
Want to make your bedroom look like a hotel room? Use these tips and tricks from designers and HGTV.
You picked the look and HGTV Magazine put it together for the DIY Network Blog Cabin 2016.
HGTV Magazine helped decorate one of the bedroom's in the 2016 DIY Network Blog Cabin. Here's how to recreate the headboard in your own home.
HGTV presents an eclectic master suite from Lauren Levant Bland, where vintage accents help create a stylish, collected look. Visit HGTV.com to see the antique trunk and other unexpected details.
With a platform bed, large area rugs and upholstered benches, this cozy French country-inspired master suite from Noelle Interiors feels truly serene. See the nautical color palette on HGTV.com.
Visit HGTV.com to see how designer Marie Flanigan layered this master bedroom with soft white furnishings and gold accents, such as a canopy bed, tufted ottoman and traditional chandelier.
Bohemian-style pillows and woven area rugs add unexpected warmth and texture to this modern white bedroom from sKout. See more of the chic yet comfortable suite on HGTV.com.
HGTV.com presents a loft-style bedroom from PRAIRIE, where vaulted ceilings and white walls pair with a mix of furniture and throws for a chic, eclectic look.
Catch up on the latest HGTV show and design news right here.
Found a living space you love in HGTV's Photo Library? Get the look in your own home with products from Wayfair.


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Visit Edmunds.com for a complete listing of local car dealerships in Springvale, Maine. Find the best deal on your next vehicle with online discount price quotes on car, truck, SUV, and minivan models. With the ability to compare prices on new and used vehicles in Springvale, Edmunds.com makes the car buying process convenient and cost-effective. Search for car dealerships in Springvale, Maine with our comprehensive dealership network and avoid the common hassles associated with car shopping.
Non Display Review Name "After a week of test driving cars we had easily narrowed it down to the Nissan Rogue. Test driving is the easy part...yesterday was the day we had to"... Read more Review by: amylynnroy
Non Display Review Name "Good salesman, knew I was hearing impaired, and treated me so. Thanks Chuck." Read more Review by: Cars12370