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Stefan O. Mueller

Bio: Stefan O. Mueller is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Estrogen receptor & Receptor. The author has an hindex of 6, co-authored 9 publications receiving 266 citations.

Papers
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Journal ArticleDOI
TL;DR: Analysis of mammary gland whole mounts showed that both stromal and epithelial ERα were required for complete mammary glands development in adult mice, however, when the mice were treated with high doses of estradiol (E2) an...
Abstract: Complete mammary gland development takes place following puberty and depends on the estrogen receptor (ER)α and the progesterone receptor (PR) and is tightly regulated by the interaction of the mammary epithelium with the stromal compartment. Studies using mammary tissues of immature mice have indicated that stromal but not epithelial ERα is required for mammary gland growth. This study investigates whether these same tissue growth requirements of neonate tissue are necessary for mammary development and response in adult mice. Mammary epithelial cells were isolated from adult mice with a targeted disruption of the ERα gene (αERKO) or from wild-type counterparts and injected into epithelial-free mammary fat pads of 3-wk-old female αERKO or wild-type mice. Ten weeks after cell injection, analysis of mammary gland whole mounts showed that both stromal and epithelial ERα were required for complete mammary gland development in adult mice. However, when the mice were treated with high doses of estradiol (E2) an...

183 citations

Journal ArticleDOI
TL;DR: In this article, the authors used the RNActive technology platform (CureVac N.V., Tubingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilised form of SARS-CoV-2 spike (S) protein encapsulated in lipid nanoparticles (LNP).
Abstract: We used the RNActive® technology platform (CureVac N.V., Tubingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV‑2 spike (S) protein encapsulated in lipid nanoparticles (LNP). This is an interim analysis of a dosage escalation phase 1 study in healthy 18–60-year-old volunteers in Hannover, Munich and Tubingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV‑2 S‑protein and receptor binding domain (RBD), and SARS-CoV‑2 neutralizing titers (MN50). In 245 volunteers who received 2 CVnCoV vaccinations (2 μg, n = 47, 4 μg, n = 48, 6 μg, n = 46, 8 μg, n = 44, 12 μg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S‑protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S‑protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 μg group. Responses to 12 μg were comparable to those observed in convalescent sera from known COVID-19 patients. In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 μg dosages elicited levels of immune responses that overlapped those observed in convalescent sera.

58 citations

Journal ArticleDOI
18 Nov 2021-Nature
TL;DR: In this paper, a head-to-head study of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in nonhuman primates was conducted.
Abstract: The CVnCoV (CureVac) mRNA vaccine for SARS-CoV-2 has recently been evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine with non-modified nucleosides but optimized non-coding regions and enhanced antigen expression. Here we report a head-to-head study of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in nonhuman primates. We immunized 18 cynomolgus macaques with two doses of 12 ug of lipid nanoparticle formulated CVnCoV, CV2CoV, or sham (N=6/group). CV2CoV induced substantially higher binding and neutralizing antibodies, memory B cell responses, and T cell responses as compared with CVnCoV. CV2CoV also induced more potent neutralizing antibody responses against SARS-CoV-2 variants, including the delta variant. Moreover, CV2CoV proved comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. While CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tract. Binding and neutralizing antibody titers correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in nonhuman primates.

49 citations

Posted ContentDOI
23 Oct 2020-bioRxiv
TL;DR: Preclinical data for clinical candidate CVnCoV, a lipid nanoparticle (LNP) encapsulated non-modified mRNA vaccine that encodes the full length, pre-fusion stabilised SARS-CoV-2 Spike (S) protein is shown, providing evidence that CVn coV represents a potent and safe vaccine candidate against Sars-Cov-2.
Abstract: The devastating SARS-CoV-2 pandemic demands rapid vaccine development and large scale production to meet worldwide needs. mRNA vaccines have emerged as one of the most promising technologies to address this unprecedented challenge. Here, we show preclinical data for our clinical candidate CVnCoV, a lipid nanoparticle (LNP) encapsulated non-modified mRNA vaccine that encodes the full length, pre-fusion stabilised SARS-CoV-2 Spike (S) protein. S translated from CVnCoV is cleaved, post-translationally modified, and presented on the cell surface, highlighting the ability of mRNA vaccines to mimic antigen presentation during viral infection. Immunisation with CVnCoV induced strong humoral responses with high titres of virus neutralizing antibodies in mice and hamsters and robust CD4+ and CD8+ T cell responses in mice. Most importantly, vaccination with CVnCoV fully protected hamster lungs from challenge with wild type SARS-CoV-2. To gain insights in the risk of vaccine-enhanced disease, hamsters vaccinated with a suboptimal dose of CVnCoV leading to breakthrough viral replication were analysed for signs of vaccine-enhanced disease. No evidence of increased viral replication or exacerbated inflammation and damage to viral target organs was detectable, giving strong evidence for a favourable safety profile of CVnCoV. Overall, data presented here provide evidence that CVnCoV represents a potent and safe vaccine candidate against SARS-CoV-2.

40 citations

Book ChapterDOI
01 Jan 2001
TL;DR: The observed physiological effects are the result of a complex interplay between the estrogen receptor, its ligand, co-regulators, and other cell signaling pathways dependent on the target tissue, as well as the cellular and genetic environment.
Abstract: Estrogenic compounds exert a vast variety of effects in wildlife and humans. Endogenous estrogens, like estradiol, regulate growth and development of their target tissues. Exogenous compounds with estrogenic and/or anti-estrogenic activities may disrupt these regulatory pathways. Environmental or industrial chemicals and phytoestrogens interfering with the hormonal or endocrine system are defined as endocrine disruptor. The estrogen receptor is the major regulatory unit within the estrogen-signaling pathway. Effects mediated by the estrogen receptor are not solely defined by its ligand by its ligand but are rather modulated by the tissue expression of the receptor, and the cellular and genetic environment. Endocrine disruptors are able to mimic estrogens by binding to the estrogen receptor and induce or inhibit estrogenic response. Phenolic compounds, pesticides, phytoestrogens, and synthetic estrogens like diethylstilbestrol are examples of endocrine disruptors or so-called endocrine active compounds. The potential of these chemicals to interfere with the endocrine system is primarily defined by their interaction with the estrogen receptor. However, the observed physiological effects are the result of a complex interplay between the estrogen receptor, its ligand, co-regulators, and other cell signaling pathways dependent on the target tissue.

34 citations


Cited by
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Journal ArticleDOI
10 Jun 2010-Nature
TL;DR: It is demonstrated that mouse mammary stem cells (MaSCs) are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors, and indicates that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.
Abstract: The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk, underpinning the benefit of endocrine therapies in the treatment of breast cancer. Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence. Conversely, there is an increased risk of breast cancer associated with pregnancy in the short term. The cellular mechanisms underlying these observations, however, are poorly defined. Here we demonstrate that mouse mammary stem cells (MaSCs) are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors. Ovariectomy markedly diminished MaSC number and outgrowth potential in vivo, whereas MaSC activity increased in mice treated with oestrogen plus progesterone. Notably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. In contrast, pregnancy led to a transient 11-fold increase in MaSC numbers, probably mediated through paracrine signalling from RANK ligand. The augmented MaSC pool indicates a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy. These findings further indicate that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.

661 citations

Journal ArticleDOI
TL;DR: All phytoestrogens tested showed reduced potencies to activate ERalpha and ERbeta compared to diethylstilbestrol on the estrogen-responsive C3 promoter compared to a consensus estrogen response element indicating a degree of promoter dependency.

502 citations

Journal ArticleDOI
TL;DR: Unique developmental features during puberty, pregnancy, lactation and post-lactation make the mammary gland a prime object to explore genetic circuits that control the specification, proliferation, differentiation, survival and death of cells.
Abstract: Unique developmental features during puberty, pregnancy, lactation and post-lactation make the mammary gland a prime object to explore genetic circuits that control the specification, proliferation, differentiation, survival and death of cells. Steroids and simple peptide hormones initiate and carry out complex developmental programmes, and reverse genetics has been used to define the underlying mechanistic connections.

489 citations

Journal ArticleDOI
15 Jun 2007-Cancer
TL;DR: Evidence to date generally supports an association between breast cancer and polycyclic aromatic hydrocarbons and polychlorinated biphenyls in conjunction with certain genetic polymorphisms involved in carcinogen activation and steroid hormone metabolism.
Abstract: Laboratory research has shown that numerous environmental pollutants cause mammary gland tumors in animals; are hormonally active, specifically mimicking estrogen, which is a breast cancer risk factor; or affect susceptibility of the mammary gland to carcinogenesis An assessment of epidemiologic research on these pollutants identified in toxicologic studies can guide future research and exposure reduction aimed at prevention The PubMed database was searched for relevant literature and systematic critical reviews were entered in a database available at URL: wwwsilentspringorg/sciencereview and URL: wwwkomenorg/environment (accessed April 10, 2007) Based on a relatively small number of studies, the evidence to date generally supports an association between breast cancer and polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in conjunction with certain genetic polymorphisms involved in carcinogen activation and steroid hormone metabolism Evidence regarding dioxins and organic solvents is sparse and methodologically limited but suggestive of an association Methodologic problems include inadequate exposure assessment, a lack of access to highly exposed and unexposed populations, and a lack of preclinical markers to identify associations that may be obscured by disease latency Among chemicals identified in toxicologic research as relevant to breast cancer, many have not been investigated in humans The development of better exposure assessment methods is needed to fill this gap In the interim, weaknesses in the epidemiologic literature argue for greater reliance on toxicologic studies to develop national policies to reduce chemical exposures that may be associated with breast cancer Substantial research progress in the last 5 years suggests that the investigation of environmental pollutants will lead to strategies to reduce breast cancer risk

463 citations

Journal ArticleDOI
TL;DR: It is shown that mammary glands reconstituted with ERα−/− mammary epithelium exposed to pregnancy hormones show increased transcription of milk protein genes, indicating that ERα signaling is not an absolute requirement for a transcriptional response toregnancy hormones.
Abstract: Estradiol is a major regulator of postnatal mammary gland development and thought to exert its effects through estrogen receptor alpha (ERalpha) expressed in the mammary gland stroma and epithelium. Previous studies, however, were confounded by the use of an ERalpha mutant strain that retains some of the protein with transactivation activity. Here, we use an ERalpha-/- mouse strain in which no ERalpha transcript can be detected to analyze mammary gland development in the complete absence of ERalpha signaling. The ERalpha-/- females show no development beyond a rudimentary ductal system. By grafting ERalpha-/- epithelium or stroma in combination with ERalpha WT stroma or epithelium, we show that the primary target for estradiol is the mammary epithelium, whereas a direct response of the mammary stroma is not required for mammary gland development to proceed normally. Mammary glands reconstituted with ERalpha-/- mammary epithelium exposed to pregnancy hormones show increased transcription of milk protein genes, indicating that ERalpha signaling is not an absolute requirement for a transcriptional response to pregnancy hormones. When ERalpha-/- mammary epithelial cells are in close vicinity to ERalpha WT cells, they proliferate and contribute to all aspects of mammary gland development, indicating that estradiol, like progesterone, orchestrates proliferation and morphogenesis by a paracrine mechanism, affecting nearby cells in the mammary epithelium.

423 citations