Androgen receptor (AR)‐dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR ...antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small‐molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen‐dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second‐generation AR antagonists.
Making the problem go away: Most prostate tumor growth is driven by the action of the androgen receptor (AR). Resistance to current chemotherapies for prostate cancer can occur when the androgen receptor is either overexpressed or mutated. Coupling of an AR agonist to an adamantyl “hydrophobic tag” resulted in a molecule that induces AR degradation, even in drug‐resistant prostate tumor cells.
Drugs that inhibit estrogen receptor alpha (ERα) or that block the production of estrogens remain frontline interventions in the treatment and management of breast cancer at all stages. However, ...resistance to endocrine therapies, especially in the setting of advanced disease, remains an impediment to durable clinical responses. Although the mechanisms underlying resistance to existing agents are complex, preclinical studies suggest that selective estrogen receptor downregulators (SERDs), molecules which eliminate ERα expression, may have particular utility in the treatment of breast cancers that have progressed on tamoxifen and/or aromatase inhibitors. The discovery and development of orally bioavailable SERDs provide the opportunity to evaluate the utility of eliminating ERα expression in advanced metastatic breast cancers.
The pH of beverages in the United States Reddy, Avanija; Norris, Don F; Momeni, Stephanie S ...
The Journal of the American Dental Association (1939),
04/2016, Letnik:
147, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Dental erosion is the chemical dissolution of tooth structure in the absence of bacteria when the environment is acidic (pH < 4.0). Research indicates that low pH is the primary determinant of a ...beverage's erosive potential. In addition, citrate chelation of calcium ions may contribute to erosion at higher pH. The authors of this study determined the erosive potential measured by the pH of commercially available beverages in the United States.
The authors purchased 379 beverages from stores in Birmingham, Alabama, and categorized them (for example, juices, sodas, flavored waters, teas, and energy drinks) and assessed their pH. They used a pH meter to measure the pH of each beverage in triplicate immediately after it was opened at a temperature of 25°C. The authors recorded the pH data as mean (standard deviation).
Most (93%, 354 of 379) beverages had a pH of less than 4.0, and 7% (25 of 379) had a pH of 4.0 or more. Relative beverage erosivity zones based on studies of apatite solubility in acid indicated that 39% (149 of 379) of the beverages tested in this study were considered extremely erosive (pH < 3.0), 54% (205 of 379) were considered erosive (pH 3.0 to 3.99), and 7% (25 of 379) were considered minimally erosive (pH ≥ 4.0).
This comprehensive pH assessment of commercially available beverages in the United States found that most are potentially erosive to the dentition.
This study's findings provide dental clinicians and auxiliaries with information regarding the erosive potential of commercially available beverages. Specific dietary recommendations for the prevention of dental erosion may now be developed based on the patient's history of beverage consumption.
Estrogen regulates a plethora of functionally dissimilar processes in a broad range of tissues. Recent progress in the study of the molecular mechanism of action of estrogen(s) has revealed why ...different cells can respond to the same hormone in a different manner. Three of these findings are of particular importance: (i) There are two genetically and functionally distinct estrogen receptors that have distinct expression patterns in vivo; (ii) the positive and negative transcriptional activities of these receptors require them to engage transcription cofactors (coactivators or corepressors) in target cells; and (iii) not all cofactors are functionally equivalent, nor are they expressed in the same manner in all cells. Thus, although the estrogen receptor is required for a cell to respond to an estrogenic stimulus, the nature and extent of that response are determined by the proteins, pathways, and processes with which the receptor interacts.
To assess the impact of an estrogenic wastewater treatment plant (WWTP) effluent on fish reproduction, white suckers (Catostomus commersoni) were collected from immediately upstream and downstream ...(effluent site) of the city of Boulder, CO, WWTP outfall. Gonadal intersex, altered sex ratios, reduced gonad size, disrupted ovarian and testicular histopathology, and vitellogenin induction consistent with exposure to estrogenic wastewater contaminants were identified in white suckers downstream from the WWTP outfall and not at the upstream site. The sex ratio was female-biased at the effluent site in both the fall of 2003 and the spring of 2004; the frequency of males at the effluent site (17-21%) was half that of the upstream site (36-46%). Intersex white suckers comprised 18-22% of the population at the effluent site. Intersex fish were not found at the upstream site. Chemical analyses determined that the WWTP effluent contained a complex mixture of endocrine-active chemicals, including 17beta-estradiol (E2) 17alpha-ethynylestradiol, alkylphenols, and bisphenol A resulting in an estimated total estrogen equivalence of up to 31 ng E2 L(-1). These results indicate that the reproductive potential of native fishes may be compromised in wastewater-dominated streams.
HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate ...gland. We demonstrate here that, in prostate cancer cells, HOXB13 is a key determinant of the response to androgens. Specifically, it was determined that HOXB13 interacts with the DNA-binding domain of AR and inhibits the transcription of genes that contain an androgen-response element (ARE). In contrast, the AR:HOXB13 complex confers androgen responsiveness to promoters that contain a specific HOXB13-response element. Further, HOXB13 and AR synergize to enhance the transcription of genes that contain a HOX element juxtaposed to an ARE. The profound effects of HOXB13 knockdown on androgen-regulated proliferation, migration, and lipogenesis in prostate cancer cells highlight the importance of the observed changes in gene expression.
Distinct magnetic properties of marine sediments that record the Palaeocene–Eocene thermal maximum (PETM) have been suggested to be due to a bacterial magnetofossil signal that is linked to enhanced ...weathering conditions during the PETM. We document the dominance of bacterial magnetite in deep-sea sediments from southern Kerguelen Plateau (Ocean Drilling Program Hole 738C, southern Ocean) not only during the PETM, but also before and after the thermal event. This occurrence of magnetofossils throughout the PETM indicates that the occurrence of bacterial magnetosomes is not due to a preservation effect. Instead, we suggest that it is due to sustained mild iron-reducing conditions that dissolved the most labile aeolian-derived iron, which favoured continued magnetotactic bacterial activity without being strong enough to dissolve the less reactive magnetite and haematite. Enhanced aeolian haematite abundances at the beginning of the PETM indicate drier conditions on the neighbouring Antarctic continent at those times. Our results provide evidence that iron fertilisation by aeolian dust was the main limiting factor that conditioned proliferation of magnetotactic bacteria in the deep sea at the southern Kerguelen Plateau, with the exception of two short periods of rapidly changing palaeoenvironmental conditions at the onset and termination of the PETM. Increased iron supply from aeolian dust, that enhanced oceanic primary productivity and subsequent delivery of organic carbon to the seafloor, along with mild iron-reducing diagenetic conditions, seem to have been necessary to provide the iron needed for magnetite biomineralization by magnetotactic bacteria to drive their marked increase in abundance in the studied PETM record from southern Kerguelen Plateau. Our analyses of a deep-sea PETM record from Hole 1051B at Blake Nose (Atlantic Ocean) failed to identify magnetofossils despite evidence for the occurrence of magnetite and haematite of probable aeolian origin. Contrasting magnetic properties at these PETM sections indicate that further work is needed to understand the palaeoenvironmental and diagenetic factors whose interactions lead to production and preservation of magnetofossils in deep-sea sediments.
► Bacterial magnetite within and around PETM sediments in Kerguelen Plateau. ► Aeolian haematite has been identified to indicate drier conditions in Antarctica at the onset of PETM. ► Magnetofossil concentrations mainly mimic changes in aeolian haematite contents. ► Iron fertilisation by dust drives proliferation of magnetotactic bacteria throughout most of the PETM. ► A complex interplay of factors drives production and preservation of magnetofossils.
Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ...ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer.
SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy-resistant ESR1(+) breast cancer.
The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone.
A SERD- or SSH-palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. See related commentary by DeMichele and Chodosh, p. 4999.
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