Regulation of Estradiol Synthesis by Aromatase Interacting Partner in Breast (AIPB).

Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high levels of estradiol. Aromatase catalyzes estradiol synthesis; however, the factors regulating aromatase activity are unknown. We identified a new 22-kDa protein, aromatase interacting partner in breast (AIPB), from the endoplasmic reticulum of human breast tissue. AIPB expression is reduced in tumorigenic breast and further reduced in triple-negative tumors. Like that of aromatase, AIPB expression is induced by nonsteroidal estrogen. We found that AIPB and aromatase interact in nontumorigenic and tumorigenic breast tissues and cells. In tumorigenic cells, conditional AIPB overexpression decreased estradiol, and blocking AIPB availability with an AIPB-binding antibody increased estradiol. Estradiol synthesis is highly increased in AIPB knockdown cells, suggesting that the newly identified AIPB protein is important for aromatase activity and a key modulator of estradiol synthesis. Thus, a change in AIPB protein expression may represent an early event in tumorigenesis and be predictive of an increased risk of developing breast cancer.

Fundus Photography vs. Ophthalmoscopy Outcomes in the Emergency Department (FOTO-ED) Phase III: Web-based, In-service Training of Emergency Providers.

We evaluated a web-based training aimed at improving the review of fundus photography by emergency providers. 587 patients were included, 12.6% with relevant abnormalities. Emergency providers spent 31 minutes (median) training and evaluated 359 patients. Median post-test score improvement was 6 percentage points (IQR: 2-14; p = 0.06). Pre- vs. post-training, the emergency providers reviewed 45% vs. 43% of photographs; correctly identified abnormals in 67% vs. 57% of cases; and correctly identified normals in 80% vs. 84%. The Fundus photography vs. Ophthalmoscopy Trial Outcomes in the Emergency Department studies have demonstrated that emergency providers perform substantially better with fundus photography than direct ophthalmoscopy, but our web-based, in-service training did not result in further improvements at our institution.

Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.

Cross-beta fibrous protein aggregates (amyloids and amyloid-based prions) are found in mammals (including humans) and fungi (including yeast), and are associated with both diseases and heritable traits. The Hsp104/70/40 chaperone machinery controls propagation of yeast prions. The Hsp70 chaperones Ssa and Ssb show opposite effects on [PSI(+)], a prion form of the translation termination factor Sup35 (eRF3). Ssb is bound to translating ribosomes via ribosome-associated complex (RAC), composed of Hsp40-Zuo1 and Hsp70-Ssz1. Here we demonstrate that RAC disruption increases de novo prion formation in a manner similar to Ssb depletion, but interferes with prion propagation in a manner similar to Ssb overproduction. Release of Ssb into the cytosol in RAC-deficient cells antagonizes binding of Ssa to amyloids. Thus, propagation of an amyloid formed because of lack of ribosome-associated Ssb can be counteracted by cytosolic Ssb, generating a feedback regulatory circuit. Release of Ssb from ribosomes is also observed in wild-type cells during growth in poor synthetic medium. Ssb is, in a significant part, responsible for the prion destabilization in these conditions, underlining the physiological relevance of the Ssb-based regulatory circuit.