Cryogenic cave carbonate and implications for thawing permafrost at Winter Wonderland Cave, Utah, USA.

Winter Wonderland Cave contains perennial ice associated with two types of cryogenic cave carbonate (CCC) formed during the freezing of water. CCCfine is characterized by relatively high δ13C values, whereas CCCcoarse exhibits notably low δ18O values indicating precipitation under (semi)closed-system conditions in a pool of residual water beneath an ice lid. Previous work has concluded that CCCcoarse forms during permafrost thaw, making the presence of this precipitate a valuable indicator of past cryospheric change. Available geochronologic evidence indicates that CCC formation in this cave is a Late Holocene or contemporary process, and field observations suggest that the cave thermal regime recently changed in a manner that permits the ingress of liquid water. This is the first documented occurence of CCCcoarse in the Western Hemisphere and one of only a few locations where these minerals have been found in association with ice. Winter Wonderland Cave is a natural laboratory for studying CCC genesis.

Status of Pharmacy Ethics Education in Australia and New Zealand.

Objective. To explore models of teaching in, resources available to, and delivery of a standardized course in pharmacy ethics. Methods. An email invitation was sent to the educator responsible for teaching pharmacy ethics at each of 19 institutions in Australia and New Zealand. Over a six- to eight-week period, semi-structured interviews were conducted in person, by email, or by phone, and were audio-recorded where possible, transcribed verbatim, and entered into data analysis software. Using an inductive analysis approach, themes related to the topics and issues discussed in the interview process were identified. Results. Of the educators invited to participate, 17 completed an interview and were included in this study. Participants reported a paucity of resources available for teaching pharmacy ethics at schools in Australia and New Zealand. Compounding this issue was the lack of expertise and ad-hoc process educators used to create their courses. Assessment methods varied between institutions. Participants felt schools needed to move toward a more standardized pharmacy ethics course with clear and defined guidelines. Conclusion. This study identified many areas in pharmacy ethics that need improvement and revealed the need to develop resources and course structure that adhere to the highest level of Miller's pyramid, while using known frameworks to evaluate ethical competency.

Application of 21-gene recurrence score results and ASTRO suitability criteria in breast cancer patients treated with intraoperative radiation therapy (IORT).

BACKGROUND: American Society for Radiation Oncology (ASTRO) suitability criteria for accelerated partial breast irradiation (APBI) and the 21-gene recurrence score (RS) were evaluated for prognostic and predictive benefit in IORT patients. METHODS: Outcomes of 184 patients completing IRB approved IORT protocol were retrospectively reviewed. Data included demographics, histopathology, RS, adjuvant therapy, locoregional (LRR) and distant recurrences (DR), and breast cancer-specific survival. RESULTS: There were 10 (5.4%) breast cancer recurrences, including one breast cancer-specific death. All 184 patients were classified by ASTRO suitability criteria (suitable: 64% (5 LRR), cautionary: 30% (3 LRR), unsuitable: 6.0% (1 LRR, 1 DR leading to death). RS were available in 114 estrogen receptor positive patients (<11: 22% (1 LRR), 11-25: 63% (1 LRR), 26-30: 9%, >30: 6%). Mean follow-up was 55 months. CONCLUSIONS: ASTRO suitability criteria for APBI and RS were useful in making prognostic and therapeutic recommendations for patients considering IORT.

Exposure from the large C-arm versus the mini C-arm using hand/wrist and elbow phantoms.

PURPOSE: This study tests the conventional wisdom that using fluoroscopy under identical geometrical conditions results in less radiation when using the mini C-arm relative to the large C-arm. METHODS: We evaluated the radiation dose for both direct exposure and scatter 2.54 cm outside the intensifier. We used 3 mini and 3 large C-arms in a vertical orientation with the image intensifier below the specimen and the source above. We used 2 specimens: a cadaver hand/wrist and a cadaver elbow. Specimens were tested both directly on the intensifier and on a hand table placed on the intensifier. RESULTS: For the same setup, use of the mini C-arm resulted in direct patient radiation exposure greater than the exposure delivered by the large C-arm. Specifically, exposure using the mini C-arm was 53% to 70% greater than that using the large C-arm. In addition, use of the hand table resulted in exposure 80% to 94% greater compared with placing the specimen directly on the intensifier. In all cases, scatter at 2.54 cm from the intensifier resulted in an average exposure of 1.5% (SD, 0.24%) of the direct beam. Tube current, and therefore machine radiation output, was approximately 13 to 14 times greater for the large C-arm. CONCLUSIONS: Direct radiation exposure to the patient and scatter to the surgeon are minimized when the C-arm is positioned with the intensifier below and the extremity is placed directly on the intensifier. Under identical geometrical conditions with the intensifier below the specimen, the large C-arm with its greater source to image intensifier distance is associated with less radiation exposure than the mini C-arm.

Anthranilamide inhibitors of factor Xa.

SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.

Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition.

Transforming growth factor beta (TGF-beta) signaling pathways regulate a wide variety of cellular processes including cell proliferation, differentiation, extracellular matrix deposition, development, and apoptosis. TGF-beta type-I receptor (TbetaRI) is the major receptor that triggers several signaling events by activating downstream targets such as the Smad proteins. The intracellular kinase domain of TbetaRI is essential for its function. In this study, we have identified a short phospho-Smad peptide, pSmad3(-3), KVLTQMGSPSIRCSS(PO4)VS as a substrate of TbetaRI kinase for in vitro kinase assays. This peptide is uniquely phosphorylated by TbetaRI kinase at the C-terminal serine residue, the phosphorylation site of its parent Smad protein in vivo. Specificity analysis demonstrated that the peptide is phosphorylated by only TbetaRI and not TGF-beta type-II receptor kinase, indicating that the peptide is a physiologically relevant substrate suitable for kinetic analysis and screening of TbetaRI kinase inhibitors. Utilizing pSmad3(-3) as a substrate, we have shown that novel pyrazole compounds are potent inhibitors of TbetaRI kinase with K(i) value as low as 15 nM. Kinetic analysis revealed that these pyrazoles act through the ATP-binding site and are typical ATP competitive inhibitors with tight binding kinetics. More importantly, these compounds were shown to inhibit TGF-beta-induced Smad2 phosphorylation in vivo in NMuMg mammary epithelial cells with potency equivalent to the inhibitory activity in the in vitro kinase assay. Cellular selectivity analysis demonstrated that these pyrazoles are capable of inhibiting activin signaling but not bone morphogenic protein or platelet-derived growth factor signal transduction pathways. Further functional analysis revealed that pyrazoles are capable of blocking the TGF-beta-induced epithelial-mesenchymal transition in NMuMg cells, a process involved in the progression of cancer, fibrosis, and other human diseases. These pyrazoles provide a foundation for future development of potent and selective TbetaRI kinase inhibitors to treat human disease.

Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.

We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.

Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.