ALBERT

Description: Postmenopausal women have an increased risk of cardiovascular disease, and heart disease is the leading cause of death in postmenopausal American women. Conventional hormone replacement therapy has been shown to result in an increase in thrombotic events in large prospective clinical trials including HERS I, and the recently halted Women’s Health Initiative. One possible mechanism for this observed increase is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory factors. An estimated 50 million American women are peri or postmenopausal and clinical therapies for menopausal symptoms remain a significant challenge in light of the known thrombotic risks. In this prospective blinded study, we examined the short-term effect of topical progesterone cream on menopausal symptom relief in 30 healthy postmenopausal women. Potential adverse effects of topical progesterone on hemostatic and inflammatory factors and cortisol levels were also examined. Subjects were randomized to first receive either 20 mg of topical progesterone cream or placebo cream for 4 weeks. Following a subsequent 4-week washout period, subjects were crossed over to either placebo cream or active drug for an additional 4-week period. In each case, progesterone and cortisol levels were monitored by salivary sampling. Baseline values, 4-week follow-up values and end-of-study values were also obtained for the Greene Climacteric Scale, total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6. For subjects receiving 20 mg of topical progesterone cream for 4 weeks, Greene Climacteric Scale scores were consistently and significantly improved (decreased) over baseline, demonstrating significant relief from menopausal symptoms. In addition, in a subpopulation of hypercortisolemic women, topical progesterone was associated with a favorable decrease in nocturnal cortisol. Surprisingly, and in sharp contrast to earlier studies with conventional hormone replacement therapy, topical progesterone had no effect on any of the hemostatic components examined: total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, and PAI-1 levels were all unchanged. Levels of CRP, TNFα and IL-6 also remained unchanged. From this study we conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.

Description: 〈span〉Mantle lithosphere heterogeneities are well documented, are ubiquitous, and have often been thought to control lithosphere-scale deformation. Here, we explore the influence of deep scarring in crustal deformation in three dimensions by considering the Ouachita orogeny in the southeastern United States, an example of a continental collision where mantle structure is present but not previously linked to the regional crustal tectonics. We present state-of-the-art continental compressional models in the presence of inherited three-dimensional lithospheric structure. Our models find that the surface expression of the Ouachita orogeny is localized by, and projected from, the controlling mantle scarring, in keeping with geological and geophysical observations. We are able to produce a large-scale arcuate orogeny with associated basin development appropriate to the Ouachita orogeny, alongside smaller-scale crustal faulting related to the region. This study offers a new and alternative hypothesis to the tectonic history of the Ouachita orogeny, with previous research having focused exclusively on crustal structures. The findings have broad implications, demonstrating the important potential role of the mantle lithosphere in controlling crustal dynamics and highlighting the requirement to consider deeper structure and processes when interpreting tectonic evolution of lithospheric-scale deformation.〈/span〉

Description: Near-surface thrust fault splays and antithetic backthrusts at the tips of major thrust fault systems can distribute slip across multiple shallow fault strands, complicating earthquake hazard analyses based on studies of surface faulting. The shallow expression of the fault strands forming the Seattle fault zone of Washington State shows the structural relationships and interactions between such fault strands. Paleoseismic studies document an ~7000 yr history of earthquakes on multiple faults within the Seattle fault zone, with some backthrusts inferred to rupture in small (M ~5.5–6.0) earthquakes at times other than during earthquakes on the main thrust faults. We interpret seismic-reflection profiles to show three main thrust faults, one of which is a blind thrust fault directly beneath downtown Seattle, and four small backthrusts within the Seattle fault zone. We then model fault slip, constrained by shallow deformation, to show that the Seattle fault forms a fault propagation fold rather than the alternatively proposed roof thrust system. Fault slip modeling shows that back-thrust ruptures driven by moderate (M ~6.5–6.7) earthquakes on the main thrust faults are consistent with the paleoseismic data. The results indicate that paleoseismic data from the back-thrust ruptures reveal the times of moderate earthquakes on the main fault system, rather than indicating smaller (M ~5.5–6.0) earthquakes involving only the backthrusts. Estimates of cumulative shortening during known Seattle fault zone earthquakes support the inference that the Seattle fault has been the major seismic hazard in the northern Cascadia forearc in the late Holocene.

Description: 〈span〉〈div〉Abstract〈/div〉Mantle lithosphere heterogeneities are well documented, are ubiquitous, and have often been thought to control lithosphere-scale deformation. Here, we explore the influence of deep scarring in crustal deformation in three dimensions by considering the Ouachita orogeny in the southeastern United States, an example of a continental collision where mantle structure is present but not previously linked to the regional crustal tectonics. We present state-of-the-art continental compressional models in the presence of inherited three-dimensional lithospheric structure. Our models find that the surface expression of the Ouachita orogeny is localized by, and projected from, the controlling mantle scarring, in keeping with geological and geophysical observations. We are able to produce a large-scale arcuate orogeny with associated basin development appropriate to the Ouachita orogeny, alongside smaller-scale crustal faulting related to the region. This study offers a new and alternative hypothesis to the tectonic history of the Ouachita orogeny, with previous research having focused exclusively on crustal structures. The findings have broad implications, demonstrating the important potential role of the mantle lithosphere in controlling crustal dynamics and highlighting the requirement to consider deeper structure and processes when interpreting tectonic evolution of lithospheric-scale deformation.〈/span〉

Description: Plate tectonic reconstructions are usually constrained by the correlation of lineaments of surface geology and crustal structures. This procedure is, however, largely dependent on and complicated by assumptions on crustal structure and thinning and the identification of the continent-ocean transition. We identify two geophysically and geometrically similar upper mantle structures in the North Atlantic and suggest that these represent remnants of the same Caledonian collision event. The identification of this structural lineament provides a sub-crustal piercing point and hence a novel opportunity to tie plate tectonic reconstructions. Further, this structure coincides with the location of some major tectonic events of the North Atlantic post-orogenic evolution such as the occurrence of the Iceland Melt Anomaly and the separation of the Jan Mayen microcontinent. We suggest that this inherited orogenic structure played a major role in the control of North Atlantic tectonic processes.

Description: The Evergreen basin is a 40-km-long, 8-km-wide Cenozoic sedimentary basin that lies mostly concealed beneath the northeastern margin of the Santa Clara Valley near the south end of San Francisco Bay (California, USA). The basin is bounded on the northeast by the strike-slip Hayward fault and an approximately parallel subsurface fault that is structurally overlain by a set of west-verging reverse-oblique faults which form the present-day southeastward extension of the Hayward fault. It is bounded on the southwest by the Silver Creek fault, a largely dormant or abandoned fault that splays from the active southern Calaveras fault. We propose that the Evergreen basin formed as a strike-slip pull-apart basin in the right step from the Silver Creek fault to the Hayward fault during a time when the Silver Creek fault served as a segment of the main route by which slip was transferred from the central California San Andreas fault to the Hayward and other East Bay faults. The dimensions and shape of the Evergreen basin, together with palinspastic reconstructions of geologic and geophysical features surrounding it, suggest that during its lifetime, the Silver Creek fault transferred a significant portion of the ~100 km of total offset accommodated by the Hayward fault, and of the 175 km of total San Andreas system offset thought to have been accommodated by the entire East Bay fault system. As shown previously, at ca. 1.5–2.5 Ma the Hayward-Calaveras connection changed from a right-step, releasing regime to a left-step, restraining regime, with the consequent effective abandonment of the Silver Creek fault. This reorganization was, perhaps, preceded by development of the previously proposed basin-bisecting Mount Misery fault, a fault that directly linked the southern end of the Hayward fault with the southern Calaveras fault during extinction of pull-apart activity. Historic seismicity indicates that slip below a depth of 5 km is mostly transferred from the Calaveras fault to the Hayward fault across the Mission seismic trend northeast of the Evergreen basin, whereas slip above a depth of 5 km is transferred through a complex zone of oblique-reverse faults along and over the northeast basin margin. However, a prominent groundwater flow barrier and related land-subsidence discontinuity coincident with the concealed Silver Creek fault, a discontinuity in the pattern of seismicity on the Calaveras fault at the Silver Creek fault intersection, and a structural sag indicative of a negative flower structure in Quaternary sediments along the southwest basin margin indicate that the Silver Creek fault has had minor ongoing slip over the past few hundred thousand years. Two earthquakes with ~M6 occurred in A.D. 1903 in the vicinity of the Silver Creek fault, but the available information is not sufficient to reliably identify them as Silver Creek fault events.

Description: Gravity and magnetic anomalies suggest that the Olympia structure beneath the southern Puget Lowland (western Washington State, U.S.) vertically displaces Eocene Crescent Formation strata. Northeast of the Olympia structure, middle Eocene Crescent Formation is beneath 4–6 km of Paleogene–Neogene and Quaternary strata of the Tacoma basin, whereas the Crescent Formation is exposed at the surface immediately to the south. Although numerous marine seismic reflection profiles have been acquired near the surface location of the Olympia structure as defined by potential field anomalies, its tectonic character remains enigmatic, in part because inlets of southern Puget Sound are too shallow for the collection of deep-penetration marine seismic profiles across the geophysical anomalies. To supplement existing shallow-marine data near the structure, we acquired 14.6 km of land-based seismic reflection data along a profile that extends from Crescent Formation exposed in the Black Hills northward across the projected surface location of the Olympia structure. The reflection seismic data image the Crescent bedrock surface to ~1 km depth beneath the southern Tacoma basin and reveal the dip on this surface to be no greater than ~10°. Although regional potential field data show a strong linear trend for the Olympia structure that implies folding over a blind thrust and/or bedrock juxtaposed against a weakly to nonmagnetic sediment section, high-resolution magnetic anomaly analysis along the land-based profile suggests that the structure is more complex. Overall, seismic and potential-field profiles presented in this study identify only minor shallow faulting within the projected surface location of the Olympia structure. We suggest that the mapped trace of the Olympia structure along the northern flank of the Black Hills, at least within the study area, is constrained by juxtaposed normal and reversely magnetized Crescent Formation units and minor tectonic deformation of Crescent Formation bedrock.

Description: Background: Talabostat (PT-100), an orally available inhibitor of dipeptidyl peptidases, is in Phase 2 studies for B-cell malignancies and solid tumors. Talabostat increases production of cytokines and chemokines in lymph nodes and spleen, stimulating both adaptive and innate immune responses (Adams S, Cancer Research, 2004;64:5471). Talabostat may thus enhance the antibody-dependent cytotoxicity of MAbs such as rituximab. Methods: This is a Phase 1 study to evaluate the safety and activity of talabostat and rituximab in patients with indolent NHL who did not respond or progressed following rituximab. Rituximab 375mg/m2 was administered weekly x 4. Total daily doses of talabostat 400μg (n=6), 600μg (n=3), or 800μg (n=6) were administered BID for 6 days following each dose of rituximab. Cytokines and chemokines were assessed pre-, 2, and 6 hours post-talabostat on Days 1, 6, 13, 20, and 27. Flow cytometry was performed at baseline and Day 28. Clinical and laboratory evaluations were performed at specified times. Adverse events (AEs) were graded per NCI-CTC and recorded throughout the study. Disease assessments were performed on Days 28 and 84. Results: 11 men and 4 women aged 48–82 with NHL (n=10) or SLL/CLL (n=5) have been treated. 9 patients completed the 28-day study: 4 at 400μg, 1 at 600μg, and 4 at 800μg. Enrollment continues at 400μg/day. The most frequent AEs have been edema (67%), nausea (47%), dizziness (40%), hypotension (33%), fatigue (33%), vomiting (33%), constipation (33%), thrombocytopenia (27%), and weight gain (27%). Grade 3 toxicities include: dizziness, myopathy (400μg/day), and 2 events of thrombocytopenia (600μg/day). Grade 3 peripheral edema, myalgia, dehydration, electrolyte imbalance, hypereosinophilia, elevated CPK (primarily CK-MM), and rhabdomyolysis were seen in 2/6 patients at 800μg/day; these events were DLTs. One partial response (PR) lasting 7 months was seen in one patient (800μg/day). A PR was seen in a second patient at 800μg/day but did not meet the strict NCI-WG criteria for response. Elevations in cytokines 〉ULN were reported across all doses following talabostat: G-CSF (13/15), IL-1β (10/15), IL-2 (7/15), IL-6 (8/15), IL-8 (8/15), IL-10 (11/15), TNF-α (11/15), and IFN-γ (3/15). At Day 28 or early termination, CD20 was decreased in most (12/15) patients. Increases were seen in the percentage of CD3 (12/15), CD3/4 (11/15) and CD3/8 (9/15). In all 5 patients with SLL/CLL, CD5+/CD20+ was