A phase I trial of Flavopiridol in relapsed multiple myeloma

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myelom

Long Term Therapy with Lenalidomide in a patient with POEMS Syndrome

Lenalidomide is an effective therapy against malignant plasma cells and a potent agent against proinflammatory and proangiogenic cytokines. The use of lenalidomide in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein with plasma cells, skin changes) has been reported, but its benefit in long-term use is not well established. A 55-year-old man with POEMS and debilitating polyneuropathy was treated with lenalidomide and dexamethasone followed by maintenance lenalidomide. He remains in haematologic remission and in complete recovery of functional status 3.5 years after diagnosis. This case supports the long-term use of lenalidomide in patients with POEMS syndrome

Improved Nonrelapse Mortality and Infection Rate with Lower Dose of Antithymocyte Globulin in Patients Undergoing Reduced-Intensity Conditioning Allogeneic Transplantation for Hematologic Malignancies

We sought to reduce the risk of infectious complications and nonrelapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (aGVHD) in patients undergoing reduced-intensity conditioning (RIC) transplantation. As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n = 39) to 6.0 mg/kg of ATG (r-ATG) (n = 33) in association with fludarabine (Flu) and busulfan (BU) RIC transplantation and then monitored patients for adverse events, relapse, and survival. Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in posttransplantation full donor-cell chimerism rates were observed between the 2 ATG-dose groups (P > .05). When R-ATG versus r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II-IV aGVHD (32% versus 27%; P = .73) or grade III-IV aGVHD (23% versus 11%; P = .28). However, the r-ATG group had significantly less cytomegalovirus (CMV) reactivation (64% versus 30%; P = .005) and bacterial infections (56% versus 18%; P = .001), a better 1-year cumulative incidence of NRM (18% versus 3%; P = .03), and a trend for better 1-year overall survival (OS) (64% versus 84%; P = .07) compared to R-ATG patients. A seemingly modest reduction in the dose of rabbit ATG did not compromise control of aGVHD or achievement of donor chimerism, but led to a significant decrease in the risk of serious infections and NRM in high-risk RIC allograft recipients

Regime shifts and panarchies in regional scale social-ecological water systems

In this article we summarize histories of nonlinear, complex interactions among societal, legal, and ecosystem dynamics in six North American water basins, as they respond to changing climate. These case studies were chosen to explore the conditions for emergence of adaptive governance in heavily regulated and developed social-ecological systems nested within a hierarchical governmental system. We summarize resilience assessments conducted in each system to provide a synthesis and reference by the other articles in this special feature. We also present a general framework used to evaluate the interactions between society and ecosystem regimes and the governance regimes chosen to mediate those interactions. The case studies show different ways that adaptive governance may be triggered, facilitated, or constrained by ecological and/or legal processes. The resilience assessments indicate that complex interactions among the governance and ecosystem components of these systems can produce different trajectories, which include patterns of (a) development and stabilization, (b) cycles of crisis and recovery, which includes lurches in adaptation and learning, and (3) periods of innovation, novelty, and transformation. Exploration of cross scale (Panarchy) interactions among levels and sectors of government and society illustrate that they may constrain development trajectories, but may also provide stability during crisis or innovation at smaller scales; create crises, but may also facilitate recovery; and constrain system transformation, but may also provide windows of opportunity in which transformation, and the resources to accomplish it, may occur. The framework is the starting point for our exploration of how law might play a role in enhancing the capacity of social-ecological systems to adapt to climate change

Facial appearance affects voting decisions

Human groups are unusual among primates in that our leaders are often 5 democratically selected. Many social judgements are made using only facial 6 information and here we examined the potential influence of facial perceptions 7 on leadership elections. We address this possibility using a case study of the 8 2004 US presidential candidates George Bush and John Kerry. We removed 9 recognition effects by applying the difference between their faces to a neutral, 10 unfamiliar face, and then measured how the difference in their facial 11 physiognomies influenced attributions and hypothetical voting decisions. The 12 ‘plus-Bush’ and ‘plus-Kerry’ faces were seen to possess different but 13 potentially valued leadership traits. For voting, preference for face version was 14 context-dependent. Raters preferred the plus-Bush face as a war-time leader 15 and the plus-Kerry face as a peace-time leader. We also examined voting to 16 computer graphic manipulations of masculinity showing that masculine faces 17 were voted for more in war-time and feminine faces in peace-time contexts, 18 suggesting that attitudes to sexual dimorphism in faces play an important role 19 in voting decisions. Both findings demonstrate that voter’s attitudes to the 20 physical appearance of politicians may interact with their perceptions of the 21 current political climate to determine voting behaviour. Such flexible 22 leadership choice may reflect the selection of leaders who are most beneficial 23 to the individuals of a group at a particular time or in a particular situation

One-year outcomes of the ARTISAN-SNM study with the Axonics System for the treatment of urinary urgency incontinence

Aims: Sacral neuromodulation (SNM) is a guideline-recommended treatment for voiding dysfunction including urgency, urge incontinence, and nonobstructive retention as well

The subtropical nutrient spiral

Author Posting. © American Geophysical Union, 2003. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 17 (2003): 1110, doi:10.1029/2003GB002085.We present an extended series of observations and more comprehensive analysis of a tracer-based measure of new production in the Sargasso Sea near Bermuda using the 3He flux gauge technique. The estimated annually averaged nitrate flux of 0.84 ± 0.26 mol m−2 yr−1 constitutes only that nitrate physically transported to the euphotic zone, not nitrogen from biological sources (e.g., nitrogen fixation or zooplankton migration). We show that the flux estimate is quantitatively consistent with other observations, including decade timescale evolution of the 3H + 3He inventory in the main thermocline and export production estimates. However, we argue that the flux cannot be supplied in the long term by local diapycnal or isopycnal processes. These considerations lead us to propose a three-dimensional pathway whereby nutrients remineralized within the main thermocline are returned to the seasonally accessible layers within the subtropical gyre. We describe this mechanism, which we call “the nutrient spiral,” as a sequence of steps where (1) nutrient-rich thermocline waters are entrained into the Gulf Stream, (2) enhanced diapycnal mixing moves nutrients upward onto lighter densities, (3) detrainment and enhanced isopycnal mixing injects these waters into the seasonally accessible layer of the gyre recirculation region, and (4) the nutrients become available to biota via eddy heaving and wintertime convection. The spiral is closed when nutrients are utilized, exported, and then remineralized within the thermocline. We present evidence regarding the characteristics of the spiral and discuss some implications of its operation within the biogeochemical cycle of the subtropical ocean.This work was supported by grants from the National Science Foundation (OCE-0221247) and NSF/ONR NOPP (N000140210370)

Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing

Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection