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The article reports on an aerial survey of waterbird breeding colonies in the Gulf Plains region in Queensland, Australia by the Carpentaria Land Council Aboriginal Corporation from 2009- 2013. The survey covered 32 active colonies with 28 colonies described for the first time. Eleven species of waterbird were recorded, mostly in terms of colony dimensions with estimates varying from hundreds to 10,000 breeding pairs. The most abundant species was the Intermediate Egret (Ardea intermedia).

Panobinostat is an oral pan-deacetylase inhibitor that synergizes with bortezomib to inhibit both the aggresome and proteasome pathways in preclinical studies. PANORAMA 2 is a phase 2 trial of panobinostat in combination with bortezomib and dexamethasone to treat patients with relapsed and bortezomib-refractory multiple myeloma (with >2 prior lines of therapy, including an immunomodulatory drug, and patients who had progressed on or within 60 days of the last bortezomib-based therapy). Fifty-five heavily pretreated patients were enrolled (median, 4 prior regimens, including a median of 2 prior bortezomib-containing regimens). The overall response rate was 34.5% (1 near-complete response and 18 partial responses). An additional 10 patients achieved minimal response, for a clinical benefit rate of 52.7%. Median exposure and progression-free survival were 4.6 and 5.4 months, respectively. In patients who achieved a response, median time to response was 1.4 months, and median duration of response was 6.0 months. Common grade 3/4 adverse events, regardless of study drug relationship, included thrombocytopenia (63.6%), fatigue (20.0%), and diarrhea (20.0%). Only 1 patient had grade 3 peripheral neuropathy. Panobinostat, when combined with bortezomib and dexamethasone, can recapture re sponses in heavily pretreated, bortezomib-refractory multiple myeloma patients. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Al‐Ani et al and Prentice et al papers. To view these articles, visit https://doi.org/10.1111/apt.15779 and https://doi.org/10.1111/apt.16065 [ABSTRACT FROM AUTHOR]

Abstract: Histone deacetylases (HDACs) mediate protein acetylation states, which in turn regulate normal cellular processes often dysregulated in cancer. These observations led to the development of HDAC inhibitors that target tumors through multiple effects on protein acetylation. Clinical evidence demonstrates that treatment with HDAC inhibitors (such as vorinostat, panobinostat, and romidepsin) in combination with other antimyeloma agents (such as proteasome inhibitors and immunomodulatory drugs) has promising antitumor activity in relapsed/refractory multiple myeloma patients. This mini-review highlights the role of protein acetylation in the development of cancers and the rationale for the use of HDAC inhibitors in this patient population. [Copyright &y& Elsevier]

This phase 1 dose-escalation study determined the maximum tolerated dose (MTD) of oral pomalidomide (4 dose levels) administered on days 1 to 21 of each 28-day cycle in patients with relapsed and refractory multiple myeloma (RRMM). After four cycles, patients who progressed or had not achieved minimal response (serum and urine M-protein reduction of ≥ 25% and ≥ 50%) could receive dexamethasone 40 mg per week. Safety and efficacy were evaluated. Thirty-eight patients who had received both bortezomib and lenalidomide (median 6 prior therapies) were enrolled; 63% were refractory to both lenalidomide and bortezomib. There were four dose-limiting toxicities (grade 4 neutropenia) at 5 mg per day and so the MTD was 4 mg per day. Rates of peripheral neuropathy and venous thromboembolism were low (⩽ 5%). Among the 38 patients enrolled (including 22 with added dexamethasone), 42% achieved minimal response or better, 21% achieved partial response or better, and 3% achieved complete response. Median duration of response, progression-free survival, and overall survival were 4.6, 4.6, and 18.3 months, respectively. Pomalidomide 4 mg per day on days 1 to 21 of each 28-day cycle, with or without dexamethasone (40 mg/week), has encouraging activity with manageable toxicity in RRMM, including those refractory to both lenalidomide and bortezomib. This study is registered at http://www.clinicaltrials.gov as #NCT00833833. [ABSTRACT FROM AUTHOR]

Branching river networks are one of the most widespread and recognizable features of Earth's landscapes and have also been discovered elsewhere in the Solar System. But the mechanisms that create these patterns and control their spatial scales are poorly understood. Theories based on probability or optimality have proven useful, but do not explain how river networks develop over time through erosion and sediment transport. Here we show that branching at the uppermost reaches of river networks is rooted in two coupled instabilities: first, valleys widen at the expense of their smaller neighbours, and second, side slopes of the widening valleys become susceptible to channel incision. Each instability occurs at a critical ratio of the characteristic timescales for soil transport and channel incision. Measurements from two field sites demonstrate that our theory correctly predicts the size of the smallest valleys with tributaries. We also show that the dominant control on the scale of landscape dissection in these sites is the strength of channel incision, which correlates with aridity and rock weakness, rather than the strength of soil transport. These results imply that the fine-scale structure of branching river networks is an organized signature of erosional mechanics, not a consequence of random topology. [ABSTRACT FROM AUTHOR]

The combination of lenalidomide-dexamethasone is active in multiple myeloma ( MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose ( MTD) of perifosine-lenalidomide-dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50-100 mg daily and lenalidomide 15-25 mg once daily on days 1-21 of each 28-d cycle, plus dexamethasone 20-40 mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3-4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5-89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine-lenalidomide-dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM. [ABSTRACT FROM AUTHOR]

Motivations for preservice teachers'' choice of teaching as a career were investigated using the Factors Influencing Teaching Choice scale (FIT-Choice scale; ). This scale was initially developed and validated in the Australian context; our study applied it across international samples from Australia, the United States, Germany, and Norway. Support for strong factorial invariance implied the scale functioned similarly, and could fruitfully be employed in different contexts. Sample comparisons revealed that motivations for teaching were more similar than they were different across these samples; whereas, perceptions about the teaching profession tended to reflect country differences. [Copyright &y& Elsevier]

Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib and MLN9708, and trials investigating these "second-generation" Pis in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of Pis in the treatment of MM, focusing on developments over the past decade. (Blood. 2012;120(5):947-959) [ABSTRACT FROM AUTHOR]

1. Plant establishment is critical for community assembly, but mechanisms regulating establishment can be obscured by covarying influences of incoming seed diversity and fine-scale spatial environmental heterogeneity (microhabitat heterogeneity). Both can maximize establishment, depending on whether species differences or environmental variability more fundamentally structures plant communities. 2. We experimentally assembled limestone-pavement herb communities to examine the relative effects of seed diversity and microhabitat heterogeneity on establishment. This included testing (i) whether effects of seed diversity strengthen with heterogeneity, as would be expected if potential niche differences are more strongly expressed in more heterogeneous environments and (ii) whether a greater number of incoming species can establish in more heterogeneous environments due to environmental filtering. Species interaction theory predicts that increased facilitation and niche complementarity with realized diversity has the potential to increase overall community density. 3. Heterogeneity operated independently of seed biodiversity and explained establishment even when spatially averaged microhabitat conditions were accounted for. Homogeneous plots sown with six species supported establishment of plant density that could be increased c. 10% by doubling added seed diversity (while holding heterogeneity constant), but increased c. 40% by holding seed diversity constant and maximizing heterogeneity. 4. Ordinations revealed that species establishment was sorted by gradients in soil pH and surface cover by moss, litter and open bedrock. Regressions indicated more species established in plots featuring a greater diversity of surface cover types and/or greater soil depth variability. Community density increased with established richness, and heterogeneity ceased to explain variance in density once established richness was included as an explanatory variable. All but one of the sown species exhibited increased population density with increased plot richness. 5. Synthesis: Community density in a high-stress environment increased with both fine-scale spatial heterogeneity and added seed diversity. However, these effects were independent of one another, and impacts of heterogeneity were stronger than those of seed diversity. Our results suggest heterogeneity promotes density indirectly, through downstream effects of enhanced establishment diversity such as facilitation. These findings confirm establishment-stage interrelationships among biodiversity, density and heterogeneity as overlooked determinants of community structure by providing important field support for ideas primarily tested in the greenhouse. [ABSTRACT FROM AUTHOR]

Species interactions affect plant diversity through the net effects of competition and facilitation, with the latter more prevalent in physically stressful environments when plant cover ameliorates abiotic stress. One explanation for species loss in invader-dominated systems is a shift in the competition-facilitation balance, with competition intensifying in areas formerly structured by facilitation. We test this possibility with a 10-site prairie meta-experiment along a 500-km latitudinal stress gradient, quantifying the relationships among abiotic stress, exotic dominance, and native plant recruitment over five years. The latitudinal gradient is inversely correlated with abiotic stress, with lower latitudes more moisture- and nutrient-limited. We observed strong negative effects by invasive dominant grasses on plant establishment, but only in northern sites with lower-stress environments. At these locations, disturbance was critical for recruitment by reducing the suppressive dominant (invasive) canopy. In more stressful environments to the south, the impacts of the dominant invaders on plant establishment became facilitative, and diversity was more limited by seed availability. Disturbance prevented recruitment because seedling survival depended on a protective plant canopy, presumably because the canopy reduced temperature or moisture stress. Seed limitation was similarly prevalent in all sites. Our work confirms the importance of facilitation as an organizing process for plants in higher-stress environments, even with transformations of species composition and dominance. It also demonstrates that the mechanisms regulating diversity, including invader impacts, can vary within the same plant community depending on environmental context. Because limits on native plant recruitment are environmentally contingent, management strategies that seek to increase diversity, including invader eradication, must account for site-level variations in the balance between biotic and abiotic constraints. [ABSTRACT FROM AUTHOR]

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year. In 2004, the patient relapsed and was enrolled in a phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and refractory MM. After eight cycles of study treatment, the patient achieved a minimal response. The patient received a total of 90 cycles of treatment with lenalidomide 5 mg given for 14 d every 21 d, and 1 mg/m2 of bortezomib initially given on days 1, 4, 8, and 11 for the first 20 cycles, and then weekly thereafter on days 1 and 8. Bortezomib was discontinued after 90 cycles, and the patient continued to receive lenalidomide monotherapy. As of cycle 100, the patient achieved a PR. Currently, she is clinically stable with response sustained for over 7 yrs. Therapy has been well tolerated with no significant long-term toxicity; no dose reductions of lenalidomide and bortezomib were required. The excellent tolerability of this steroid-free approach and the durable response seen underscore the potential benefits of participating in early-phase clinical trials evaluating novel therapies and new drug combinations. This case further supports that combination treatment with lenalidomide and bortezomib is an effective therapy in the management of patients with relapsed and refractory MM. [ABSTRACT FROM AUTHOR]

This paper presents a dynamic recurrent neuro-fuzzy system (DRNFS) with short memory for obstacle avoidance of mobile robots in unknown environments. The DRNFS is developed to avoid obstacles through supervised learning from a set of obstacle-avoidance trajectories provided by a human driver. The feedback connections added in the second layer of the DRNFS make the system cope with temporal problems, which allows the robot to memorize the previous environment information. The parameters and structure of the DRNFS can be automatically optimized through the learning process. The parameter optimization is realized by the ordered derivative algorithm, and the structure simplification is completed by the fuzzy rules similarity measure. Simulation results are presented to verify the feasibility of the proposed system. [ABSTRACT FROM AUTHOR]

In a retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory multiple myeloma (MM; Ν = 3846), the overall incidence rate (IR, events per 100 patientyears) of second primary malignancies (SPMs) was 3.62. IR of invasive (hematologic and solid tumor) SPMs was 2.08, consistent with the background incidence of developing cancer. In a separate analysis of pooled data from pivotal phase 3 trials of relapsed or refractory MM (N = 703), the overall IR of SPMs was 3.98 (95% confidence interval [CI], 2.51- 6.31) with lenalidomide/dexamethasone and 1.38 (95% CI, 0.44-4.27) with placebo/ dexamethasone; IRs of nonmelanoma skin cancers were 2.40 (95% CI, 1.33-4.33) and 0.91 (95% CI, 0.23-3.66), respectively; IRs of invasive SPMs were 1.71 (95% CI, 0.86-3.43) and 0.91 (95% CI, 0.23-3.66), respectively. The risk of SPMs must be taken into account before initiating lenalidomide treatment. In the context of the observed survival benefit in relapsed or refractory MM patients, the benefit/risk profile of lenalidomide/dexamethasone remains positive. [ABSTRACT FROM AUTHOR]

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease. [ABSTRACT FROM AUTHOR]

Promotional upgrades to auction listings are now a ubiquitous feature of auction Web sites. We examine 705 auctions of a single consumer-electronic product on eBay and test whether use of various promotions results in a greater probability of sale or a higher realized price. We find that promotions that focus on display enhancements, such as border, bold, or highlight, are not worth the cost. However, the subtitle promotional tool is effective and worth the cost. We also find interesting results regarding seller reputation: although seller reputation does not increase the probability of a sale overall, it can result in higher realized price if a reputable seller is selected. Implications for promoting on eBay are discussed. [ABSTRACT FROM AUTHOR]

This study draws on signaling theory to test whether seller and product characteristics impact the use of display-type versus informational-type promotion on eBay. The authors predict that display-type promotion is used by less-experienced sellers who cannot promote on the basis of their own seller ratings. The authors predict that experienced sellers, on the other hand, prefer informational promotion since their high ratings make seller-provided statements more credible. In addition to seller characteristics, the authors predict that product characteristics, such as price and product condition, also impact promotion. It is expected that higher prices drive greater investments in display-type promotions overall, even if such promotion is less effective. Finally, it is hypothesized that the better the condition of the product, the greater the use of informational promotion since this kind of disclosure is especially influential. The hypotheses were tested using a large data set of auction data from eBay and received excellent support. Implications and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant signalling through central 5-HT2C receptor pathways has been implicated in various psychiatric disorders but this has not been amenable to experimental investigation in the absence of a valid in-vivo biomarker of functional 5-HT2C neurotransmission. One approach is drug-challenge pharmaco-magnetic resonance imaging (phMRI). We have previously shown that intravenous administration of the 5-HT2C agonist m-chlorophenylpiperazine (mCPP) elicits increases in blood oxygenation dependent signal (BOLD) in regions consistent with the distribution of 5-HT2C receptors. In the current study we determined whether BOLD signal responses to mCPP could be blocked by pre-treatment with a 5-HT2C antagonist. Healthy male volunteers received oral mirtazapine, 5-HT2/5-HT3 receptor antagonist, or placebo 90min prior to intravenous mCPP challenge phMRI. BOLD signal increases following mCPP infusion occurred in areas known to be rich in 5-HT2C receptors such as the substantia nigra, hypothalamus, pallidum and amygdala. These responses were attenuated by mirtazapine pre-treatment. The results suggest that mCPP-challenge phMRI produces reliable patterns of response that are mediated by 5-HT2C receptors; these responses may therefore be useful in-vivo measures of 5-HT2C function in psychiatric disorders. [Copyright &y& Elsevier]

Summary Despite recent advances in treatment that have significantly improved overall survival, multiple myeloma (MM) remains incurable. Although rituximab, the first monoclonal antibody (MAb) evaluated in MM treatment, provided only very limited benefit, research is ongoing into a number of other MAbs directed against a variety of MM-related target antigens. Given the inherent immune dysfunction associated with MM, newer strategies that may enhance immune function in conjunction with antibodies may also provide a more fruitful clinical approach. Potential MAb targets in MM include growth factors and their receptors, other signalling molecules, and antigens expressed exclusively or predominantly on MM cells. MAb therapy involves a range of mechanisms, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, interference with receptor-ligand interactions, and MAb conjugation to radioisotopes or toxins. The antigens currently targeted in MM therapy are discussed, along with the development status of the corresponding MAb therapeutics. Elotuzumab, an anti-CS1 MAb, has recently achieved clinically meaningful responses when combined with lenalidomide or bortezomib in patients with relapsed and relapsed/refractory MM. Other MAbs are also showing early promise. More ongoing clinical research is required to identify optimal combination regimens and biomarkers that may help predict response to specific MAb-based combinations. [ABSTRACT FROM AUTHOR]

Summary Novel therapies have transformed the treatment paradigm for multiple myeloma with significant improvements in survival now seen in both younger and older patients. Nonetheless, the disease is heterogeneous and high-risk patients in particular continue to have poor outcome. Moreover, the disease remains incurable. Efforts to refine risk stratification and disease characteristics continue with the use of cytogenetics, enhanced imaging techniques and other new technologies, such as genomics. The integration of novel therapies into induction therapy, consolidation and maintenance continues to evolve, and the appropriate use of combination strategies including proteasome inhibition and immunomodulatory treatment is emerging as a platform with application across the disease spectrum. Despite these advances, resistance to novel agents occurs and so the identification of new targets and the recognition of clonal heterogeneity are especially important as improvements to current treatment strategies are developed, with the goal of further improving patient outcome. [ABSTRACT FROM AUTHOR]

This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m) + bortezomib (0·7-1·3 mg/m) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m and bortezomib at 1·3 mg/m. Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM. [ABSTRACT FROM AUTHOR]

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP ( n = 338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1·03 (95% confidence interval 0·76-1·39); P = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS ( P < 0·0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival. [ABSTRACT FROM AUTHOR]

Abstract: Background: Serum free light chains (SFLC) are used to manage patients with light chain or hyposecretory myeloma, and may also be useful in patients with intact immunoglobulin myeloma (IIMM), because their shorter half-life may enable earlier indication of relapse/response than electrophoretic M-spikes or heavy chain (IgGA) immunonephelometry. Methods: One thousand five SFLC, M-spike, and IgGA concentrations were compared at multiple time points during the treatment of 17 myeloma patients, followed over 7.7–63.4months. Changes in these analytes were evaluated in context with changes in disease status and treatment. Results: 14/17 (82%) patients showed synchrony between M-spike, IgGA, and SFLC measurements. SFLC changes preceded M-spike/IgGA in 1 patient, and lagged behind M-spike/IgGA in 2 patients. In eight patients, SFLC showed short-term fluctuations unaccompanied by changes in M-spike, IgGA, or clinical treatment. Conclusions: In 16/17 intact immunoglobulin myeloma patients tested frequently over ~3years, SFLC performed no better than M-spike and did not add value to conventional serum electrophoresis. [Copyright &y& Elsevier]

Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti-apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL-6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib-induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a B cell neoplasm of the bone marrow with a complex array of clinical manifestations including anemia, bone lesions, hypercalcemia, renal dysfunction, and compromised immune function. It accounts for 10%-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. The diagnosis of MM is based on the presence of neoplastic plasma cells in the bone marrow or other extramedullary sites, along with evidence of disease-related organ dysfunction. Although the disease remains incurable, significant advances in both basic and translational research have enhanced understanding of disease pathogenesis and guided the development of new and more effective therapies. These agents include the immunomodulatory drugs thalidomide and lenalidomide, the proteasome inhibitor bortezomib, and other therapeutics that are currently being evaluated. This review highlights important historical landmarks in the field of MM, examines the pathogenesis and clinical manifestations of the disease, and outlines principles of both diagnosis and treatment of MM. [ABSTRACT FROM AUTHOR]

1. Current views of anthropogenic environments emphasize the extreme novelty of urban and industrial ecosystems. Proponents of reconciliation ecology argue that we need to use such habitats to conserve biodiversity, given the inadequacy of natural reserve systems. 2. Some of the harshest anthropogenic ecosystems may be able to support indigenous biodiversity due to their structural or functional resemblance to natural ecosystems, habitats, or microsites that may be present in the region but not part of the historic ecosystem on a particular site. Here we review recent work that evaluates similarities between urban and industrial ecosystems and natural analogues, and explore the potential for these in reconciliation ecology. 3. We find that artificial habitats represent a gradient of ecological novelty which may be independent of the degree of human influence. While hard-surfaced habitats such as walls and quarries are the most investigated artificial analogues (of natural rock pavements and cliffs), there are many other examples spanning a range of habitats in both terrestrial and marine settings. Analogous ecosystems may be present in the region but limits to dispersal can prevent appropriate species from reaching urban or industrial sites, and small differences in abiotic conditions can sometimes prevent colonization by native biota in otherwise similar artificial habitats. We suggest that a search for habitat analogues represents an important principle to guide reconciliation ecology in urban and industrial lands. In constrast, analogous ecosystems may also support pest species that exploit the similarities between anthropogenic habitats and their ancestral habitats. 4. Synthesis and applications. Identifying analogous habitats and ecosystems could enhance biodiversity conservation and ecosystem services in anthropogenic environments. Abiotic and biotic differences between artificial analogues and natural systems can be frequently overcome by ecological engineering to make the environment more suitable for native biodiversity, and/or assisted dispersal to allow suitable native organisms to reach appropriate sites within artificial ecosystems. Altering some habitats to become less analogous may help reduce impacts of pest species in urban and industrial areas. [ABSTRACT FROM AUTHOR]

Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open-label multicentre study, we compared 1·3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource-based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Tanespimycin, a heat shock protein 90 (HSP90) inhibitor, induces apoptosis in drug-sensitive and -resistant MM cell lines and in tumour cells from patients with relapsed MM. In this phase 1 dose-escalation study, the safety, plasma pharmacokinetics, and biological/antitumour activity of tanespimycin were evaluated in heavily pretreated patients with relapsed/refractory MM. Tanespimycin (150–525 mg/m2) was given on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles. Non-haematological AEs included diarrhoea (59%), back pain (35%), fatigue (38%), and nausea (35%); haematological AEs included anaemia (24%) and thrombocytopenia (21%). One patient (3%) achieved minimal response (MR), with a progression-free survival (PFS) of 3 months, a 41% decrease from baseline in urine M protein, and a 33% decrease from baseline in serum M protein. Fifteen patients (52%) achieved SD with a median PFS of 2·1 months; 5/15 had reductions in serum M protein ranging from 7% to 38% and in urine M protein ranging from 6% to 91%. Mean HSP70 levels increased from day 1 h 0 to day 1 h 4 with further increases on day 11 h 0 and day 11 h 4, consistent with a therapeutic treatment effect. Tanespimycin monotherapy was well tolerated and demonstrated activity across all doses tested. [ABSTRACT FROM AUTHOR]

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for ≥14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD. [Copyright &y& Elsevier]

The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI]=13.3%-14.1%). The mean incidence of VOD was significantly lower between 1979-1994 than between 1994-2007 (11.5% [95% CI, 10.9%-12.1%] vs 14.6% [95% CI, 14.0%-15.2%]; P <.05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%-88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome. [Copyright &y& Elsevier]

Abstract: Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT2C-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic. [Copyright &y& Elsevier]

A list of theses and dissertations related to hymnody is presented including "Singing to Zion: A Study of Music in the Lives of Mormon Pioneers and Early Mormonism," by Troy D. Allan, "Hymns and Children's Choirs: An Apology and an Approach," by Elizabeth Amy Calhoun, and "A Trajectory of Psalms," by Norma Halmagyi Hanson.

The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1·3 mg/m2 (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade ≥3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade ≥3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade ≥2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade ≥2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome. [ABSTRACT FROM AUTHOR]

This study assessed the effects of a session of eye movement desensitization and reprocessing (EMDR) with auditory alternating bilateral stimulation (ABS) using functional magnetic resonance imaging (fMRI) of brain activations. A case study was conducted with a female participant who was suffering from posttraumatic stress disorder following a severe assault. The fMRI scan began with safe-place imagery, for purposes of comparison, and then attention to the trauma memory without ABS. After this, ABS was provided as she began using EMDR procedures to process the traumatic memory. At postsession, the traumatic memory showed robust and significant changes on self-report measures. The initiation of the EMDR protocol with provision of ABS was associated with a marked change in brain activation within the prefrontal cortex demonstrating a ventromedial shift. The authors argue that the structure of the EMDR protocol encourages such a ventromedial activation, which is then intensified by ABS to overcome the block to information processing that has been preventing natural healing from occurring spontaneously. [ABSTRACT FROM AUTHOR]

Abstract: The large (L) proteins of non-segmented negative stranded (NNS) RNA viruses contain the core RNA dependent RNA polymerase activity for RNA replication and transcription as well as the activities for polyadenylating and capping the mRNA transcripts and for methylating the cap structures. There is currently no structural information available for these large multi-functional proteins. Phylogenetic analyses have led to the division of the L protein primary structure into six functional domains of high conservation that are linked by variable regions. The studies in this report investigate the role of specific amino acids within domain VI of the VSV L protein, which contains a 2′-O-ribose methyltransferase (MTase) domain. We generated a structural homology model of residues 1644–1842 within domain VI based on the crystal structure determined for the known 2′-O-ribose MTase of E. coli, RrmJ. The information generated by this homology model directed us to residues structurally important for MTase activity and SAM binding. Selected residues were analyzed by site-specific mutagenesis and the mutant L proteins were assayed for their effects on RNA synthesis and cap methylation. The goal of this study was to functionally test the model in order to gain insight into the structural constraints of this region of the L protein. The data presented here revealed specific mutations that affect transcription, replication, and 5′ cap methylation, many of which resulted in polymerases temperature sensitive for RNA synthesis. [Copyright &y& Elsevier]

Health-related quality of life (HRQL) was prospectively measured during the phase III APEX trial of bortezomib versus dexamethasone in relapsed multiple myeloma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core (QLQ-C30) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (NTX) side-effects questionnaires were administered at baseline and every 6 weeks up to 42 weeks. Patients receiving bortezomib (1·3 mg/m2, days 1, 4, 8 and 11 for eight 3-week cycles, then days 1, 8, 15 and 22 for three 5-week cycles; n = 296) demonstrated significantly better mean Global Health Status over the study versus patients receiving dexamethasone (40 mg/d, days 1–4, 9–12, and 17–20 for four 5-week cycles, then days 1–4 only for five 4-week cycles; n = 302), plus significantly better physical health, role, cognitive, and emotional functioning scores, lower dyspnoea and sleep symptom scores, and better NTX questionnaire score, using multiple imputation to account for missing data. Results were similar using available-data analyses. Sensitivity analyses suggested that improved HRQL with bortezomib is at least partially explained by improved survival. These results show that bortezomib was associated with significantly better multidimensional HRQL compared with dexamethasone, consistent with the better clinical outcomes seen with bortezomib. [ABSTRACT FROM AUTHOR]

We previously demonstrated that a portion, or perhaps all, of the residues between 931 and 1000 of apolipoprotein (apo) B100 are required for the initiation of apoB-containing particle assembly. Based on our structural model of the first 1000 residues of apoB (designated as apoB:1000), we hypothesized that this domain folds into a three-sided lipovitellin-like "lipid pocket" via a hairpinbridge mechanism. We proposed that salt bridges are formed between four tandem charged residues 717-720 in the turn of the hairpin bridge and four tandem complementary residues 997-1000 located at the C-terminal end of the model. To identify the specific motif within residues 931 and 1000 that is critical for apoB particle assembly, apoB:956 and apoB:986 were produced. To test the hairpin-bridge hypothesis, the following mutations were made: 1) residues 997-1000 deletion (apoB:996), 2) residues 717-720 deletion (apoB:1000Δ717-720), and 3) substitution of charged residues 997-1000 with alanines (apoB:996 + 4Ala).Characterization of particles secreted by stable transformants of McA-RH7777 cells demonstrated the following. 1) ApoB:956 did not form stable particles and was secreted as large lipid-rich aggregates. 2) ApoB:986 formed both a lipidated particle that was denser than HDL3 and largelipid-richaggregates. 3)Compared with wild-type apoB:1000, apoB:1000Δ717-720 displayed the following: (i) significantly diminished capacity to form intact lipidated particles and (ii) increased propensity to form large lipid-rich aggregates. 4)In striking contrast to wild-type apoB:1000, (i) apoB:996 and apoB:996+4Ala were highly susceptible to intracellular degradation, (ii) only a small proportion of the secreted proteins formed stable HDL3-like lipoproteins, and (iii) a majority of the secreted proteins formed large lipid-rich aggregates. We conclude that the first 1000 amino acid residues of human apoB100 are required for the initiation of nascent apoB-containing lipoprotein assembly, and residues 717-720 and 997-1000 play key roles in this process, perhaps via a hairpin-bridge mechanism. [ABSTRACT FROM AUTHOR]

Haematological toxicities and thromboembolic (TE) events are common complications of myeloma therapy. TE risk may be elevated with combination regimens, notably thalidomide/lenalidomide plus high-dose dexamethasone; concomitant erythropoietin appears to further increase the risk with lenalidomide–dexamethasone. We characterised thrombocytopenia and neutropenia in the phase 3 APEX (Assessment of Proteasome Inhibition for Extending Remissions) study of bortezomib versus high-dose dexamethasone in relapsed myeloma, and calculated the incidences of deep-vein thrombosis (DVT)/pulmonary embolism (PE) with: bortezomib or dexamethasone ± erythropoietin in APEX; bortezomib ± dexamethasone ± erythropoietin in two phase 2 studies of relapsed/refractory myeloma. Bortezomib-associated thrombocytopenia and neutropenia were transient, predictable and manageable; mean platelet and neutrophil counts followed a cyclical pattern, and improved over the treatment course. Grade 3/4 thrombocytopenia incidence was higher with bortezomib versus dexamethasone (26%/4% vs. 5%/1%), but significant bleeding events were comparable (4% vs. 5%). DVT/PE incidence was low (≤3·1%) in all analyses; addition of dexamethasone/erythropoietin did not affect TE risk. In APEX, TE risk appeared lower with bortezomib versus dexamethasone. Bortezomib caused transient and cyclical thrombocytopenia and was not associated with elevated TE risk, alone or with dexamethasone ± erythropoietin. Preliminary data suggest bortezomib may reduce the thrombogenic potential of combination regimens via inhibition of platelet function or other mechanism-specific effects on coagulation. [ABSTRACT FROM AUTHOR]

The professional plans, satisfaction levels, demographic characteristics, perceptions and motivations of different teacher types distinguished by cluster analysis were investigated among graduate-entry primary and secondary teacher education candidates (N =510) from three Australian universities in an ongoing longitudinal study. Participants provided quantitative and qualitative survey data at two time-points: at their entry to teacher education, and immediately prior to completion of their qualification. Teacher types were classified via cluster analysis on the basis of their exit levels of planned effort and persistence within the teaching profession, and their professional development and leadership aspirations. Three distinct types were identified: “highly engaged persisters”, “highly engaged switchers”, and “lower engaged desisters”. Differences in motivations for having chosen teaching as a career, perceptions about the profession, and career intentions were contrasted for the three types, and demographic characteristics compared. [Copyright &y& Elsevier]

Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib ( n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159). CR was associated with significantly longer median TFI (24·1 vs. 6·9/6·4 months) and TTAT (27·1 vs. 13·6/14 months) versus VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared to have prolonged median TFI (3·8 vs. 2·3 months), TTAT (8·7 vs. 6·2 months), TTP (4·9 vs. 2·8 months) and OS (24·9 vs. 18·7 months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting. [ABSTRACT FROM AUTHOR]

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade ≤2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease, demonstrating modest single-agent activity in relapsed/refractory multiple myeloma. [ABSTRACT FROM AUTHOR]

The automobile brake-by-wire (BBW) system, which is also called the electromechanical brake system, has become a promising vehicle braking control scheme that enables many new driver interfaces and enhanced performances without a mechanical or hydraulic backup. In this paper, we survey BBW control systems with focuses on fault tolerance design and vehicle braking control schemes. At first, the system architecture of BBW systems is described. Fault tolerance design is then discussed to meet the high requirements of reliability and safety of BBW systems. A widely used braking model and several braking control schemes are investigated. Although previous work focused on antilock and antislip braking controls on a single wheel basis, we present a whole-vehicle control scheme to enhance vehicle stability and safety. Simulations based on the whole-vehicle braking model validate a proposed fuzzy logic control scheme in the lateral and yaw stability controls of vehicles. [ABSTRACT FROM AUTHOR]

Abstract: Decision making is guided by the likely consequences of behavioural choices. Neuronal correlates of financial reward have been described in a number of functional imaging studies in humans. Areas implicated in reward include ventral striatum, dopaminergic midbrain, amygdala and orbitofrontal cortex. Response to loss has not been as extensively studied but may involve prefrontal and medial temporal cortices. It has been proposed that increased sensitivity to reward and reduced sensitivity to punishment underlie some of the psychopathology in impulsive personality disordered individuals. However, few imaging studies using reinforcement tasks have been conducted in this group. In this fMRI study, we investigate the effects of positive (monetary reward) and negative (monetary loss) outcomes on BOLD responses in two target selection tasks. The experimental group comprised eight people with Cluster B (antisocial and borderline) personality disorder, whilst the control group contained fourteen healthy participants. A key finding was the absence of prefrontal responses and reduced BOLD signal in the subcortical reward system in the PD group during positive reinforcement. Impulsivity scores correlated negatively with prefrontal responses in the PD but not the control group during both, reward and loss. Our results suggest dysfunctional responses to rewarding and aversive stimuli in Cluster B personality disordered individuals but do not support the notion of hypersensitivity to reward and hyposensitivity to loss. [Copyright &y& Elsevier]

Abstract: Maturation of the hepatitis C virus (HCV) polyprotein occurs by a series of proteolytic processes catalyzed by host cell proteases and the virally encoded proteases NS2 and NS3. Although several peptidomimetic inhibitors of NS3 protease have been published, only a few small molecule inhibitors have been reported. In an effort to improve screening efficiency by minimizing the spectral interference of various test compounds, a substrate that contains the longer wavelength fluorescence resonance energy transfer (FRET) pair, TAMRA/QSY-7, was devised. For the optimized substrate T-Abu-Q, with sequence Ac-Asp-Glu-Lys(TAMRA)-Glu-Glu-Abu-Ψ(COO)Ala-Ser-Lys(QSY-7)-amide, the kinetic parameters with HCV NS3 protease are K m =30μM, k cat =0.6s−1, and k cat/K m =20,100s−1 M−1. We show that this substrate is suitable for inhibitor analysis and mechanistic studies so long as the substrate concentration is low enough (0.5μM) to avoid complications from high inner filter effects. The substrate is especially useful with ultra-high-density screening formats, such as microarrayed compound screening technology, because there is less spectral interference from the compounds being tested than with more traditional (EDANS/DABCYL) FRET protease substrates. The merits of the new substrate, as well as potential applications of this FRET pair to other protease substrates, are discussed. [Copyright &y& Elsevier]

Abstract: Children''s voluntary reading positively correlates with school grades, vocabulary growth, reading comprehension, verbal fluency, general information, and attitudes towards reading. Drawing on qualitative interviews collected alongside six waves of longitudinal survey data in an urban setting in eastern USA, We argue that voluntary reading by adolescents also provides learning opportunities that scaffold identity formation, afford ‘spaces’ where youth rehearse and relationally enact gender roles, ethnic/racial identification, and fashion educational aspirations. The interviews with African American and European American youth were conducted in five visits and spanned 3 years through senior high school and 1 year post-high school. Methods of inductive and narrative analysis identified patterns of benefits and potential drawbacks of voluntary reading. Amount of voluntary reading was affected by school, family, and social and work commitment pressures, and fulfilled a number of broad roles. What and how youth were reading was as important as the amount. Significantly, reading allowed adolescents to explore possible selves—an interest in historical figures helped one African American male to develop values resisting stereotypes of male or African American, just as an African American female came to resist conforming to gender and racial stereotypes in dress and occupational ambitions. Relationships between voluntary reading habits, family context and educational aspirations were identifiable for a number of the interviewees. [Copyright &y& Elsevier]

Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age ≥65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated substantial clinical activity in these patients. Response rate (34–40% vs. 13–19%), including complete response rate (5–8% vs. 0–1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-treated patients aged ≥65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed multiple myeloma. [ABSTRACT FROM AUTHOR]

Abstract: Fatty acid amide hydrolase (FAAH) is the enzyme responsible for the rapid degradation of fatty acid amides such as the endocannabinoid anandamide. Inhibition of FAAH activity has been suggested as a therapeutic approach for the treatment of chronic pain, depression and anxiety, through local activation of the cannabinoid receptor CB1. We have developed a high throughput screening assay for identification of FAAH inhibitors using a novel substrate, decanoyl 7-amino-4-methyl coumarin (D-AMC) that is cleaved by FAAH to release decanoic acid and the highly fluorescent molecule 7-amino-4-methyl coumarin (AMC). This assay gives an excellent signal window for measuring FAAH activity and, as a continuous assay, inherently offers improved sensitivity and accuracy over previously reported endpoint assays. The assay was validated using a panel of known FAAH inhibitors and purified recombinant human FAAH, then converted to a 384 well format and used to screen a large library of compounds (>600,000 compounds) to identify FAAH inhibitors. This screen identified numerous novel FAAH inhibitors of diverse chemotypes. These hits confirmed using a native FAAH substrate, anandamide, and had very similar rank order potency to that obtained using the D-AMC substrate. Collectively these data demonstrate that D-AMC can be successfully used to rapidly and effectively identify novel FAAH inhibitors for potential therapeutic use. [Copyright &y& Elsevier]

The authors apply current influential models from the motivational literature to develop the comprehensive factors influencing teaching choice (FIT-Choice) scale, to measure factors influencing the choice to teach for beginning preservice teacher education candidates. They validate the scale using 2 large cohorts (N = 488; 652) and describe the factors that teacher education candidates identified as most important in their decision to teach. Furthermore, the authors examine longitudinal relationships for participants who have now completed their teaching qualification (N = 294) to determine how entry motivations relate to exit levels of teaching engagement and professional development aspirations. The study makes several important theoretical contributions: The authors extend the values component of the expectancy-value motivational framework, go beyond high school students to examine career choices of adults, and specifically examine the domain of teaching as a career choice. The new FIT-Choice measure provides a theoretical and analytical framework to help guide future investigations in this area. Understanding teacher candidates' motivations for choosing teaching has implications for teacher education planning and curriculum design, teacher recruitment authorities, and government and intergovernmental planning and policy decisions—especially when many. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin lymphoma. Numerous treatments for this disease are available, but despite high overall response rates, relapse occurs in almost all patients, and survival has typically been no more than 5 years. Treatment options for relapsed patients include pulsed dexamethasone; cyclophosphamide-based therapy; doxorubicin-based regimens; melphalan and prednisone; thalidomide with or without dexamethasone; bortezomib; and high-dose chemotherapy supported by autologous or allogeneic stem cell transplantation. Relapsed disease is more difficult to treat, and patients characteristically become resistant to therapy. As a result of the numerous potential complications of multiple myeloma, including fatigue, bone pain, renal dysfunction, increased susceptibility to infection, and spinal cord compression, quality of life has a significant role in the choice of therapy. New strategies in the treatment of relapsed disease are focusing on therapy that is targeted to various cell-signaling pathways and microenvironmental interactions involved in the pathogenesis of multiple myeloma. As they become available, these strategies are showing promise in the treatment of both relapsed and refractory disease, the most recent being the potent thalidomide analog lenalidomide. Research efforts are also concentrated on improving front-line therapy to reduce the rate of relapse so that, ultimately, survival may be extended and patient outcome improved. [ABSTRACT FROM AUTHOR]