Publications by authors named "Michael D Craig"

33 Publications

Does aerial baiting for controlling feral cats in a heterogeneous landscape confer benefits to a threatened native meso-predator?

PLoS One 2021 7;16(5):e0251304. Epub 2021 May 7.

Biodiversity and Conservation Science, Department of Biodiversity, Conservation and Attractions, Western Australia, Australia.

Introduced mammalian predators can have devastating impacts on recipient ecosystems and disrupt native predator-prey relationships. Feral cats (Felis catus) have been implicated in the decline and extinction of many Australian native species and developing effective and affordable methods to control them is a national priority. While there has been considerable progress in the lethal control of feral cats, effective management at landscape scales has proved challenging. Justification of the allocation of resources to feral cat control programs requires demonstration of the conservation benefit baiting provides to native species susceptible to cat predation. Here, we examined the effectiveness of a landscape-scale Eradicat® baiting program to protect threatened northern quolls (Dasyurus hallucatus) from feral cat predation in a heterogeneous rocky landscape in the Pilbara region of Western Australia. We used camera traps and GPS collars fitted to feral cats to monitor changes in activity patterns of feral cats and northern quolls at a baited treatment site and unbaited reference site over four years. Feral cat populations appeared to be naturally sparse in our study area, and camera trap monitoring showed no significant effect of baiting on cat detections. However, mortality rates of collared feral cats ranged from 18-33% after baiting, indicating that the program was reducing cat numbers. Our study demonstrated that feral cat baiting had a positive effect on northern quoll populations, with evidence of range expansion at the treatment site. We suggest that the rugged rocky habitat preferred by northern quolls in the Pilbara buffered them to some extent from feral cat predation, and baiting was sufficient to demonstrate a positive effect in this relatively short-term project. A more strategic approach to feral cat management is likely to be required in the longer-term to maximise the efficacy of control programs and thereby improve the conservation outlook for susceptible threatened fauna.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251304PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104397PMC
May 2021

Global meta-analysis of tree decline impacts on fauna.

Biol Rev Camb Philos Soc 2021 May 5. Epub 2021 May 5.

Centre for Terrestrial Ecosystem Science and Sustainability, Harry Butler Institute, Murdoch University, 90 South Street, Murdoch, Perth, WA, 6150, Australia.

Significant portions of the world's forests have been impacted by severe and large-scale tree declines characterised by gradual but widespread loss of vigour and subsequent death of either single or several tree species. Tree deaths represent a threat for fauna that are dependent on forest habitats for their survival. Although tree declines have received considerable scientific attention, surprisingly, little is known about their impacts on fauna. In total, we calculated 631 effect sizes across 59 studies that quantified the impact of tree declines on animal abundance. Data representing 186 bird species indicated an overall increase in bird abundance in response to tree declines (meta-analysis mean ± estimation g = 0.172 ± 0.053 [CI 0.069 to 0.275], P = 0.001); however, there was substantial variability in responses (significant heterogeneity P < 0.001) with a strong influence of diet as well as nesting guild on bird responses. Granivores (especially ground-foraging species, e.g. Passerellidae species), bark-foraging insectivores (e.g. woodpeckers), as well as ground- and cavity-nesting species apparently benefitted from tree declines, while nectarivorous birds [and, although not significant, aerially foraging insectivores (e.g. flycatchers) and leaf-gleaning insectivores (canopy-feeding)] were less common in the presence of tree declines. Data representing 33 mammal species indicate a tendency for detrimental effects of tree declines on mammals that use trees as refuges, while aerial foragers (i.e. bats) may benefit from opening up the canopy. Overall the average effect for mammals was neutral (meta-analysis mean estimation g = -0.150 ± 0.145 [-0.433 to 0.134], P = 0.302). Data representing 20 reptile species showed an insufficient range of responses to determine any diet or foraging effect on their responses. Data for 28 arthropod taxa should be considered with caution, as we could not adequately separate taxa according to their specialisations and reliance on key habitat. The data broadly suggest a detrimental effect of tree declines (meta-analysis mean estimation g = -0.171 ± 0.072 [-0.311 to -0.031], P = 0.017) with ground-foraging arthropods (e.g. detritivores and predators such as spiders and centipedes) more likely to be detrimentally impacted by tree declines. The range of responses to tree declines signifies substantially altered animal communities. In many instances, altered ecosystem function due to loss of key animal services will represent a significant threat to forest health.
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http://dx.doi.org/10.1111/brv.12725DOI Listing
May 2021

Quantifying and addressing the prevalence and bias of study designs in the environmental and social sciences.

Nat Commun 2020 12 11;11(1):6377. Epub 2020 Dec 11.

Voimalohi Oy, Voimatie 23, Voimatie, 91100, Ii, Finland.

Building trust in science and evidence-based decision-making depends heavily on the credibility of studies and their findings. Researchers employ many different study designs that vary in their risk of bias to evaluate the true effect of interventions or impacts. Here, we empirically quantify, on a large scale, the prevalence of different study designs and the magnitude of bias in their estimates. Randomised designs and controlled observational designs with pre-intervention sampling were used by just 23% of intervention studies in biodiversity conservation, and 36% of intervention studies in social science. We demonstrate, through pairwise within-study comparisons across 49 environmental datasets, that these types of designs usually give less biased estimates than simpler observational designs. We propose a model-based approach to combine study estimates that may suffer from different levels of study design bias, discuss the implications for evidence synthesis, and how to facilitate the use of more credible study designs.
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http://dx.doi.org/10.1038/s41467-020-20142-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733498PMC
December 2020

Mitigation translocation as a management tool.

Conserv Biol 2020 Nov 19. Epub 2020 Nov 19.

Behavioural Ecology Laboratory, School of Molecular and Life Sciences, Curtin University, Kent Street, Bentley, Perth, WA, 6102, Australia.

Mitigation translocation is a subgroup of conservation translocation, categorized by a crisis-responsive time frame and the immediate goal of relocating individuals threatened with death. However, the relative successes of conservation translocations with longer time frames and broader metapopulation- and ecosystem-level considerations have been used to justify the continued implementation of mitigation translocations without adequate post hoc monitoring to confirm their effectiveness as a conservation tool. Mitigation translocations now outnumber other conservation translocations, and understanding the effectiveness of mitigation translocations is critical given limited global conservation funding especially if the mitigation translocations undermine biodiversity conservation by failing to save individuals. We assessed the effectiveness of mitigation translocations by conducting a quantitative review of the global literature. A total of 59 mitigation translocations were reviewed for their adherence to the adaptive scientific approach expected of other conservation translocations and for the testing of management options to continue improving techniques for the future. We found that mitigation translocations have not achieved their potential as an effective applied science. Most translocations focused predominantly on population establishment- and persistence-level questions, as is often seen in translocations more broadly, and less on metapopulation and ecosystem outcomes. Questions regarding the long-term impacts to the recipient ecosystem (12% of articles) and the carrying capacity of translocation sites (24% of articles) were addressed least often, despite these factors being more likely to influence ultimate success. Less than half (47%) of studies included comparison of different management techniques to facilitate practitioners selecting the most effective management actions for the future. To align mitigation translocations with the relative success of other conservation translocations, it is critical that future mitigation translocations conform to an established experimental approach to improve their effectiveness. Effective mitigation translocations will require significantly greater investment of time, expertise, and resources in the future.
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http://dx.doi.org/10.1111/cobi.13667DOI Listing
November 2020

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia.

Clin Lymphoma Myeloma Leuk 2020 04 6;20(4):226-233.e1. Epub 2019 Nov 6.

Division of Hematology and Oncology, Department of Medicine, Seidman Cancer Center, Case Comprehensive Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH. Electronic address:

Background: Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.

Patients And Methods: Primary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle.

Results: Twenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3.

Conclusion: Multiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.
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http://dx.doi.org/10.1016/j.clml.2019.10.018DOI Listing
April 2020

Fire-mediated habitat change regulates woodland bird species and functional group occurrence.

Ecol Appl 2019 12 27;29(8):e01997. Epub 2019 Sep 27.

Biodiversity and Conservation Science, Department of Biodiversity, Conservation and Attractions, Locked Bag 104, Bentley Delivery Centre, Bentley, Western Australia, 6983, Australia.

In an era characterized by recurrent large wildfires in many parts of the globe, there is a critical need to understand how animal species respond to fires, the rates at which populations can recover, and the functional changes fires may cause. Using quantified changes in habitat parameters over a ~400-yr post-fire chronosequence in an obligate-seeding Australian eucalypt woodland, we build and test predictions of how birds, as individual species and aggregated into functional groups according to their use of specific habitat resources, respond to time since fire. Individual bird species exhibited four generalized response types to time since fire: incline, decline, delayed, and bell. All significant relationships between bird functional group richness or abundance and time since fire were consistent with predictions based on known time-since-fire-associated changes in habitat features putatively important for these bird groups. Consequently, we argue that the bird community is responding to post-fire successional changes in habitat as per the habitat accommodation model, rather than to time since fire per se, and that our functional framework will be of value in predicting bird responses to future disturbances in this and other obligate-seeder forest and woodland ecosystems. Most bird species and functional groups that were affected by time since fire were associated with long-unburned woodlands. In the context of recent large, stand-replacement wildfires that have affected a substantial proportion of obligate-seeder eucalypt woodlands, and the multi-century timescales over which post-fire succession occurs, it would appear preferable from a bird conservation perspective if fires initiating loss of currently long-unburned woodlands were minimized. Once long-unburned woodlands are transformed by fire into recently burned woodlands, there is limited scope for alternative management interventions to accelerate the rate of habitat development after fire, or supplement the resources formerly provided to birds by long-unburned woodlands, with the limited exception of augmenting hollow availability for key hollow-nesting species.
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http://dx.doi.org/10.1002/eap.1997DOI Listing
December 2019

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

Acta Haematol 2020 17;143(1):40-50. Epub 2019 Jul 17.

Yale University, New Haven, Connecticut, USA,

Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data.

Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease.

Methods: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days.

Results: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months.

Conclusions: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.
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http://dx.doi.org/10.1159/000500666DOI Listing
April 2020

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

Cancer 2019 05 29;125(9):1507-1517. Epub 2019 Jan 29.

University of Washington Medical Center, Seattle, Washington.

Background: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1.

Methods: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis.

Results: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89).

Conclusions: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.
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http://dx.doi.org/10.1002/cncr.31861DOI Listing
May 2019

Patterns of Relapse After Salvage Autologous Stem Cell Transplant for Hodgkin's Lymphoma: Should Sites of Relapse Relative to Initially Involved Sites Be Used to Guide Indications for Peri-Transplant Radiation Therapy.

Pract Radiat Oncol 2019 May 21;9(3):e290-e297. Epub 2018 Dec 21.

Department of Radiation Oncology, West Virginia University, Morgantown, West Virginia. Electronic address:

Purpose: We aimed to assess patterns of relapse in patients undergoing salvage autologous stem cell transplant (ASCT) for relapsed Hodgkin lymphoma in the modern era with the hypothesis that patients who suffer a relapse at initially involved sites are at increased risks of relapse post-ASCT that may help guide the application of peri-transplant radiation therapy.

Methods And Materials: A retrospective review was conducted of 38 patients undergoing ASCT between 2002 and 2017 for relapsed or refractory Hodgkin lymphoma. The site of relapse at the time of ASCT and subsequent relapses were compared with sites of the initial involvement at the time of diagnosis using follow-up imaging (most commonly positron emission computed tomography). Relapse and overall survival rates were calculated from the date of ASCT using the Kaplan-Meier method with a multivariate analysis, completed using a Cox multivariate analysis.

Results: The median follow-up time was 38 months (interquartile range, 18-66 months). Twenty-two patients (58%) suffered a relapse after ASCT at a median time to relapse of 9.1 months (interquartile range, 2.9-12.3 months) with a 5-year risk of relapse of 58% (95% confidence interval [CI], 41%-75%). On univariate analysis, relapse at an initially involved site was significant for higher rates of relapse at 71% at 5-years (95% CI, 52%-90%) compared with relapse at initially uninvolved sites at 30% (95% CI, 2%-58%; P = .05). The relapse rate was also significantly higher in patients age <30 years at the time of diagnosis at 80% (95% CI, 59%-100%) compared with 40% (95% CI, 18%-62%) at 5 years in patients aged >30 years (P < .01). On multivariate analysis, relapse at initially involved sites was significant for higher rates of relapse (hazard ratio: 8.3; 95% CI, 1.2-57.4; P = .03).

Conclusions: Relapses at initially involved sites may potentially increase the risk of relapse after ASCT. Additional studies are needed to clarify whether this should be used as an additional factor to guide recommendations for peri-transplant radiation therapy.
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http://dx.doi.org/10.1016/j.prro.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631314PMC
May 2019

Ethical birding call playback and conservation.

Conserv Biol 2019 04 25;33(2):469-471. Epub 2019 Jan 25.

School of Biological Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, 6009, Australia.

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http://dx.doi.org/10.1111/cobi.13199DOI Listing
April 2019

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma.

Haematologica 2018 09 28;103(9):1518-1526. Epub 2018 Jun 28.

Winship Cancer Institute of Emory University, Atlanta, GA, USA.

This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. .
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http://dx.doi.org/10.3324/haematol.2017.185991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119151PMC
September 2018

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

Lancet 2018 05 24;391(10135):2116-2127. Epub 2018 May 24.

Stanford University School of Medicine, Stanford, CA, USA.

Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT.

Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34).

Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001).

Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated.

Funding: Merck & Co., Inc.
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http://dx.doi.org/10.1016/S0140-6736(18)30631-7DOI Listing
May 2018

Survival of Lymphoma Patients Experiencing Relapse or Progression after an Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 05 2;24(5):983-988. Epub 2018 Feb 2.

Division of Hematology, Oncology & Transplantation, University of Minnesota, Minneapolis, Minnesota.

Outcome and management of patients who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has evolved in the recent decade. Using a multi-institutional retrospective database we report the predictive factors and survival of lymphoma patients who relapse after allo-HCT. We evaluated 495 allo-HCT recipients transplanted between 2000 and 2015 at 3 academic US medical centers. Landmark analysis evaluating predictive factors was performed at 1 month after allo-HCT relapse with a primary endpoint of postrelapse overall survival (PR-OS). A total of 175 lymphoma patients (35%) experienced relapse after allo-HCT. Of these, 126 patients, median age 46 years (range, 19 to 71), were assessable. Most patients (86%) received subsequent therapy; 80 patients received targeted agents and 19 donor lymphocyte infusion. On univariate analysis median PR-OS for patients with Hodgkin lymphoma was 47.9 months compared with 11.3 months in patients with indolent and 10.1 months in aggressive non-Hodgkin lymphoma (P = .04). On multivariate analysis postrelapse therapy administration (no therapy versus targeted therapy: hazard ratio, .21 [95% confidence interval, .10 to .45]; no therapy versus nontargeted therapy: hazard ratio, .26 [95% confidence interval, .11 to .57]), late relapse 130 days after allo-HCT (relative to early relapse: hazard ratio, .25; P < .001), and Eastern Cooperative Oncology Group performance status of 0 to 1 (versus Eastern Cooperative Oncology Group performance status ≥ 2: hazard ratio, .49; P = .003) were associated with a significantly reduced risk of mortality. Patients relapsing ≥ 130 days from the time of allo-HCT yielded PR-OS of 48.8 months compared with 6.5 months in patients with early relapse (P < .001). Our data suggest that in the modern era, therapies used for patients experiencing lymphoma relapse after allo-HCT can extend survival.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.015DOI Listing
May 2018

Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States.

Clin Lymphoma Myeloma Leuk 2017 04 10;17(4):193-200. Epub 2017 Jan 10.

Department of Medical Oncology, Yale University, New Haven, CT.

Background: With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States.

Results: A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01).

Conclusion: The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.
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http://dx.doi.org/10.1016/j.clml.2016.10.001DOI Listing
April 2017

The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project.

Ecol Evol 2017 01 16;7(1):145-188. Epub 2016 Dec 16.

Imperial College London South Kensington London UK.

The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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http://dx.doi.org/10.1002/ece3.2579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215197PMC
January 2017

A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.

Cancer 2017 Apr 2;123(7):1174-1183. Epub 2016 Dec 2.

Department of Medical Oncology, Yale University, New Haven, Connecticut.

Background: Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States.

Methods: Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided.

Results: Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]).

Conclusions: To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650190PMC
April 2017

Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia.

Mol Cancer Res 2016 10 29;14(10):909-919. Epub 2016 Jun 29.

Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia. Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia.

Acute lymphoblastic leukemia (ALL) has many features in common with normal B-cell progenitors, including their ability to respond to diverse signals from the bone marrow microenvironment (BMM) resulting in regulation of cell-cycle progression and survival. Bone marrow-derived cues influence many elements of both steady state hematopoiesis and hematopoietic tumor cell phenotypes through modulation of gene expression. miRNAs are one regulatory class of small noncoding RNAs that have been shown to be increasingly important in diverse settings of malignancy. In the current study, miRNA profiles were globally altered in ALL cells following exposure to primary human bone marrow niche cells, including bone marrow stromal cells (BMSC) and primary human osteoblasts (HOB). Specifically, mature miR-221 and miR-222 transcripts were decreased in ALL cells cocultured with BMSC or HOB, coincident with increased p27 (CDKN1B), a previously validated target. Increased p27 protein in ALL cells exposed to BMSC or HOB is consistent with accumulation of tumor cells in the G phase of the cell cycle and resistance to chemotherapy-induced death. Overexpression of miR-221 in ALL cells during BMSC or HOB coculture prompted cell-cycle progression and sensitization of ALL cells to cytotoxic agents, blunting the protective influence of the BMM. These novel observations indicate that BMM regulation of miR-221/222 contributes to marrow niche-supported tumor cell quiescence and survival of residual cells.

Implications: Niche-influenced miR-221/222 may define a novel therapeutic target in ALL to be combined with existing cytotoxic agents to more effectively eradicate refractory disease that contributes to relapse. Mol Cancer Res; 14(10); 909-19. ©2016 AACR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065748PMC
http://dx.doi.org/10.1158/1541-7786.MCR-15-0474DOI Listing
October 2016

Hematopoietic Progenitor Cell Mobilization with Ifosfamide, Carboplatin, and Etoposide Chemotherapy versus Plerixafor-Based Strategies in Patients with Hodgkin and Non-Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2016 10 21;22(10):1773-1780. Epub 2016 Jun 21.

Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Studies comparing the efficacy and safety of chemo-mobilization with ifosfamide, carboplatin, and etoposide (ICE) ± rituximab with plerixafor-based approaches in lymphoma patients have not been performed. We analyzed hematopoietic progenitor cell mobilization outcomes in lymphoma patients undergoing chemo-mobilization with ICE (n = 35) compared with either routine plerixafor (n = 30) or "just in time" (JIT) plerixafor-based mobilization (n = 33). Chemo-mobilization provided a significantly higher total CD34(+) cell yield (median collection, 5.35 × 10(6) cells/kg for ICE versus 3.15 × 10(6) cells/kg for routine plerixafor and 3.6 × 10(6) cells/kg for JIT plerixafor, P < .001). The median day 1 yield of CD34(+) cells was not significantly different (median, 2.2 × 10(6) cells/kg in ICE versus 1.9 × 10(6) cells/kg in upfront plerixafor versus 1.7 × 10(6) cells/kg in JIT plerixafor, P = .20). There was no significant difference in the 3 groups in terms of total number of apheresis sessions performed (median, 2 in each group; P = .78). There were no mobilization failures (inability to collect at least 2 × 10(6) cells/kg) in the chemo-mobilization group, whereas 5 patients (16.7%) in the routine plerixafor and 3 patients (9.1%) in JIT group had mobilization failure (P = .04). Mean time to neutrophil engraftment was faster in the chemo-mobilization group, 10.3 days (±1.2) compared with 12.1 days (±3.6) in the routine plerixafor group and 11.6 days (±3.0) in the JIT group (P < .001) and mean time to platelet engraftment was 13.7 days (±.7) in ICE versus 20.3 days (±1.6) in routine plerixafor versus 17.1 days (± .9) in JIT group (P < .001). Red blood cell transfusions were significantly higher in the chemo-mobilization group (34.3% versus 0 versus 3.2% versus 1, P < .001) and so were the platelet transfusions (22.9% versus 0 versus 0, P < .001). Excluding the cost of chemotherapy administration, chemo-mobilization was associated with significantly less mobilization cost (average cost $17,601.76 in ICE versus $28,963.05 in routine and $25,679.81 in JIT, P < .001). Our data suggests that chemo-mobilization with ICE provides a higher total CD34(+) cell yield, lower rates of mobilization failure, faster engraftment, and lower cost compared to plerixafor-based approaches with comparable toxicity profile between the groups, except for higher transfusion requirements with chemo-mobilization.
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http://dx.doi.org/10.1016/j.bbmt.2016.06.016DOI Listing
October 2016

Do state-and-transition models derived from vegetation succession also represent avian succession in restored mine pits?

Ecol Appl 2015 Oct;25(7):1790-806

State-and-transition models are increasingly used as a tool to inform management of post-disturbance succession and effective conservation of biodiversity in production landscapes. However, if they are to do this effectively, they need to represent faunal, as well as vegetation, succession. We assessed the congruence between vegetation and avian succession by sampling avian communities in each state of a state-and-transition model used to inform management of post-mining restoration in a production landscape in southwestern Australia. While avian communities differed significantly among states classified as on a desirable successional pathway, they did not differ between desirable and deviated states of the same post-mining age. Overall, we concluded there was poor congruence between vegetation and avian succession in this state-and-transition model. We identified four factors that likely contributed to this lack of congruence, which were that long-term monitoring of succession in restored mine pits was not used to update and improve models, states were not defined based on ecological processes and thresholds, states were not defined by criteria that were important in structuring the avian community, and states were not based on criteria that related to values in the reference community. We believe that consideration of these four factors in the development of state-and-transition models should improve their ability to accurately represent faunal, as well as vegetation, succession. Developing state-and-transition models that better incorporate patterns of faunal succession should improve the ability to manage post-disturbance succession across a range of ecosystems for biodiversity conservation.
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http://dx.doi.org/10.1890/14-1519.1DOI Listing
October 2015

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

Lancet Oncol 2015 Sep 30;16(9):1025-1036. Epub 2015 Jul 30.

Sunesis Pharmaceuticals, South San Francisco, CA, USA.

Background: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia.

Methods: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801.

Findings: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]).

Interpretation: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia.

Funding: Sunesis Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(15)00201-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822512PMC
September 2015

Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma.

Cancer Chemother Pharmacol 2015 Jul 26;76(1):211-6. Epub 2015 May 26.

Rocky Mountain Cancer Centers, 1700 S. Potomac Street, Aurora, CO, 80012, USA,

Purpose: Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine's effect on cardiac repolarization in treatment-naïve adults with advanced indolent NHL/mantle cell lymphoma (MCL).

Methods: In this multicenter, open-label, phase 3 study, patients received 6-8 28-day cycles of bendamustine (90 mg/m(2), days 1 and 2) and rituximab (375 mg/m(2), day 1). Exclusions included a history of cardiac conditions with potential for QT prolongation. The primary endpoint was change in Fridericia-corrected QT (QTcF; 3 electrocardiograms per time point) on day 2 of cycle 1, from just before infusion to end of infusion (immediately postinfusion, coinciding with maximum plasma concentration of bendamustine). Change 1 h postinfusion was also measured. Exploratory assessments included specific QTcF outlier analyses (new QTcF >500 ms, change >60 ms) and morphological changes.

Results: Of the 54 enrolled patients (mean age, 62.9 years), 53 received ≥1 dose; 49 completed ≥6 cycles. Mean QTcF change from baseline was 6.7 ms at end of infusion; no mean changes >20 ms were detected ≤1 h postinfusion. No patients met specific outlier criteria at end of infusion or 1 h postinfusion. No morphological changes were detected.

Conclusions: In this small treatment-naïve population with advanced NHL/MCL, bendamustine did not produce a clinically relevant increase in mean QTcF on the second infusion day. The potential for delayed effects on QT interval after 1 h was not evaluated.
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http://dx.doi.org/10.1007/s00280-015-2776-xDOI Listing
July 2015

A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients.

Clin Lymphoma Myeloma Leuk 2015 Jul 16;15(7):428-432.e2. Epub 2015 Feb 16.

Department of Medicine, Seidman Cancer Center, University Hospitals, Case Medical Center, Cleveland, OH.

Background: Midostaurin is a novel, orally available Fms-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor that induces cell cycle arrest and apoptosis of leukemic cells expressing mutant and wild type FLT3 receptors, and has shown potential synergism with cytotoxic chemotherapy.

Patients And Methods: We conducted a phase I study of azacitidine (intravenous 75 mg/m(2) daily for 7 days) with escalating doses of oral midostaurin (25 mg twice per day [b.i.d.], 50 mg b.i.d., and 75 mg b.i.d.) on days 8 to 21 of a 28-day cycle in untreated acute myeloid leukemia (AML) in older patients and/or relapsed AML. Patients were eligible regardless of FLT3 mutation status. Trough blood samples for pharmacokinetics were obtained on days 8, 15, and 21 before midostaurin dosing.

Results: Seventeen patients with a median age of 73 (range, 57-83) years were enrolled; 5 patients had previous conventional treatment and none of the patients had FLT3 mutations. Dose-limiting toxicities were not observed. Hospitalizations, primarily for infections, occurred in one-third of treatment cycles. Fourteen patients were evaluable for response: 3 attained complete remission and 2 had hematologic improvement. Median (range) survival from enrollment was 6 (1 to ≥ 19) months. Three patients died within 60 days of enrollment (2 progressive disease, 1 non-dose-limiting toxicity, treatment-related). Pharmacokinetic data at 75 mg orally b.i.d. showed increased trough levels of midostaurin during cycle 2 compared with cycle 1 and persistent and increasing levels of its active metabolite, CGP52421.

Conclusion: The combination of sequential azacitidine and midostaurin is safe and tolerable with response rates comparable with azacitidine alone and should be studied further in FLT3 mutation-positive AML.
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http://dx.doi.org/10.1016/j.clml.2015.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484305PMC
July 2015

Contribution of genetics to ecological restoration.

Mol Ecol 2015 Jan 24;24(1):22-37. Epub 2014 Nov 24.

School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA, 6150, Australia.

Ecological restoration of degraded ecosystems has emerged as a critical tool in the fight to reverse and ameliorate the current loss of biodiversity and ecosystem services. Approaches derived from different genetic disciplines are extending the theoretical and applied frameworks on which ecological restoration is based. We performed a search of scientific articles and identified 160 articles that employed a genetic approach within a restoration context to shed light on the links between genetics and restoration. These articles were then classified on whether they examined association between genetics and fitness or the application of genetics in demographic studies, and on the way the studies informed restoration practice. Although genetic research in restoration is rapidly growing, we found that studies could make better use of the extensive toolbox developed by applied fields in genetics. Overall, 41% of reviewed studies used genetic information to evaluate or monitor restoration, and 59% provided genetic information to guide prerestoration decision-making processes. Reviewed studies suggest that restoration practitioners often overlook the importance of including genetic aspects within their restoration goals. Even though there is a genetic basis influencing the provision of ecosystem services, few studies explored this relationship. We provide a view of research gaps, future directions and challenges in the genetics of restoration.
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http://dx.doi.org/10.1111/mec.12995DOI Listing
January 2015

An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes.

Leuk Res Rep 2014 5;3(2):58-61. Epub 2014 Jul 5.

Division of Oncology, Washington University Medical School, St. Louis, MO, USA.

Alisertib (MLN8237) is an investigational, oral, selective, Aurora A kinase (AAK) inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome received alisertib 50 mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence) included 1 complete response lasting >1 year. No responses were observed in MDS patients. Adverse events >30% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence.
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http://dx.doi.org/10.1016/j.lrr.2014.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110881PMC
July 2014

Reply to S. Fuji et al.

J Clin Oncol 2014 Jun 5;32(17):1860-1. Epub 2014 May 5.

West Virginia University, Morgantown, WV.

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http://dx.doi.org/10.1200/JCO.2014.55.4048DOI Listing
June 2014

Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease.

J Clin Oncol 2013 Dec 28;31(35):4416-23. Epub 2013 Oct 28.

All authors: West Virginia University, Morgantown, WV.

Purpose: Graft-versus-host disease (GVHD) is major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Atorvastatin is a potent immunomodulatory agent that holds promise as a novel and safe agent for acute GVHD prophylaxis.

Patients And Methods: We conducted a phase II trial to evaluate the safety and efficacy of atorvastatin administration for GVHD prophylaxis in both adult donors and recipients of matched sibling allogeneic HCT. Atorvastatin (40 mg per day orally) was administered to sibling donors, starting 14 to 28 days before the anticipated first day of stem-cell collection. In HCT recipients (n = 30), GVHD prophylaxis consisted of tacrolimus, short-course methotrexate, and atorvastatin (40 mg per day orally).

Results: Atorvastatin administration in healthy donors and recipients was not associated with any grade 3 to 4 adverse events. Cumulative incidence rates of grade 2 to 4 acute GVHD at days +100 and +180 were 3.3% (95% CI, 0.2% to 14.8%) and 11.1% (95% CI, 2.7% to 26.4%), respectively. One-year cumulative incidence of chronic GVHD was 52.3% (95% CI, 27.6% to 72.1%). Viral and fungal infections were infrequent. One-year cumulative incidences of nonrelapse mortality and relapse were 9.8% (95% CI, 1.4% to 28%) and 25.4% (95% CI, 10.9% to 42.9%), respectively. One-year overall survival and progression-free survival were 74% (95% CI, 58% to 96%) and 65% (95% CI, 48% to 87%), respectively. Compared with baseline, atorvastatin administration in sibling donors was associated with a trend toward increased mean plasma interleukin-10 concentrations (5.6 v 7.1 pg/mL; P = .06).

Conclusion: A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic HCT seems to be a feasible, safe, and potentially effective strategy to prevent acute GVHD.
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http://dx.doi.org/10.1200/JCO.2013.50.8747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842909PMC
December 2013

Who's for dinner? High-throughput sequencing reveals bat dietary differentiation in a biodiversity hotspot where prey taxonomy is largely undescribed.

Mol Ecol 2014 08 31;23(15):3605-17. Epub 2013 Oct 31.

School of Veterinary and Life Sciences, Murdoch University, 90 South Street, Murdoch, WA, 6150, Australia.

Effective management and conservation of biodiversity requires understanding of predator-prey relationships to ensure the continued existence of both predator and prey populations. Gathering dietary data from predatory species, such as insectivorous bats, often presents logistical challenges, further exacerbated in biodiversity hot spots because prey items are highly speciose, yet their taxonomy is largely undescribed. We used high-throughput sequencing (HTS) and bioinformatic analyses to phylogenetically group DNA sequences into molecular operational taxonomic units (MOTUs) to examine predator-prey dynamics of three sympatric insectivorous bat species in the biodiversity hotspot of south-western Australia. We could only assign between 4% and 20% of MOTUs to known genera or species, depending on the method used, underscoring the importance of examining dietary diversity irrespective of taxonomic knowledge in areas lacking a comprehensive genetic reference database. MOTU analysis confirmed that resource partitioning occurred, with dietary divergence positively related to the ecomorphological divergence of the three bat species. We predicted that bat species' diets would converge during times of high energetic requirements, that is, the maternity season for females and the mating season for males. There was an interactive effect of season on female, but not male, bat species' diets, although small sample sizes may have limited our findings. Contrary to our predictions, females of two ecomorphologically similar species showed dietary convergence during the mating season rather than the maternity season. HTS-based approaches can help elucidate complex predator-prey relationships in highly speciose regions, which should facilitate the conservation of biodiversity in genetically uncharacterized areas, such as biodiversity hotspots.
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http://dx.doi.org/10.1111/mec.12531DOI Listing
August 2014

Warm Autoimmune Hemolytic Anemia with a Direct Antiglobulin Test Positive for C3 and Negative for IgG: A Case Study and Analytical Literature Review of Incidence and Severity.

Clin Med Insights Case Rep 2013 2;6:57-60. Epub 2013 Apr 2.

Department of Medicine, Integris Southwest Medical Center, Oklahoma City, OK.

Polygenic IgG autoantibodies are implicated in majority of the cases of warm autoimmune hemolytic anemia (WAIHA). In some of these cases, complement (C3) proteins accompany the IgG antibodies. WAIHA mediated by C3 alone is relatively rare. We present an interesting case of WAIHA with a direct antiglobulin test (DAT) positive for C3 but negative for IgG in a 79-year-old woman and perform an analytical literature review of the incidence and severity of this clinical entity.
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http://dx.doi.org/10.4137/CCRep.S11469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623608PMC
May 2013

A multicenter phase II study of darinaparsin in relapsed or refractory Hodgkin's and non-Hodgkin's lymphoma.

Am J Hematol 2012 Jan 12;87(1):111-4. Epub 2011 Nov 12.

Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Florida, USA.

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http://dx.doi.org/10.1002/ajh.22232DOI Listing
January 2012