Connecting the multiple dimensions of global soil fungal diversity.

How the multiple facets of soil fungal diversity vary worldwide remains virtually unknown, hindering the management of this essential species-rich group. By sequencing high-resolution DNA markers in over 4000 topsoil samples from natural and human-altered ecosystems across all continents, we illustrate the distributions and drivers of different levels of taxonomic and phylogenetic diversity of fungi and their ecological groups. We show the impact of precipitation and temperature interactions on local fungal species richness (alpha diversity) across different climates. Our findings reveal how temperature drives fungal compositional turnover (beta diversity) and phylogenetic diversity, linking them with regional species richness (gamma diversity). We integrate fungi into the principles of global biodiversity distribution and present detailed maps for biodiversity conservation and modeling of global ecological processes.

Global patterns in endemicity and vulnerability of soil fungi.

Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms.

Phase 1 Trial Evaluating Vorinostat Plus Bortezomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma.

INTRODUCTION: Bortezomib plus lenalidomide and dexamethasone (VRD) is a standard induction therapy for newly diagnosed multiple myeloma (NDMM) patients. Given preclinical and clinical data suggesting the synergistic activity of the histone deacetylase inhibitor vorinostat with both bortezomib and lenalidomide for the treatment of multiple myeloma, we hypothesized that adding vorinostat to VRD (R2V2) would increase the rate and the quality of responses to induction treatment. Here we report the results of a phase 1 trial (NCT01038388) evaluating R2V2 as up-front treatment for NDMM patients. PATIENTS AND METHODS: R2V2 was tested as induction therapy in a dose-escalation phase 1 study in 30 NDMM patients deemed eligible for autologous stem-cell transplantation. Treatment consisted of 4 induction cycles with R2V2, followed by either autologous stem-cell transplantation or 4 additional R2V2 cycles and lenalidomide maintenance therapy. RESULTS: The maximum tolerated dose of vorinostat was 200 mg daily. The most common adverse events were gastrointestinal (87%), fatigue and peripheral neuropathy (60%), and thrombocytopenia (33%). R2V2 induced an objective response in 96% of patients, with 48% obtaining at least a complete remission. Median progression-free survival was 52 months, with 77% of patients alive at 5 years. CONCLUSION: R2V2 as induction treatment for NDMM patients resulted in remarkable response rates at the cost of increased toxicity.

Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study.

Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431).

Implementation of a Complex Intervention to Support Leadership Development in Nursing Homes: A Multimethod Participatory Study.

Leadership is key to quality improvement in nursing homes. This article reports on the initial analysis of the transformational My Home Life Leadership Support program for nursing home managers being implemented in Scotland. It analyses learning from a multimethod participatory descriptive study. Contribution analysis theory informed the evaluation. Evidence-Based Practice, Relationship-Centered Care, Appreciative Inquiry, and Caring Conversations informed the intervention to develop transformational leadership. Data generation methods included baseline and postintervention questionnaires to describe culture change within the study population, together with more in-depth qualitative data generated from group discussions throughout the leadership support program. Qualitative data analysis was an iterative collaborative process with participants to generate themes about the impact of the program on themselves and their practice. Data showed positive changes in managers' perceptions of their self-awareness, leadership communication and relationship skills, and development of positive cultures. This model offers lessons for those interested in ways to approach the emotional, educational, and cultural dynamics of change in other human service contexts.

Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma.

Carfilzomib (Kyprolis®), a second generation proteasome inhibitor, is FDA approved for single-agent use among relapsed/refractory multiple myeloma (MM). To enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib with other novel agents. TG02, a multi-kinase inhibitor, targets JAK2 and CDK9. The rationale for co-treatment with carfilzomib and TG02 is that both independently target Mcl-1 and most myeloma cells are dependent on this anti-apoptotic protein for survival. We observed at least additive effects using the combination treatment in MM cell lines and patient samples. To determine how the bone marrow environment affects the efficacy of the combination we conducted co-culture experiments with Hs-5 stromal cells. We also examined the mechanism of increased apoptosis by determining the affect on expression of the Bcl-2 family of proteins. We found that carfilzomib increases NOXA mRNA expression, as expected, and TG02 treatment caused a decrease in Mcl-1 protein but not mRNA levels. Consistent with this possibility, we find silencing CDK9 does not change carfilzomib sensitivity in the same manner as addition of TG02. Since changes in Mcl-1 protein occur in the presence of a proteasome inhibitor we hypothesize that regulation of Mcl-1 translation is the most likely mechanism. Taken together our data suggest that dual inhibition of Mcl-1 via decreased expression and the induction of its antagonist NOXA by the combination of carfilzomib and TG02 is active in myeloma and warrants further testing preclinically and in clinical trials. Moreover, regulation of Mcl-1 by TG02 is more complex than initially appreciated.

Fungal biogeography. Global diversity and geography of soil fungi.

Fungi play major roles in ecosystem processes, but the determinants of fungal diversity and biogeographic patterns remain poorly understood. Using DNA metabarcoding data from hundreds of globally distributed soil samples, we demonstrate that fungal richness is decoupled from plant diversity. The plant-to-fungus richness ratio declines exponentially toward the poles. Climatic factors, followed by edaphic and spatial variables, constitute the best predictors of fungal richness and community composition at the global scale. Fungi show similar latitudinal diversity gradients to other organisms, with several notable exceptions. These findings advance our understanding of global fungal diversity patterns and permit integration of fungi into a general macroecological framework.