Addressing pollination deficits in orchard crops through habitat management for wild pollinators

There is increasing evidence that farmers in many areas are achieving below maximum yields due to insufficient pollination. Practical and effective approaches are needed to maintain wild pollinator populations within agroecosystems so they can deliver critical pollination services that underpin crop production. We established nesting and wildflower habitat interventions in 24 UK apple orchards and measured effects on flower-visiting insects and the pollination they provide, exploring how this was affected by landscape context. We quantified the extent of pollination deficits and assessed whether the management of wild pollinators can reduce deficits and deliver improved outcomes for growers over 3 years. Wildflower interventions increased solitary bee numbers visiting apple flowers by over 20%, but there was no effect of nesting interventions. Other pollinator groups were influenced by both local and landscape-scale factors, with bumblebees and hoverflies responding to the relative proportion of semi-natural habitat at larger spatial scales (1000 m), while honeybees and other flies responded at 500 m or less. By improving fruit number and quality, pollinators contributed more than £16 k per hectare. However, deficits (where maximum potential was not being reached due to a lack of pollination) were recorded and the extent of these varied across orchards, and from year to year, with a 22% deficit in output in the worst (equivalent to ~£14 k/ha) compared to less than 3% (equivalent to ~£2 k/ha) in the best year. Although no direct effect of our habitat interventions on deficits in gross output was observed, initial fruit set and seed set deficits were reduced by abundant bumblebees, and orchards with a greater abundance of solitary bees saw lower deficits in fruit size. The abundance of pollinators in apple orchards is influenced by different local and landscape factors that interact and vary between years. Consequently, pollination, and the extent of economic output deficits, also vary between orchards and years. We highlight how approaches, including establishing wildflower areas and optimizing the ratio of cropped and non-cropped habitats can increase the abundance of key apple pollinators and improve outcomes for growers

Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. INTERPRETATION: Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. FUNDING:Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Critical metal enrichment in crustal melts: the role of metamorphic mica

Rare metals like Li, Be, V, Co, Nb, In, Cs, Sn, Ta, and W are considered critical resources and can be significantly enriched in granites and pegmatites. However the mechanisms of their enrichment in granitic magmas remain poorly understood. Many metal-enriched granitic magmas form through mica dehydration reactions during high-grade metamorphism. The preferential incorporation of these metals into micas provides a mechanism for their concentration and mobilisation during crustal anatexis. Comprehensive datasets of these elements and their partitioning in metamorphic micas across different metamorphic grades are currently lacking. We present the first extensive in-situ LA-ICP-MS element dataset collected from metasediment hosted muscovite and biotite from three different metamorphic cross-sections traversing sub-greenschist (~400ºC) to granulite-facies conditions (>900ºC). Within the same sample Li, V, Co, Cs, and Ta are more concentrated in biotite, while Be, In, Sn, and W concentrations are higher in muscovite. Sub-solidus micas record only non-systematic compositional variations between samples. Supra-solidus biotites show systematic depletion in Li, Be, Sn and Cs and enrichment in V and Co with increasing temperature in the highest-grade (muscovite absent) samples. Indium and W concentrations reach peak concentrations in biotite at 750ºC and 850ºC respectively. Muscovites record systematic enrichment in In and W and depletion in Be, Sn and Cs with increasing metamorphic grade. These distinctive trends appear independent of geological/tectonic setting (i.e. continental collision and crustal thinning). Our dataset highlights the importance of higher-temperature melting (>750ºC) and in particular, biotite breakdown reactions for the release of Li, Be, Sn, Cs and W into crustal melts

Stem cell factor/c-Kit signalling in normal and androgenetic alopecia hair follicles

Androgens stimulate many hair follicles to alter hair colour and size via the hair growth cycle; in androgenetic alopecia tiny, pale hairs gradually replace large, pigmented ones. Since stem cell factor (SCF) is important in embryonic melanocyte migration and maintaining adult rodent pigmentation, we investigated SCF/c-Kit signalling in human hair follicles to determine whether this was altered in androgenetic alopecia. Quantitative immunohistochemistry detected three melanocyte-lineage markers and c-Kit in four focus areas: the epidermis, infundibulum, hair bulb (where pigment is formed) and mid-follicle outer root sheath (ORS). Colocalisation confirmed melanocyte c-Kit expression; cultured follicular melanocytes also exhibited c-Kit. Few ORS cells expressed differentiated melanocyte markers or c-Kit, but NKI/beteb antibody, which also recognises early melanocyte-lineage antigens, identified fourfold more cells, confirmed by colocalisation. Occasional similar bulbar cells were seen. Melanocyte distribution, concentration and c-Kit expression were unaltered in balding follicles. Androgenetic alopecia cultured dermal papilla cells secreted less SCF, measured by ELISA, than normal cells. This identifies three types of melanocyte-lineage cells in human follicles. The c-Kit expression by dendritic, pigmenting, bulbar melanocytes and rounded, differentiated, non-pigmenting ORS melanocytes implicate SCF in maintaining pigmentation and migration into regenerating hair bulbs. Less differentiated, c-Kit-independent cells in the mid-follicle ORS stem cell niche and occasionally in the bulb, presumably a local reserve for long scalp hair growth, implicate other factors in activating stem cells. Androgens appear to reduce alopecia hair colour by inhibiting dermal papilla SCF production, impeding bulbar melanocyte pigmentation. These results may facilitate new treatments for hair colour changes in hirsutism, alopecia or greying

Addressing pollination deficits in orchard crops through habitat management for wild pollinators

There is increasing evidence that farmers in many areas are achieving below maximum yields due to insufficient pollination. Practical and effective approaches are needed to maintain wild pollinator populations within agroecosystems so they can deliver critical pollination services which underpin crop production. We established nesting and wildflower habitat interventions in 24 UK apple orchards and measured effects on flower-visiting insects and the pollination they provide, exploring how this was affected by landscape context. We quantified the extent of pollination deficits and assessed whether the management of wild pollinators can reduce deficits and deliver improved outcomes for growers over three years. Wildflower interventions increased solitary bee numbers visiting apple flowers by over 20% but there was no effect of nesting interventions. Other pollinator groups were influenced by both local and landscape-scale factors, with bumblebees and hoverflies responding to the relative proportion of semi-natural habitat at larger spatial scales (1000 m) while honeybees and other flies responded at 500 m or less. By improving fruit number and quality, pollinators contributed more than £15k per hectare. However, deficits (where maximum potential was not being reached due to a lack of pollination) were recorded and the extent of these varied across orchards, and from year to year, with a 22% deficit in the worst (~£11k/ha) compared to less than 3% (~£1k/ha) in the best year. Although no direct effect of our habitat interventions on deficits in gross output was observed, initial fruit set and seed set deficits were reduced by abundant bumblebees, and orchards with a greater abundance of solitary bees saw lower deficits in fruit size. The abundance of pollinators in apple orchards is influenced by different local and landscape factors which interact and vary between years. Consequently, pollination, and the extent of economic output deficits, also vary between orchards and years. We highlight how approaches, including establishing wildflower areas and optimising the ratio of cropped and non-cropped habitats can increase the abundance of key apple pollinators and improve outcomes for growers