Spatial heterogeneity of global forest aboveground carbon stocks and fluxes constrained by spaceborne lidar data and mechanistic modeling.

Forest carbon is a large and uncertain component of the global carbon cycle. An important source of complexity is the spatial heterogeneity of vegetation vertical structure and extent, which results from variations in climate, soils, and disturbances and influences both contemporary carbon stocks and fluxes. Recent advances in remote sensing and ecosystem modeling have the potential to significantly improve the characterization of vegetation structure and its resulting influence on carbon. Here, we used novel remote sensing observations of tree canopy height collected by two NASA spaceborne lidar missions, Global Ecosystem Dynamics Investigation and ICE, Cloud, and Land Elevation Satellite 2, together with a newly developed global Ecosystem Demography model (v3.0) to characterize the spatial heterogeneity of global forest structure and quantify the corresponding implications for forest carbon stocks and fluxes. Multiple-scale evaluations suggested favorable results relative to other estimates including field inventory, remote sensing-based products, and national statistics. However, this approach utilized several orders of magnitude more data (3.77 billion lidar samples) on vegetation structure than used previously and enabled a qualitative increase in the spatial resolution of model estimates achievable (0.25° to 0.01°). At this resolution, process-based models are now able to capture detailed spatial patterns of forest structure previously unattainable, including patterns of natural and anthropogenic disturbance and recovery. Through the novel integration of new remote sensing data and ecosystem modeling, this study bridges the gap between existing empirically based remote sensing approaches and process-based modeling approaches. This study more generally demonstrates the promising value of spaceborne lidar observations for advancing carbon modeling at a global scale.

Development of autotaxin inhibitors: A series of tetrazole cinnamides.

A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments.

The Laser Vegetation Detecting Sensor: A Full Waveform, Large-Footprint, Airborne Laser Altimeter for Monitoring Forest Resources.

The use of satellite-borne large-footprint LiDAR (light detection and ranging) systems allows for the acquisition of forest monitoring data. This paper mainly describes the design, use, operating principles, installation and data properties of the new Laser Vegetation Detecting Sensor (LVDS), a LiDAR system designed and developed at the Academy of Forest Inventory and Planning (AFIP) and the Beijing Institute of Telemetry (BIT). Data from LVDS were used to calculate the mean height of forest trees on sample plots using data collected in the Hunan province of China. The results show that the full waveform data obtained by LVDS has the ability to accurately characterize forest height. The mean absolute percentage error of mean forest height per plot in flat areas was 6.8%, with a mean absolute deviation of 0.78 m. The airborne LVDS system provides prototype data sets and a platform for instrument proof-of-concept studies for China's Terrestrial Ecosystem Carbon Monitoring (TECM) mission, which is an Earth remote sensing satellite due for launch in 2020. The information produced by LVDS allows for forest structure studies with high accuracy and coverage of large areas.

Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma.

BACKGROUND: It is unclear whether patients with early-stage Hodgkin's lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy. METHODS: Patients with newly diagnosed stage IA or stage IIA Hodgkin's lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group. RESULTS: A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkin's lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkin's lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3). CONCLUSIONS: The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkin's lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).

Synthesis of a Novel Type of 2,3'-BIMs via Platinum-Catalysed Reaction of Indolylallenes with Indoles.

Optimisation, scope and mechanism of the platinum-catalysed addition of indoles to indolylallenes is reported here to give 2,3'-BIMs with a novel core structure very relevant for pharmaceutical industry. The reaction is modulated by the electronic properties of the substituents on both indoles, with the 2,3'-BIMs favoured when electron donating groups are present. Although simple at first, a complex mechanism has been uncovered that explains the different behaviour of these systems with platinum when compared with other metals (e.g. gold). Detailed labelling studies have shown Pt-catalysed 6-endo-trig cyclisation of the indollylallene as the first step of the reaction and the involvement of two cyclic vinyl-platinum intermediates in equilibrium through a platinum carbene, as the key intermediates of the catalytic cycle towards the second nucleophilic attack and formation of the BIMs.

Precision and cost considerations for two-stage sampling in a panelized forest inventory design.

Due to the relatively high cost of measuring sample plots in forest inventories, considerable attention is given to sampling and plot designs during the forest inventory planning phase. A two-stage design can be efficient from a field work perspective as spatially proximate plots are grouped into work zones. A comparison between subsampling with units of unequal size (SUUS) and a simple random sample (SRS) design in a panelized framework assessed the statistical and economic implications of using the SUUS design for a case study in the Northeastern USA. The sampling errors for estimates of forest land area and biomass were approximately 1.5-2.2 times larger with SUUS prior to completion of the inventory cycle. Considerable sampling error reductions were realized by using the zones within a post-stratified sampling paradigm; however, post-stratification of plots in the SRS design always provided smaller sampling errors in comparison. Cost differences between the two designs indicated the SUUS design could reduce the field work expense by 2-7 %. The results also suggest the SUUS design may provide substantial economic advantage for tropical forest inventories, where remote areas, poor access, and lower wages are typically encountered.

Integrating LIDAR and forest inventories to fill the trees outside forests data gap.

Forest inventories are commonly used to estimate total tree biomass of forest land even though they are not traditionally designed to measure biomass of trees outside forests (TOF). The consequence may be an inaccurate representation of all of the aboveground biomass, which propagates error to the outputs of spatial and process models that rely on the inventory data. An ideal approach to fill this data gap would be to integrate TOF measurements within a traditional forest inventory for a parsimonious estimate of total tree biomass. In this study, Light Detection and Ranging (LIDAR) data were used to predict biomass of TOF in all "nonforest" Forest Inventory and Analysis (FIA) plots in the state of Maryland. To validate the LIDAR-based biomass predictions, a field crew was sent to measure TOF on nonforest plots in three Maryland counties, revealing close agreement at both the plot and county scales between the two estimates. Total tree biomass in Maryland increased by 25.5 Tg, or 15.6%, when biomass of TOF were included. In two counties (Carroll and Howard), there was a 47% increase. In contrast, counties located further away from the interstate highway corridor showed only a modest increase in biomass when TOF were added because nonforest conditions were less common in those areas. The advantage of this approach for estimating biomass of TOF is that it is compatible with, and explicitly separates TOF biomass from, forest biomass already measured by FIA crews. By predicting biomass of TOF at actual FIA plots, this approach is directly compatible with traditionally reported FIA forest biomass, providing a framework for other states to follow, and should improve carbon reporting and modeling activities in Maryland.

Psychosocial factors associated with impact of cancer in longterm haematological cancer survivors.

To assess the impact of cancer (IOC) on subsequent quality of life (QOL), 718 long-term haematological cancer survivors completed validated psychosocial, functional and QOL scales, including IOC. Fifteen percent reported significant psychological distress, 18% high levels of fatigue and 10% moderate to severe functional impairment. These groups of participants also showed poorer QOL. There were no significant differences in psychological distress (P = 0·76), fatigue (P = 0·23) or functional impairment (P = 0·74) across different cancer subtypes. Two separate hierarchical regression analyses examined the combined association of disease-type, psychosocial and other factors on negative and positive IOC scores respectively. Higher negative IOC scores were significantly associated (P ≤ 0·001) with medical comorbidity, psychological distress, lower social support, high fatigue levels and functional impairment. Paediatric patients (diagnosed at <17 years) had significantly higher negative IOC scores than adult patients (P = 0·001); greater years since diagnosis was significantly (P < 0·001) associated with less negative IOC. Higher positive IOC was associated with acute leukaemia (P = 0·01); lower positive IOC with paediatric patients (P < 0·001), white ethnicity (P < 0·001), higher education (P = 0·003), no partner (P = 0·01) and lower social support (P = 0·01). Screening for medical comorbidity, psychological distress and fatigue identifies those needing most support and should allow earlier interventions to address negative and positive IOC to improve the well-being of cancer survivors.

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium.

The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy.

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the ß-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.

Spatial predictions of tree density and tree height across Mexico forests using ensemble learning and forest inventory data.

The National Forestry Commission of Mexico continuously monitors forest structure within the country's continental territory by the implementation of the National Forest and Soils Inventory (INFyS). Due to the challenges involved in collecting data exclusively from field surveys, there are spatial information gaps for important forest attributes. This can produce bias or increase uncertainty when generating estimates required to support forest management decisions. Our objective is to predict the spatial distribution of tree height and tree density in all Mexican forests. We performed wall-to-wall spatial predictions of both attributes in 1-km grids, using ensemble machine learning across each forest type in Mexico. Predictor variables include remote sensing imagery and other geospatial data (e.g., mean precipitation, surface temperature, canopy cover). Training data is from the 2009 to 2014 cycle (n > 26,000 sampling plots). Spatial cross validation suggested that the model had a better performance when predicting tree height r 2 = .35 [.12, .51] (mean [min, max]) than for tree density r 2 = .23 [.05, .42]. The best predictive performance when mapping tree height was for broadleaf and coniferous-broadleaf forests (model explained ~50% of variance). The best predictive performance when mapping tree density was for tropical forest (model explained ~40% of variance). Although most forests had relatively low uncertainty for tree height predictions, e.g., values <60%, arid and semiarid ecosystems had high uncertainty, e.g., values >80%. Uncertainty values for tree density predictions were >80% in most forests. The applied open science approach we present is easily replicable and scalable, thus it is helpful to assist in the decision-making and future of the National Forest and Soils Inventory. This work highlights the need for analytical tools that help us exploit the full potential of the Mexican forest inventory datasets.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.

BACKGROUND: Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. METHODS: The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m(2) every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. FINDINGS: 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9% (95% CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6% (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44-0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5%) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2%) in the observation group (p=0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95% CI 0·51-1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group and 84 (17%) in the observation group (risk ratio 1·46, 95% CI 1·14-1·87; p=0·0026). Infections (grades 2-4) were the most common adverse event, occurring in 197 (39%) and 123 (24%) patients, respectively (risk ratio 1·62, 95% CI 1·35-1·96; p<0·0001). INTERPRETATION: 2 years of rituximab maintenance therapy after immunochemotherapy as first-line treatment for follicular lymphoma significantly improves PFS. FUNDING: Groupe d'Etude des Lymphomes de l'Adulte (GELA) and F Hoffmann-La Roche.

From libraries to candidate: the discovery of new ultra long-acting dibasic ß2-adrenoceptor agonists.

Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious ß(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.

Inventory methods for trees in nonforest areas in the Great Plains States.

The US Forest Service's Forest Inventory and Analysis (FIA) program collects information on trees in areas that meet its definition of forest. However, the inventory excludes trees in areas that do not meet this definition, such as those found in urban areas, in isolated patches, in areas with sparse or predominantly herbaceous vegetation, in narrow strips (e.g., shelterbelts), or in riparian areas. In the Great Plains States, little is known about the tree resource in these noninventoried, nonforest areas, and there is a great deal of concern about the potential impact of invasive pests, such as the emerald ash borer. To address this knowledge gap, FIA's National Inventory and Monitoring Applications Center has partnered with state cooperators and others in a project called the Great Plains Initiative to design and implement an inventory of trees in nonforest areas. The goal of the inventory is to characterize the nonforest tree resource using methods compatible with those of FIA so a holistic understanding of the resource can be obtained by integrating the two surveys. The goal of this paper is to describe the process of designing and implementing the survey, including plot and sample design, and to present some example results from a reporting tool we developed.

C(sp3)-C(sp3) coupling of non-activated alkyl-iodides with electron-deficient alkenes via visible-light/silane-mediated alkyl-radical formation.

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides. An interaction between a silane and an alkyl iodide is excited by irradiation with visible light to trigger carbon-iodide bond homolysis and form the alkyl radical. We show how this method can be developed into an operationally simple and general Giese addition reaction that can tolerate a range of sensitive functionalities not normally explored in established approaches to this strategically important transformation. The new method requires no photocatalyst or other additives and uses only commerical tris(trimethylsilyl)silane and visible light to effectively combine a broad range of alkyl halides with activated alkenes to form C(sp3)-C(sp3) bonds embedded within complex frameworks.

Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies.

We have previously reported presentation serum selenium level to be predictive of outcome in diffuse large B-cell lymphoma. This has now been studied in a further 430 patients, 163 with acute myeloid leukaemia (AML), 156 with Hodgkin Lymphoma (HL), and 111 with Follicular Lymphoma (FL). Serum selenium was below the UK normal reference range in 45% of patients, and correlated with serum albumin (r=0·24-0·46, P<0·001-0·003) in all tumour types. Independent predictors of presentation selenium were; French-American-British subtype and albumin (P<0·001 for both) in AML, haemoglobin (P=0·002) and B-symptoms (P=0·01) in HL, and albumin (P<0·001) in FL. In AML and HL, response to first line therapy was lower in patients with low serum selenium, but selenium was no longer predictive of response when other variables were entered into a multivariate model. Low selenium was also associated with a worse overall survival in FL [Hazard Ratio (HR) 2·3, 95% confidence interval (CI) 1·4, 4·0] and a trend to a worse overall survival in AML (HR 1·43, 95% CI 0·96, 2·13) by univariate Cox regression analysis, but not by multivariate analysis. In conclusion, low serum selenium is associated with a worse outcome in patients with haematological malignancies, but is not independently predictive, suggesting that it reflects other factors.

Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia.

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.