CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma.

Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70-targeted allogeneic CAR T cells. SIGNIFICANCE: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.

Research Progress on the Antioxidant Activity of Natural Diarylheptanoids: Mechanisms and Structure-activity Relationships.

Antioxidant research has recently become a popular topic. Medicinal plants are important sources of novel active compounds. Diarylheptanoids, a typical family of secondary plant metabolites, are of great interest owing to their extensive spectrum of biological activities. They possess a unique 1,7-diphenylmethane structural skeleton. Thus, this review summarizes the natural linear or macrocyclic diarylheptanoids with antioxidant activity in the last two decades. In addition, the relationships between the structural characteristics of natural diarylheptanoids and their antioxidant capacity were also discussed. All the available data highlight the potential of natural diarylheptanoids as novel antioxidants.

The effect of emotion regulation on empathic ability in Chinese nursing students: The parallel mediating role of emotional intelligence and self-consistency congruence.

AIM: This study aims to explore the influence of emotion regulation on empathic ability among undergraduate nursing students, as well as the mediating role of emotional intelligence and self-consistency congruence. DESIGN: A cross-sectional study was employed to examine the relationship between the emotion regulation and empathic ability in Chinese nursing students. METHODS: A total of 761 undergraduate nursing students were surveyed using the Interpersonal Reactivity Index (Chinese version), the Gross Emotion Regulation Questionnaire, Wang and Law's Emotional Intelligence Scale and the Self-Harmony Scale. RESULTS: There was a significant positive correlation between emotion regulation, empathic ability and self-harmony. Significant positive correlations were also found between emotion regulation, empathic ability and emotional intelligence. Mediation analysis revealed that self-harmony and emotional intelligence partially mediated the predictive relationship between emotion regulation and empathic ability, with self-harmony showing a more significant mediating effect. CONCLUSION: The findings suggest that emotion regulation among undergraduate nursing students indirectly influences their empathic ability through parallel mediating effects of self-harmony and emotional intelligence.

Integrative virtual nursing simulation in teaching cardiopulmonary resuscitation: A blended learning approach.

BACKGROUND: Online learning resources facilitated educational development during the COVID-19 pandemic. This study focuses on the integration of online virtual simulation with interactive exercises and offline low-fidelity simulation for the first time to explore the impact on CPR skills. METHODS: First year nursing students from a medical college participated as volunteers in this study. They were divided randomly into two groups with both having a cardiopulmonary resuscitation (CPR) lesson with the same timings and objectives. The experimental group (n = 36) adopted a blended learning method, with virtual simulation and low-fidelity simulation as resources; the control group (n = 36) used the same method without virtual simulation. The same lecturers taught both classes. Students' self-directed learning (SDL) and critical thinking skills were assessed before and after the intervention and their CPR skills were examined afterward. RESULTS: The experimental group exhibited significantly greater improvement in their SDL abilities and CPR skills. By contrast, we found no statistical differences in their critical thinking abilities. CONCLUSIONS: During CPR training, blended learning method was used to integrate virtual nursing simulation in teaching, which effectively improved students' SDL and CPR skills.

Adolescent resilience and mobile phone addiction in Henan Province of China: Impacts of chain mediating, coping style.

BACKGROUND: As mobile phone use grows, so it brings benefits and risks. As an important part of adolescents healthy growth, resilience plays an indispensable role. Thus, it is important to identify when mobile phone use of an adolescent becomes an addiction. This study proposed to explore the effects of adolescent resilience on mobile phone addiction, and tested the mediating role of coping style and depression, anxiety, and stress (DASS) on phone addiction among 2,268 adolescents in the Henan province, China. METHODS: The adolescents were surveyed via an online questionnaire, a mobile phone addiction index (MPAI), a depression, anxiety, and stress scale with 21 items (DASS-21), the Resilience Scale for Chinese Adolescents (RSCA), and the Simplified coping style questionnaire (SCSQ), and we used structural equation modeling to examine the correlations and moderation effects. All data analyses were performed using SPSS 26.0 and Amos 23.0. RESULTS: The results show that adolescences resilience were negatively related to negative coping, DASS, and mobile phone addiction; both coping style and DASS could mediate the relationship between adolescent resilience and mobile phone addiction among Chinese adolescents. The relationship between adolescent resilience and mobile phone addiction in Chinese adolescents was mediated by the chain of coping styles and DASS. CONCLUSIONS: There is a negative relationship which exists between resilience and mobile phone addiction in this population. In addition, stress, anxiety, depression, and coping style significantly influence the risk of adolescent mobile phone addiction and play an intermediary role in Chinese adolescent resilience and mobile phone addiction.

Research progress on the antiviral activities of natural products and their derivatives: Structure-activity relationships.

Viruses spread rapidly and are well-adapted to changing environmental events. They can infect the human body readily and trigger fatal diseases. A limited number of drugs are available for specific viral diseases, which can lead to non-efficacy against viral variants and drug resistance, so drugs with broad-spectrum antiviral activity are lacking. In recent years, a steady stream of new viral diseases has emerged, which has prompted development of new antiviral drugs. Natural products could be employed to develop new antiviral drugs because of their innovative structures and broad antiviral activities. This review summarizes the progress of natural products in antiviral research and their bright performance in drug resistance issues over the past 2 decades. Moreover, it fully discusses the effect of different structural types of natural products on antiviral activity in terms of structure-activity relationships. This review could provide a foundation for the development of antiviral drugs.

The Impact of Adolescent Resilience on Mobile Phone Addiction During COVID-19 Normalization and Flooding in China: A Chain Mediating.

Natural disasters cause long-term psychological problems and increase substance use in some adults. However, it is unclear whether disasters also lead to these problems in adolescents. We hypothesized the influence of adolescent resilience on mobile phone addiction during the normalization of COVID-19 and flooding. We tested the mediating role of coping style and depression, anxiety, and stress (DASS) on phone addiction among 1,751 adolescents in the Henan Province in China. The adolescents were surveyed via an online questionnaire, and we used structural equation modeling to examine the correlations and moderation effects. The results show that coping style and DASS could mediate the relationship between adolescent resilience and mobile phone addiction among Chinese adolescents. A chain of coping styles and DASS mediated the relationship between adolescent resilience and mobile phone addiction in Chinese adolescents.

R3-MYB transcription factor LcMYBx from Litchi chinensis negatively regulates anthocyanin biosynthesis by ectopic expression in tobacco.

Anthocyanin accumulation is one of the remarkable physiological changes during fruit ripening. In plants, anthocyanin synthesis is regulated by MYB activators, but the MYB repressors has been recognized recently. Here, we isolated a repressor of anthocyanin synthesis, LcMYBx, from Litchi chinensis Sonn. LcMYBx encoded a typical R3-MYB protein and contained a conserved [D/E]Lx2[R/K]x3Lx6Lx3R motif for interacting with bHLH proteins. Overexpression of LcMYBx in tobacco suppressed anthocyanin accumulation resulting in faded petals from pale-pink to almost white. Gene expression analysis showed the strong down-regulation of endogenous anthocyanin structural and regulatory genes by LcMYBx overexpression. Yeast two-hybrid and bimolecular fluorescence complementation assays indicated that LcMYBx could interact with the transcription factors LcbHLH1 and LcbHLH3. Transient promoter activation assays showed that LcMYBx could inhibit the activation capacity of LcMYB1-LcbHLH3 complex for LcDFR gene. These results suggest that LcMYBx competed with LcMYB1 to LcbHLHs, thus preventing the activation of LcDFR by LcMYB1-LcbHLHs complex and negatively controlling anthocyanin biosynthesis.

2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation (Part 3 - Recommendations on Immunogenicity Assay Strategies, NAb Assays, Biosimilars and FDA/EMA Immunogenicity Guidance/Guideline, Gene & Cell Therapy and Vaccine Assays).

The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity). Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation) and Part 2B (Regulatory Input) are published in volume 13 of Bioanalysis, issues 4 and 5 (2020), respectively.

Determinants of normal nutrition among 0-59-month-old Filipino children living in low-income households.

BACKGROUND: An alternative concept in understanding malnutrition among 0 to 59-month-old children from low-income households is to look at and understand factors contributing to their good nutritional status. AIM: (a) Compared nutritional status of children across age groups in terms of weight-for-age, length/height-for-age, weight-for-length/height and body mass index-for-age z scores; (b) determined and compared selected characteristics of children and mothers across age; (c) identified factors affecting normal nutritional status of these children. METHODS: Cross-sectional data from the Philippines' 8th National Nutrition Survey among 1,990 children. Differences in mean values measured using analysis of variance; chi-square test for assessing significance of association between children with normal nutritional status across child and maternal characteristics; and multivariate logistic regression to calculate adjusted odds ratio (AORs). RESULTS: Younger (AOR =1.63-2.54), female children (AOR=1.20), mothers neither pregnant nor lactating (AOR=1.18), have high school, vocational (AOR=1.65) or college level education (AOR=2.02), household use of water-sealed toilet (AOR=1.26), having nuclear family types (AOR=1.25) indicated protection against undernutrition. Behavior-related factors that significantly predict normal nutrition among the children were "acceptable" food consumption score among households (0 to 5 and 6 to 23 months old), delivery in health facilities (6 to 23 months old) and household use of water-sealed toilets (24 to 59 months). CONCLUSION: Based on the findings, activities and programs can be tailored around the behavior-related factors identified depending on the target age group, and pursued in crafting interventions to maintain normal nutrition among the children.

Analysis of fast structured dictionary learning.

Sparsity-based models and techniques have been exploited in many signal processing and imaging applications. Data-driven methods based on dictionary and sparsifying transform learning enable learning rich image features from data and can outperform analytical models. In particular, alternating optimization algorithms have been popular for learning such models. In this work, we focus on alternating minimization for a specific structured unitary sparsifying operator learning problem and provide a convergence analysis. While the algorithm converges to the critical points of the problem generally, our analysis establishes under mild assumptions, the local linear convergence of the algorithm to the underlying sparsifying model of the data. Analysis and numerical simulations show that our assumptions hold for standard probabilistic data models. In practice, the algorithm is robust to initialization.

Assessing school-lunch feeding and nutrition education strategy for healthier kids in selected Philippine public schools.

BACKGROUND: Nutrition interventions during the early years of a child's life are anchored on the need to provide good nutrition and proper health care to optimize their growth potential as adults. In the Philippines, undernutrition is a persistent problem among 0-10 year old Filipino children. In this age group, children consume a diet poor in quantity and quality. AIM: This study aimed to assess the effects of a school-lunch and nutrition education intervention among schoolchildren in terms of attaining good nutrition. METHOD: Using a quasi-experimental design, children aged 7-9 years from public elementary schools in the province of Laguna, Philippines were categorized into three intervention groups and one non-intervention group. Anthropometric measurements; nutrition knowledge, attitude and behavior; and food intake among children and households were collected at baseline and endline periods. SPSS for Windows version 16 and Stata version 15 were utilized for data analysis. RESULTS: Mean scores on knowledge, attitude and behavior of schoolchildren in intervention groups increased significantly at endline (p<0.05). Protein requirement was met by more children and households than the energy requirement. Most children with normal nutritional status after the interventions (25.3%) belonged to the group with the complete intervention of school-lunch and nutrition education. CONCLUSIONS: The provision of both school-lunch feeding and nutrition education is effective in improving the knowledge, attitude and behavior scores and nutritional status of schoolchildren. The adoption and institutionalization of complete intervention with school-lunch and nutrition education in elementary public schools should be pursued.

Genome-wide identification and expression analysis of SWEET gene family in Litchi chinensis reveal the involvement of LcSWEET2a/3b in early seed development.

BACKGROUND: SWEETs (Sugar Will Eventually be Exported transporters) function as sugar efflux transporters that perform diverse physiological functions, including phloem loading, nectar secretion, seed filling, and pathogen nutrition. The SWEET gene family has been identified and characterized in a number of plant species, but little is known about in Litchi chinensis, which is an important evergreen fruit crop. RESULTS: In this study, 16 LcSWEET genes were identified and nominated according to its homologous genes in Arabidopsis and grapevine. Multiple sequence alignment showed that the 7 alpha-helical transmembrane domains (7-TMs) were basically conserved in LcSWEETs. The LcSWEETs were divided into four clades (Clade I to Clade IV) by phylogenetic tree analysis. A total of 8 predicted motifs were detected in the litchi LcSWEET genes. The 16 LcSWEET genes were unevenly distributed in 9 chromosomes and there was one pairs of segmental duplicated events by synteny analysis. The expression patterns of the 16 LcSWEET genes showed higher expression levels in reproductive organs. The temporal and spatial expression patterns of LcSWEET2a and LcSWEET3b indicated they play central roles during early seed development. CONCLUSIONS: The litchi genome contained 16 SWEET genes, and most of the genes were expressed in different tissues. Gene expression suggested that LcSWEETs played important roles in the growth and development of litchi fruits. Genes that regulate early seed development were preliminarily identified. This work provides a comprehensive understanding of the SWEET gene family in litchi, laying a strong foundation for further functional studies of LcSWEET genes and improvement of litchi fruits.

Genetic dissection of developmental responses of agro-morphological traits under different doses of nutrient fertilizers using high-density SNP markers.

The production and productivity of rice (Oryza sativa L.) are primarily influenced by the application of the critical nutrients nitrogen (N), phosphorus (P), and potassium (K). However, excessive application of these fertilizers is detrimental to the environment and increases the cost of production. Hence, there is a need to develop varieties that simultaneously increase yields under both optimal and suboptimal rates of fertilizer application by maximizing nutrient use efficiency (NuUE). To unravel the hidden genetic variation and understand the molecular and physiological mechanisms of NuUE, three different mapping populations (MPs; BC1F5) derived from three donors (Haoannong, Cheng-Hui 448, and Zhong 413) and recipient Weed Tolerant Rice 1 were developed. A total of three favorable agronomic traits (FATs) were considered as the measure of NuUE. Analysis of variance and descriptive statistics indicated the existence of genetic variation for NuUE and quantitative inheritance of FATs. The genotypic data from single-nucleotide polymorphism (SNP) markers from Tunable Genotyping-By-Sequencing (tGBS) and phenotypic values were used for locating the genomic regions conferring NuUE. A total of 19 quantitative trait loci (QTLs) were detected, out of which 11 QTLs were putative on eight chromosomes, which individually explained 17.02% to 34.85% of the phenotypic variation. Notably, qLC-II_1 and qLC-II_11 detected at zero fertilizer application showed higher performance for LC under zero percentage of NPK fertilizer. The remarkable findings of the present study are that the detected QTLs were associated in building tolerance to low/no nutrient application and six candidate genes on chromosomes 2 and 5 within these putative QTLs were found associated with low nutrient tolerance and related to several physiological and metabolic pathways involved in abiotic stress tolerance. The identified superior introgressed lines (ILs) and trait-associated genetic regions can be effectively used in marker-assisted selection (MAS) for NuUE breeding programs.

Fast Hyperspectral Diffuse Optical Imaging Method with Joint Sparsity.

Diffuse optical tomography (DOT) is an important functional imaging modality in clinical diagnosis and treatment. As the number of wavelengths in the acquired DOT data grows, it becomes very challenging to reconstruct diffusion and absorption coefficients of tissue, i.e., a DOT image. In this paper, we consider the hyperspectral DOT (hyDOT) inverse problem as a multiple-measurement vector (MMV) problem by exploiting the joint sparsity of the images to be reconstructed. Then we propose a fast stochastic greedy algorithm based on the MMV stochastic gradient matching pursuit (MStoGradMP) and the mini-batching technique. Numerical results show that the proposed algorithm can achieve higher reconstruction accuracy with significantly reduced running time than the related gradient descent method with sparsity regularization.

CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial.

CUDC-907 is a first-in-class, oral small molecule inhibitor of both HDAC (class I and II) and PI3K (class Iα, ß, and δ) enzymes, with demonstrated anti-tumor activity in multiple pre-clinical models, including MYC-driven ones. In this report, we present the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), with a particular focus on those with MYC-altered disease. Thirty-seven DLBCL patients were enrolled, 14 with confirmed MYC-altered disease. Twenty-five patients received monotherapy treatment, and 12 received the combination of CUDC-907 with rituximab. CUDC-907 monotherapy and combination demonstrated similar safety profiles consisting primarily of Grade 1/2 hematologic and gastrointestinal events. The most frequently reported Grade ≥3 treatment-related events were thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia. Eleven responses (5 complete responses and 6 partial responses) were reported, for a response rate of 37% (11 out of 30) in evaluable patients [30% (11 out of 37) including all patients]. The objective response rate in evaluable MYC-altered DLBCL patients was 64% (7 out of 11; 4 complete responses and 3 partial responses), while it was 29% (2 out of 7) in MYC unaltered, and 17% (2 out of 12) in those with unknown MYC status. Median duration of response was 11.2 months overall; 13.6 months in MYC-altered patients, 6.0 months in MYC unaltered, and 7.8 months in those with MYC status unknown. The tolerable safety profile and encouraging evidence of durable anti-tumor activity, particularly in MYC-altered patients, support the continued development of CUDC-907 in these populations of high unmet need. (clinicaltrials.gov identifier: 01742988).

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers.

Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285-99. ©2016 AACR.

Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.

BACKGROUND: Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. METHODS: This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988. FINDINGS: Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine [20%] of 44 patients), neutropenia (three [7%]), and hyperglycaemia (three [7%]). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose. INTERPRETATION: The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing. FUNDING: Curis, Inc, and the Leukemia and Lymphoma Society.

Carbon storage in China's forest ecosystems: estimation by different integrative methods.

Carbon (C) storage for all the components, especially dead mass and soil organic carbon, was rarely reported and remained uncertainty in China's forest ecosystems. This study used field-measured data published between 2004 and 2014 to estimate C storage by three forest type classifications and three spatial interpolations and assessed the uncertainty in C storage resulting from different integrative methods in China's forest ecosystems. The results showed that C storage in China's forest ecosystems ranged from 30.99 to 34.96 Pg C by the six integrative methods. We detected 5.0% variation (coefficient of variation, CV, %) among the six methods, which was influenced mainly by soil C estimates. Soil C density and storage in the 0-100 cm soil layer were estimated to be 136.11-153.16 Mg C·ha(-1) and 20.63-23.21 Pg C, respectively. Dead mass C density and storage were estimated to be 3.66-5.41 Mg C·ha(-1) and 0.68-0.82 Pg C, respectively. Mean C storage in China's forest ecosystems estimated by the six integrative methods was 8.557 Pg C (25.8%) for aboveground biomass, 1.950 Pg C (5.9%) for belowground biomass, 0.697 Pg C (2.1%) for dead mass, and 21.958 Pg C (66.2%) for soil organic C in the 0-100 cm soil layer. The R:S ratio was 0.23, and C storage in the soil was 2.1 times greater than in the vegetation. Carbon storage estimates with respect to forest type classification (38 forest subtypes) were closer to the average value than those calculated using the spatial interpolation methods. Variance among different methods and data sources may partially explain the high uncertainty of C storage detected by different studies. This study demonstrates the importance of using multimethodological approaches to estimate C storage accurately in the large-scale forest ecosystems.

Carbon storage in Chinese grassland ecosystems: Influence of different integrative methods.

The accurate estimate of grassland carbon (C) is affected by many factors at the large scale. Here, we used six methods (three spatial interpolation methods and three grassland classification methods) to estimate C storage of Chinese grasslands based on published data from 2004 to 2014, and assessed the uncertainty resulting from different integrative methods. The uncertainty (coefficient of variation, CV, %) of grassland C storage was approximately 4.8% for the six methods tested, which was mainly determined by soil C storage. C density and C storage to the soil layer depth of 100 cm were estimated to be 8.46 ± 0.41 kg C m(-2) and 30.98 ± 1.25 Pg C, respectively. Ecosystem C storage was composed of 0.23 ± 0.01 (0.7%) above-ground biomass, 1.38 ± 0.14 (4.5%) below-ground biomass, and 29.37 ± 1.2 (94.8%) Pg C in the 0-100 cm soil layer. Carbon storage calculated by the grassland classification methods (18 grassland types) was closer to the mean value than those calculated by the spatial interpolation methods. Differences in integrative methods may partially explain the high uncertainty in C storage estimates in different studies. This first evaluation demonstrates the importance of multi-methodological approaches to accurately estimate C storage in large-scale terrestrial ecosystems.