ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was ...conducted to determine its recommended phase II dose (RP2D).
This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.
No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a
of 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.
ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.
.
To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma.
We conducted a double-blinded randomized ...phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1
and/or -A2
-resected patients with residual tumor ≤1 cm
received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2 or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter.
ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (
= 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit.
PFS was significantly improved in ICT-107-treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.
Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) ...Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.
Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.
Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.
AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.
NCT, NCT03400917 , Registered 10 January 2018.
Increasing water and radiation use efficiencies (WUE and RUE, respectively) are critical to enhance crop production. Exploring genetic variability in WUE and RUE is necessary to improve these traits. ...The objectives of this research were to evaluate eight sorghum Sorghum bicolor (L.) Moench genotypes for biomass production, WUE, and RUE and to test whether the differences in WUE among sorghum genotypes were associated with increased biomass production or decreased water use under field conditions. The WUE was estimated as the slope of the regression of aboveground biomass on cumulative water use for specified sampling intervals. The RUE was estimated as the slope of the regression of aboveground biomass on cumulative intercepted photosynthetically active radiation (IPAR). Sorghum genotypes showed significant differences in biomass production, WUE, and RUE. The WUE varied from 3.39 ± 0.80 to 5.42 ± 0.80 g kg−1 in 2009 and from 4.04 ± 0.58 to 7.63 ± 0.58 g kg−1 in 2010. Similarly, RUE varied from 2.13 ± 0.33 to 3.53 ± 0.31 g MJ−1 IPAR in 2009 and from 2.08 ± 0.35 to 3.83 ± 0.33 g MJ−1 IPAR in 2010. Among the eight sorghum genotypes tested in this study, IS 27111 and IS 27150 had the largest biomass production, WUE, and RUE. The WUE was more strongly correlated to biomass production than to water use. This result implies that it is possible to improve WUE without compromising biomass production. The sorghum genotypes evaluated for biomass production, WUE, and RUE in this study offer useful plant materials for identifying the mechanisms causing differences in these traits.
•The Great Plains exhibits 9–12 subregions of seasonal drought variability.•Several subregions demonstrate significant wetting trends.•Drought in the Great Plains has become more variable across ...space and time.
Identification of subregions that share similar historical drought variability provides useful information for drought monitoring, mitigation planning, and resource allocation. This study examined space-time historical drought variability for the Great Plains spanning from 1901 to 2015 by using rotated Empirical Orthogonal Functions (rEOFs). The Standardized Precipitation-Evapotranspiration Index (SPEI) on a three-month timescale was utilized to examine spatial and temporal changes in agricultural drought. We propose a new procedure for identifying the number of rEOFs to be selected for reconstructing subregions. Drought event intensities of moderate, severe, and extreme categories increased in recent years although the number of drought events decreased. Seasonal rEOFs demonstrated that 9–12 subregions were adequate to explain a significant proportion of the original variability in the Great Plains. The time series for each subregion was highly correlated to the original SPEI data and reflected the seasonal meteorological processes that drive drought variability. Several significant wetting trends were found, and there was statistical evidence that drought and wetting event severities had increased for a few subregions. Summer drought has become more variable across space and time, indicating that a more diverse set of resources and strategies might be needed to mitigate impacts of spatially-variable drought and wetting events in coming decades. Winter season drought has become less variable, indicating that perhaps resources could be consolidated when dealing with impacts on a larger scale; however, less variability implies that drought and wetting events may occur across larger regions of the Great Plains during a given season.
Pulsed amplitude modulation (PAM) chlorophyll a fluorescence provides information about photosynthetic energy transduction. When reliably measured, chlorophyll a fluorescence provides detailed ...information about critical in vivo photosynthetic processes. Such information has recently provided novel and critical insights into how the yield potential of crops can be improved and it is being used to understand remotely sensed fluorescence, which is termed solar‐induced fluorescence and will be solely measured by a satellite scheduled to be launched this year. While PAM chlorophyll a fluorometers measure fluorescence intensity per se, herein we articulate the axiomatic criteria by which instrumentally detected intensities can be assumed to assess fluorescence yield, a phenomenon quite different than fluorescence intensity and one that provides critical insight about how solar energy is variably partitioned into the biosphere. An integrated mathematical, phenomenological, and practical discussion of many useful chlorophyll a fluorescence parameters is presented. We draw attention to, and provide examples of, potential uncertainties that can result from incorrect methodological practices and potentially problematic instrumental design features. Fundamentals of fluorescence measurements are discussed, including the major assumptions underlying the signals and the methodological caveats about taking measurements during both dark‐ and light‐adapted conditions. Key fluorescence parameters are discussed in the context of recent applications under environmental stress. Nuanced information that can be gleaned from intra‐comparisons of fluorescence‐derived parameters and intercomparisons of fluorescence‐derived parameters with those based on other techniques is elucidated.
PAM chlorophyll a fluorometers detect ‘intensities’ that are presumed to represent chlorophyll fluorescence yield (ΦF), the latter of which provides information about how photosynthetic organisms variably partition solar energy into the biosphere. Yet exactly how and why detected intensities can be assumed to represent ΦF is not always explicitly stated in the literature. Therefore, from the outset, we derive the meaning of ΦF from first principles and state what criteria are required for instrumentally detected intensities to represent ΦF. We then include a section where the mathematical expressions of key ΦF parameters are juxtaposed with their respective experimental phenomena.
Carbon isotope discrimination (CID) has been suggested as an indirect selection criterion for grain yield under drought stress in wheat (Triticum aestivum L.). However, the association between CID ...and grain yield varies greatly among different studies. In this study, conducted in western Kansas, a temperate semi-arid region, the genetic variation of grain CID and its association with grain yield and other agronomic traits were examined using 43 preliminary and 15 advanced breeding lines under dryland conditions. The 43 preliminary breeding lines were tested in three environments while the 15 advanced breeding lines were tested in one environment. Results showed that both preliminary and advanced breeding lines had significant genetic variations and relatively small coefficients of variation in grain CID, indicating grain CID as a promising trait for selection in wheat breeding programs. In the trials for the preliminary breeding lines, the association between grain CID and grain yield was significant (P < 0.05) and positive in all three environments with Pearson correlation coefficients ranging from 0.34 to 0.74. This correlation was stronger in a trial with expected post-anthesis drought stress. However, there was only a weak positive correlation between grain CID and grain yield in the trial for the advanced breeding lines. Winter injury may have confounded the grain CID and yield relationship. This study also revealed a significant (P < 0.05) and negative correlation between grain CID and grain protein content in all four trials with Pearson correlation coefficients ranging from −0.43 to −0.65, suggesting a possible impact on baking quality while selecting high grain CID. Therefore, our results suggest that grain CID could be useful for grain yield prediction in semi-arid areas with moderate drought stress. However, precaution should be taken for selecting grain CID because of the effect of environment on its association with grain yield and its negative correlation with protein content.
The introgression from wild relatives have a great potential to broaden the availability of beneficial allelic diversity for crop improvement in breeding programs. Here, we assessed the impact of the ...introgression from 21 diverse accessions of
Aegilops tauschii
, the diploid ancestor of the wheat D genome, into 6 hard red winter wheat cultivars on yield and yield component traits. We used 5.2 million imputed D genome SNPs identified by the whole-genome sequencing of parental lines and the sequence-based genotyping of introgression population, including 351 BC
1
F
3:5
lines. Phenotyping data collected from the irrigated and non-irrigated field trials revealed that up to 23% of the introgression lines (ILs) produce more grain than the parents and check cultivars. Based on 16 yield stability statistics, the yield of 12 ILs (3.4%) was stable across treatments, years, and locations; 5 of these lines were also high yielding lines, producing 9.8% more grain than the average yield of check cultivars. The most significant SNP- and haplotype-trait associations were identified on chromosome arms 2DS and 6DL for the spikelet number per spike (SNS), on chromosome arms 2DS, 3DS, 5DS, and 7DS for grain length (GL) and on chromosome arms 1DL, 2DS, 6DL, and 7DS for grain width (GW). The introgression of haplotypes from
A. tauschii
parents was associated with an increase in SNS, which was positively correlated with a heading date (HD), whereas the haplotypes from hexaploid wheat parents were associated with an increase in GW. We show that the haplotypes on 2DS associated with an increase in the spikelet number and HD are linked with multiple introgressed alleles of
Ppd-D1
identified by the whole-genome sequencing of
A. tauschii
parents. Meanwhile, some introgressed haplotypes exhibited significant pleiotropic effects with the direction of effects on the yield component traits being largely consistent with the previously reported trade-offs, there were haplotype combinations associated with the positive trends in yield. The characterized repertoire of the introgressed haplotypes derived from
A. tauschii
accessions with the combined positive effects on yield and yield component traits in elite germplasm provides a valuable source of alleles for improving the productivity of winter wheat by optimizing the contribution of component traits to yield.
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