A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651.

Can we harness digital technologies and physiology to hasten genetic gain in US maize breeding?

Plant physiology can offer invaluable insights to accelerate genetic gain. However, translating physiological understanding into breeding decisions has been an ongoing and complex endeavor. Here we demonstrate an approach to leverage physiology and genomics to hasten crop improvement. A half-diallel maize (Zea mays) experiment resulting from crossing 9 elite inbreds was conducted at 17 locations in the USA corn belt and 6 locations at managed stress environments between 2017 and 2019 covering a range of water environments from 377 to 760 mm of evapotranspiration and family mean yields from 542 to 1,874 g m-2. Results from analyses of 35 families and 2,367 hybrids using crop growth models linked to whole-genome prediction (CGM-WGP) demonstrated that CGM-WGP offered a predictive accuracy advantage compared to BayesA for untested genotypes evaluated in untested environments (r = 0.43 versus r = 0.27). In contrast to WGP, CGMs can deal effectively with time-dependent interactions between a physiological process and the environment. To facilitate the selection/identification of traits for modeling yield, an algorithmic approach was introduced. The method was able to identify 4 out of 12 candidate traits known to explain yield variation in maize. The estimation of allelic and physiological values for each genotype using the CGM created in silico phenotypes (e.g. root elongation) and physiological hypotheses that could be tested within the breeding program in an iterative manner. Overall, the approach and results suggest a promising future to fully harness digital technologies, gap analysis, and physiological knowledge to hasten genetic gain by improving predictive skill and definition of breeding goals.

Two decades of harnessing standing genetic variation for physiological traits to improve drought tolerance in maize.

We review approaches to maize breeding for improved drought tolerance during flowering and grain filling in the central and western US corn belt and place our findings in the context of results from public breeding. Here we show that after two decades of dedicated breeding efforts, the rate of crop improvement under drought increased from 6.2 g m-2 year-1 to 7.5 g m-2 year-1, closing the genetic gain gap with respect to the 8.6 g m-2 year-1 observed under water-sufficient conditions. The improvement relative to the long-term genetic gain was possible by harnessing favourable alleles for physiological traits available in the reference population of genotypes. Experimentation in managed stress environments that maximized the genetic correlation with target environments was key for breeders to identify and select for these alleles. We also show that the embedding of physiological understanding within genomic selection methods via crop growth models can hasten genetic gain under drought. We estimate a prediction accuracy differential (Δr) above current prediction approaches of ~30% (Δr=0.11, r=0.38), which increases with increasing complexity of the trait environment system as estimated by Shannon information theory. We propose this framework to inform breeding strategies for drought stress across geographies and crops.

Identification of environment types and adaptation zones with self-organizing maps; applications to sunflower multi-environment data in Europe.

KEY MESSAGE: We evaluate self-organizing maps (SOM) to identify adaptation zones and visualize multi-environment genotypic responses. We apply SOM to multiple traits and crop growth model output of large-scale European sunflower data. Genotype-by-environment interactions (G × E) complicate the selection of well-adapted varieties. A possible solution is to group trial locations into adaptation zones with G × E occurring mainly between zones. By selecting for good performance inside those zones, response to selection is increased. In this paper, we present a two-step procedure to identify adaptation zones that starts from a self-organizing map (SOM). In the SOM, trials across locations and years are assigned to groups, called units, that are organized on a two-dimensional grid. Units that are further apart contain more distinct trials. In an iterative process of reweighting trial contributions to units, the grid configuration is learnt simultaneously with the trial assignment to units. An aggregation of the units in the SOM by hierarchical clustering then produces environment types, i.e. trials with similar growing conditions. Adaptation zones can subsequently be identified by grouping trial locations with similar distributions of environment types across years. For the construction of SOMs, multiple data types can be combined. We compared environment types and adaptation zones obtained for European sunflower from quantitative traits like yield, oil content, phenology and disease scores with those obtained from environmental indices calculated with the crop growth model Sunflo. We also show how results are affected by input data organization and user-defined weights for genotypes and traits. Adaptation zones for European sunflower as identified by our SOM-based strategy captured substantial genotype-by-location interaction and pointed to trials in Spain, Turkey and South Bulgaria as inducing different genotypic responses.

An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis.

BACKGROUND AND AIMS: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS: A phase-2 dose-escalating study was carried out. F-652 (10 µg/kg, 30 µg/kg, or 45 µg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS: F-652 is safe in doses up to 45 µg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.

Reproductive resilience but not root architecture underpins yield improvement under drought in maize.

Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) might underpin the 3-fold increase in maize (Zea mays L.) grain yield over the last century. Here we show that both RSA and yield have changed with decades of maize breeding, but not the crop water uptake. Results from X-ray phenotyping in controlled environments showed that single cross (SX) hybrids have smaller root systems than double cross (DX) hybrids for root diameters between 2465 µm and 181µm (P<0.05). Soil water extraction measured under field conditions ranged between 2.6 mm d-1 and 2.9 mm d-1 but were not significantly different between SX and DX hybrids. Yield and yield components were higher for SX than DX hybrids across densities and irrigation (P<0.001). Taken together, the results suggest that changes in RSA were not the cause of increased water uptake but an adaptation to high-density stands used in modern agriculture. This adaptation may have contributed to shift in resource allocation to the ear and indirectly improved reproductive resilience. Advances in root physiology and phenotyping can create opportunities to maintain long-term genetic gain in maize, but a shift from ideotype to crop and production system thinking will be required.

Tackling G × E × M interactions to close on-farm yield-gaps: creating novel pathways for crop improvement by predicting contributions of genetics and management to crop productivity.

KEY MESSAGE: Climate change and Genotype-by-Environment-by-Management interactions together challenge our strategies for crop improvement. Research to advance prediction methods for breeding and agronomy is opening new opportunities to tackle these challenges and overcome on-farm crop productivity yield-gaps through design of responsive crop improvement strategies. Genotype-by-Environment-by-Management (G × E × M) interactions underpin many aspects of crop productivity. An important question for crop improvement is "How can breeders and agronomists effectively explore the diverse opportunities within the high dimensionality of the complex G × E × M factorial to achieve sustainable improvements in crop productivity?" Whenever G × E × M interactions make important contributions to attainment of crop productivity, we should consider how to design crop improvement strategies that can explore the potential space of G × E × M possibilities, reveal the interesting Genotype-Management (G-M) technology opportunities for the Target Population of Environments (TPE), and enable the practical exploitation of the associated improved levels of crop productivity under on-farm conditions. Climate change adds additional layers of complexity and uncertainty to this challenge, by introducing directional changes in the environmental dimension of the G × E × M factorial. These directional changes have the potential to create further conditional changes in the contributions of the genetic and management dimensions to future crop productivity. Therefore, in the presence of G × E × M interactions and climate change, the challenge for both breeders and agronomists is to co-design new G-M technologies for a non-stationary TPE. Understanding these conditional changes in crop productivity through the relevant sciences for each dimension, Genotype, Environment, and Management, creates opportunities to predict novel G-M technology combinations suitable to achieve sustainable crop productivity and global food security targets for the likely climate change scenarios. Here we consider critical foundations required for any prediction framework that aims to move us from the current unprepared state of describing G × E × M outcomes to a future responsive state equipped to predict the crop productivity consequences of G-M technology combinations for the range of environmental conditions expected for a complex, non-stationary TPE under the influences of climate change.

Breeding drought-tolerant maize hybrids for the US corn-belt: discovery to product.

Germplasm, genetics, phenotyping, and selection, combined with a clear definition of product targets, are the foundation of successful hybrid maize breeding. Breeding maize hybrids with superior yield for the drought-prone regions of the US corn-belt involves integration of multiple drought-specific technologies together with all of the other technology components that comprise a successful maize hybrid breeding programme. Managed-environment technologies are used to enable scaling of precision phenotyping in appropriate drought environmental conditions to breeding programme level. Genomics and other molecular technologies are used to study trait genetic architecture. Genetic prediction methodology was used to breed for improved yield performance for drought-prone environments. This was enabled by combining precision phenotyping for drought performance with genetic understanding of the traits contributing to successful hybrids in the target drought-prone environments and the availability of molecular markers distributed across the maize genome. Advances in crop growth modelling methodology are being used to evaluate the integrated effects of multiple traits for their combined effects and evaluate drought hybrid product concepts and guide their development and evaluation. Results to date, lessons learned, and future opportunities for further improving the drought tolerance of maize for the US corn-belt are discussed.

Andrographis paniculata extract (HMPL-004) for active ulcerative colitis.

OBJECTIVES: Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1ß and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. METHODS: A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. RESULTS: In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. CONCLUSIONS: Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.

Extending the breeder's equation to take aim at the target population of environments.

A major focus for genomic prediction has been on improving trait prediction accuracy using combinations of algorithms and the training data sets available from plant breeding multi-environment trials (METs). Any improvements in prediction accuracy are viewed as pathways to improve traits in the reference population of genotypes and product performance in the target population of environments (TPE). To realize these breeding outcomes there must be a positive MET-TPE relationship that provides consistency between the trait variation expressed within the MET data sets that are used to train the genome-to-phenome (G2P) model for applications of genomic prediction and the realized trait and performance differences in the TPE for the genotypes that are the prediction targets. The strength of this MET-TPE relationship is usually assumed to be high, however it is rarely quantified. To date investigations of genomic prediction methods have focused on improving prediction accuracy within MET training data sets, with less attention to quantifying the structure of the TPE and the MET-TPE relationship and their potential impact on training the G2P model for applications of genomic prediction to accelerate breeding outcomes for the on-farm TPE. We extend the breeder's equation and use an example to demonstrate the importance of the MET-TPE relationship as a key component for the design of genomic prediction methods to realize improved rates of genetic gain for the target yield, quality, stress tolerance and yield stability traits in the on-farm TPE.

Validity of an NGS-based multiple gene panel in identifying actionable mutations for patients with NSCLC in a Chinese hospital.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. A number of targeted therapies have been approved for clinical use or are in clinical trials. Next generation sequencing (NGS) is widely applied in the identification of actionable genomic alterations and enables personalized cancer therapy for patients. Several multiple-gene panels are available in China for the practice of precision medicine-based cancer therapy. However, the efficiency of these panels requires evaluation. The current study investigated 23 NSCLC samples using a custom designed panel of complete coding regions of ~180 cancer driver genes (FD-180) and whole exome sequencing for control samples, obtained from white blood cell samples. The results obtained suggested that actionable mutations with available targeted therapeutic options were identified in 69.6% of cases, including 60.9% of therapeutic targets recommended by the National Comprehensive Cancer Network guidelines. Furthermore, 8.7% of patients had a gene mutation that potentially qualified them for clinical trials or associated off-label therapies. As such, the results obtained in the current study demonstrated the reliability of the targeted NGS panel and its potential use for identifying actionable gene alterations and designing personalized therapies for patients with NSCLC.

Molecular mutation characteristics of mismatch and homologous recombination repair genes in gastrointestinal cancer.

Gastrointestinal cancer is one of the most common types of cancer with high mortality rates. Mutations in several genes are reportedly involved in the progression of gastrointestinal cancer, including tumor protein 53 (TP53), APC regulator of WNT signaling pathway (APC), KRAS proto-oncogene GTPase (KRAS) and erb-b2 receptor tyrosine kinase 2 (ERBB2). Most notably, there are numerous mutations in DNA repair genes, including mismatch repair (MMR) and homologous recombination (HR) genes. The focus of the present study was to investigate the effects of MMR and HR gene mutations on genomic instability in gastrointestinal cancer. Using targeted capture and massively parallel genomic sequencing, 137 gastrointestinal cancer patients were analyzed for somatic single-nucleotide variants (SNVs) and insertion-deletion (indel) mutations in the exon regions of 183 cancer driver genes, including 4 MMR genes [MutL homolog MLH1, MLH2, MLH6 and PMS1 homolog 2, mismatch repair system component (PMS2)] and 15 HR genes [BRCA1 DNA repair associated (BRCA1), BRCA2 DNA repair associated (BRCA2), ATM serine/threonine kinase (ATM), phosphatase and tensin homolog, BLM RecQ like helicase, FA complementation group A, FA complementation group C, FA complementation group D2, FA complementation group E, FA complementation group F, FA complementation group G, nibrin, partner and localizer of BRCA2 and Werner syndrome RecQ like helicase]. A number of frequently mutated genes, including but not limited to, mechanistic target of rapamycin kinase, neurofibromin 1, APC and, in particular, DNA repair genes, including PMS2, ATM and BRCA2, were identified. Frequency analysis was performed based on the SNVs and indels in the 183 genes to indirectly indicate the relative status of genomic instability in each patient. Correlation analysis suggested that MMR and HR gene mutations directly affected the count of SNVs and indels. Overall, 56 of the gastrointestinal cancer patients (40%) were found to have an inactivation mutation (stopgain/frameshift/splicing) in one or more of the four MMR genes, whereas 112 patients (82%) harbored at least one HR gene inactivation mutation. In addition, patients with MMR or HR inactivation variants had more SNVs and indels compared with patients with no such mutations. No other clinical characteristics (including sex and age) appeared to have a statistically significant impact. Further analysis indicated that different MMR or HR genes exerted distinct effects on genomic instability. The results obtained in the current study may lay a foundation for investigations into the tumorigenic process and for the development of novel therapeutic strategies for the treatment of gastrointestinal cancer.

Canadian Medical Education Journal Survey evaluations of University of British Columbia residents' education and attitudes regarding palliative care and physician assisted death.

BACKGROUND: Little prior research has been conducted regarding resident physicians' opinions on the subject of Physician Assisted Death (PAD), despite past surveys ascertaining the attitudes of practicing physicians towards PAD in Canada. We solicited British Columbia residents' opinions on the amount of education they receive about palliative care and physician assisted death, and their attitudes towards the implementation of PAD. METHODS: We conducted a cross sectional, anonymous online survey with the resident physicians of British Columbia, Canada. Questions included: close-ended questions, graded Likert scale questions, and comments. RESULTS: Among the respondents (n=299, response rate 24%), 44% received ≥5 hours of education in palliative care, 40% received between zero and four hours of education, and 16% reported zero hours. Of all respondents, 75% had received no education about PAD and the majority agreed that there should be more education about palliative care (74%) and PAD (85%). Only 35% of residents felt their program provided them with enough education to make an informed decision about PAD, yet 59% would provide a consenting patient with PAD. Half of the respondents believed PAD would ultimately be provided by palliative care physicians. INTERPRETATION: Residents desire further education about palliative care and PAD. Training programs should consider conducting a thorough needs assessment and implementing structured education to meet this need.

Hospital resource use and cost of treatment with linezolid versus teicoplanin for treatment of serious gram-positive bacterial infections among hospitalized patients from South America and Mexico: results from a multicenter trial.

BACKGROUND: Linezolid is a novel oxazolidinone antibiotic that is effective for the treatment of gram-positive bacterial infections. The oral formulation has the potential to reduce length of stay (LOS) when used as a substitute for parenteral glycopeptide antibiotics. In a recent multinational trial comparing linezolid (i.v. followed by oral administration) with teicoplanin (i.v. alone or switched to i.m. administration), linezolid was found to have better efficacy (P = 0.005) and similar safety for treating serious gram-positive infections. OBJECTIVE: The purpose of this study was to compare hospital resource use (primarily LOS) and cost of treatment between linezolid and teicoplanin for hospitalized patients with serious gram-positive infections in South America and Mexico using data from the multinational trial. METHODS: In a multinational, Phase IIIb, open-label, comparator-controlled trial, data were collected from hospitalized patients in centers in 6 South America can countries and Mexico with suspected or confirmed serious gram-positive infections. Patients were randomly assigned to receive i.v. linezolid 600 mg BID (for the entire treatment period [7-28 days] or switched to oral linezolid 600 mg BID) or i.v. teicoplanin (for the entire treatment period or switched to i.m. teicoplanin) dosed per approved prescription information. Data on direct medical resource utilization were collected for each patient, including duration and doses of study medication, location of hospitalization and LOS, comedications, tests and procedures, and outpatient service usage. Unit costs for the medical resources were obtained from secondary sources. RESULTS: A total of 203 patients (97 treated with linezolid and 106 treated with teicoplanin) were enrolled from these 7 countries. The unadjusted results showed that compared with teicoplanin, patients treated with linezolid had a 3.1-day shorter mean i.v. antibiotic treatment duration (P < 0.001), a 2.0- to 2.2-day shorter median and mean LOS (P = 0.03), and a 311 US dollars lower mean total cost of treatment (P = NS). After controlling for age, race, sex, site of infection, inpatient location when the antibiotic treatment started, number of historical and current comorbidities, and whether the patient had a diagnosis of systemic inflammatory response syndrome or sepsis, the multivariate adjusted results were similar to the unadjusted results. The linezolid group had a 1.6-day shorter adjusted LOS or 66% greater odds of early discharge (P = 0.049) and a 335 US dollars lower adjusted mean total cost of treatment (P = NS). CONCLUSION: Linezolid was associated with shorter LOS and duration of IV antibiotic treatment than teicoplanin for serious gram-positive infections in the population studied. Linezolid therapy has the potential to reduce the total cost of treatment.

An economic evaluation of a European cohort from a multinational trial of linezolid versus teicoplanin in serious Gram-positive bacterial infections: the importance of treatment setting in evaluating treatment effects.

In a recent multinational trial, hospital resource use and total cost of treatment were compared between linezolid and teicoplanin for severe Gram-positive bacterial infections among 227 European hospitalised patients. The results show that the linezolid group had a 3.2-day (6.3 for linezolid versus 9.5 for teicoplanin groups) shorter mean intravenous antibiotic treatment duration. Certain baseline variables, particularly the inpatient location at enrolment and the presence of outpatient/home parenteral antibiotic therapy (OHPAT), had substantial effects on length of stay (LOS) and cost of treatment. After adjusting for the between-treatment difference in these two variables and other baseline variables, the results showed non-significant shorter LOS and lower mean total cost of treatment for the linezolid group among patients with no access to OHPAT.

Mitogenic influence of human R-spondin1 on the intestinal epithelium.

Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection into mice, the protein induced rapid onset of crypt cell proliferation involving beta-catenin stabilization, possibly by a process that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced intestinal mucositis and may have therapeutic application in gastrointestinal diseases.

Human Crossveinless-2 is a novel inhibitor of bone morphogenetic proteins.

Drosophila Crossveinless-2 (dCV-2) is required for local activation of Mad phosphorylation in the fruit fly wing and has been postulated to be a positive regulator of BMP-mediated signaling. In contrast, the presence of 5 Chordin-like cysteine-rich domains in the CV-2 protein suggests that CV-2 belongs to a family of well-established inhibitors of BMP function that includes Chordin and Sog [Development 127 (2000) 3947]. We have identified a human homolog of Drosophila CV-2 (hCV-2). Here we show that purified recombinant hCV-2 protein inhibits BMP-2 and BMP-4 dependent osteogenic differentiation of W-20-17 cells, as well as BMP dependent chondrogenic differentiation of ATDC5 cells. Interestingly, hCV-2 messenger RNA is expressed at high levels in human primary chondrocytes, whereas expression in primary human osteoblasts is low. These results suggest that hCV-2 may regulate BMP responsiveness of osteoblasts and chondrocytes in vivo. Taken together we have shown that contrary to the function predicted from the fruit fly, Crossveinless-2 is a novel inhibitor of BMP function.