Insect herbivores depend on their host plants to acquire macro- and micronutrients. Here we asked how a specialist herbivore and damaging maize pest, the western corn rootworm, finds and accesses ...plant-derived micronutrients. We show that the root-feeding larvae use complexes between iron and benzoxazinoid secondary metabolites to identify maize as a host, to forage within the maize root system, and to increase their growth. Maize plants use these same benzoxazinoids for protection against generalist herbivores and, as shown here, for iron uptake. We identify an iron transporter that allows the corn rootworm to benefit from complexes between iron and benzoxazinoids. Thus, foraging for an essential plant-derived complex between a micronutrient and a secondary metabolite shapes the interaction between maize and a specialist herbivore.
Tailoring defense responses to different attackers is important for plant performance. Plants can use secondary metabolites with dual functions in resistance and defense signaling to mount ...herbivore-specific responses. To date, the specificity and evolution of this mechanism are unclear. Here, we studied the functional architecture, specificity, and genetic basis of defense regulation by benzoxazinoids in cereals. We document that DIMBOA-Glc induces callose as an aphid resistance factor in wheat.
-methylation of DIMBOA-Glc to HDMBOA-Glc increases plant resistance to caterpillars but reduces callose inducibility and resistance to aphids. DIMBOA-Glc induces callose in wheat and maize, but not in
, while the glucosinolate 4MO-I3M does the opposite. We identify a wheat
-methyltransferase (TaBX10) that is induced by caterpillar feeding and converts DIMBOA-Glc to HDMBOA-Glc in vitro. While the core pathway of benzoxazinoid biosynthesis is conserved between wheat and maize, the wheat genome does not contain close homologs of the maize DIMBOA-Glc
-methyltransferase genes, and
is only distantly related. Thus, the functional architecture of herbivore-specific defense regulation is similar in maize and wheat, but the regulating biosynthetic genes likely evolved separately. This study shows how two different cereal species independently achieved herbivore-specific defense activation by regulating secondary metabolite production.
International guidelines recommend endoscopic surveillance of premalignant gastric lesions. However, the diagnostic yield and preventive effect require further study. We therefore aimed to assess the ...incidence of neoplastic progression and to assess the ability of various tests to identify patients most at risk for progression.
Patients from the Netherlands and Norway with a previous diagnosis of atrophic gastritis (AG), intestinal metaplasia (IM) or dysplasia were offered endoscopic surveillance. All histological specimens were assessed according to the updated Sydney classification and the operative link on gastric intestinal metaplasia (OLGIM) system. In addition, we measured serum pepsinogens (PG) and gastrin-17.
279 (mean age 57.9 years, SD 11.4, male/female 137/142) patients were included and underwent at least one surveillance endoscopy during follow-up. The mean follow-up time was 57 months (SD 36). Four subjects (1.4%) were diagnosed with high-grade adenoma/dysplasia or invasive neoplasia (ie, gastric cancer) during follow-up. Two of these patients were successfully treated with endoscopic submucosal dissection, while the other two underwent a total gastrectomy. Compared with patients with extended AG/IM (PGI/II≤3 and/or OGLIM stage III-IV), patients with limited AG/IM (PG I/II>3 and OLGIM stage 0-II) did not develop high-grade adenoma/dysplasia or invasive neoplasia during follow-up (p=0.02).
In a low gastric cancer incidence area, a surveillance programme can detect gastric cancer at an early curable stage with an overall risk of neoplastic progression of 0.3% per year. Use of serological markers in endoscopic surveillance programmes may improve risk stratification.
Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded ...protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).
Abstract
Background and study aims
Gastric cancer (GC) is usually preceded by premalignant gastric lesions (GPLs) such as gastric intestinal metaplasia (GIM). Information on risk factors associated ...with neoplastic progression of GIM are scarce. This study aimed to identify predictors for progression of GIM in areas with low GC incidence.
Patients and methods
The Progression and Regression of Precancerous Gastric Lesions (PROREGAL) study includes patients with GPL. Patients underwent at least two upper endoscopies with random biopsy sampling. Progression of GIM means an increase in severity according to OLGIM (operative link on gastric intestinal metaplasia) during follow-up (FU). Family history and lifestyle factors were determined through questionnaires. Serum
Helicobacter pylori
infection, pepsinogens (PG), gastrin-17 and GC-associated single nucleotide polymorphisms (SNPs) were determined. Cox regression was performed for risk analysis and a chi-squared test for analysis of single nucleotide polymorphisms.
Results
Three hundred and eight patients (median age at inclusion 61 years, interquartile range (IQR: 17; male 48.4 %; median FU 48 months, IQR: 24) were included. During FU, 116 patients (37.7 %) showed progression of IM and six patients (1.9 %) developed high-grade dysplasia or GC. The minor allele (C) on
TLR4
(rs11536889) was inversely associated with progression of GIM (OR 0.6; 95 %CI 0.4–1.0). Family history (HR 1.5; 95 %CI 0.9–2.4) and smoking (HR 1.6; 95 %CI 0.9–2.7) showed trends towards progression of GIM. Alcohol use, body mass index, history of
H. pylori
infection, and serological markers were not associated with progression.
Conclusions
Family history and smoking appear to be related to an increased risk of GIM progression in low GC incidence countries.
TLR4
(rs11536889) showed a significant inverse association, suggesting that genetic information may play a role in GIM progression.
Summary Background TNF inhibitors have improved treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are ...expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity. Methods The study is a randomised, non-inferiority, double-blind, phase 4 trial with 52 weeks of follow-up. Adult patients on stable treatment with infliximab originator treated in a hospital setting for at least 6 months were eligible for participation. Patients with informed consent were randomised in a 1:1 ratio to either continued infliximab originator or to switch to CT-P13 treatment, with unchanged dosing regimen. Data were collected at infusion visits in 40 Norwegian study centres. Patients, assessors, and patient care providers were masked to treatment allocation. The primary endpoint was disease worsening during 52-week follow-up. 394 patients in the primary per-protocol set were needed to show a non-inferiority margin of 15%, assuming 30% disease worsening in each group. This trial is registered with ClinicalTrials.gov , number NCT02148640. Findings Between Oct 24, 2014, and July 8, 2015, 482 patients were enrolled and randomised (241 to infliximab originator, 241 to CT-P13 group; one patient was excluded from the full analysis and safety set for CT-P13) and 408 were included in the per-protocol set (202 in the infliximab originator group and 206 in the CT-P13 group). 155 (32%) patients in the full analysis set had Crohn's disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference −4·4%, 95% CI −12·7 to 3·9). The frequency of adverse events was similar between groups (for serious adverse events, 24 10% for infliximab originator vs 21 9% for CT-P13; for overall adverse events, 168 70% vs 164 68%; and for adverse events leading to discontinuation, nine 4% vs eight 3%, respectively). Interpretation The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases. Funding Norwegian Ministry of Health and Care Services.
Background
The NOR-SWITCH main and extension trials demonstrated that switching from originator to biosimilar infliximab (CT-P13) is efficacious and safe across six diseases. However, a subgroup ...analysis of Crohn’s disease (CD) in the main trial displayed a close to significant difference favouring originator infliximab, and more scientific data have therefore been requested.
Objective
The aim was to assess treatment efficacy, safety, and immunogenicity in an explorative subgroup analysis in CD and ulcerative colitis (UC) in the NOR-SWITCH trials.
Patients and Methods
The 52-week, randomised, non-inferiority, double-blind, multicentre, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety, and immunogenicity in CD and UC were assessed throughout the 78-week study period.
Results
The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. Demographic and baseline characteristics were comparable in both treatment arms within patient groups. There were no differences in the main and extension trials regarding changes in activity indices, C-reactive protein, faecal calprotectin, patient’s and physician’s global assessment of disease activity and patient-reported outcome measures in CD and UC. Moreover, comparable results were also demonstrated for trough serum levels, presence of anti-drug antibodies, and reported adverse events.
Conclusion
Efficacy, safety, and immunogenicity of both the originator and biosimilar infliximab were comparable in CD and UC in the NOR-SWITCH main and extension trials. These explorative subgroup analyses confirm that there are no significant concerns related to switching from originator infliximab to CT-P13 in CD and UC.
Trial Registration
ClinicalTrials.gov, number NCT02148640.
Background and objectives
The 52‐week, randomized, double‐blind, noninferiority, government‐funded NOR‐SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar ...CT‐P13 was not inferior to continued treatment with infliximab originator. The NOR‐SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT‐P13 throughout the 78‐week study period (maintenance group) versus patients switched to CT‐P13 at week 52 (switch group). The primary outcome was disease worsening during follow‐up based on disease‐specific composite measures.
Methods
Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis.
Results
Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per‐protocol set). Adjusted risk difference was 5.9% (95% CI −1.1 to 12.9). Frequency of adverse events, anti‐drug antibodies, changes in generic disease variables and disease‐specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases.
Conclusion
The NOR‐SWITCH extension showed no difference in safety and efficacy between patients who maintained CT‐P13 and patients who switched from originator infliximab to CT‐P13, supporting that switching from originator infliximab to CT‐P13 is safe and efficacious.
Click here to view the Editorial comment by Dr. Kay
While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) ...with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance.
BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs).
Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months interquartile range (IQR): 26.5-37.6 months and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination 15.4 months; 95% confidence interval (CI) 9.2-18.0 months and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), hazard ratio (HR) = 0.96; 95% CI 0.68-1.37. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively.
No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.
•A randomised trial comparing bevacizumab plus osimertinib versus osimertinib alone in EGFR-mutant NSCLC with T790M mutations.•The primary endpoint was investigator-assessed PFS.•No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone.•TRAEs of grade ≥3 were more common in patients on combination than osimertinib alone.
This study aimed to examine the aetiology of acute diarrhoea and the relapse rate in 100 client-owned dogs presented to a first-opinion clinic. History, physical examination, faecal testing and owner ...questionnaire data were collected at initial presentation (T0) and at either the time of relapse or at a recheck performed within 3months. All dogs received treatment according to their clinical signs. Of 96 dogs that completed the study, 37 (38.5%) relapsed during the study period, 21 (21.9%) relapsed within 3months, and 16 others (16.6%) at 3months to 1year after initial examination. Dogs that had undergone a change in housing location within 1month prior to presentation and dogs <1year old were significantly more likely to have positive parasitological analyses (P=0.02 and P=0.001, respectively). Pica was a risk factor for relapse (P=0.0002).
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