2,221 research outputs found
Water Table Management Reduces Tile Nitrate Loss in Continuous Corn and in a Soybean-Corn Rotation
Water table management systems can be designed to alleviate soil water excesses and deficits, as well as reduce nitrate leaching losses in tile discharge. With this in mind, a standard tile drainage (DR) system was compared over 8 years (1991 to 1999) to a controlled tile drainage/subirrigation (CDS) system on a low-slope (0.05 to 0.1%) Brookston clay loam soil (Typic Argiaquoll) in southwestern Ontario, Canada. In the CDS system, tile discharge was controlled to prevent excessive drainage, and water was pumped back up the tile lines (subirrigation) to replenish the crop root zone during water deficit periods. In the first phase of the study (1991 to 1994), continuous corn (Zea mays, L.) was grown with annual nitrogen (N) fertilizer inputs as per local soil test recommendations. In the second phase (1995 to 1999), a soybean (Glycine max L., Merr.)-corn rotation was used with N fertilizer added only during the two corn years. In Phase 1 when continuous corn was grown, CDS reduced total tile discharge by 26% and total nitrate loss in tile discharge by 55%, compared to DR. In addition, the 4-year flow weighted mean (FWM) nitrate concentration in tile discharge exceeded the Canadian drinking water guideline (10 mg N l–1) under DR (11.4 mg N l–1), but not under CDS (7.0 mg N l–1). In Phase 2 during the soybean-corn rotation, CDS reduced total tile discharge by 38% and total nitrate loss in tile discharge by 66%, relative to DR. The 4-year FWM nitrate concentration during Phase 2 in tile discharge was below the drinking water guideline for both DR (7.3 mg N l–1) and CDS (4.0 mg N l–1). During both phases of the experiment, the CDS treatment caused only minor increases in nitrate loss in surface runoff relative to DR. Hence CDS decreased FWM nitrate concentrations, total drainage water loss, and total nitrate loss in tile discharge relative to DR. In addition, soybean-corn rotation reduced FWM nitrate concentrations and total nitrate loss in tile discharge relative to continuous corn. CDS and crop rotations with reduced N fertilizer inputs can thus improve the quality of tile discharge water substantially
Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies
Combination; Drug therapy; ImmunotherapyCombinació; Terà pia farmacològica; Immunoterà piaCombinación; Terapia farmacológica; InmunoterapiaBackground Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab.
Methods Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).
Results In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline.
Conclusions Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.This study was sponsored by Novartis Pharmaceuticals Corporation and preliminary results were previously presented at ASCO 2018
Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial
RET inhibition; Pralsetinib; Targeted therapyInhibiciĂłn de RET; Pralsetinib; Terapia dirigidaInhibiciĂł de RET; Pralsetinib; TerĂ pia dirigidaBackground
RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study.
Patients and methods
ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety.
Results
Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs.
Conclusions
Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.This work was supported by Blueprint Medicines Corporation and F. Hoffmann-La Roche, Ltd, Switzerland (no grant number)
Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
CLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation
Characterization of Mucosal Dysbiosis of Early Colonic Neoplasia.
Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesions in the colon that can be detected by high-definition chromoendoscopy with contrast dye spray. Although frequently associated with synchronous adenomas, their role in colorectal tumor development, particularly in the proximal colon, is still not clear. The goal of this study was to evaluate the profile of colon-adherent bacteria associated with proximal ACF and to investigate their relationship to the presence and subtype of synchronous polyps present throughout the colon. Forty-five subjects undergoing a screening or surveillance colonoscopy were included in this retrospective study. Bacterial cells adherent to the epithelia of ACF and normal mucosal biopsies were visualized by in situ hybridization within confocal tissue sections. ACF showed significantly greater heterogeneity in their bacterial microbiome profiles compared with normal mucosa. One of the bacterial community structures we characterized was strongly correlated with the presence of synchronous polyps. Finally, using DNA mass spectrometry to evaluate a panel of colorectal cancer hotspot mutations present in the ACF, we found that thre
Suppression of Phase Separation in LiFePO4 Nanoparticles During Battery Discharge
Using a novel electrochemical phase-field model, we question the common
belief that LixFePO4 nanoparticles separate into Li-rich and Li-poor phases
during battery discharge. For small currents, spinodal decomposition or
nucleation leads to moving phase boundaries. Above a critical current density
(in the Tafel regime), the spinodal disappears, and particles fill
homogeneously, which may explain the superior rate capability and long cycle
life of nano-LiFePO4 cathodes.Comment: 27 pages, 8 figure
Atom laser coherence and its control via feedback
We present a quantum-mechanical treatment of the coherence properties of a
single-mode atom laser. Specifically, we focus on the quantum phase noise of
the atomic field as expressed by the first-order coherence function, for which
we derive analytical expressions in various regimes. The decay of this function
is characterized by the coherence time, or its reciprocal, the linewidth. A
crucial contributor to the linewidth is the collisional interaction of the
atoms. We find four distinct regimes for the linewidth with increasing
interaction strength. These range from the standard laser linewidth, through
quadratic and linear regimes, to another constant regime due to quantum
revivals of the coherence function. The laser output is only coherent (Bose
degenerate) up to the linear regime. However, we show that application of a
quantum nondemolition measurement and feedback scheme will increase, by many
orders of magnitude, the range of interaction strengths for which it remains
coherent.Comment: 15 pages, 6 figures, revtex
MINI01.01: Whole Body and Intracranial Efficacy of Ceritinib in ALK-inhibitor Naïve Patients with ALK+ NSCLC and Brain Metastases: Results of ASCEND 1 and 3: Topic: Medical Oncology
Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide
Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Ă…, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable
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