The effect of bedrock permeability and underlying catchment boundaries on stream base flow mean transit time (MTT) and MTT scaling relationships in headwater catchments is poorly understood. Here we ...examine the effect of bedrock permeability on MTT and MTT scaling relations by comparing 15 nested research catchments in western Oregon; half within the HJ Andrews Experimental Forest and half at the site of the Alsea Watershed Study. The two sites share remarkably similar vegetation, topography, and climate and differ only in bedrock permeability (one poorly permeable volcanic rock and the other more permeable sandstone). We found longer MTTs in the catchments with more permeable fractured and weathered sandstone bedrock than in the catchments with tight, volcanic bedrock (on average, 6.2 versus 1.8 years, respectively). At the permeable bedrock site, 67% of the variance in MTT across catchments scales was explained by drainage area, with no significant correlation to topographic characteristics. The poorly permeable site had opposite scaling relations, where MTT showed no correlation to drainage area but the ratio of median flow path length to median flow path gradient explained 91% of the variance in MTT across seven catchment scales. Despite these differences, hydrometric analyses, including flow duration and recession analysis, and storm response analysis, show that the two sites share relatively indistinguishable hydrodynamic behavior. These results show that similar catchment forms and hydrologic regimes hide different subsurface routing, storage, and scaling behavior—a major issue if only hydrometric data are used to define hydrological similarity for assessing land use or climate change response.
Key Points:
MTT scaling relationships controlled by bedrock permeability
Similar catchment morphology and hydrologic regime can mask different MTTs
Catchment intercomparison reveals difference in celerity‐velocity relationships
In Part 1 of this two‐part series, Hale and McDonnell (2016) showed that bedrock permeability controlled base flow mean transit times (MTTs) and MTT scaling relations across two different catchment ...geologies in western Oregon. This paper presents a process‐based investigation of storage and release in the more permeable catchments to explain the longer MTTs and (catchment) area‐dependent scaling. Our field‐based study includes hydrometric, MTT, and groundwater dating to better understand the role of subsurface catchment storage in setting base flow MTTs. We show that base flow MTTs were controlled by a mixture of water from discrete storage zones: (1) soil, (2) shallow hillslope bedrock, (3) deep hillslope bedrock, (4) surficial alluvial plain, and (5) suballuvial bedrock. We hypothesize that the relative contributions from each component change with catchment area. Our results indicate that the positive MTT‐area scaling relationship observed in Part 1 is a result of older, longer flow path water from the suballuvial zone becoming a larger proportion of streamflow in a downstream direction (i.e., with increasing catchment area). Our work suggests that the subsurface permeability structure represents the most basic control on how subsurface water is stored and therefore is perhaps the best direct predictor of base flow MTT (i.e., better than previously derived morphometric‐based predictors). Our discrete storage zone concept is a process explanation for the observed scaling behavior of Hale and McDonnell (2016), thereby linking patterns and processes at scales from 0.1 to 100 km2.
Key Points:
Distinct subsurface storage zones with unique water ages identified
Dynamic mixture of storage zones sets stream water mean transit time
Subsurface permeability contrasts dictate storage zone discretization
Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination ...therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity.
BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In
xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a
-mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in
and
models of acquired resistance to single-agent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway (NCT01781429, NCT02296242, and NCT02608229).
.
Anemia caused by chronic kidney disease and other chronic diseases or conditions can be managed by the treatment of biologic-based erythropoiesis stimulating agents (ESAs). Although these ESAs are ...successful in treating these anemic conditions, a small molecule-based anti-anemia medicine can potentially revolutionize the treatment of anemia by bringing convenience to patients and being cost effective. Prolyl hydroxylase domain-containing protein (PHD) inhibitors may provide an opportunity for the development of small molecule anti-anemia medicines.
This review covers efforts to target PHD enzymes for stabilization of hypoxia-inducible factor (HIF)-alpha subunits under normal oxygen levels as an attractive strategy to upregulate the expression of erythropoietin and genes involved in iron metabolism for the treatment of anemia.
The reader will gain a brief summary of recent advances in HIF and PHD biology and a review of patents/patent applications on the subject of PHD inhibitors as HIF stabilizers for the treatment of anemia.
Several classes of PHD enzyme inhibitors have been disclosed and several are currently in clinical trials for the development of small molecule-based therapeutics for the treatment of anemia.
Radiologic pattern has been shown to predict survival in patients with fibrosing interstitial lung disease. The additional prognostic value of fibrosis extent by quantitative computed tomography (CT) ...is unknown.
We hypothesized that fibrosis extent provides information beyond visually assessed CT pattern that is useful for outcome prediction.
We performed a retrospective analysis of chest CT, demographics, longitudinal pulmonary function, and transplantation-free survival among participants in the Pulmonary Fibrosis Foundation Patient Registry. CT pattern was classified visually according to the 2018 usual interstitial pneumonia criteria. Extent of fibrosis was objectively quantified using data-driven textural analysis. We used Kaplan-Meier plots and Cox proportional hazards and linear mixed-effects models to evaluate the relationships between CT-derived metrics and outcomes.
Visual assessment and quantitative analysis were performed on 979 enrollment CT scans. Linear mixed-effect modeling showed that greater baseline fibrosis extent was significantly associated with the annual rate of decline in forced vital capacity. In multivariable models that included CT pattern and fibrosis extent, quantitative fibrosis extent was strongly associated with transplantation-free survival independent of CT pattern (hazard ratio, 1.04; 95% confidence interval, 1.04-1.05;
< 0.001; C statistic = 0.73).
The extent of lung fibrosis by quantitative CT is a strong predictor of physiologic progression and survival, independent of visually assessed CT pattern.
The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally ...bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.
Background
Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may ...prime a patient’s immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma.
Methods
This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months).
Results
A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%,
p
= 0.041).
Conclusions
This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development.
Trial Registration
NCT02301611.
The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic ...properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.
Background
A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV ...melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods.
Methods
The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups.
Results
144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%,
p
= 0.010) and OS (94.2% vs. 69.8% vs. 70.9%,
p
= 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity.
Conclusions
Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.
The discovery of 1,3,8-triazaspiro4.5decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is ...described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro4.5decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
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