In contrast to the dominant multiattribute commodity view of outdoor recreation settings, wilderness users are described as having emotional and symbolic ties to the setting that are manifested as ...attachment to the site and the wilderness concept. Data from four wilderness areas show stronger place and wilderness attachment to be associated with previous visits, rural residence, a setting (as opposed to activity or group) focus, visiting alone and on weekdays, hunting in the area, and sensitivity to site impacts and horse encounters. Place attachment is also associated with a lack of nonwilderness substitutes and lower income and education. Wilderness attachment is associated with membership in wilderness and conservation organizations, visits to more wilderness areas, a preference for longer visits, participation in nature study, and sensitivity to sight and sound intrusions and hiker encounters. The importance of understanding emotional and symbolic values of natural resources is discussed in relation to managing recreation user conflicts and public involvement in wildland resource planning.
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•Computational models of fire debris used to train a neural network.•Neural network prediction of probability of ignitable liquid residue in fire debris.•Trained network performance ...tested on laboratory-prepared fire debris samples.•Neural network results combined with decision theory for sample classification.
Neural networks are a class of biologically inspired machine learning models that are used for classification and regression problems. This work assesses the classification performance of neural networks on ground-truth fire debris samples using ions that are representative of several compound classes that are typically present in ignitable liquids. An optimal neural network model was selected from a subset of candidate models that were trained on in-silico mixed fire debris samples from the National Center for Forensic Science Substrate and Ignitable Liquid Reference Collection databases. An optimal decision threshold was determined using a defined ratio of misclassification costs. A cost ratio corresponding to a false positive classification having a cost that is 10 times greater than a false negative classification resulted in a decision threshold of log likelihood ratio of 0.966. This decision threshold resulted in a false positive rate of 0.07 and a true positive rate of 0.59 for the ground-truth validation data. This study demonstrates the selection of an optimal decision threshold using ROC analysis and exhibits the potential of neural network models for the evaluation of fire debris evidence.
Abstract
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (IBR) is FDA approved for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, IBR responses are incomplete in ...majority of cases, and not durable in MCL and high-risk CLL. We hypothesize that de novo resistance, incomplete responses, and rapid recurrence can be due to adaptive signaling that should be cotargeted with BTK to achieve deeper and durable responses. We previously showed that venetoclax (VEN), an inhibitor of Bcl-2, generates synergistic cytotoxicity with IBR in MCL lines (Axelrod et al. Leukemia 2014;28:407-10). Recently, we extended these findings to circulating leukemic B cells in CLL, MCL (Jayappa et al. ASH 2016), and follicular lymphoma (FL) patient PBMCs treated ex vivo. Based on these results we initiated a phase I/Ib trial for IBR+VEN combination in MCL.
Our ex vivo cytotoxicity studies showed a surprisingly high frequency of de novo resistance to IBR+VEN. Resistance did not correlate with previous therapy or clinical characteristics of patients. However, FACS analysis of primary CLL cells showed that cells displaying an “activation” phenotype (CD5+/CD19+/CD69+) were less sensitive to cytotoxicity of IBR+VEN, suggesting that cellular activation by extrinsic factors could generate drug resistance. To test this, we cocultured or preincubated CLL patient PBMCs with various stromal cells, cytokines, and other agonists and found that soluble CD40L, IL10, and CpG oligodeoxynucleotides (ODN) generated variable resistance to IBR+VEN in CLL samples, with CpG ODN, a specific TLR9 agonist, being the most effective. The combination of CpG ODN, sCD40L, and IL10 (“agonist mix”) generated near-complete resistance to IBR+VEN in most CLL(N=22)/MCL(N=7)/FL(N=4) patient PBMCs. The agonist mix treatment significantly upregulated nuclear localization of RelA and RelB proteins in CLL/MCL/FL cells analyzed by ImageStream, suggesting activation of NF-kB signaling. Agonist mix treatment also induced the NF-kB dependent overexpression of anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, and inhibitors of NF-kB or of upregulated anti-apoptotic proteins overcame this drug resistance (Jayappa et al. ASH 2016).
To further explore the role of TLR9 and other innate immune receptors in resistance, we performed IBR+VEN cytotoxicity analysis in CLL/MCL patient PBMCs cocultured with agonists of various TLRs and NOD1/2 receptors. Preliminary results showed that TLR9 agonist CpG ODN generated significant resistance to IBR+VEN in most CLL/MCL samples, and agonists of TLR1/2, TLR7, and NOD1/2 induced a moderate level of resistance in a MCL sample. The CpG ODN treatment induced a significant increase in NF-kB signaling measured by increased nuclear localization of RelB in CLL patient samples. To determine if soluble agonists in the extranodal macroenvironment of patients could generate NF-kB dependent resistance to IBR+VEN, we analyzed drug cytotoxicity in CLL(N=6) and MCL(N=1) patient PBMCs cultured with autologous plasma. We found that preincubation with autologous plasma induced variable levels of resistance to IBR+VEN in CLL/MCL samples, but did not induce resistance to a NF-kB inhibitor BMS-345541. In conclusion, soluble factors in the patient nodal/extranodal macroenvironment, particularly a TLR9 agonist, generate resistance to IBR+VEN by activating NF-kB signaling and overexpression of multiple anti-apoptotic proteins. The same resistance mechanism, based on innate immune signaling, occurs in three mature B-cell malignancies, CLL, MCL and FL, that differ in etiology and clinical course. The signaling pathway responsible for resistance contains new targets for therapeutic intervention with potential to prevent or reverse resistance to IBR and VEN in these and perhaps other cancers as well.
Citation Format: Kallesh D. Jayappa, Craig A. Portell, Vicki L. Gordon, Timothy P. Bender, Michael E. Williams, Michael J. Weber. Soluble agonists in the in vivo macroenvironment generate phenotypic de novo resistance to BTK/Bcl-2 targeted therapies in diverse B-cell malignancies abstract. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 08.
Abstract
Background
The ε4 variant of
APOE
is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). It remains unclear if the ε4 protein increases AD risk through a gain of ...abnormal function, or whether it functions less well than the ε3 protein. Framed bluntly: Would knocking down ε4 in an ε4 carrier increase or decrease AD risk?
Method
We searched whole‐exomes and whole‐genomes from ∼47,000 older controls and AD cases in the Alzheimer’s Disease Sequencing Project (ADSP) looking for early loss‐of‐function variants on
APOE
. Five of 26,605 older controls carried a loss‐of‐function variant while only one of 20,856 AD cases did (
Figure.1A/B
). We reasoned that if ε4 does not function as well as ε3, then loss‐of‐function of either ε3 or ε4 should have an ε4‐like impact on risk. However, if ε4 is inherently detrimental, loss‐of‐function of ε4, specifically, should have a protective effect.
Result
Loss of ε3 was seen in two cognitively healthy ε3 homozygotes, last assessed at ages 82 and 88. This suggests that the ε3/null effective genotype is not a strong driver of AD risk. Subject 6‐nominally ε3/ε4 but effectively ε4/null ‐developed symptoms at 75 and died at 87 with autopsy‐confirmed AD, with an age‐at‐onset similar to typical ε3/ε4 (μ = 73.5y), but later typical than ε4/ε4 (μ = 69.7y). This suggests that the loss of ε3 does not result in an ε4‐like phenotype, as seen with Subjects 3 and 5. The most illustrative phenotypes are seen in Subjects 1 and 2 who are nominally ε3/ε4 but effectively ε3/null. Subject 2 was cognitively healthy at 79, with normal levels of amyloid and tau in cerebrospinal fluid at 76, while 2/3rds of ε3/ε4 are amyloid‐positive by 75. Subject 1 was assessed as cognitively normal at 90, died the same year, and had no amyloid pathology, and no amyloid deposits in the cerebral blood vessels, making him a prominent outlier compared to 1700 ε3/ε4 individuals in NACC (
Figure.1C
).
Conclusion
Taken together, these results provide the strongest human genetics evidence yet available to support the hypothesis that ε4 drives AD risk through a gain of abnormal function and that reducing ε4 should be expected to reduce AD risk.
The most prevalent approach to understanding recreation experiences in resource management has been a motivational research program that views satisfaction as an appropriate indicator of experience ...quality. This research explores a different approach to studying the quality of recreation experiences. Rather than viewing recreation experiences as a linear sequence of events beginning with expectations and ending with outcomes that are then cognitively compared to determine experience quality, this alternative approach views recreation as an emergent experience motivated by the not very well-defined goal of acquiring stories that ultimately enrich one's life. Further, it assumes that the nature of human experience is best characterized by situated freedom in which the environment sets boundaries that constrain the nature of the experience, but that within those boundaries recreationists are free to experience the world in unique and variable ways. Therefore this alternative approach seeks a more context specific description of the setting/experience relationship that is intended to complement more general management frameworks (e.g., the Recreation Opportunity Spectrum) developed in conjunction with the motivational research program.
Abstract Importance Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, ...standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core Outcome Sets (COS) are agreed standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. Objective To identify and reach consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) Core Domain Set for PG clinical trials. Design Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥70% of participants rating a domain as ‘extremely important’ and <15% of participants voting ‘not important’, followed by an international meeting to reach consensus on the core domain set (consensus: <30% disagreement). Setting Item generation discussions and consensus meetings were hosted via online video conferences. Delphi exercise and consensus voting were performed using Qualtrics electronic survey software. Participants Adults with PG, healthcare professionals, researchers, and industry representatives. Findings Collaborative discussions and systematic review yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed three lowest priority domains (Laboratory Tests, Treatment Costs, and Disease Impact on Family) and ranked Pain, Quality of Life, and Physical Symptoms as the highest priority prospective domains. Consensus was reached on the domains of Pain, Quality of Life, and Clinical Signs. The domain of disease course/disease progression narrowly failed to reach consensus for inclusion in the core set (32.2% of participants voted no). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. Conclusions and Relevance The UPGRADE Core Domain Set for PG clinical trials has been agreed by international multi-stakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a core outcome set.
Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol ...moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum (ER) cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
Aster non-vesicular transport is a targetable pathway for regulation of dietary cholesterol absorption.
