Publications by authors named "David Dawson"

230 Publications

Dysregulation of mannose-6-phosphate dependent cholesterol homeostasis in acinar cells mediates pancreatitis.

J Clin Invest 2021 Jun 15. Epub 2021 Jun 15.

Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, United States of America.

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene coding for a key enzyme in M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of non-esterified cholesterol in lysosomes/autolysosomes, its' depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab-/- and experimental models involve disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab-/- liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab-/- mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.
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http://dx.doi.org/10.1172/JCI146870DOI Listing
June 2021

The urbanisation-environment conflict: Insights from material stock and productivity of transport infrastructure in Hanoi, Vietnam.

J Environ Manage 2021 Jun 10;294:113007. Epub 2021 Jun 10.

Graduate School of Environmental Studies, Nagoya University, Nagoya, Japan.

Developing regions experience rapid population growth and urbanisation, which require large quantities of materials for civil infrastructure. The production of construction materials, especially for urban transport systems, however, contributes to local and global environmental change. Political agendas may overlook the environmental implications of urban expansion, as economic growth tends to be prioritised. While elevating the standard of living is imperative, decision-making without careful environmental assessments can undermine the overall welfare of society. In this study, we evaluate the material demand and in-use stock productivity for the large-scale development plan for transport infrastructure in the city of Hanoi, Vietnam, from 2010 to 2030, combining geospatial and socioeconomic data with statistics on roads and railways. The results show that the total material stock could rise threefold from 66 Tg in 2010 to 269 Tg in 2030, which roughly translates to an addition of 30 Empire State Buildings per year by mass. The materials we account are required for construction exceed the availability of local sand and will need to be gathered farther away. Furthermore, the material stock productivity of the transport infrastructure appears to have been declining overall since 2010, and this trend may continue to 2030. These findings demonstrate the importance of informing urban planning with a comprehensive assessment of construction materials demand, supply capacity, and environmental impacts. Policy priorities for improving the in-use stock productivity are also recommended towards achieving a more efficient utilisation of natural resources.
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http://dx.doi.org/10.1016/j.jenvman.2021.113007DOI Listing
June 2021

WNT Ligand Dependencies in Pancreatic Cancer.

Front Cell Dev Biol 2021 28;9:671022. Epub 2021 Apr 28.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA, United States.

WNT signaling promotes the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) through wide-ranging effects on cellular proliferation, survival, differentiation, stemness, and tumor microenvironment. Of therapeutic interest is a genetically defined subset of PDAC known to have increased WNT/β-catenin transcriptional activity, growth dependency on WNT ligand signaling, and response to pharmacologic inhibitors of the WNT pathway. Here we review mechanisms underlying WNT ligand addiction in pancreatic tumorigenesis, as well as the potential utility of therapeutic approaches that functionally antagonize WNT ligand secretion or frizzled receptor binding.
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http://dx.doi.org/10.3389/fcell.2021.671022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113755PMC
April 2021

Role of stromal activin A in human pancreatic cancer and metastasis in mice.

Sci Rep 2021 Apr 12;11(1):7986. Epub 2021 Apr 12.

Department of Medicine, University of Washington College of Medicine, 1959 NE Pacific Street, RR-512, Box 356020, Seattle, WA, 98195-6420, USA.

Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the cancers with the highest mortality rates. Activin A has been implicated in colon cancer and its stroma but its role in the stroma of PDAC has not been elucidated. Activin A expression in cancer and stroma was assessed in human PDAC tissue microarrays (TMA). Activin A expression in human TMA is significantly higher in cancer samples, with expression in stroma correlated with shorter survival. Cultured pancreatic stellate cells (PSC) were found to secrete high levels of activin A resulting in PDAC cell migration that is abolished by anti-activin A neutralizing antibody. KPC mice treated with anti-activin A neutralizing antibody were evaluated for tumors, lesions and metastases quantified by immunohistochemistry. KPC mice with increased tumor burden express high plasma activin A. Treating KPC mice with an activin A neutralizing antibody does not reduce primary tumor size but decreases tumor metastases. From these data we conclude that PDAC patients with high activin A expression in stroma have a worse prognosis. PSCs secrete activin A, promoting increased PDAC migration. Inhibition of activin A in mice decreased metastases. Hence, stroma-rich PDAC patients might benefit from activin A inhibition.
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http://dx.doi.org/10.1038/s41598-021-87213-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042028PMC
April 2021

Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth.

Nat Cell Biol 2021 03 8;23(3):232-242. Epub 2021 Mar 8.

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.
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http://dx.doi.org/10.1038/s41556-021-00644-7DOI Listing
March 2021

NAD depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Department of Surgery, University of California, Los Angeles, CA 90095;

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.
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http://dx.doi.org/10.1073/pnas.2012469118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923374PMC
February 2021

A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems.

Nat Ecol Evol 2021 02 4;5(2):219-230. Epub 2021 Jan 4.

Department of Geography, Texas A&M University, College Station, TX, USA.

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human-nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits.
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http://dx.doi.org/10.1038/s41559-020-01358-zDOI Listing
February 2021

X-aptamers targeting Thy-1 membrane glycoprotein in pancreatic ductal adenocarcinoma.

Biochimie 2021 Feb 23;181:25-33. Epub 2020 Nov 23.

The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA; Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. Electronic address:

Modified DNA aptamers incorporated with amino-acid like side chains or drug-like ligands can offer unique advantages and enhance specificity as affinity ligands. Thy-1 membrane glycoprotein (THY1 or CD90) was previously identified as a biomarker candidate of neovasculature in pancreatic ductal adenocarcinoma (PDAC). The current study developed and evaluated modified DNA X-aptamers targeting THY1 in PDAC. The expression and glycosylation of THY1 in PDAC tumor tissues were assessed using immunohistochemistry and quantitative proteomics. Bead-based X-aptamer library that contains 10 different sequences was used to screen for high affinity THY1 X-aptamers. The sequences of the X-aptamers were analyzed with the next-generation sequencing. The affinities of the selected X-aptamers to THY1 were quantitatively evaluated with flow cytometry. Three high affinity THY1 X-aptamers, including XA-B217, XA-B216 and XA-A9, were selected after library screening and affinity binding evaluation. These three X-aptamers demonstrated a high binding affinity and specificity to THY1 protein and the THY1 expressing cell lines, using THY1 antibody as a comparison. The development of these X-aptamers provides highly specific and non-immunogenic affinity ligands for THY1 binding in the context of biomarker development and clinical applications. They could be further exploited to assist molecular imaging of PDAC targeting THY1.
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http://dx.doi.org/10.1016/j.biochi.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863625PMC
February 2021

Searching for laws of economics: causality, conservation, and ideology.

Authors:
David C Dawson

Am J Physiol Cell Physiol 2021 03 25;320(3):C428-C447. Epub 2020 Nov 25.

Oregon Health & Science University, Portland, Oregon.

This review is intended for scientists who may be curious about "laws" of economics. Here, I search for laws governing value, including the value of money (inflation). I begin by searching out early scientists, e.g., Aristotle, Copernicus, and Galileo, who contributed to theories of value, or who, like Isaac Newton and J. Willard Gibbs, inspired students of political economy and thereby profoundly influenced the evolution of economic thinking. From a period ranging from Aristotle to John Stuart Mill in the mid-nineteenth century, I extract two candidates for "laws" of economics, one the well-known "law of supply and demand" (LSD) and the other, less well-known, "Fisher's equation of exchange" (FEE). LSD, in one form or another, has been central to the development of economic thought, but it has proven impossible to express LSD in any compact, deterministic form with causal implications. I propose, however, that, as suggested by Irving Fisher early in the twentieth century and 100 years later by Nobelist Thomas Schelling, FEE is analogous to the first law of thermodynamics (FLT). I argue that both FEE and FLT can be viewed as "accounting identities," pertaining to energies in the case of FLT and money in the case of FEE. Both, however, suffer from a similar limitation: neither provides any information concerning causal relations among the relevant variables. I reflect upon the impact of the absence of firm, fact-based, economic laws with causal implications on modern economic policy, allowing it to be dominated by ideologies damaging to American society.
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http://dx.doi.org/10.1152/ajpcell.00324.2020DOI Listing
March 2021

Building on the RCP FallSafe care bundles: Is observation and review the key to reducing inpatient falls? The Northumbria experience 2013-2020.

Clin Med (Lond) 2020 11;20(6):545-550

Northumbria Healthcare NHS Foundation Trust, North Shields, UK.

The Royal College of Physicians (RCP) FallSafe care bundles are the recommended foundation for inpatient falls prevention in the UK. Yet there is a paucity of data to support its widespread use and the reductions in falls demonstrated in the original pilot and in subsequent small studies have not yet been reproduced in larger patient groups. Northumbria Healthcare NHS Foundation Trust (NHCFT) has seen a significant reduction in falls, falls per 1,000 bed days and harm from falls between 2013-2020 when combining the RCP FallSafe care bundles with a supportive observation policy (SOP) related to falls prevention. Highlighting the potential cost savings (∼£5.3 million over a 3-year period) has supported the growth and development of the NHCFT inpatient falls prevention service and the implementation of the SOP.
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http://dx.doi.org/10.7861/clinmed.2020-0482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687313PMC
November 2020

Poorly differentiated histologic grade correlates with worse survival in SMAD4 negative pancreatic adenocarcinoma patients.

J Surg Oncol 2021 Feb 4;123(2):389-398. Epub 2020 Nov 4.

Department of Surgery, UCLA David Geffen School of Medicine, Los Angeles, California, USA.

Background And Objectives: This study investigated the influence of the transcription factor SMAD4 on overall patient survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC).

Methods: The SMAD4 status of 125 surgically resected PDAC specimens at a large academic center from 2014 to 2017 was routinely determined prospectively and correlated with clinicopathologic characteristics and overall survival.

Results: SMAD4 loss was identified in 62% of patients and was not associated with overall survival (OS). On multivariate Cox proportional hazards survival analysis, histologic grade was the best predictor of survival in the SMAD4(-) population (adjusted hazard ratio = 4.8, p < .0001). In the SMAD4(+) population, histologic grade was not associated with survival on multivariate analysis. In the SMAD4(-) population, median OS for well/moderately differentiated patients and poorly differentiated patients was 39.6 and 8.6 months, respectively.

Conclusion: In this large cohort of resected PDAC, routine SMAD4 assessment identified a subpopulation of patients with SMAD4(-) and histologically poorly differentiated tumors that had significantly poor prognosis with median OS of 8.6 months. Characterization of the role of SMAD4 within the context of poorly differentiated tumors may help settle the controversy regarding SMAD4 in PDAC and lead to identification of personalized therapeutic strategies for subgroups of PDAC.
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http://dx.doi.org/10.1002/jso.26279DOI Listing
February 2021

COVID-19: Psychological flexibility, coping, mental health, and wellbeing in the UK during the pandemic.

J Contextual Behav Sci 2020 Jul 30;17:126-134. Epub 2020 Jul 30.

University of Lincoln, School of Psychology, University of Lincoln, Brayford Wharf East, Lincoln, LN5 7AY, UK.

The COVID-19 pandemic has profoundly altered the daily lives of many people across the globe, both through the direct interpersonal cost of the disease, and the governmental restrictions imposed to mitigate its spread and impact. The UK has been particularly affected and has one of the highest mortality rates in Europe. In this paper, we examine the impact of COVID-19 on psychological health and well-being in the UK during a period of 'lockdown' (15th-21st May 2020) and the specific role of as a potential mitigating process. We observed clinically high levels of distress in our sample (N = 555). However, psychological flexibility was significantly and positively associated with greater wellbeing, and inversely related to anxiety, depression, and COVID-19-related distress. Avoidant coping behaviour was positively associated with all indices of distress and negatively associated with wellbeing, while engagement in approach coping only demonstrated weaker associations with outcomes of interest. No relationship between adherence to government guidelines and psychological flexibility was found. In planned regression models, psychological flexibility demonstrated incremental predictive validity for all distress and wellbeing outcomes (over and above both demographic characteristics and COVID-19-specific coping responses). Furthermore, psychological flexibility and COVID-19 outcomes were only part-mediated by coping responses to COVID-19, supporting the position that psychological flexibility can be understood as an overarching response style that is distinct from established conceptualisations of coping. We conclude that psychological flexibility represents a promising candidate process for understanding and predicting how an individual may be affected by, and cope with, both the acute and longer-term challenges of the pandemic.
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http://dx.doi.org/10.1016/j.jcbs.2020.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392106PMC
July 2020

Review: The effectiveness of Theraplay for children under 12 - a systematic literature review.

Child Adolesc Ment Health 2020 Aug 6. Epub 2020 Aug 6.

School of Psychology, Doctorate in Clinical Psychology (DClinPsy), University of Lincoln, Lincoln, UK.

Background: Theraplay is a relationship-focused model of treatment based on attachment theory involving both adult and child. The study aims to review the quality of Theraplay research and Theraplay's effectiveness for children aged 12 years and under with a range of presenting difficulties, to inform future practice and identify areas for further research.

Methods: A systematic literature search was conducted using PsycINFO, CINAHL, MEDLINE and Web of Science. Quantitative studies using Theraplay only as a treatment for children aged 12 years and under with any presenting difficulty were identified. Additional manual searching was conducted, including eligible studies' reference lists. Critical appraisal tools were used to provide a narrative synthesis of Theraplay's effectiveness and research quality.

Results: Only six eligible articles were identified, meaning there was a lack of rigorous evidence eligible to offer conclusions into Theraplay's effectiveness. The review highlighted the small evidence base, mixed quality research methodology and high levels of heterogeneity in how Theraplay is practiced and evaluated. Of the eligible studies, Theraplay was found promising in its effectiveness when used with internalising and externalising difficulties, dual diagnoses and developmental disabilities.

Conclusions: Theraplay is regularly practiced across the world; however, the evidence base of rigorous research to inform Theraplay's effectiveness and mechanisms of change is lacking. Firm conclusions could not be offered, although Theraplay was shown to be promising intervention for some presentations. Further research into Theraplay's effectiveness and key mechanisms of change are recommended to enhance the quality and depth of Theraplay literature.
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http://dx.doi.org/10.1111/camh.12416DOI Listing
August 2020

Interpretation of peripheral arterial and venous Doppler waveforms: A consensus statement from the Society for Vascular Medicine and Society for Vascular Ultrasound.

Vasc Med 2020 10 15;25(5):484-506. Epub 2020 Jul 15.

Division of Vascular Surgery, University of Washington School of Medicine, Seattle, WA, USA.

This expert consensus statement on the interpretation of peripheral arterial and venous spectral Doppler waveforms was jointly commissioned by the Society for Vascular Medicine (SVM) and the Society for Vascular Ultrasound (SVU). The consensus statement proposes a standardized nomenclature for arterial and venous spectral Doppler waveforms using a framework of key major descriptors and additional modifier terms. These key major descriptors and additional modifier terms are presented alongside representative Doppler waveforms, and nomenclature tables provide context by listing previous alternate terms to be replaced by the new major descriptors and modifiers. Finally, the document reviews Doppler waveform alterations with physiologic changes and disease states, provides optimization techniques for waveform acquisition and display, and provides practical guidance for incorporating the proposed nomenclature into the final interpretation report.
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http://dx.doi.org/10.1177/1358863X20937665DOI Listing
October 2020

Increasing Temperature and Relative Humidity Accelerates Inactivation of SARS-CoV-2 on Surfaces.

mSphere 2020 07 1;5(4). Epub 2020 Jul 1.

National Biodefense Analysis and Countermeasures Center (NBACC), Operated by Battelle National Biodefense Institute (BNBI) for the U.S. Department of Homeland Security Science and Technology Directorate, Fort Detrick, Maryland, USA

Coronavirus disease 2019 (COVID-19) was first identified in China in late 2019 and is caused by newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Previous studies had reported the stability of SARS-CoV-2 in cell culture media and deposited onto surfaces under a limited set of environmental conditions. Here, we broadly investigated the effects of relative humidity, temperature, and droplet size on the stability of SARS-CoV-2 in a simulated clinically relevant matrix dried on nonporous surfaces. The results show that SARS-CoV-2 decayed more rapidly when either humidity or temperature was increased but that droplet volume (1 to 50 μl) and surface type (stainless steel, plastic, or nitrile glove) did not significantly impact decay rate. At room temperature (24°C), virus half-life ranged from 6.3 to 18.6 h depending on the relative humidity but was reduced to 1.0 to 8.9 h when the temperature was increased to 35°C. These findings suggest that a potential for fomite transmission may persist for hours to days in indoor environments and have implications for assessment of the risk posed by surface contamination in indoor environments. Mitigating the transmission of SARS-CoV-2 in clinical settings and public spaces is critically important to reduce the number of COVID-19 cases while effective vaccines and therapeutics are under development. SARS-CoV-2 transmission is thought to primarily occur through direct person-to-person transfer of infectious respiratory droplets or through aerosol-generating medical procedures. However, contact with contaminated surfaces may also play a significant role. In this context, understanding the factors contributing to SARS-CoV-2 persistence on surfaces will enable a more accurate estimation of the risk of contact transmission and inform mitigation strategies. To this end, we have developed a simple mathematical model that can be used to estimate virus decay on nonporous surfaces under a range of conditions and which may be utilized operationally to identify indoor environments in which the virus is most persistent.
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http://dx.doi.org/10.1128/mSphere.00441-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333574PMC
July 2020

Moving toward consensus for the best method to test for venous reflux in the vascular laboratory.

Authors:
David L Dawson

J Vasc Surg Venous Lymphat Disord 2020 07;8(4):501-502

Department of Surgery, Baylor Scott & White Health System, Temple, Tex. Electronic address:

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http://dx.doi.org/10.1016/j.jvsv.2020.03.015DOI Listing
July 2020

Investigation of Chocolate Matrix Interference on Cannabinoid Analytes.

J Agric Food Chem 2020 May 12;68(20):5699-5706. Epub 2020 May 12.

CW Analytical, 851 81st Avenue, Suite D, Oakland, California 94621, United States.

The first known findings of chocolate matrix interference on cannabinoid analytes is reported. Stock solutions of four biogenic cannabinoids (Δ-tetrahydrocannabinol, cannabidiol, cannabinol, and cannabigerol) and one synthetic cannabinoid (cannabidiol dimethyl ether) are subjected to milk chocolate, dark chocolate, and cocoa powder. A clear trend of matrix interference is observed, which correlates to several chemical factors. The amount of chocolate present is directly proportional to the degree of matrix interference, which yields lower percent recovery rates for the cannabinoid analyte. Structural features on the cannabinoid analytes are shown to affect matrix interference, because cannabinoids with fewer phenolic -OH groups suffer from increased signal suppression. Additionally, aromatization of the -menthyl moiety appears to correlate with enhanced matrix effects from chocolate products high in cocoa solids. These findings represent the first known documentation of chocolate matrix interference in cannabinoid analysis, which potentially has broad implications for complex matrix testing in the legal industry.
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http://dx.doi.org/10.1021/acs.jafc.0c01161DOI Listing
May 2020

Congenital left common carotid artery absence with internal and external carotid aberrancy.

J Vasc Surg Cases Innov Tech 2020 Mar 12;6(1):55. Epub 2020 Feb 12.

Section of Vascular Surgery, Olin E. Teague Veterans' Medical Center, Temple, Tex.

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http://dx.doi.org/10.1016/j.jvscit.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016347PMC
March 2020

A spatial framework to explore needs and opportunities for interoperable urban flood management.

Philos Trans A Math Phys Eng Sci 2020 Apr 17;378(2168):20190205. Epub 2020 Feb 17.

School of Architecture, Design and Built Environment, Nottingham Trent University, NG1 4FQ Nottingham, UK.

Managing current and future urban flood risks must consider the connection (i.e. interoperability) between existing (and new) infrastructure systems to manage stormwater (pluvial flooding). Yet, due to a lack of systematic approaches to identify interoperable flood management interventions, opportunities are missed to combine investments of existing infrastructure (e.g. drainage, roads, land use and buildings) with blue-green infrastructure (e.g. sustainable urban drainage systems, green roofs, green spaces). In this study, a spatial analysis framework is presented combining hydrodynamic modelling with spatial information on infrastructure systems to provide strategic direction for systems-level urban flood management (UFM). The framework is built upon three categories of data: (i) flood hazard areas (i.e. characterize the spatial flood problem); (ii) flood source areas (i.e. areas contributing the most to surface flooding); (iii) the interoperable potential of different systems (i.e. which infrastructure systems can contribute to water management functions). Applied to the urban catchment of Newcastle-Upon-Tyne (UK), the study illustrates the novelty of combining spatial data sources in a systematic way, and highlights the spatial (dis)connectivity in terms of flood source areas (where most of the flood management intervention is required) and the benefit areas (where most of the reduction in flooding occurs). The framework provides a strategic tool for managing stormwater pathways from an interoperable perspective that can help city-scale infrastructure development that considers UFM across multiple systems. This article is part of the theme issue 'Urban flood resilience'.
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http://dx.doi.org/10.1098/rsta.2019.0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061964PMC
April 2020

Habitat use, movement and activity of two large-bodied native riverine fishes in a regulated lowland weir pool.

J Fish Biol 2020 Mar 23;96(3):782-794. Epub 2020 Feb 23.

Department of Environment, Land, Water and Planning, Arthur Rylah Institute for Environmental Research, Heidelberg, Australia.

The construction of dams and weirs, and associated changes to hydrological and hydraulic (e.g., water level and velocity) characteristics of rivers is a key environmental threat for fish. These multiple stressors potentially can affect fish in a variety of ways, including by causing changes in their movement, habitat use and activity. Understanding how and why these changes occur can inform management efforts to ameliorate these threats. In this context, we used acoustic telemetry to examine habitat use, longitudinal movement and activity of two lowland river fishes, Murray cod Maccullochella peelii and golden perch Macquaria ambigua, in a weir pool environment in south-eastern Australia. We compared our results to published studies on riverine populations to determine if their behaviours are similar (or not). We show that M. peelii and M. ambigua in a weir pool exhibited some similar behaviours to conspecific riverine populations, such as strong site fidelity and use of woody habitat for M. ambigua. However, some behaviours, such as large-scale (tens-hundreds of kilometres) movements documented for riverine populations, were rarely observed. These differences potentially reflect flow regulation (e.g., stable water levels, loss of hydraulic cues) in the weir pool. The two species also exhibited contrasting responses to dissolved oxygen conditions in the weir pool, which may reflect differences in their life history. Overall, this study shows that although some aspects of these two native fishes' life history can continue despite flow regulation, other aspects may change in weir pools, potentially impacting on long-term population persistence.
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http://dx.doi.org/10.1111/jfb.14275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079010PMC
March 2020

Identification of the Active Catalyst for Nickel-Catalyzed Stereospecific Kumada Coupling Reactions of Ethers.

Chemistry 2020 Mar 21;26(14):3044-3048. Epub 2020 Feb 21.

Department of Chemistry, University of California, Irvine, Irvine, CA, 92697, USA.

A series of nickel complexes in varying oxidation states were evaluated as precatalysts for the stereospecific cross-coupling of benzylic ethers. These results demonstrate rapid redox reactions of precatalysts, such that the oxidative state of the precatalyst does not dictate the oxidation state of the active catalyst in solution. These data provide the first experimental evidence for a Ni -Ni catalytic cycle for a stereospecific alkyl-alkyl cross-coupling reaction, including spectroscopic analysis of the catalyst resting state.
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http://dx.doi.org/10.1002/chem.202000215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872209PMC
March 2020

Investigating PSMA-Targeted Radioligand Therapy Efficacy as a Function of Cellular PSMA Levels and Intratumoral PSMA Heterogeneity.

Clin Cancer Res 2020 06 13;26(12):2946-2955. Epub 2020 Jan 13.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), California.

Purpose: Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA cells in a tumor.

Experimental Design: RM1 cells expressing different levels of PSMA (PSMA, PSMA, PSMA, PSMA; study 1) or a mix of PSMA and PSMA RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received Lu- (studies 1-3) or Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.

Results: Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with Lu-PSMA617 uptake and the degree of DNA damage. Compared with Lu-PSMA617, Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.

Conclusions: In the current models, both the degree of PSMA expression and the fraction of PSMA cells correlate with Lu-/Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299755PMC
June 2020

Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression.

Theranostics 2020 1;10(2):829-840. Epub 2020 Jan 1.

Department of Surgery, UCLA, Los Angeles, CA, 90095, USA.

Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.
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http://dx.doi.org/10.7150/thno.40195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929997PMC
April 2021

Clinical Utility of Obtaining Endoscopic Ultrasound-Guided Fine-Needle Biopsies for Histologic Analyses of Pancreatic Cystic Lesions.

Gastroenterology 2020 02 16;158(3):475-477.e1. Epub 2019 Nov 16.

Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2019.10.048DOI Listing
February 2020

A comparison between auto-scored apnea-hypopnea index and oxygen desaturation index in the characterization of positional obstructive sleep apnea.

Nat Sci Sleep 2019 12;11:69-78. Epub 2019 Jul 12.

Advanced Brain Monitoring, Inc. , Carlsbad, CA, USA.

Objective: Evaluate the concordance between overall and positional oxygen desaturation indices (ODI) and apnea-hypopnea indices (AHI) according to two different definitions for positional obstructive sleep apnea (POSA).

Methods: A total of 184 in-home polysomnograms were edited to simulate Level III home sleep apnea tests (HSAT) with the auto-scored AHI and ODI based on recording time. POSA was determined using 132 records with an AHI≥5 and at least 20 mins of recording time in both supine and non-supine positions. POSA was defined independently for the AHI and ODI based on ratios of overall/non-supine event/h ≥1.4 (O/NS) and supine/non-supine event/h≥2.0 (S/NS).

Results: Correlation between the AHI and ODI was 0.97 overall, 0.94 for supine, and 0.96 for non-supine recording times (all <0.001). For most records, differences between the AHI and ODI were small, with only 14% of the records having a AHI-ODI difference exceeding >5/hr, and 6% exceeding >10 events/hr. The positive and negative percent agreements were uniformly good to excellent across varying clinical POSA cutoffs; percent agreements (positive, negative) were: AHI≥5=0.99, 0.78; AHI≥10=0.96, 0.89; and AHI≥15=0.96, 0.89. Cohen's Kappa scores also showed substantial agreement for overall as well as supine and non-supine positions across varying clinical cutoffs of the AHI. Frequency of POSA was reproducibly uniform between 59% and 61% for both POSA criteria. When the O/NS and S/NS definitions conflicted in POSA characterization, O/NS was superior for identifying patients who might exhibit a greater response to supine restriction positional therapy.

Conclusions: Auto-scored positional oximetry is a clinically viable alternative to an auto-scored Level III HSAT AHI in the characterization of POSA based on a 3% desaturation.
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http://dx.doi.org/10.2147/NSS.S204830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634301PMC
July 2019

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity.

Proc Natl Acad Sci U S A 2019 07 2;116(29):14724-14733. Epub 2019 Jul 2.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL 60612;

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.
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http://dx.doi.org/10.1073/pnas.1813012116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642408PMC
July 2019

Educational resources for vascular laboratory education in vascular surgery residencies and fellowships: Survey of Vascular Surgery Program Directors.

J Vasc Surg 2019 Jun 6;69(6):1918-1923. Epub 2019 Jan 6.

Division of Vascular Surgery, University of California, Davis, Davis, Calif.

Objective: The Registered Physician in Vascular Interpretation (RPVI) credential is a prerequisite for certification by the Vascular Surgery Board of the American Board of Surgery. Of concern, as more current trainees and recent program graduates take the Physician Vascular Interpretation (PVI) examination, vascular surgery trainee pass rates have decreased. Residents and fellows have a lower PVI examination pass rates than practicing vascular surgeons. The purpose of this study was to assess current vascular laboratory (VL) training for vascular surgery residents and fellows and to identify gaps that residency and fellowship programs might address.

Methods: Program directors (PDs) of Accreditation Council for Graduate Medical Education-accredited vascular surgery programs (107 fellowships, 53 integrated residency programs) were surveyed using a web-based tool. Responses were submitted anonymously. Data collected included information about the program, the PD, accreditation status of the VL, and the curriculum used to meet the PVI prerequisites. Concurrent data (June 2017) on the credentials of all PDs were obtained from the Alliance for Physician Certification and Advancement (APCA).

Results: Sixty-one of 117 PDs participated in the survey (52% response rate). Of these, 44 individuals (72% of responders) reported they held the RPVI and/or Registered Vascular Technologist credential. Records from APCA indicated that 51 of 117 PDs of accredited vascular surgery residencies and fellowships (44%) had an RPVI/Registered Vascular Technologist credential. Ninety-four percent reported that their VL was accredited. Practical VL experience for trainees was reported to be 20 hours or less by 62% of respondents. The use of a structured curriculum for practical experience was reported by only 15 programs. Programs with fellowships established for more than 10 years were more likely to have a structured program for didactic instruction (P = .03). Only 23 programs reported a dedicated VL rotation. Didactic instruction provided was 20 hours or less for 75% of the cohort.

Conclusions: In the absence of a standardized VL curriculum, there is variation in the VL instruction provided to trainees. Fellowship programs with longer histories have more structured instruction, but time allocated to VL education is substantially less than the 30 hours of didactic and 40 hours of practical experience recommended by the APCA. Programs and learners may benefit from the development of VL training guidelines and curriculum resources.
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http://dx.doi.org/10.1016/j.jvs.2018.10.070DOI Listing
June 2019

Invited commentary.

Authors:
David L Dawson

J Vasc Surg 2019 01;69(1):295

Sacramento, Calif.

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http://dx.doi.org/10.1016/j.jvs.2018.08.146DOI Listing
January 2019

A Prognostic Scoring System for the Prediction of Metastatic Recurrence Following Curative Resection of Pancreatic Neuroendocrine Tumors.

J Gastrointest Surg 2019 07 23;23(7):1392-1400. Epub 2018 Oct 23.

Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA.

Background: Patients with early-stage pancreatic neuroendocrine tumors (PNETs) may develop metastatic recurrences despite undergoing potentially curative pancreas resections. We sought to identify factors predictive of metastatic recurrences and develop a prognostication strategy to predict recurrence-free survival (RFS) in resected PNETs.

Methods: Patients with localized PNETs undergoing surgical resection between 1989 and 2015 were identified. Univariate and multivariate analysis were used to identify potential predictors of post-resection metastasis. A score-based prognostication system was devised using the identified factors. The bootstrap model validation methodology was utilized to estimate the external validity of the proposed prognostication strategy.

Results: Of the 140 patients with completely resected early-stage PNETs, overall 5- and 10-year RFS were 84.6% and 67.1%, respectively. The median follow-up was 56 months. Multivariate analysis identified tumor size > 5 cm, Ki-67 index 8-20%, lymph node involvement, and high histologic grade (G3, or Ki-67 > 20%) as independent predictors of post-resection metastatic recurrence. A scoring system based on these factors stratified patients into three prognostic categories with distinct 5-year RFS: 96.9%, 54.8%, and 33.3% (P < 0.0001). The bootstrap model validation methodology projected our proposed prognostication strategy to retain a high predictive accuracy even when applied in an external dataset (validated c-index of 0.81).

Conclusions: The combination of tumor size, LN status, grade, and Ki-67 was identified as the most highly predictive indicators of metastatic recurrences in resected PNETs. The proposed prognostication strategy may help stratify patients for adjuvant therapies, enhanced surveillance protocols and future clinical trials.
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http://dx.doi.org/10.1007/s11605-018-4011-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736531PMC
July 2019

The effectiveness and acceptability of a guided self-help Acceptance and Commitment Therapy (ACT) intervention for psychogenic nonepileptic seizures.

Epilepsy Behav 2018 11 17;88:332-340. Epub 2018 Oct 17.

Trent Doctorate in Clinical Psychology, University of Lincoln, Brayford Wharf East, Lincoln LN5 7AY, UK.

This study utilized a nonconcurrent case-series design to examine the effectiveness and acceptability of a guided self-help Acceptance and Commitment Therapy (ACT) intervention for people with psychogenic nonepileptic seizures. A key aim of the study was to investigate the relationship between psychological flexibility (a key process within ACT), psychological health, quality of life, and seizure frequency. Six participants completed the study, with reliable and clinically significant changes in psychological flexibility, quality of life, and psychological health observed in the majority of participants. Notable reductions in self-reported seizure frequency were also observed. The implications of these findings for clinical practice are discussed and recommendations for future research suggested.
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http://dx.doi.org/10.1016/j.yebeh.2018.09.039DOI Listing
November 2018