Receptors for advanced glycation end-products (RAGEs) are multiligand cell surface receptors highly expressed in the lung that contribute to alveolar epithelial cell differentiation during ...embryogenesis and the modulation of pulmonary inflammation during disease. When RAGEs are overexpressed throughout embryogenesis, severe lung hypoplasia ensues, culminating in perinatal lethality. However, the possible mechanisms that lead to the disappearance of pulmonary tissue remain unclear. A time course of lung organogenesis, commencing on Embryonic Day (E) 12.5, demonstrated that increased RAGE expression primarily alters lung morphogenesis beginning on E16.5. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunohistochemistry and immunoblotting for active caspase-3 confirmed a shift toward apoptosis in lungs from RAGE-overexpressing mice, compared with wild-type control mice. This observation supports previous work where electron microscopy identified the cellular blebbing of alveolar epithelium in embryonic RAGE-overexpressing mice. Assaying for NF-κB also revealed elevated nuclear translocation in lungs from transgenic mice compared with control mice. An RT-PCR assessment of genes regulated by NF-κB demonstrated the elevated expression of Fas ligand, suggesting increased activity of the Fas-mediated signal transduction pathway in which ligand-receptor interactions trigger cell death. These data provide evidence that the expression of RAGEs must be tightly regulated during homeostatic organogenesis. Further elucidations of the RAGE signaling potentially involved in cell-cycle abnormalities may provide insights into the progression of RAGE-mediated lung diseases.
Due to evolutionary conservation of biology, experimental knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately ...physiology. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small molecules. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biologically active compounds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compounds. We present examples of novel compounds that inhibit the therapeutically relevant fatty acid synthase and desaturase (Fas1p and Ole1p), and demonstrate how the individual profiles facilitate hypothesis-driven experiments to delineate compound mechanism of action. Importantly, the scale and diversity of tested compounds yields a dataset where the number of modulated pathways approaches saturation. This resource can be used to map novel biological connections, and also identify functions for unannotated genes. We validated hypotheses generated by global two-way hierarchical clustering of profiles for (i) novel compounds with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background American Indian/Alaska Native (AI/AN) patients with cancer have the lowest survival rates of all racial and ethnic groups, possibly because they are less likely to receive “best ...practice” surgical care than patients of other races. Methods Prospective cohort study comparing adherence with generic and cancer-specific guidelines on processes of surgical care between AI/AN and non-Hispanic white (NHW) patients in Washington State (2010 to 2014) was conducted. Results A total of 156 AI/AN and 6,030 NHW patients underwent operations for 10 different cancers, and had similar mean adherence to generic surgical guidelines (91.5% vs 91.9%, P = .57). AI/AN patients with breast cancer less frequently received preoperative diagnostic core needle biopsy (81% vs 94%, P = .004). AI/AN patients also less frequently received care adherent to prostate cancer-specific guidelines (74% vs 92%, P = .001). Conclusion Although AI/ANs undergoing cancer operations in Washington receive similar overall best practice surgical cancer care to NHW patients, there remain important, modifiable disparities that may contribute to their lower survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to ...induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.
Potential Biocides: Iodine‐Producing Pyrotechnics Oxley, Jimmie C.; Smith, James L.; Porter, Matthew M. ...
Propellants, explosives, pyrotechnics,
August 2017, 2017-08-00, 20170801, Volume:
42, Issue:
8
Journal Article
Peer reviewed
Currently there is a need for specialized pyrotechnic materials to combat the threat of biological weapons. Materials have been characterized based on their potential to produce heat and molecular ...iodine gas (I2) to kill spore‐forming bacteria (e. g. anthrax). One formulation, already proven to kill anthrax simulants, is diiodine pentoxide with aluminum; however, it suffers from poor stability and storage problems. The heat and iodine gas output from this mixture and candidate replacement mixtures were measured with bomb calorimetry and extraction and analysis of I2 by UV‐Vis. Of the mixtures analyzed, calcium iodate and aluminum was found to be the highest producer of I2. The heat output of this mixture and others can be tuned by adding more fuel, with the cost of some iodine. Products of combustion were analyzed by thermal analysis (SDT), XPS, XRD, and LC/MS. Evidence for various metal iodides and metal oxides was collected with these methods.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hedgehog (Hh) signaling determines cell fate during development and can drive tumorigenesis. We performed a screen for new compounds that can impinge on Hh signaling downstream of Smoothened (Smo). A ...series of cyclohexyl-methyl aminopyrimidine chemotype compounds ('CMAPs') were identified that could block pathway signaling in a Smo-independent manner. In addition to inhibiting Hh signaling, the compounds generated inositol phosphates through an unknown GPCR. Correlation of GPCR mRNA expression levels with compound activity across cell lines suggested the target to be the orphan receptor GPR39. RNA interference or cDNA overexpression of GPR39 demonstrated that the receptor is necessary for compound activity. We propose a model in which CMAPs activate GPR39, which signals to the Gli transcription factors and blocks signaling. In addition to the discovery of GPR39 as a new target that impinges on Hh signaling, we report on small-molecule modulators of the receptor that will enable in vitro interrogation of GPR39 signaling in different cellular contexts.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diabetes prevention remains a top public health priority; digital approaches are potential solutions to existing scalability and accessibility challenges. There remains a gap in our understanding of ...the relationship between effectiveness, costs, and potential for sustained implementation of digital diabetes prevention strategies within typical healthcare settings.
To describe the methods and design of a type 1 hybrid effectiveness-implementation trial of a digital diabetes prevention program (DPP) using the iPARIHS and RE-AIM frameworks.
The trial will contrast the effects of two DPP interventions: (1) small group, in-person class, and (2) a digital DPP consisting of small group support, personalized health coaching, digital tracking tools, and weekly behavior change curriculum. Each intervention includes personal action planning with a focus on key elements of the lifestyle intervention from the CDC National DPP. Adults at risk for diabetes (BMI ≥25 and 5.7% ≤ HbA1c ≤ 6.4) will be randomly assigned to either the intervention group (n = 241) or the small group (n = 241). Assessment of primary (HbA1c) and secondary (weight loss, costs, cardiovascular risk factors) outcomes will occur at baseline, 4, and 12 months. Additionally, the trial will explore the potential for future adoption, implementation, and sustainability of the digitally-based intervention within a regional healthcare system based on key informant interviews and assessments of organizational administrators and primary care physicians.
This trial of a digital DPP will allow the research team to determine the relationships between reach, effectiveness, implementation, and costs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To examine changes in cardiovascular disease (CVD) risk outcomes of overweight/obese adults with prediabetes.
Using data from a randomized control trial of digital diabetes prevention program (d‐DPP) ...with 599 participants. We applied the atherosclerotic CVD (ASCVD) risk calculator to predict 10-year CVD risk for d‐DPP and small education (comparison) groups. Between-group risk changes at 4 and 12 months were compared using a repeated measures linear mixed-effect model. We examined within-group differences in proportion of participants over time for specific CVD risk factors using generalized estimating equations.
We found no differences between baseline 10-year ASCVD risk. Relative to the comparison group, the d‐DPP group experienced greater reductions in predicted 10-year ASCVD risk at each follow-up visit and a significant group difference at 4 months (−0.96%; 95% confidence interval: −1.58%, −0.34%) (but not at 12 months). Additionally, we observed that the d‐DPP group experienced a decreased proportion of individuals with hyperlipidemia (18% and 16% from baseline to 4 and 12 months), high-risk total cholesterol (8% from baseline to 12 months), and being insufficiently active (26% and 22% from baseline to 4 and 12 months at follow-up time points.
Our findings suggest that a digitally adapted DPP may promote the prevention of cardiometabolic disease among overweight/obese individuals with prediabetes. However, given the lack of maintenance of effect on ASCVD risk at 12 months, there may also be a need for additional interventions to sustain the effect detected at 4 months.
•The 10-year CVD risk was reduced by 0.96% with a d‐DPP at 4 months.•The proportion of people with cardiometabolic risk factors was reduced in a d‐DPP.•Targeting peoples with prediabetes at intermediate or high ASCVD risk at baseline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Single-particle analysis of biosensors that use charge transfer as the means for analyte-dependent signaling with semiconductor nanoparticles, or quantum dots, was examined. Single-particle analysis ...of biosensors that use energy transfer show analyte-dependent switching of nanoparticle emission from off to on. The charge-transfer-based biosensors reported here show constant emission, where the analyte (maltose) increases the emission intensity. By monitoring the same nanoparticles under various conditions, a single charge-transfer-based biosensor construct (one maltose binding protein, one protein attachment position for the reductant, one type of nanoparticle) showed a dynamic range for analyte (maltose) detection spanning from 100 pM to 10 μM while the emission intensities increase from 25 to 175% at the single-particle level. Since these biosensors were immobilized, the correlation between the detected maltose concentration and the maltose-dependent emission intensity increase could be examined. Minimal correlation between maltose detection limits and emission increases was observed, suggesting a variety of reductant-nanoparticle surface interactions that control maltose-dependent emission intensity responses. Despite the heterogeneous responses, monitoring biosensor emission intensity over 5 min provided a quantifiable method to monitor maltose concentration. Immobilizing and tracking these biosensors with heterogeneous responses, however, expanded the analyte-dependent emission intensity and the analyte dynamic range obtained from a single construct. Given the wide dynamic range and constant emission of charge-transfer-based biosensors, applying these single molecule techniques could provide ultrasensitive, real-time detection of small molecules in living cells.
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IJS, KILJ, NUK, PNG, UL, UM
An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but ...with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium‐dependent phosphate cotransporter NPT2b, LY3358966. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle‐treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.
NPT2 inhibition, effect on intestinal phosphate absorption.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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