Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. ...Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the βTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.
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•Screen identifies TRIB2 as a critical Wnt/TCF target and effector in liver cancer•Liver cancer cell-specific Wnt transcriptional output is regulated by FoxA1/2•TRIB2 promotes YAP stabilization through interaction with the E3 ligase βTrCP•TRIB2 relieves C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Properties related to the combustion, stability, and compatibility of blends composed of high-viscosity heavy fuel oil (HFO) and highly acidic pyrolysis bio-oil were determined to assess the utility ...of bio-oil as a marine fuel. The addition of bio-oil was shown to be fully stable with HFO at blend levels up to 50 mass % for up to 2 weeks. Bio-oil concentrations as low as 5 mass % significantly reduced the viscosity of HFO at 25 and 50 °C. Aging studies at 50 and 90 °C showed that the HFO inhibited the polymerization of bio-oil. The heating value and lubricity showed a linear dependency with bio-oil content, and combustion quality was acceptable for blends containing up to 15% bio-oil. The highly acidic bio-oil was found to be corrosive to carbon steel, 2.25Cr-1Mo steel, and 409 stainless steels, but not 304L and 316L. When blended into HFO at levels less than 19 mass %, no measurable corrosion was observed on any of the steel materials, but a 50 mass % concentration produced low-to-moderate corrosion in the carbon steel, 2.25Cr-1Mo steel, and 409 stainless steel grades. The combination of good blend stability, polymerization inhibition, reduced viscosity, and acceptable compatibility for low blend levels suggests that bio-oils may be suitable for use as a marine fuel.
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IJS, KILJ, NUK, PNG, UL, UM
Anthropogenic secondary organic aerosol (ASOA), formed from anthropogenic emissions of organic compounds, constitutes a substantial fraction of the mass of submicron aerosol in populated areas around ...the world and contributes to poor air quality and premature mortality. However, the precursor sources of ASOA are poorly understood, and there are large uncertainties in the health benefits that might accrue from reducing anthropogenic organic emissions. We show that the production of ASOA in 11 urban areas on three continents is strongly correlated with the reactivity of specific anthropogenic volatile organic compounds. The differences in ASOA production across different cities can be explained by differences in the emissions of aromatics and intermediate- and semi-volatile organic compounds, indicating the importance of controlling these ASOA precursors. With an improved model representation of ASOA driven by the observations, we attribute 340 000 PM2.5-related premature deaths per year to ASOA, which is over an order of magnitude higher than prior studies. A sensitivity case with a more recently proposed model for attributing mortality to PM2.5 (the Global Exposure Mortality Model) results in up to 900 000 deaths. A limitation of this study is the extrapolation from cities with detailed studies and regions where detailed emission inventories are available to other regions where uncertainties in emissions are larger. In addition to further development of institutional air quality management infrastructure, comprehensive air quality campaigns in the countries in South and Central America, Africa, South Asia, and the Middle East are needed for further progress in this area.
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here we find that transcriptional activation mediated by the Gli ...family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture and for Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 activation in the mouse pancreas accelerates Kras-driven tumor formation, underscoring the importance of Gli transcription factors in pancreatic tumorigenesis. Interestingly, we demonstrate Gli-regulated I-kappa-B kinase epsilon (IKBKE) and NF-κB activity in pancreatic cancer cells and show that this activity is a critical downstream mediator for Gli-dependent PDAC cell transformation and survival. Together, these studies demonstrate the requirement for Gli in Kras-dependent pancreatic epithelial transformation, suggest a mechanism of Gli-NF-κB oncogenic activation, and provide genetic evidence supporting the therapeutic targeting of Gli activity in pancreatic cancer.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background:
Anterior closing wedge osteotomy of the proximal tibia may be considered in revision anterior cruciate ligament (ACL) reconstruction surgery for patients with excessive posterior tibial ...slope (PTS).
Purpose:
(1) To determine the ratio of wedge thickness to degrees of correction for supratubercle (ST) versus transtubercle (TT) osteotomies for anterior closing wedge osteotomies and (2) to evaluate the accuracy of ST and TT osteotomies in achieving slope correction.
Study Design:
Controlled laboratory study.
Methods:
The computed tomography (CT) scans of 38 knees in 37 patients undergoing revision ACL reconstruction were used to simulate both ST and TT osteotomies. A 10° wedge was simulated in all CT models. The height of the wedge along the anterior tibia was recorded for each of the 2 techniques. The ratio of wedge height to achieved degree of correction was calculated. ST and TT osteotomies were performed on 3-dimensional (3D)–printed tibias of the 12 patients from the study group with the greatest PTS, after the desired degree of correction was determined. Pre- and postosteotomy slopes were measured for each tibia, and the actual change in slope was compared with the intended slope correction.
Results:
According to CT measurements, the ratio of wedge height to degree of correction was 0.99 ± 0.07 mm/deg for the ST osteotomy and 0.83 ± 0.06 mm/deg for the TT osteotomy (P < .001). When these ratios were used to perform simulated osteotomies on the twelve 3D-printed tibias, the mean slope correction was within 1° to 2° of the intended slope correction, regardless of osteotomy location (ST or TT) or whether slope was measured on the medial or lateral plateau. The ST technique tended to undercorrect and the TT technique tended to overcorrect.
Conclusion:
When anterior tibial closing wedge osteotomies were removed to correct excessive PTS, removing a wedge with a ratio of 1 mm of wedge height for every 1° of intended correction for an ST technique and a ratio of 0.8 mm to 1° for a TT technique resulted in overall average slope correction within 1° to 2° of the target.
Clinical Relevance:
The calculated ratios will allow clinicians to more accurately correct PTS when performing anterior closing wedge tibial osteotomy.
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FSPLJ, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
IMPORTANCE: Distal symmetric polyneuropathy (DSP) is a prevalent condition that results in high costs from diagnostic testing. However, the role of neurologists and diagnostic tests in patient care ...is unknown. OBJECTIVE: To determine how often neurologists and diagnostic tests influence the diagnosis and management of DSP in a community setting. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, we used a validated case-capture method (International Classification of Diseases, Ninth Revision screening technique with subsequent medical record abstraction) to identify all patients with a new DSP diagnosis treated by community neurologists in Nueces County, Texas, who met the Toronto Diabetic Neuropathy Expert Group consensus criteria for probable DSP. Using a structured data abstraction process, we recorded diagnostic test results, diagnoses rendered (before and after testing), and subsequent management from April 1, 2010, through March 31, 2011. MAIN OUTCOMES AND MEASURES: Changes in DSP cause and management after diagnostic testing by neurologists. RESULTS: We identified 458 patients with DSP followed up for a mean (SD) of 435.3 (44.1) days. Neurologists identified a cause of DSP in 291 patients (63.5%) before their diagnostic testing. Seventy-one patients (15.5%) had a new DSP cause discovered after testing by neurologists. The most common new diagnoses were prediabetes (28 6.1%), vitamin B12 deficiency (20 4.4%), diabetes mellitus (8 1.7%), and thyroid disease (8 1.7%). Management changes were common (289 63.1%) and usually related to neuropathic pain management (224 48.9%). A potential disease-modifying management change was made in 113 patients (24.7%), with the most common changes being diabetes management in 45 (9.8%), treatment with vitamins in 39 (8.5%), diet and exercise in 33 (7.2%), and adjustment of thyroid medications in 10 (2.2%). Electrodiagnostic testing and magnetic resonance imaging of the neuroaxis rarely led to management changes. CONCLUSIONS AND RELEVANCE: Neurologists diagnosed the cause of DSP in nearly two-thirds of patients before their diagnostic testing. Inexpensive blood tests for diabetes, thyroid dysfunction, and vitamin B12 deficiency allowed neurologists to identify a new cause of DSP in 71 patients (15.5%). In contrast, expensive electrodiagnostic tests and magnetic resonance imaging rarely changed patient care.
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