Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma.

BackgroundPlexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called "benign" tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown.MethodsNext generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment.ResultsEight patients with PF were identified and 5 patients' tumors were analyzed by NGS. An index case had a mono-allelic PTCH1 deletion of exons 15-24 and a second case, identified in a validation cohort, also had a PTCH1 gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components, SMO and GLI1, as well as GLI1 transcriptional targets, CCND1 and HHIP. In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing.ConclusionsFor the first time, we report a novel association between PTCH1 inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST

Pharmacist and Data-driven Quality Improvement in Primary Care (P-DQIP):A qualitative study of anticipated implementation factors informed by the Theoretical Domains Framework

Objectives: The quality and safety of drug therapy in primary care are global concerns. The Pharmacist and Data driven Quality Improvement in Primary care (P-DQIP) intervention aims to improve prescribing safety via an informatics tool which facilitates proactive management of drug therapy risks (DTRs) by health-board employed pharmacists with established roles in general practices. Study objectives were (1) to identify and prioritise factors that could influence P-DQIP implementation from the perspective of practice pharmacists, and (2) to identify potentially effective, acceptable and feasible strategies to support P-DQIP implementation. Design: Semi-structured face-to-face interviews using a Theoretical Domains Framework (TDF) informed topic guide. The framework method was used for data analysis. Identified implementation factors were prioritised for intervention based on research team consensus. Candidate intervention functions, behaviour change techniques (BCTs) and policies targeting these were identified from the Behaviour Change Wheel. The final intervention content and modes of delivery were agreed with local senior pharmacists. Setting: General practices from three Health and Social Care Partnerships (HSCPs) in NHS Tayside. Participants: 14 NHS employed practice pharmacists. Results: Identified implementation factors were linked to thirteen theoretical domains (all except intentions) and six (skill, memory/attention/decision-making, behavioural regulation, reinforcement, environmental context/resources, social influences) were prioritised. Three intervention functions (training, enablement, and environmental restructuring) were relevant and were served by two policy categories (guidelines, communication/marketing) and eight BCTs (Instructions on how to perform a behaviour, problem solving, action planning, prompt/cues, goal setting, self-monitoring, feedback, restructuring the social environment). Intervention components encompass an informatics tool, written educational material, a workshop for pharmacists, promotional activities, and small financial incentives. Conclusions: This study explored pharmacists’ perceptions of implementation factors which could influence management of DTRs in general practices to inform implementation of P-DQIP, which will initially be implemented in one Scottish health board with parallel evaluation of effectiveness and implementation

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

Evolution of Debris‐Flow Initiation Mechanisms and Sediment Sources During a Sequence of Postwildfire Rainstorms

Wildfire alters vegetation cover and soil hydrologic properties, substantially increasing the likelihood of debris flows in steep watersheds. Our understanding of initiation mechanisms of postwildfire debris flows is limited, in part, by a lack of direct observations and measurements. In particular, there is a need to understand temporal variations in debris-flow likelihood following wildfire and how those variations relate to wildfire-induced hydrologic and geomorphic changes. In this study, we use a combination of in situ measurements, hydrologic monitoring equipment, and numerical modeling to assess the impact of wildfire-induced hydrologic and geomorphic changes on debris-flow initiation during seven postwildfire rainstorms. We predict the impact of hillslope erosion on debris-flow initiation by combining terrestrial laser scanning surveys of a hillslope burned during the 2016 Fish Fire with numerical modeling of sediment transport throughout a 0.12-km(2) basin in southern California. We use measurements of sediment thickness within the channel to constrain numerical experiments and to assess the role of channel sediment supply on debris-flow initiation. Results demonstrate that debris flows initiated during rainstorms where hillslopes contributed minimally to the event sediment yield and suggest that large inputs of sediment from rill and gully networks are not essential for runoff-generated debris flows. Simulations suggest that both the gradual entrainment of sediment and the mass failure of channel bed sediment can increase sediment concentration to levels associated with debris flows. Finally, postwildfire debris-flow initiation appears closely linked to the same rainfall intensity-duration threshold despite temporal changes in the sediment source, initiation processes, and hydraulic roughness.U.S. Geological Survey (USGS) Landslide Hazards ProgramPublic domain articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Potable Water Reuse through Advanced Membrane Technology

© 2018 American Chemical Society. Recycling water from municipal wastewater offers a reliable and sustainable solution to cities and regions facing shortage of water supply. Places including California and Singapore have developed advanced water reuse programs as an integral part of their water management strategy. Membrane technology, particularly reverse osmosis, has been playing a key role in producing high quality recycled water. This feature paper highlights the current status and future perspectives of advanced membrane processes to meet potable water reuse. Recent advances in membrane materials and process configurations are presented and opportunities and challenges are identified in the context of water reuse

kNN Classification of Epilepsy Brainwaves

Epilepsy is a disorder of the normal brain function by the existence of abnormal synchronous discharges in large groups of neurons in brain structures and it is estimated about 1% of the world’s population suffers from this disease [Tzallas et al., 2009]. It has been reported that the brainwave of Epilepsy patient mostly in sharp, spike and complex wave pattern [Tzallas et al., 2009]. In addition, Epilepsy brainwaves pattern lies in wide variety of Electroencephalogram (EEG) signals in formed of low-amplitude and polyspikes activity [Vargas et al., 2011]. Generally, this disease was examined through the brainwaves or EEG signals by clinical neurulogists. An EEG is a device to record the brainwaves in term of electrical activity from the brain. Brain patterns from wave shapes that are commonly sinusoidal and measured from peak to peak that range from 0.5 μV to 100 μV in amplitude. Moreover, the brainwaves have been categorized into four frequency bands, Beta (>13 Hz), Alpha (8-13 Hz), Theta (4-8 Hz) and Delta (0.5-4 Hz). All the frequency bands will be used to characterize the Epilepsy brainwave in terms of amplitude (voltage) and frequency [Mustafa et al., 2013]. The Epilepsy brainwaves were downloaded from http://www.vis.caltech.edu/~rodri/data.htm of Fp1 and Fp2 channels which is from rats. The brainwaves consists Epilepsy and non-Epilepsy samples. Then, the brainwaves were pre-processed to remove artefact (noise). Various methods had been introduced to detect spike-wave discharge in Epilepsy patient brainwave. Brainwave is nonstationary signal, therefore, time-frequency analysis is appropriate methods to analyse the signals[Tzallas et al., 2009, Vargas et al., 2011]. One of the most popular time-frequency analyses is ShortTime Fourier Transform (STFT). After the brainwaves were pre-processed, STFT was employed to the clean brainwaves. The STFT spectrogram was generated for four frequency bands of the samples

Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure