Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3

Background: The rearranged during transfection (RET) gene encodes a single-pass receptor whose proper expression and function are essential for the development of enteric nervous system. Mutations in RET regulatory regions are also associated with Hirschsprung disease (HSCR) (aganglionosis of the colon). We previously showed that 2 polymorphisms in RET promoter are associated with the increased risk of HSCR. These single nucleotide polymorphisms overlap with the NK2 homeobox 1 (Nkx2-1) binding motif interrupting the physical interaction of NKX2-1 with the RET promoter and result in reduced RET transcription. In this study, we further delineated Nkx2-1-mediated RET Transcription. Methods and results: First, we demonstrated that PHOX2B, like SOX10 and NKX2-1, is expressed in the mature enteric ganglions of human gut by immunohistochemistry. Second, subsequent dual-luciferase-reporter studies indicated that Nkx2-1 indeed works coordinately with Phox2b and Sox10, but not Pax3, to mediate RET transcription. In addition, identification of Phox2b responsive region in RET promoter further provides solid evidence of the potential functional interaction between Phox2b and RET. Conclusion: In sum, Phox2b and Sox10 act together with Nkx2.1 to modify RET signaling and this interaction may also contribute to HSCR susceptibility. © 2009 Elsevier Inc. All rights reserved.postprin

Hedgehog/notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans

Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway- based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest-related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR.published_or_final_versio

Event Monitoring System to Classify Unexpected Events for Production Planning

[EN] Production planning prepares companies to a future production scenario. The decision process followed to obtain the production plan considers real data and estimated data of this future scenario. However, these plans can be affected by unexpected events that alter the planned scenario and in consequence, the production planning. This is especially critical when the production planning is ongoing. Thus providing information about these events can be critical to reconsider the production planning. We herein propose an event monitoring system to identify events and to classify them into different impact levels. The information obtained from this system helps to build a risk matrix, which determines the significance of the risk from the impact level and the likelihood. A prototype has been built following this proposal.This research has been carried out in the framework of the project GV/2014/010 funded by the Generalitat Valenciana (Identificacion de la informacion proporcionada por los nuevos sistemas de deteccion accesibles mediante internet en el ambito de las "sensing enterprises" para la mejora de la toma de decisiones en la planificacion de la produccion).Boza, A.; Alarcón Valero, F.; Alemany Díaz, MDM.; Cuenca, L. (2017). Event Monitoring System to Classify Unexpected Events for Production Planning. Lecture Notes in Business Information Processing. 291:140-154. https://doi.org/10.1007/978-3-319-62386-3_7S140154291Barták, R.: On the boundary of planning and scheduling: a study (1999)Buzacott, J.A., Corsten, H., Gössinger, R., Schneider, H.M.: Production Planning and Control: Basics and Concepts. Oldenbourg Wissenschaftsverlag, München (2012)Özdamar, L., Bozyel, M.A., Birbil, S.I.: A hierarchical decision support system for production planning (with case study). Eur. J. Oper. Res. 104(3), 403–422 (1998)Van Wezel, W., Van Donk, D.P., Gaalman, G.: The planning flexibility bottleneck in food processing industries. J. Oper. Manag. 24(3), 287–300 (2006)Shamsuzzoha, A.H., Rintala, S., Cunha, P.F., Ferreira, P.S., Kankaanpää, T., Maia Carneiro, L.: Event monitoring and management process in a non-hierarchical business network. In: Intelligent Non-hierarchical Manufacturing Networks, pp. 349–374. Wiley, Hoboken (2013)Sacala, I.S., Moisescu, M.A., Repta, D.: Towards the development of the future internet based enterprise in the context of cyber-physical systems. In: 19th International Conference on Control Systems and Computer Science, CSCS 2013, pp. 405–412 (2013)Chen, K.C.: Decision support system for tourism development: system dynamics approach. J. Comput. Inf. Syst. 45(1), 104–112 (2004)Boza, A., Alemany, M.M.E., Vicens, E., Cuenca, L.: Event management in decision-making processes with decision support systems. In: 5th International Conference on Computers Communications and Control (2014)Liao, S.-H.: Expert system methodologies and applications–a decade review from 1995 to 2004. Expert Syst. Appl. 28(1), 93–103 (2005)ISO: 73: 2009: Risk management vocabulary. International Organization for Standardization (2009)Chan, F.T.S., Au, K.C., Chan, P.L.Y.: A decision support system for production scheduling in an ion plating cell. Expert Syst. Appl. 30(4), 727–738 (2006)Weinstein, L., Chung, C.-H.: Integrating maintenance and production decisions in a hierarchical production planning environment. Comput. Oper. Res. 26(10–11), 1059–1074 (1999)Poon, T.C., Choy, K.L., Chan, F.T.S., Lau, H.C.W.: A real-time production operations decision support system for solving stochastic production material demand problems. Expert Syst. Appl. 38(5), 4829–4838 (2011)SAP AG: SAP AG 2014. Next-Generation Business and the Internet of Things. Studio SAP | 27484enUS (14/03) (2014)Carneiro, L.M., Cunha, P., Ferreira, P.S., Shamsuzzoha, A.: Conceptual framework for non-hierarchical business networks for complex products design and manufacturing. Procedia CIRP 7, 61–66 (2013)Vargas, A., Cuenca, L., Boza, A., Sacala, I., Moisescu, M.: Towards the development of the framework for inter sensing enterprise architecture. J. Intell. Manuf. 26, 55–72 (2016)Barash, G., Bartolini, C., Wu, L.: Measuring and improving the performance of an IT support organization in managing service incidents, pp. 11–18 (2007)Liu, R., Kumar, A., van der Aalst, W.: A formal modeling approach for supply chain event management. Decis. Support Syst. 43(3), 761–778 (2007)Söderholm, A.: Project management of unexpected events. Int. J. Proj. Manag. 26(1), 80–86 (2008)Bearzotti, L.A., Salomone, E., Chiotti, O.J.: An autonomous multi-agent approach to supply chain event management. Int. J. Prod. Econ. 135(1), 468–478 (2012)Baron, M.M., Pate-Cornell, M.E.: Designing risk-management strategies for critical engineering systems. IEEE Trans. Eng. Manag. 46(1), 87–100 (1999)Bartolini, C., Stefanelli, C., Tortonesi, M.: SYMIAN: analysis and performance improvement of the IT incident management process. IEEE Trans. Netw. Serv. Manag. 7(3), 132–144 (2010)Cox Jr., L.A.: What’s wrong with risk matrices? Risk Anal. Int. J. 28(2), 497–512 (2008)Shim, J.P., Warkentin, M., Courtney, J.F., Power, D.J., Sharda, R., Carlsson, C.: Past, present, and future of decision support technology. Decis. Support Syst. 33(2), 111–126 (2002)Steiger, D.M.: Enhancing user understanding in a decision support system: a theoretical basis and framework (2015). http://dx.doi.org/10.1080/07421222.1998.11518214Turban, E., Aronson, J., Liang, T.-P.: Decision Support Systems and Intelligent Systems, 7th edn. Pearson Prentice Hall, Upper Saddle River (2005)Turban, E., Watkins, P.R.: Integrating expert systems and decision support systems, 10, 121–136 (1986)Cohen, D., Asín, E.: Sistemas de información para los negocios: un enfoque de toma de decisiones. McGraw-Hill, New York City (2001)Boza, A., Cortés, B., Alemany, M.M.E., Vicens, E.: Event monitoring software application for production planning systems. In: Cortés, P., Maeso-González, E., Escudero-Santana, A. (eds.) Enhancing Synergies in a Collaborative Environment. Springer, Heidelberg (2015). doi: 10.1007/978-3-319-14078-0_14Boza, A., Alarcón, F., Alemany, M.M.E., Cuenca, L.: Event classification system to reconsider the production planning. 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Multimodality Treatment with Conventional Transcatheter Arterial Chemoembolization and Radiofrequency Ablation for Unresectable Hepatocellular Carcinoma

Background/Aims: To evaluate the efficacy of multimodality treatment consisting of conventional transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in patients with non-resectable and non-ablatable hepatocellular carcinoma (HCC). Methods: In this retrospective study, 85 consecutive patients with HCC (59 solitary, 29 multifocal HCC) received TACE followed by RFA between 2001 and 2010. The mean number of tumors per patient was 1.6 +/- 0.7 with a mean size of 3.0 +/- 0.9 cm. Both local efficacy and patient survival were evaluated. Results: Of 120 treated HCCs, 99 (82.5%) showed a complete response (CR), while in 21 HCCs (17.5%) a partial response was depicted. Patients with solitary HCC revealed CR in 91% (51/56); in patients with multifocal HCC (n = 29) CR was achieved in 75% (48 of 64 HCCs). The median survival for all patients was 25.5 months. The 1-, 2-, 3- and 5-year survival rates were 84.6, 58.7, 37.6 and 14.6%, respectively. Statistical analysis revealed a significant difference in survival between Barcelona Clinic Liver Cancer (BCLC) A (73.4 months) and B (50.3 months) patients, while analyses failed to show a difference for Child-Pugh score, Cancer of Liver Italian Program (CLIP) score and tumor distribution pattern. Conclusion: TACE combined with RFA provides an effective treatment approach with high local tumor control rates and promising survival data, especially for BCLC A patients. Randomized trials are needed to compare this multimodality approach with a single modality approach for early-stage HCC. Copyright (C) 2011 S. Karger AG, Base

Direct aperture optimization as a means of reducing the complexity of intensity modulated radiation therapy plans

Intensity Modulated Radiation Therapy (IMRT) is a means of delivering radiation therapy where the intensity of the beam is varied within the treatment field. This is done by dividing a large beam into many small beamlets. Dose constraints are assigned to both the target and sensitive structures and computerised inverse optimization is performed to find the individual weights of this large number of beamlets. The computer adjusts the intensities of these beamlets according to the required planning dose objectives. The optimized intensity patterns are then decomposed into a series of deliverable multi leaf collimator (MLC) shapes in the sequencing step

Medication administration errors for older people in long-term residential care

Background Older people in long-term residential care are at increased risk of medication errors. The purpose of this study was to evaluate a computerised barcode medication management system designed to improve drug administrations in residential and nursing homes, including comparison of error rates and staff awareness in both settings. Methods All medication administrations were recorded prospectively for 345 older residents in thirteen care homes during a 3-month period using the computerised system. Staff were surveyed to identify their awareness of administration errors prior to system introduction. Overall, 188,249 attempts to administer medication were analysed to determine the prevalence of potential medication administration errors (MAEs). Error classifications included attempts to administer medication at the wrong time, to the wrong person or discontinued medication. Analysis compared data at residential and nursing home level and care and nursing staff groups. Results Typically each resident was exposed to 206 medication administration episodes every month and received nine different drugs. Administration episodes were more numerous (p < 0.01) in nursing homes (226.7 per resident) than in residential homes (198.7). Prior to technology introduction, only 12% of staff administering drugs reported they were aware of administration errors being averted in their care home. Following technology introduction, 2,289 potential MAEs were recorded over three months. The most common MAE was attempting to give medication at the wrong time. On average each resident was exposed to 6.6 potential errors. In total, 90% of residents were exposed to at least one MAE with over half (52%) exposed to serious errors such as attempts to give medication to the wrong resident. MAEs rates were significantly lower (p < 0.01) in residential homes than nursing homes. The level of non-compliance with system alerts was low in both settings (0.075% of administrations) demonstrating virtually complete error avoidance. Conclusion Potentially inappropriate administration of medication is a serious problem in long-term residential care. A computerised barcode system can accurately and automatically detect inappropriate attempts to administer drugs to residents. This tool can reliably be used by care staff as well as nurses to improve quality of care and patient safety

Assessing the accuracy of an inter-institutional automated patient-specific health problem list

<p>Abstract</p> <p>Background</p> <p>Health problem lists are a key component of electronic health records and are instrumental in the development of decision-support systems that encourage best practices and optimal patient safety. Most health problem lists require initial clinical information to be entered manually and few integrate information across care providers and institutions. This study assesses the accuracy of a novel approach to create an inter-institutional automated health problem list in a computerized medical record (MOXXI) that integrates three sources of information for an individual patient: diagnostic codes from medical services claims from all treating physicians, therapeutic indications from electronic prescriptions, and single-indication drugs.</p> <p>Methods</p> <p>Data for this study were obtained from 121 general practitioners and all medical services provided for 22,248 of their patients. At the opening of a patient's file, all health problems detected through medical service utilization or single-indication drug use were flagged to the physician in the MOXXI system. Each new arising health problem were presented as 'potential' and physicians were prompted to specify if the health problem was valid (Y) or not (N) or if they preferred to reassess its validity at a later time.</p> <p>Results</p> <p>A total of 263,527 health problems, representing 891 unique problems, were identified for the group of 22,248 patients. Medical services claims contributed to the majority of problems identified (77%), followed by therapeutic indications from electronic prescriptions (14%), and single-indication drugs (9%). Physicians actively chose to assess 41.7% (n = 106,950) of health problems. Overall, 73% of the problems assessed were considered valid; 42% originated from medical service diagnostic codes, 11% from single indication drugs, and 47% from prescription indications. Twelve percent of problems identified through other treating physicians were considered valid compared to 28% identified through study physician claims.</p> <p>Conclusion</p> <p>Automation of an inter-institutional problem list added over half of all validated problems to the health problem list of which 12% were generated by conditions treated by other physicians. Automating the integration of existing information sources provides timely access to accurate and relevant health problem information. It may also accelerate the uptake and use of electronic medical record systems.</p

The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer

Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine (£2132) and tegafur with uracil (£3385) were lower than costs for the intravenous Mayo regimen (£3593) and infusional regimens on the de Gramont (£6255) and Modified de Gramont (£3485) schedules over the same treatment period. Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter