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Sample records for premature contractions apcs

  1. The circadian variation of premature atrial contractions

    DEFF Research Database (Denmark)

    Larsen, Bjørn Strøier; Kumarathurai, Preman; Nielsen, Olav W

    2016-01-01

    AIMS: The aim of the study was to assess a possible circadian variation of premature atrial contractions (PACs) in a community-based population and to determine if the daily variation could be used to assess a more vulnerable period of PACs in predicting later incidence of atrial fibrillation (AF...... variation in heart rate. After adjusting for relevant risk factors, the risk of AF was equal in all time intervals throughout the day. CONCLUSION: Premature atrial contractions showed a circadian variation in subjects with frequent PACs. No specific time interval of the day was more predictive of AF than...

  2. Workup and management of patients with frequent premature ventricular contractions.

    Science.gov (United States)

    Giles, Katie; Green, Martin S

    2013-11-01

    Premature ventricular contractions (PVCs) are a frequently encountered entity in clinical cardiology. They rarely affect prognosis or management. However, they might produce bothersome symptoms and, in select individuals with a high PVC burden, they might contribute to left ventricular (LV) dysfunction. Workup of patients with very frequent PVCs consists of a thorough history and physical examination to screen for underlying cardiac disease and potential triggers. Routine investigations include a standard 12-lead electrocardiogram, as well as an echocardiogram. A Holter monitor should be performed in those with severe symptoms, a history of syncope, or a malignant family history. Exercise stress testing has a role in evaluating for ischemia and in the assessment of patients with exertional symptoms. More advanced testing is not warranted if these initial investigations are reassuring. Referral to an arrhythmia specialist should be considered in patients with LV dysfunction whose PVC burden exceeds 15%. Frequent ventricular ectopy represents a rare, but reversible cause of LV dysfunction and these patients should be further evaluated for possible catheter ablation. Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  3. Frequent premature ventricular contractions in an orbital spaceflight participant.

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    Jennings, Richard T; Stepanek, Jan P; Scott, Luis R; Voronkov, Yury I

    2010-06-01

    Commercial spaceflight participants on orbital flights typically are older than career astronauts and they often have medical conditions that have not been studied at high g or in microgravity. This is a case report of a 56-yr-old orbital spaceflight participant with essential tremor and frequent premature ventricular contractions that occurred at rates up to 7000 per day. Before training and spaceflight, he was required to complete extensive clinical investigations to demonstrate normal cardiac structures and the absence of cardiac pathology. The evaluation included signal averaged ECG, transthoracic stress echocardiography, exercise tolerance tests, electrophysiological studies, cardiac MRI, electron beam CT, Holter monitoring, and overnight oximetry. While no cardiac pathology was demonstrated, the Russian medical team required that the PVCs be treated prior to training and spaceflight. For the initial flight, a selective beta-1 receptor beta blocker was used and for the second a calcium channel blocker was used in combination with a nonselective beta blocker for tremor control. Analogue environment testing assured that this combination of medications was compatible. The spaceflight participant's PVCs were incompletely suppressed with a low-dose selective beta-1 blocker, but were well suppressed by a calcium channel blocker. He tolerated in-flight periodic use of a nonselective beta blocker in combination with a calcium channel blocker. In-flight ECG and blood pressure monitoring results were normal, and an ECG obtained midmission and on landing day showed successful PVC suppression. He did not have any cardiac difficulty with launch, on-orbit operations, entry, or recovery

  4. Level of C - reactive protein as an indicator for prognosis of premature uterine contractions.

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    Najat Nakishbandy, Bayar M; Barawi, Sabat A M

    2014-01-01

    high concentrations of maternal C-reactive protein have been associated with adverse pregnancy outcome, and premature uterine contraction may be predicted by elevated levels of C-reactive protein. This may ultimately be simple and cost-effective enough to introduce as a low-risk screening program. an observational case control study was performed from May 1st, 2010 to December 1st, 2010 at Maternity Teaching Hospital-Erbil/ Kurdistan Region/ Iraq. The sample size was (200) cases. Hundred of them were presented with premature uterine contractions at 24(+0)-36(+6) weeks. The other hundred were control group at same gestational ages. The level of C-reactive protein was determined in both groups and both groups were followed till delivery. (93) out of (100) women with premature uterine contractions had elevated level of C-Reactive protein and 91% delivered prematurely while in the control group only (9) out of (100) women had elevated level of C-reactive protein and only 8% of them delivered preterm. Differences were statistically highly significant. C-reactive protein can be used as a biomarker in prediction of premature delivery when it is associated with premature uterine contractions. As well it can be used as a screening test to detect cases that are at risk of premature delivery.

  5. Premature Contractions

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    ... and Live Our Interactive Cardiovascular Library has detailed animations and illustrations to help you learn about conditions, ... Tools & Resources Popular Articles 1 Understanding Blood Pressure Readings 2 Sodium and Salt 3 Heart Attack Symptoms ...

  6. Recruitment pattern of sympathetic muscle neurons during premature ventricular contractions in heart failure patients and controls.

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    Maslov, Petra Zubin; Breskovic, Toni; Brewer, Danielle N; Shoemaker, J Kevin; Dujic, Zeljko

    2012-12-01

    Premature ventricular contractions (PVC) elicit larger bursts of multiunit muscle sympathetic nerve activity (MSNA), reflecting the ability to increase postganglionic axonal recruitment. We tested the hypothesis that chronic heart failure (CHF) limits the ability to recruit postganglionic sympathetic neurons as a response to PVC due to the excessive sympathetic activation in these patients. Sympathetic neurograms of sufficient signal-to-noise ratio were obtained from six CHF patients and from six similarly aged control individuals. Action potentials (APs) were extracted from the multiunit sympathetic neurograms during sinus rhythm bursts and during the post-PVC bursts. These APs were classified on the basis of the frequency per second, the content per burst, and the peak-to-peak amplitude, which formed the basis of binning the APs into active clusters. Compared with controls, CHF had higher APs per burst and higher number of active clusters per sinus rhythm burst (P < 0.05). Compared with sinus rhythm bursts, both groups increased AP frequency and the number of active clusters in the post-PVC burst (P < 0.05). However, compared with controls, the increase in burst integral, AP frequency, and APs per burst during the post-PVC burst was less in CHF patients. Nonetheless, the PVC-induced increase in active clusters per burst was similar between the groups. Thus, these CHF patients retained the ability to recruit larger APs but had a diminished ability to increase overall AP content.

  7. Premature ventricular contraction detection combining deep neural networks and rules inference.

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    Zhou, Fei-Yan; Jin, Lin-Peng; Dong, Jun

    2017-06-01

    Premature ventricular contraction (PVC), which is a common form of cardiac arrhythmia caused by ectopic heartbeat, can lead to life-threatening cardiac conditions. Computer-aided PVC detection is of considerable importance in medical centers or outpatient ECG rooms. In this paper, we proposed a new approach that combined deep neural networks and rules inference for PVC detection. The detection performance and generalization were studied using publicly available databases: the MIT-BIH arrhythmia database (MIT-BIH-AR) and the Chinese Cardiovascular Disease Database (CCDD). The PVC detection accuracy on the MIT-BIH-AR database was 99.41%, with a sensitivity and specificity of 97.59% and 99.54%, respectively, which were better than the results from other existing methods. To test the generalization capability, the detection performance was also evaluated on the CCDD. The effectiveness of the proposed method was confirmed by the accuracy (98.03%), sensitivity (96.42%) and specificity (98.06%) with the dataset over 140,000 ECG recordings of the CCDD. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Ventricular premature contraction in hypertrophic cardiomyopathy and essential hypertension with left ventricular hypertrophy

    International Nuclear Information System (INIS)

    Kobiki, Naoki

    1989-01-01

    In order to investigate the relationship of different morbid states of the hypertrophied myocardium to the appearance of ventricular premature contraction (VPC), we compared the VPC findings from Holter ECG with those of UCG and stress thallium-201 myocardial SPECT scintigraphy (stress scinti) in 31 patients with hypertrophic cardiomyopathy (HCM) and 20 with essential hypertension (HT). The HCM patients consisted of 21 with asymmetric hypertrophy (ASH), 3 with symmetric hypertrophy (SH), and 7 with apical hypertrophy (APH). We recognized positive findings on the stress scinti such as fixed perfusion defect (FD) or reversible perfusion defect (RD) in 11 patients (ASH 10, APH 1) out of 31 patients with HCM (35%). Positive findings were observed in only one patient out of 20 with HT (5%). We recognized a high grade VPC (grade 4a and 4b of Lown's criteria) in 8 of 11 scinti positive patients with HCM (ASH 7, APH 1)(73%), while high grade VPC appeared in 5 (all of them are ASH) out of 20 scinti negative patients with HCM (25%). Therefore, these findings suggest that high grade VPCs in HCM occur in relation to a myocardial perfusion defect. (author)

  9. Management of Arrhythmias in Athletes: Atrial Fibrillation, Premature Ventricular Contractions, and Ventricular Tachycardia.

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    Lai, Ernest; Chung, Eugene H

    2017-10-09

    Management of atrial fibrillation, premature ventricular contractions, and ventricular tachycardia without underlying cardiac disease or arrhythmogenic conditions differs in athletes from the general population. Athletes tend to be younger, healthier individuals with few comorbidities. Therapies that work well in the general population may not be appropriate or preferable for athletes. Management strategies include deconditioning, pharmacologic therapy, such as rate control with β-blockers or non-dihydropyridine calcium channel blockers and rhythm control with class I or class III antiarrhythmic drugs, and catheter ablation. Deconditioning is not preferred by athletes because of lost playing time. Pharmacologic therapy is well tolerated among most individuals, but is not as favorable in athletes. Rate control medications can reduce performance and β-blockers, in particular, are prohibited in many sports. Antiarrhythmic drugs are preferred over rate control with athletes, but many, especially younger athletes, may not like the idea of long-term medical therapy. Catheter ablation has been proven to be safe and efficacious, may eliminate the need for long-term medical therapy, and is supported by the major societies (AHA, ACC, ESC).

  10. Detection of premature ventricular contractions on a ventricular electrocardiogram for patients with left ventricular assist devices.

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    Park, Sung Min; Lee, Jin Hong; Choi, Seong Wook

    2014-12-01

    The ventricular electrocardiogram (v-ECG) was developed for long-term monitoring of heartbeats in patients with a left ventricular assist device (LVAD) and does not normally have the functionality necessary to detect additional heart irregularities that can progress to critical arrhythmias. Although the v-ECG has the benefits of physiological optimization and counterpulsation control, when abnormal heartbeats occur, the v-ECG does not show the distinct abnormal waveform that enables easy detection of an abnormal heartbeat among normal heartbeats on the conventional ECG. In this study, the v-ECGs of normal and abnormal heartbeats are compared with each other with respect to peak-to-peak voltage, area, and maximal slopes, and a new method to detect abnormal heartbeats is suggested. In a series of animal experiments with three porcine models (Yorkshire pigs weighing 30-40 kg), a v-ECG and conventional ECG were taken simultaneously during LVAD perfusion. Clinical experts found 104 abnormal heartbeats from the saved conventional ECG data and confirmed that the other 3159 heartbeats were normal. Almost all of the abnormal heartbeats were premature ventricular contractions (PVCs), and there was short-term tachycardia for 3 s. A personal computer was used to automatically detect abnormal heartbeats with the v-ECG according to the new method, and its results were compared with the clinicians' results. The new method found abnormal heartbeats with 90% accuracy, and less than 15% of the total PVCs were missed. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  11. Dynamic Changes of QRS Morphology of Premature Ventricular Contractions During Ablation in the Right Ventricular Outflow Tract: A Case Report.

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    Yue-Chun, Li; Jia-Feng, Lin; Jia-Xuan, Lin

    2015-10-01

    Electrocardiographic characteristics can be useful in differentiating between right ventricular outflow tract (RVOT) and aortic sinus cusp (ASC) ventricular arrhythmias. Ventricular arrhythmias originating from ASC, however, show preferential conduction to RVOT that may render the algorithms of electrocardiographic characteristics less reliable. Even though there are few reports describing ventricular arrhythmias with ASC origins and endocardial breakout sites of RVOT, progressive dynamic changes in QRS morphology of the ventricular arrhythmias during ablation obtained were rare.This case report describes a patient with symptomatic premature ventricular contractions of left ASC origin presenting an electrocardiogram (ECG) characteristic of right ventricular outflow tract before ablation. Pacing at right ventricular outflow tract reproduced an excellent pace map. When radiofrequency catheter ablation was applied to the right ventricular outflow tract, the QRS morphology of premature ventricular contractions progressively changed from ECG characteristics of right ventricular outflow tract origin to ECG characteristics of left ASC origin.Successful radiofrequency catheter ablation was achieved at the site of the earliest ventricular activation in the left ASC. The distance between the successful ablation site of the left ASC and the site with an excellent pace map of the RVOT was 20 mm.The ndings could be strong evidence for a preferential conduction via the myocardial bers from the ASC origin to the breakout site in the right ventricular outflow tract. This case demonstrates that ventricular arrhythmias with a single origin and exit shift may exhibit QRS morphology changes.

  12. Bayesian Classification Models for Premature Ventricular Contraction Detection on ECG Traces.

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    Casas, Manuel M; Avitia, Roberto L; Gonzalez-Navarro, Felix F; Cardenas-Haro, Jose A; Reyna, Marco A

    2018-01-01

    According to the American Heart Association, in its latest commission about Ventricular Arrhythmias and Sudden Death 2006, the epidemiology of the ventricular arrhythmias ranges from a series of risk descriptors and clinical markers that go from ventricular premature complexes and nonsustained ventricular tachycardia to sudden cardiac death due to ventricular tachycardia in patients with or without clinical history. The premature ventricular complexes (PVCs) are known to be associated with malignant ventricular arrhythmias and sudden cardiac death (SCD) cases. Detecting this kind of arrhythmia has been crucial in clinical applications. The electrocardiogram (ECG) is a clinical test used to measure the heart electrical activity for inferences and diagnosis. Analyzing large ECG traces from several thousands of beats has brought the necessity to develop mathematical models that can automatically make assumptions about the heart condition. In this work, 80 different features from 108,653 ECG classified beats of the gold-standard MIT-BIH database were extracted in order to classify the Normal, PVC, and other kind of ECG beats. Three well-known Bayesian classification algorithms were trained and tested using these extracted features. Experimental results show that the F1 scores for each class were above 0.95, giving almost the perfect value for the PVC class. This gave us a promising path in the development of automated mechanisms for the detection of PVC complexes.

  13. Increased Ventricular Premature Contraction Frequency During REM Sleep in Patients with Coronary Artery Disease and Obstructive Sleep Apnea

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    Mari A. Watanabe

    2008-11-01

    Full Text Available Background Patients with obstructive sleep apnea are reported to have a peak of sudden cardiac death at night, in contrast to patients without apnea whose peak is in the morning. We hypothesized that ventricular premature contraction (VPC frequency would correlate with measures of apnea and sympathetic activity.Methods Electrocardiograms from a sleep study of 125 patients with coronary artery disease were evaluated. Patients were categorized by apnea-hypopnea index (AHI into Moderate (AHI 15 apnea groups. Sleep stages studied were Wake, S1, S2, S34, and rapid eye movement (REM. Parameters of a potent autonomically-based risk predictor for sudden cardiac death called heart rate turbulence were calculated.Results There were 74 Moderate and 51 Severe obstructive sleep apnea patients. VPC frequency was affected significantly by sleep stage (Wake, S2 and REM, F=5.8, p<.005 and by AHI (F=8.7, p<.005. In Severe apnea patients, VPC frequency was higher in REM than in Wake (p=.011. In contrast, patients with Moderate apnea had fewer VPCs and exhibited no sleep stage dependence (p=.19. Oxygen desaturation duration per apnea episode correlated positively with AHI (r2=.71, p<.0001, and was longer in REM than in non-REM (p<.0001. The heart rate turbulence parameter TS correlated negatively with oxygen desaturation duration in REM (r2=.06, p=.014.Conclusions Higher VPC frequency coupled with higher sympathetic activity caused by longer apnea episodes in REM sleep may be one reason for increased nocturnal death in apneic patients.

  14. Fine particulate air pollution and premature atrial contractions: The REasons for Geographic And Racial Differences in Stroke study.

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    O'Neal, Wesley T; Soliman, Elsayed Z; Efird, Jimmy T; Judd, Suzanne E; Howard, Virginia J; Howard, George; McClure, Leslie A

    2017-05-01

    Several reports have suggested that particulate matter (PM) exposure increases the risk for atrial arrhythmias. However, data from large-scale epidemiologic studies supporting this hypothesis are lacking. We examined the association of PM <2.5 μm in diameter (PM 2.5 ) concentration with premature atrial contractions (PACs) in 26,609 (mean age=65±9.4 years; 55% female; 41% black) participants from the REGARDS (REasons for Geographic And Racial Differences in Stroke) study. Estimates of short- (2 weeks) and long-term (1 year) PM 2.5 exposure were computed before each participant's baseline visit using geographic information system data on the individual level at the coordinates of study participants' residences. PACs were identified from baseline electrocardiograms. A total of 2140 (8.2%) participants had evidence of PACs on the baseline electrocardiogram. Short-term PM 2.5 (per 10 μg/m 3 ) exposure was not associated with PACs (OR=1.09, 95% CI=0.98, 1.23). Increases in long-term PM 2.5 (per 10 μg/m 3 ) were associated with PACs (OR=1.40, 95% CI=1.10, 1.78). Interactions were not detected for short- and long-term PM 2.5 exposure by age, sex, or race. Long- but not short-term PM 2.5 exposure is associated with PACs. This suggests a role for long-term PM 2.5 exposure in initiating supraventricular arrhythmias that are triggered by PACs.

  15. Premature Ventricular Contraction Coupling Interval Variability Destabilizes Cardiac Neuronal and Electrophysiological Control: Insights from Simultaneous Cardio-Neural Mapping

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    Hamon, David; Rajendran, Pradeep S.; Chui, Ray W.; Ajijola, Olujimi A.; Irie, Tadanobu; Talebi, Ramin; Salavatian, Siamak; Vaseghi, Marmar; Bradfield, Jason S.; Armour, J. Andrew; Ardell, Jeffrey L.; Shivkumar, Kalyanam

    2017-01-01

    Background Variability in premature ventricular contraction (PVC) coupling interval (CI) increases the risk of cardiomyopathy and sudden death. The autonomic nervous system regulates cardiac electrical and mechanical indices, and its dysregulation plays an important role in cardiac disease pathogenesis. The impact of PVCs on the intrinsic cardiac nervous system (ICNS), a neural network on the heart, remains unknown. The objective was to determine the effect of PVCs and CI on ICNS function in generating cardiac neuronal and electrical instability using a novel cardio-neural mapping approach. Methods and Results In a porcine model (n=8) neuronal activity was recorded from a ventricular ganglion using a microelectrode array, and cardiac electrophysiological mapping was performed. Neurons were functionally classified based on their response to afferent and efferent cardiovascular stimuli, with neurons that responded to both defined as convergent (local reflex processors). Dynamic changes in neuronal activity were then evaluated in response to right ventricular outflow tract PVCs with fixed short, fixed long, and variable CI. PVC delivery elicited a greater neuronal response than all other stimuli (P<0.001). Compared to fixed short and long CI, PVCs with variable CI had a greater impact on neuronal response (P<0.05 versus short CI), particularly on convergent neurons (P<0.05), as well as neurons receiving sympathetic (P<0.05) and parasympathetic input (P<0.05). The greatest cardiac electrical instability was also observed following variable (short) CI PVCs. Conclusions Variable CI PVCs affect critical populations of ICNS neurons and alter cardiac repolarization. These changes may be critical for arrhythmogenesis and remodeling leading to cardiomyopathy. PMID:28408652

  16. Premature Ventricular Contraction Coupling Interval Variability Destabilizes Cardiac Neuronal and Electrophysiological Control: Insights From Simultaneous Cardioneural Mapping.

    Science.gov (United States)

    Hamon, David; Rajendran, Pradeep S; Chui, Ray W; Ajijola, Olujimi A; Irie, Tadanobu; Talebi, Ramin; Salavatian, Siamak; Vaseghi, Marmar; Bradfield, Jason S; Armour, J Andrew; Ardell, Jeffrey L; Shivkumar, Kalyanam

    2017-04-01

    Variability in premature ventricular contraction (PVC) coupling interval (CI) increases the risk of cardiomyopathy and sudden death. The autonomic nervous system regulates cardiac electrical and mechanical indices, and its dysregulation plays an important role in cardiac disease pathogenesis. The impact of PVCs on the intrinsic cardiac nervous system, a neural network on the heart, remains unknown. The objective was to determine the effect of PVCs and CI on intrinsic cardiac nervous system function in generating cardiac neuronal and electric instability using a novel cardioneural mapping approach. In a porcine model (n=8), neuronal activity was recorded from a ventricular ganglion using a microelectrode array, and cardiac electrophysiological mapping was performed. Neurons were functionally classified based on their response to afferent and efferent cardiovascular stimuli, with neurons that responded to both defined as convergent (local reflex processors). Dynamic changes in neuronal activity were then evaluated in response to right ventricular outflow tract PVCs with fixed short, fixed long, and variable CI. PVC delivery elicited a greater neuronal response than all other stimuli ( P <0.001). Compared with fixed short and long CI, PVCs with variable CI had a greater impact on neuronal response ( P <0.05 versus short CI), particularly on convergent neurons ( P <0.05), as well as neurons receiving sympathetic ( P <0.05) and parasympathetic input ( P <0.05). The greatest cardiac electric instability was also observed after variable (short) CI PVCs. Variable CI PVCs affect critical populations of intrinsic cardiac nervous system neurons and alter cardiac repolarization. These changes may be critical for arrhythmogenesis and remodeling, leading to cardiomyopathy. © 2017 American Heart Association, Inc.

  17. Premature Ventricular Contractions (PVCs)

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    ... adrenaline in the body that may be caused by caffeine, tobacco, exercise or anxiety Injury to the heart muscle from coronary artery disease, congenital heart disease, high blood pressure or heart failure Risk factors The following can ...

  18. APC/C--the master controller of origin licensing?

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    Sivaprasad, Umasundari; Machida, Yuichi J; Dutta, Anindya

    2007-02-23

    DNA replication must be tightly controlled to prevent initiation of a second round of replication until mitosis is complete. So far, components of the pre-replicative complex (Cdt1, Cdc6 and geminin) were considered key players in this regulation. In a new study, Machida and Dutta have shown that depletion of Emi1 caused cells to replicate their DNA more than once per cell cycle 1. This effect was dependent on the ability of Emi1 to inhibit the APC/C. In addition to its role in regulating entry into mitosis, oscillation of APC/C activity regulates pre-RC formation: high APC/C activity in late M/G1 allows pre-RC formation and low APC/C activity in S/G2 prevents pre-RC formation for a second time thereby preventing rereplication. Each redundant pathway to prevent rereplication is dependent on regulating one of the pre-RC components, and all of the pathways are co-regulated by Emi1 through the APC/C. In this commentary we discuss how this new role of Emi1 adds to our understanding of the regulation of replication initiation. We also review the literature to analyze whether APC/C has a role in regulating endoreduplication (a normal state of polyploidy in some differentiated cells). Similarly a role of premature APC/C activation in genomic instability of tumors is discussed.

  19. APC/C – the master controller of origin licensing?

    Directory of Open Access Journals (Sweden)

    Dutta Anindya

    2007-02-01

    Full Text Available Abstract DNA replication must be tightly controlled to prevent initiation of a second round of replication until mitosis is complete. So far, components of the pre-replicative complex (Cdt1, Cdc6 and geminin were considered key players in this regulation. In a new study, Machida and Dutta have shown that depletion of Emi1 caused cells to replicate their DNA more than once per cell cycle 1. This effect was dependent on the ability of Emi1 to inhibit the APC/C. In addition to its role in regulating entry into mitosis, oscillation of APC/C activity regulates pre-RC formation: high APC/C activity in late M/G1 allows pre-RC formation and low APC/C activity in S/G2 prevents pre-RC formation for a second time thereby preventing rereplication. Each redundant pathway to prevent rereplication is dependent on regulating one of the pre-RC components, and all of the pathways are co-regulated by Emi1 through the APC/C. In this commentary we discuss how this new role of Emi1 adds to our understanding of the regulation of replication initiation. We also review the literature to analyze whether APC/C has a role in regulating endoreduplication (a normal state of polyploidy in some differentiated cells. Similarly a role of premature APC/C activation in genomic instability of tumors is discussed.

  20. Dictionary-based monitoring of premature ventricular contractions: An ultra-low-cost point-of-care service.

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    Bollepalli, S Chandra; Challa, S Sastry; Anumandla, Laxminarayana; Jana, Soumya

    2018-04-25

    While cardiovascular diseases (CVDs) are prevalent across economic strata, the economically disadvantaged population is disproportionately affected due to the high cost of traditional CVD management, involving consultations, testing and monitoring at medical facilities. Accordingly, developing an ultra-low-cost alternative, affordable even to groups at the bottom of the economic pyramid, has emerged as a societal imperative. Against this backdrop, we propose an inexpensive yet accurate home-based electrocardiogram (ECG) monitoring service. Specifically, we seek to provide point-of-care monitoring of premature ventricular contractions (PVCs), high frequency of which could indicate the onset of potentially fatal arrhythmia. Note that the first-generation telecardiology system acquires the ECG, transmits it to a professional diagnostic center without processing, and nearly achieves the diagnostic accuracy of a bedside setup. In the process, such a system incurs high bandwidth cost and requires the physicians to process the entire record for diagnosis. To reduce cost, current telecardiology systems compress data before transmitting. However, the burden on physicians remains undiminished. In this context, we develop a dictionary-based algorithm that reduces not only the overall bandwidth requirement, but also the physicians workload by localizing anomalous beats. Specifically, we detect anomalous beats with high sensitivity and only those beats are then transmitted. In fact, we further compress those beats using class-specific dictionaries subject to suitable reconstruction/diagnostic fidelity. Finally, using Monte Carlo cross validation on MIT/BIH arrhythmia database, we evaluate the performance of the proposed system. In particular, with a sensitivity target of at most one undetected PVC in one hundred beats, and a percentage root mean squared difference less than 9% (a clinically acceptable level of fidelity), we achieved about 99.15% reduction in bandwidth cost

  1. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting.

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    Hankey, William; Frankel, Wendy L; Groden, Joanna

    2018-03-01

    The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis, and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions, or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

  2. Awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation: 5 years experience

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    Giuseppe La Pera

    2014-06-01

    Full Text Available Objectives: To assess the cure rate of patients with premature ejaculation who underwent a treatment involving: 1 awareness of the pelvic floor muscles 2 learning the timing of execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase 3 pelvic floor rehabilitation (bio feed back, pelvic exercises and electrostimulation. Materials and methods: We recruited 78 patients with lifelong premature ejaculation who completed the training. The patients were informed of the role of the pelvic floor. They were taught to carry out the execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase to control the ejaculatory reflex. In order to improve the awareness, the tone and the endurance of the pelvic floor muscles, patients were treated with the rehabilitation of pelvic floor (RPF consisting mainly in biofeedback, pelvic exercises and in some cases also in electro-stimulation (ES. The training was carried out for a period of about 2-6 months with an average of 2-5 visits per cycle. Results: 54% of patients who completed the training were cured of premature ejaculation and learned over time to be able to postpone the ejaculation reflex. In a subgroup of 26 patients was also measured the IELT which on the average increased from < 2 minutes to >10 minutes. The best results occurred mainly in patients aged less than 35 where the cure rate was 65%. There were no side effects. Conclusions: In this study, approximately half of patients with premature ejaculation were cured after applying the above treatment.This therapy, necessitates a fairly long period of time (2-6 months and a great commitment on the part of the patient, nevertheless it can be a valid and effective treatment for patients with premature ejaculation. This treatment makes the patient independent in that he is not bound to specific times for taking medication. Furthermore there are no

  3. Germline APC mutations in hepatoblastoma.

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    Yang, Adeline; Sisson, Rebecca; Gupta, Anita; Tiao, Greg; Geller, James I

    2018-04-01

    Conflicting reports on the frequency of germline adenomatous polyposis coli (APC) gene mutations in patients with hepatoblastoma (HB) have called into question the clinical value of APC mutation testing on apparently sporadic HB. An Institutional Review Board approved retrospective review of clinical data collected from patients with HB who received APC testing at our institution was conducted. All HB patients seen at Cincinnati Children's Hospital Medical Center were eligible for testing. Potential genotype/phenotype correlations were assessed. As of July 2015, 29 patients with HB had received constitutional APC testing. Four (14%) were found to have APC pathogenic truncations of the APC protein and in addition two (7%) had APC missense variants of unknown clinical significance. Two patients (7%) had family histories indicative of familial adenomatous polyposis (FAP). Response to chemotherapy tracked differently in APC pathogenic cases, with a slower imaging response despite an equivalent or slightly faster α-fetoprotein (AFP) response. The prevalence of pathogenic APC variants in apparently sporadic HB may be higher than previously detected. Differences in time to imaging response, despite similar AFP response, may impact surgical planning. All patients with HB warrant germline APC mutation testing for underlying FAP. © 2017 Wiley Periodicals, Inc.

  4. Importance of Close Follow-Up in the Fetus with Premature Atrial Contractions Accompanied by Atrial Septal Aneurysm: A Case Report

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    Yilmaz Yozgat

    2013-01-01

    Full Text Available Rhythms that derive from parts of atria other than the sinus node are called premature atrial contractions (PACs. Vast majority of fetal PACs are idiopathic. Fetal PACs usually have a good prognosis and disappear spontaneously during pregnancy or after delivery. Development of fetal tachycardia or fetal bradycardia is rarely reported during follow-up of fetuses diagnosed with PACs. To the best of our knowledge, coexistence of tachycardia and bradycardia leading to hemodynamic impairment has not yet been reported. We present a fetus diagnosed with PACs and atrial septal aneurysm (ASA on the 23rd week of gestation proceeding to fetal bradycardia and fetal tachycardia and consequently hemodynamic impairment. We suggest closer follow-up of fetuses with PACs accompanied by ASA.

  5. Rca1 inhibits APC-Cdh1(Fzr) and is required to prevent cyclin degradation in G2.

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    Grosskortenhaus, Ruth; Sprenger, Frank

    2002-01-01

    We demonstrate that Rca1 is an essential inhibitor of the anaphase-promoting complex/cyclosome (APC) in Drosophila. APC activity is restricted to mitotic stages and G1 by its activators Cdc20-Fizzy (Cdc20(Fzy)) and Cdh1-Fizzy-related (Cdh1(Fzr)), respectively. In rca1 mutants, cyclins are degraded prematurely in G2 by APC-Cdh1(Fzr)-dependent proteolysis, and cells fail to execute mitosis. Overexpression of Cdh1(Fzr) mimics the rca1 phenotype, and coexpression of Rca1 blocks this Cdh1(Fzr) function. We show that Rca1 and Cdh1(Fzr) are in a complex that also includes the APC component Cdc27. Previous studies have shown that phosphorylation of Cdh1 prevents its interaction with the APC. Our data reveal a different mode of APC regulation by Rca1 at the G2 stage, when low Cdk activity is unable to inhibit Cdh1(Fzr) interaction.

  6. HRV changes before and after radiofrequency ablation in patients with different origin of right ventricular outflow tract ventricular premature contraction

    Directory of Open Access Journals (Sweden)

    Yi-Ming Ma

    2017-04-01

    Full Text Available Objective: To observe the HRV changes before and after the radiofrequency current catheter ablationventricular premature beats originated from different site of right ventricular outflow tract. Methods: A total of 102 patients with frequent RVOT-VPC admitted to our hospital were accepted radiofrequency current catheter ablation (RF. According to the origin of RVOT-VPC, it was divided into 2 groups, one is from ventricular septum, and the other one is from free wall, and in each group, male and female are observed separately. Results: (1 HRV before RF ablation: 1 rMSSD in the female patients with RVOT-VPC from free wall was significantly lower than those from septum; 2 frequency domain index (W, LF were higher than normal range, and in male patients, LF/HF1. (2 HRV after RF ablation: 1 Significant changes were found in female patients with RVOT-VPC from septum, rMSSD, PNN50, HF and LF decreased; 2 In female patients with RVOT-VPC from free wall, rMSSD decreased; 3 In male patients, there were no significant HRV changes found before and after RF ablation. (3 Heart rate changes: 1 In female patients with RVOT-VPC from septum, heart rate decreased significantly [(76.47±9.47 bpm vs (69.29±14.59 bpm]. 2 No significant changes were found in male patients. Conclusion: In patients with RVOT-PVC sympathetic and vagus excitability increased, and after catheter ablation, in female patients with RVOT-PVC originated from septum, the HRV index relating to sympathetic and vagus excitability significantly decreased.

  7. Immunopurification of adenomatous polyposis coli (APC) proteins

    Science.gov (United States)

    2013-01-01

    Background The adenomatous polyposis coli (APC) tumour suppressor gene encodes a 2843 residue (310 kDa) protein. APC is a multifunctional protein involved in the regulation of β-catenin/Wnt signalling, cytoskeletal dynamics and cell adhesion. APC mutations occur in most colorectal cancers and typically result in truncation of the C-terminal half of the protein. Results In order to investigate the biophysical properties of APC, we have generated a set of monoclonal antibodies which enable purification of recombinant forms of APC. Here we describe the characterisation of these anti-APC monoclonal antibodies (APC-NT) that specifically recognise endogenous APC both in solution and in fixed cells. Full-length APC(1–2843) and cancer-associated, truncated APC proteins, APC(1–1638) and APC(1–1311) were produced in Sf9 insect cells. Conclusions Recombinant APC proteins were purified using a two-step affinity approach using our APC-NT antibodies. The purification of APC proteins provides the basis for detailed structure/function analyses of full-length, cancer-truncated and endogenous forms of the protein. PMID:24156781

  8. Electrocardiogram PR Interval Is a Surrogate Marker to Predict New Occurrence of Atrial Fibrillation in Patients with Frequent Premature Atrial Contractions.

    Science.gov (United States)

    Chun, Kwang Jin; Hwang, Jin Kyung; Choi, So Ra; Park, Seung-Jung; On, Young Keun; Kim, June Soo; Park, Kyoung-Min

    2016-04-01

    The clinical significance of prolonged PR interval has not been evaluated in patients with frequent premature atrial contractions (PACs). We investigated whether prolonged PR interval could predict new occurrence of atrial fibrillation (AF) in patients with frequent PACs. We retrospectively analyzed 684 patients with frequent PACs (> 100 PACs/day) who performed repeated 24-hour Holter monitoring. Prolonged PR interval was defined as longer than 200 msec. Among 684 patients, 626 patients had normal PR intervals (group A) and 58 patients had prolonged PR intervals (group B). After a mean follow-up of 59.3 months, 14 patients (24.1%) in group B developed AF compared to 50 patients (8.0%) in group A (P PR interval (hazard ratio [HR], 1.950; 95% CI, 1.029-3.698; P = 0.041), age (HR, 1.033; 95% CI, 1.006-1.060; P = 0.015), and left atrial (LA) dimension (HR, 1.061; 95% CI, 1.012-1.112; P = 0.015) were associated with AF occurrence. Prolonged PR interval, advanced age, and enlarged LA dimension are independent risk factors of AF occurrence in patients with frequent PACs.

  9. Analysis of Morphological Characteristics and Origins of Idiopathic Premature Ventricular Contractions Under a 12-Lead Electrocardiogram in Children with Structurally Normal Hearts.

    Science.gov (United States)

    Jiang, Jianbin; He, Yuee; Qiu, Huixian; Zhang, Yuanhai; Chu, Maoping; Li, Yuechun; Chen, Qi

    2017-10-21

    Up to 40% of healthy children have premature ventricular complexes or contractions (PVCs) detected with 24-hour Holter monitoring. We aimed to investigate the morphological characteristics and origins of idiopathic PVCs under a 12-lead electrocardiogram in children with structurally normal hearts. All asymptomatic monomorphic PVC patients with structurally normal hearts under 18 years of age were included in this retrospective study. Characteristics of PVCs in lead V 1 under a 12-lead electrocardiogram were classified as left bundle branch block (PVC-LBBB) or right bundle branch block (PVC-RBBB). According to limb leads, PVC-LBBB or PVC-RBBB was divided into: PVCs-LBBB type I; PVCs-LBBB type II; PVCs-RBBB type I; PVCs-RBBB type II; and PVCs-RBBB type III. Out of 178 PVC patients, 94 cases of PVCs-LBBB (PVCs-LBBB type I = 60; PVCs-LBBB type II = 34) and 84 cases of PVCs-RBBB (PVCs-RBBB type I = 3; PVCs-RBBB type II = 55; PVCs-RBBB type III = 26) were identified. The frequency of PVCs-LBBB type I increased with age and the frequency of PVCs-RBBB type II and III decreased with age. Among the children monitor tested, from 1 years old to 18 years old, PVCs originating from the left or right ventricular outflow tract gradually increased with age, while PVCs originating from the branch sources decreased with age.

  10. Germline Missense Changes in the APC Gene and Their Relationship to Disease.

    Science.gov (United States)

    Scott, Rodney J; Crooks, Renee; Rose, Lindy; Attia, John; Thakkinstian, Ammarin; Thomas, Lesley; Spigelman, Allan D; Meldrum, Cliff J

    2004-05-15

    Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of the disease known as attenuated FAP. Virtually all mutations that have been described in the APC gene result in the formation of a premature stop codon and very little is known about missense mutations apart from a common Ashkenazi Jewish mutation (1307 K) and a British E1317Q missense change. The incidence of missense mutations in the APC gene has been underreported since the APC gene lends itself to analysis using an artificial transcription and translation assay known as the Protein Truncation Test (PTT) or the In Vitro Synthetic Protein assay (IVSP).In this report we have used denaturing high performance liquid chromatography to analyse the entire coding sequence of the APC gene to determine if a cohort of patients adhering to the diagnostic criteria of FAP to assess the frequency of missense mutations in the APC gene. Altogether 112 patients were studied and 22 missense mutations were identified. From the total of 22 missense changes, 13 were silent changes and the remaining 9 resulted in amino acid substitutions. One or more of these changes were identified multiple times in 62.5% of the population under study.The results reveal that missense mutations in the APC gene appear not to radically alter protein function but may be associated with more subtle processing of RNA transcripts which in turn could result in the expression of differentially spliced forms of the APC gene which may interfere with the functional activity of the APC protein.

  11. Germline Missense Changes in the APC Gene and Their Relationship to Disease

    Directory of Open Access Journals (Sweden)

    Scott Rodney J

    2004-05-01

    Full Text Available Abstract Familial adenomatous polyposis (FAP is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of the disease known as attenuated FAP. Virtually all mutations that have been described in the APC gene result in the formation of a premature stop codon and very little is known about missense mutations apart from a common Ashkenazi Jewish mutation (1307 K and a British E1317Q missense change. The incidence of missense mutations in the APC gene has been underreported since the APC gene lends itself to analysis using an artificial transcription and translation assay known as the Protein Truncation Test (PTT or the In Vitro Synthetic Protein assay (IVSP. In this report we have used denaturing high performance liquid chromatography to analyse the entire coding sequence of the APC gene to determine if a cohort of patients adhering to the diagnostic criteria of FAP to assess the frequency of missense mutations in the APC gene. Altogether 112 patients were studied and 22 missense mutations were identified. From the total of 22 missense changes, 13 were silent changes and the remaining 9 resulted in amino acid substitutions. One or more of these changes were identified multiple times in 62.5% of the population under study. The results reveal that missense mutations in the APC gene appear not to radically alter protein function but may be associated with more subtle processing of RNA transcripts which in turn could result in the expression of differentially spliced forms of the APC gene which may interfere with the functional activity of the APC protein.

  12. Premature menopause.

    Science.gov (United States)

    Okeke, Tc; Anyaehie, Ub; Ezenyeaku, Cc

    2013-01-01

    Premature menopause affects 1% of women under the age of 40 years. The women are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. There is need to use simplified protocols and improved techniques in oocyte donation to achieve pregnancy and mother a baby in those women at risk. Review of the pertinent literature on premature menopause, selected references, internet services using the PubMed and Medline databases were included in this review. In the past, pregnancy in women with premature menopause was rare but with recent advancement in oocyte donation, women with premature menopause now have hoped to mother a child. Hormone replacement therapy is beneficial to adverse consequences of premature menopause. Women with premature menopause are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. Public enlightenment and education is important tool to save those at risk.

  13. Fatigue as Presenting Symptom and a High Burden of Premature Ventricular Contractions Are Independently Associated With Increased Ventricular Wall Stress in Patients With Normal Left Ventricular Function.

    Science.gov (United States)

    van Huls van Taxis, Carine F B; Piers, Sebastiaan R D; de Riva Silva, Marta; Dekkers, Olaf M; Pijnappels, Daniël A; Schalij, Martin J; Wijnmaalen, Adrianus P; Zeppenfeld, Katja

    2015-12-01

    High idiopathic premature ventricular contractions (PVC) burden has been associated with PVC-induced cardiomyopathy. Patients may be symptomatic before left ventricular (LV) dysfunction develops. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and circumferential end-systolic wall stress (cESS) on echocardiography are markers for increased ventricular wall stress. This study aimed to evaluate the relation between presenting symptoms, PVC burden, and increased ventricular wall stress in patients with frequent PVCs and preserved LV function. Eighty-three patients (41 men; 49±15 years) with idiopathic PVCs and normal LV function referred for PVC ablation were included. Type of symptoms (palpitations, fatigue, and [near-]syncope), PVC burden on 24-hour Holter, NT-proBNP levels, and cESS on echocardiography were assessed before and 3 months after ablation. Sustained successful ablation was defined as ≥80% PVC burden reduction during follow-up. Patients were symptomatic for 24 months (Q1-Q3, 16-60); 73% reported palpitations, 47% fatigue, and 30% (near-)syncope. Baseline PVC burden was 23±13%, median NT-proBNP 92 pg/mL (Q1-Q3 50-156), and cESS 143±35 kdyne/cm(2). Fatigue was associated with higher baseline NT-proBNP and cESS (PFatigue was independently associated with a significantly larger reduction in NT-proBNP. In patients with nonsuccessful ablation, NT-proBNP and cESS remained unchanged. In patients with frequent PVCs and preserved LV function, fatigue was associated with higher baseline NT-proBNP and cESS, and with a significantly larger reduction in NT-proBNP after sustained successful ablation. These findings support a link between fatigue and PVC-induced increased ventricular wall stress, despite preserved LV function. © 2015 American Heart Association, Inc.

  14. Molecular dissection of the APC/C inhibitor Rca1 shows a novel F-box-dependent function

    OpenAIRE

    Zielke, Norman; Querings, Silvia; Grosskortenhaus, Ruth; Reis, Tânia; Sprenger, Frank

    2006-01-01

    Rca1 (regulator of Cyclin A)/Emi (early mitotic inhibitor) proteins are essential inhibitors of the anaphase-promoting complex/cyclosome (APC/C). In Drosophila, Rca1 is required during G2 to prevent premature cyclin degradation by the Fizzy-related (Fzr)-dependent APC/C activity. Here, we present a structure and function analysis of Rca1 showing that a carboxy-terminal fragment is sufficient for APC/C inhibition. Rca1/Emi proteins contain a conserved F-box and interact with components of the ...

  15. The interrelationship between APC/C and Plk1 activities in centriole disengagement

    Directory of Open Access Journals (Sweden)

    Toshiyuki Hatano

    2012-09-01

    Mother–daughter centriole disengagement, the necessary first step in centriole duplication, involves Plk1 activity in early mitosis and separase activity after APC/C activity mediates securin degradation. Plk1 activity is thought to be essential and sufficient for centriole disengagement with separase activity playing a supporting but non-essential role. In separase null cells, however, centriole disengagement is substantially delayed. The ability of APC/C activity alone to mediate centriole disengagement has not been directly tested. We investigate the interrelationship between Plk1 and APC/C activities in disengaging centrioles in S or G2 HeLa and RPE1 cells, cell types that do not reduplicate centrioles when arrested in S phase. Knockdown of the interphase APC/C inhibitor Emi1 leads to centriole disengagement and reduplication of the mother centrioles, though this is slow. Strong inhibition of Plk1 activity, if any, during S does not block centriole disengagement and mother centriole reduplication in Emi1 depleted cells. Centriole disengagement depends on APC/C–Cdh1 activity, not APC/C–Cdc20 activity. Also, Plk1 and APC/C–Cdh1 activities can independently promote centriole disengagement in G2 arrested cells. Thus, Plk1 and APC/C–Cdh1 activities are independent but slow pathways for centriole disengagement. By having two slow mechanisms for disengagement working together, the cell ensures that centrioles will not prematurely separate in late G2 or early mitosis, thereby risking multipolar spindle assembly, but rather disengage in a timely fashion only late in mitosis.

  16. Premature infant

    Science.gov (United States)

    ... matter Infection or neonatal sepsis Low blood sugar (hypoglycemia) Neonatal respiratory distress syndrome, extra air in the tissue ... Outlook (Prognosis) Prematurity used to be a major cause of infant deaths. Improved medical and nursing techniques ...

  17. Different Phenotypic Consequences of Simultaneous Versus Stepwise Apc Loss

    OpenAIRE

    Fischer, Jared M; Miller, Ashleigh J; Shibata, Darryl; Liskay, R Michael

    2011-01-01

    APC is considered a gatekeeper for colorectal cancer (CRC). Cells with heterozygous APC mutations have altered expression profiles suggesting that the first APC hit may help set the stage for subsequent transformation. Therefore, we measured transformation efficiency following what we have designated as “simultaneous” versus “stepwise” Apc loss. We combined a conditional Apc allele (ApcCKO ) with a Cre reporter gene and an out-of-frame Cre allele (Pms2cre ) that stochastically becomes functio...

  18. Premature Ejaculation

    Science.gov (United States)

    ... include the following: Anxiety about performance Guilty feelings Depression Stress Relationship problems Men who have a low amount of a special ... on your favorite sports team. Psychological assistance Anxiety, depression ... may help men who have premature ejaculation. Some antidepressants seem to ...

  19. Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry

    DEFF Research Database (Denmark)

    Hein, Jamin B; Nilsson, Jakob

    2016-01-01

    Proper cell-cycle progression requires tight temporal control of the Anaphase Promoting Complex/Cyclosome (APC/C), a large ubiquitin ligase that is activated by one of two co-activators, Cdh1 or Cdc20. APC/C and Cdc20 are already present during interphase but APC/C-Cdc20 regulation during...... this window of the cell cycle, if any, is unknown. Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity. Preventing Cdc20 phosphorylation results in pre-mature activation of the APC/C-Cdc20 and several substrates, including cyclin B1 and A2......, are destabilized which lengthens G2 and slows mitotic entry. Expressing non-degradable cyclin A2 but not cyclin B1 restores mitotic entry in these cells. We have thus uncovered a novel positive feedback loop centred on cyclin A2-Cdk2 inhibition of interphase APC/C-Cdc20 to allow further cyclin A2 accumulation...

  20. APC implementation in Chandra Asri - ethylene plant

    Science.gov (United States)

    Sidiq, Mochamad; Mustofa, Ali

    2017-05-01

    Nowadays, the modern process plants are continuously improved for maximizing production, Optimization of the energy and raw material and reducing the risk. Due to many disturbances appearance between the process units, hence, the failure of one unit might have a bad effect on the overall productivity. Ethylene Plant have significant opportunities for using Advanced Process Control (APC) technologies to improve operation stability, push closer to quality or equipment limit, and improve the capability of process units to handle disturbances. APC implementation had considered a best answer for solving multivariable control problem. PT. Chandra Asri Petrochemical, Tbk (CAP) operates a large naphtha cracker complex at Cilegon, Indonesia. To optimize the plant operation and to enhance the benefit, Chandra Asri has been decided to implement Advance Process Control (APC) for ethylene plant. The APC implementation technology scopes at CAP are as follows: 1. Hot Section : Furnaces, Quench Tower 2. Cold Section : Demethanizer, Deethanizer, Acetylene Converter, Ethylene Fractionator, Depropanizer, Propylene Fractionator, Debutanizer

  1. Data sharing system for lithography APC

    Science.gov (United States)

    Kawamura, Eiichi; Teranishi, Yoshiharu; Shimabara, Masanori

    2007-03-01

    We have developed a simple and cost-effective data sharing system between fabs for lithography advanced process control (APC). Lithography APC requires process flow, inter-layer information, history information, mask information and so on. So, inter-APC data sharing system has become necessary when lots are to be processed in multiple fabs (usually two fabs). The development cost and maintenance cost also have to be taken into account. The system handles minimum information necessary to make trend prediction for the lots. Three types of data have to be shared for precise trend prediction. First one is device information of the lots, e.g., process flow of the device and inter-layer information. Second one is mask information from mask suppliers, e.g., pattern characteristics and pattern widths. Last one is history data of the lots. Device information is electronic file and easy to handle. The electronic file is common between APCs and uploaded into the database. As for mask information sharing, mask information described in common format is obtained via Wide Area Network (WAN) from mask-vender will be stored in the mask-information data server. This information is periodically transferred to one specific lithography-APC server and compiled into the database. This lithography-APC server periodically delivers the mask-information to every other lithography-APC server. Process-history data sharing system mainly consists of function of delivering process-history data. In shipping production lots to another fab, the product-related process-history data is delivered by the lithography-APC server from the shipping site. We have confirmed the function and effectiveness of data sharing systems.

  2. Premature delivery

    Directory of Open Access Journals (Sweden)

    Bernardita Donoso Bernales

    2012-09-01

    Full Text Available Preterm delivery is the single most important cause of perinatal morbidity and mortality. In Chile, preterm births have increased in the past decade, although neonatal morbidity and mortality attributable to it shows a downward trend, thanks to improvements in neonatal care of premature babies, rather than the success of obstetric preventive and therapeutic strategies. This article describes clinical entities, disease processes and conditions that constitute predisposing factors of preterm birth, as well as an outline for the prevention and clinical management of women at risk of preterm birth.

  3. Mechanism of APC/CCDC20 activation by mitotic phosphorylation.

    Science.gov (United States)

    Qiao, Renping; Weissmann, Florian; Yamaguchi, Masaya; Brown, Nicholas G; VanderLinden, Ryan; Imre, Richard; Jarvis, Marc A; Brunner, Michael R; Davidson, Iain F; Litos, Gabriele; Haselbach, David; Mechtler, Karl; Stark, Holger; Schulman, Brenda A; Peters, Jan-Michael

    2016-05-10

    Chromosome segregation and mitotic exit are initiated by the 1.2-MDa ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) and its coactivator CDC20 (cell division cycle 20). To avoid chromosome missegregation, APC/C(CDC20) activation is tightly controlled. CDC20 only associates with APC/C in mitosis when APC/C has become phosphorylated and is further inhibited by a mitotic checkpoint complex until all chromosomes are bioriented on the spindle. APC/C contains 14 different types of subunits, most of which are phosphorylated in mitosis on multiple sites. However, it is unknown which of these phospho-sites enable APC/C(CDC20) activation and by which mechanism. Here we have identified 68 evolutionarily conserved mitotic phospho-sites on human APC/C bound to CDC20 and have used the biGBac technique to generate 47 APC/C mutants in which either all 68 sites or subsets of them were replaced by nonphosphorylatable or phospho-mimicking residues. The characterization of these complexes in substrate ubiquitination and degradation assays indicates that phosphorylation of an N-terminal loop region in APC1 is sufficient for binding and activation of APC/C by CDC20. Deletion of the N-terminal APC1 loop enables APC/C(CDC20) activation in the absence of mitotic phosphorylation or phospho-mimicking mutations. These results indicate that binding of CDC20 to APC/C is normally prevented by an autoinhibitory loop in APC1 and that its mitotic phosphorylation relieves this inhibition. The predicted location of the N-terminal APC1 loop implies that this loop controls interactions between the N-terminal domain of CDC20 and APC1 and APC8. These results reveal how APC/C phosphorylation enables CDC20 to bind and activate the APC/C in mitosis.

  4. Premature aging

    International Nuclear Information System (INIS)

    Sassaki, Hideo

    1992-01-01

    The hypothesis that radiation may accelerate aging phenomenon has been studied extensively, using the population of A-bomb survivors. In this paper, non-specific radiation-induced premature aging is discussed with a review of the literature. Cardiac lipofuscin, papillary fibrosis, aortic extensibility, hexamine/collagen ratio in the skin and aorta, testicular changes, giant hepatic cell nucleus, and neurofibril changes have so far been studied pathologically in the context of A-bomb radiation. Only testicular sclerosis has been found to correlate with distance from the hypocenter. Suggestive correlation was found to exist between the hexamine/collagen ratio in the skin and aorta and A-bomb radiation. Grip strength and hearing ability were decreased in the group of 100 rad and the group of 50-99 rad, respectively. The other physiological data did not definitely correlate with A-bomb radiation. Laboratory data, including erythrocyte sedimentation rate, α and β globulin levels, phytohemagglutinin reaction, T cell counts, erythrocyte glycophorin-A, the incidence of cerebral stroke, ischemic heart disease, and cataract were age-dependent and correlated with A-bomb radiation. These findings indicated that the occurrence of arteriosclerosis-related diseases, changes in immunological competence, and some pathological and physiological findings altered with advancing age, suggesting the correlation with A-bomb radiation. In general, it cannot be concluded that there is a positive correlation between A-bomb radiation and the premature aging. (N.K.) 51 refs

  5. Sumoylation promotes optimal APC/C Activation and Timely Anaphase.

    Science.gov (United States)

    Lee, Christine C; Li, Bing; Yu, Hongtao; Matunis, Michael J

    2018-03-08

    The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin E3 ligase that functions as the gatekeeper to mitotic exit. APC/C activity is controlled by an interplay of multiple pathways during mitosis, including the spindle assembly checkpoint (SAC), that are not yet fully understood. Here, we show that sumoylation of the APC4 subunit of the APC/C peaks during mitosis and is critical for timely APC/C activation and anaphase onset. We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core. Our findings provide evidence of an important regulatory role for SUMO modification and binding in affecting APC/C activation and mitotic exit. © 2018, Lee et al.

  6. Idiopathic premature ventricular contractions and ventricular tachycardias originating from the vicinity of tricuspid annulus: Results of radiofrequency catheter ablation in thirty-five patients

    Directory of Open Access Journals (Sweden)

    Yue-Chun Li

    2012-07-01

    Full Text Available Abstract Background In recent years, catheter ablation has increasingly been used for ablation of idiopathic premature ventricular complexes (PVCs or ventricular tachycardias (IVTs. However, the mapping and catheter ablation of the arrhythmias originating from the vicinity of tricuspid annulus (TA may not be fully understood. This study aimed to investigate electrophysiologic characteristics and effects of radiofrequency catheter ablation (RFCA for patients with symptomatic PVCs and IVTs originating from the vicinity of TA. Methods Characteristics of body surface electrocardiogram (ECG and electrophysiologic recordings were analyzed in 35 patients with symptomatic PVCs/ IVTs originating from the vicinity of TA. RFCA was performed using pace mapping and activation mapping. Results Among the 35 patients with PVCs/IVTs arising from the vicinity of TA, complete elimination of PVCs/IVTs could be achieved by RFCA in 32 patients (success rate 91.43% during a median follow-up period of 21 months. PVCs/IVTs originating from the vicinity of TA had distinctive ECG characteristics that were useful for identifying the precise origin. An rS pattern was recorded in lead V1 in 93.1% of patients with PVCs/IVTs from the free wall of TA, vs 16.7% of patients with PVCs/IVTs from the septal TA, whereas a QS pattern in lead V1 occurred in 83.3% of patients with PVCs/IVTs from the septal TA vs 6.9% of patients with PVCs from the free wall of the TA. The precordial R wave transition occurred by lead V3 or earlier in all patients with PVCs/IVTs originating from the septal portion of the TA, as compared to transition beyond V3 in all patients with PVCs/IVTs from the free wall of the TA. Conclusions RFCA is an effective curative therapy for symptomatic PVCs/IVTs originating from the vicinity of TA. There are specific characteristics in ECG and the ablation site could be located by ECG analysis.

  7. Your Premature Baby

    Science.gov (United States)

    ... volunteer leader Partner Spotlight Become a partner World Prematurity Day What's happening in your area Find out ... 3 weeks after a premature birth. Retinopathy of prematurity (ROP) . This is an abnormal growth of blood ...

  8. Early or Premature Menopause

    Science.gov (United States)

    ... email updates Enter email Submit Early or premature menopause Menopause that happens before age 40 is called ... What is the difference between early and premature menopause? Early or premature menopause happens when ovaries stop ...

  9. APC functions at the centrosome to stimulate microtubule growth.

    Science.gov (United States)

    Lui, Christina; Ashton, Cahora; Sharma, Manisha; Brocardo, Mariana G; Henderson, Beric R

    2016-01-01

    The adenomatous polyposis coli (APC) tumor suppressor is multi-functional. APC is known to localize at the centrosome, and in mitotic cells contributes to formation of the mitotic spindle. To test whether APC contributes to nascent microtubule (MT) growth at interphase centrosomes, we employed MT regrowth assays in U2OS cells to measure MT assembly before and after nocodazole treatment and release. We showed that siRNA knockdown of full-length APC delayed both initial MT aster formation and MT elongation/regrowth. In contrast, APC-mutant SW480 cancer cells displayed a defect in MT regrowth that was unaffected by APC knockdown, but which was rescued by reconstitution of full-length APC. Our findings identify APC as a positive regulator of centrosome MT initial assembly and suggest that this process is disrupted by cancer mutations. We confirmed that full-length APC associates with the MT-nucleation factor γ-tubulin, and found that the APC cancer-truncated form (1-1309) also bound to γ-tubulin through APC amino acids 1-453. While binding to γ-tubulin may help target APC to the site of MT nucleation complexes, additional C-terminal sequences of APC are required to stimulate and stabilize MT growth. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Premature ejaculation

    Directory of Open Access Journals (Sweden)

    Chris G McMahon

    2007-01-01

    Full Text Available Premature ejaculation (PE is a common male sexual disorder. Recent normative data suggests that men with an intravaginal ejaculatory latency time (IELT of less than 1 minute have "definite" PE, while men with IELTs between 1 and 1.5 minutes have "probable" PE. Although there is insufficient empirical evidence to identify the etiology of PE, there is limited correlational evidence to suggest that men with PE have high levels of sexual anxiety and inherited altered sensitivity of central 5-HT (5-hydroxytryptamine, serotonin receptors. Pharmacological modulation of the ejaculatory threshold using off-label daily or on-demand selective serotonin re-uptake inhibitors is well tolerated and offers patients a high likelihood of achieving improved ejaculatory control within a few days of initiating treatment, consequential improvements in sexual desire and other sexual domains. Investigational drugs such as the ejaculo-selective serotonin transport inhibitor, dapoxetine represent a major development in sexual medicine. These drugs offer patients the convenience of on-demand dosing, significant improvements in IELT, ejaculatory control and sexual satisfaction with minimal adverse effects.

  11. Premature ejaculation.

    Science.gov (United States)

    McMahon, Chris G

    2007-04-01

    Premature ejaculation (PE) is a common male sexual disorder. Recent normative data suggests that men with an intravaginal ejaculatory latency time (IELT) of less than 1 minute have "definite" PE, while men with IELTs between 1 and 1.5 minutes have "probable" PE. Although there is insufficient empirical evidence to identify the etiology of PE, there is limited correlational evidence to suggest that men with PE have high levels of sexual anxiety and inherited altered sensitivity of central 5-HT (5-hydroxytryptamine, serotonin) receptors. Pharmacological modulation of the ejaculatory threshold using off-label daily or on-demand selective serotonin re-uptake inhibitors is well tolerated and offers patients a high likelihood of achieving improved ejaculatory control within a few days of initiating treatment, consequential improvements in sexual desire and other sexual domains. Investigational drugs such as the ejaculo-selective serotonin transport inhibitor, dapoxetine represent a major development in sexual medicine. These drugs offer patients the convenience of on-demand dosing, significant improvements in IELT, ejaculatory control and sexual satisfaction with minimal adverse effects.

  12. Analysis of APC allelic imbalance/loss of heterozygosity and APC protein expression in cutaneous squamous cell carcinomas.

    LENUS (Irish Health Repository)

    Gray, Sarah E

    2012-02-01

    BACKGROUND: The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC). AIM: To determine the role played by APC gene in the genesis of cutaneous SCC. MATERIALS AND METHODS: Allelic imbalance\\/loss of heterozygosity (AI\\/LOH) was examined in twenty-two histologically confirmed cutaneous squamous cell carcinomas (SCC) using microsatellite markers, proximal to the APC gene. Immunohistochemical analysis of APC protein expression was also examined in the cutaneous SCC. RESULTS: AI\\/LOH was detected in 60% of the SCC samples using D5S346 marker (proximal to the APC gene). Ninty-five percent of the SCC samples showed positive reduced APC expression, however the localization of the APC protein was abnormal. CONCLUSION: The abnormal expression of APC suggests that APC gene may play a role in cutaneous SCC development.

  13. Cancer stemness in Apc- vs. Apc/KRAS-driven intestinal tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Mehrnaz Ghazvini

    Full Text Available Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in Apc/KRAS tumours, they appear to be very rare (<10(-6 in the Apc-mutant adenomas. In contrast, the Lin(-CD24(hiCD29(+ subpopulation of adenocarcinoma cells appear to be enriched in CSCs with increased levels of active β-catenin. Expression profiling analysis of the CSC-enriched subpopulation confirmed their enhanced Wnt activity and revealed additional differential expression of other signalling pathways, growth factor binding proteins, and extracellular matrix components. As expected, genes characteristic of the Paneth cell lineage (e.g. defensins are co-expressed together with stem cell genes (e.g. Lgr5 within the CSC-enriched subpopulation. This is of interest as it may indicate a cancer stem cell niche role for tumor-derived Paneth-like cells, similar to their role in supporting Lgr5(+ stem cells in the normal intestinal crypt. Overall, our results indicate that oncogenic KRAS activation in Apc-driven tumours results in the expansion of the CSCs compartment by increasing ®-catenin intracellular stabilization.

  14. Molecular mechanism of APC/C activation by mitotic phosphorylation.

    Science.gov (United States)

    Zhang, Suyang; Chang, Leifu; Alfieri, Claudio; Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-05-12

    In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our

  15. Article Processing Charges and OpenAPC

    CERN Multimedia

    CERN. Geneva

    2017-01-01

    The publication landscape is about to change. While being largely operated by subscription based journals in the past, recent political decisions force the publishing industry towards OpenAccess. Especially, the publication of the Finch report in 2012 put APC based Gold OpenAccess models almost everywhere on the agenda. These models also require quite some adoptions for library work flows to handle payments, bills and centralized funds for publication fees. Sometimes handled in specialized systems (e.g. first setups in Jülich) pretty early on discussions started to handle APCs in local repositories which would also hold the OpenAccess content resulting from these fees, e.g. the University of Regenburg uses ePrints for this purpose. Backed up by the OpenData movmement, libraries also saw opportunity to exchange data about fees payed. Thus, OpenAPC.de was born in 2014 on github to facilitate this exchange and aggregate large amounts of data for evaluation and comparison. Using the repository to hold payment d...

  16. Apnea of prematurity

    Science.gov (United States)

    ... medlineplus.gov/ency/article/007227.htm Apnea of prematurity To use the sharing features on this page, ... down or stops from any cause. Apnea of prematurity refers to short episodes of stopped breathing in ...

  17. Molecular dissection of the APC/C inhibitor Rca1 shows a novel F-box-dependent function.

    Science.gov (United States)

    Zielke, Norman; Querings, Silvia; Grosskortenhaus, Ruth; Reis, Tânia; Sprenger, Frank

    2006-12-01

    Rca1 (regulator of Cyclin A)/Emi (early mitotic inhibitor) proteins are essential inhibitors of the anaphase-promoting complex/cyclosome (APC/C). In Drosophila, Rca1 is required during G2 to prevent premature cyclin degradation by the Fizzy-related (Fzr)-dependent APC/C activity. Here, we present a structure and function analysis of Rca1 showing that a carboxy-terminal fragment is sufficient for APC/C inhibition. Rca1/Emi proteins contain a conserved F-box and interact with components of the Skp-Cullin-F-box (SCF) complex. So far, no function has been ascribed to this domain. We find that the F-box of Rca1 is dispensable for APC/C-Fzr inhibition during G2. Nevertheless, we show that Rca1 has an additional function at the G1-S transition, which requires the F-box. Overexpression of Rca1 accelerates the G1-S transition in an F-box-dependent manner. Conversely, S-phase entry is delayed in cells in which endogenous Rca1 is replaced by a transgene lacking the F-box. We propose that Rca1 acts as an F-box protein in an as yet uncharacterized SCF complex, which promotes S-phase entry.

  18. Pharmacotherapy for premature ejaculation

    NARCIS (Netherlands)

    Waldinger, Marcel D

    2014-01-01

    PURPOSE OF REVIEW: As there are various drugs and different treatment strategies to delay ejaculation, a review of the current drug treatments for premature ejaculation is relevant for daily clinical practice. RECENT FINDINGS: There are four premature ejaculation subtypes: lifelong premature

  19. Retinopathy of Prematurity

    Science.gov (United States)

    Steinweg, Sue Byrd; Griffin, Harold C.; Griffin, Linda W.; Gingras, Happy

    2005-01-01

    The eyes of premature infants are especially vulnerable to injury after birth. A serious complication is called retinopathy of prematurity (ROP), which is abnormal growth of the blood vessels in an infant's eye. Retinopathy of prematurity develops when abnormal blood vessels grow and spread throughout the retina, which is the nerve tissue at the…

  20. Early diagnostic potential of APC hypermethylation in esophageal cancer

    Directory of Open Access Journals (Sweden)

    Wang B

    2018-02-01

    Full Text Available Bujiang Wang,1 Haojun Song,1 Haizhong Jiang,1 Yangbo Fu,1 Xiaoyun Ding,1 Chongchang Zhou2 1Department of Gastroenterology, Laboratory of Digestive Diseases, Ningbo First Hospital, Ningbo, 2Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China Background: The hypermethylation of APC gene is observed in various cancers, including esophageal cancer (EC. However, the association between APC methylation and the initiation and progression of EC is poorly understood. Purpose and methods: The current study systematically reviewed studies on abnormal methylation of APC in EC and quantitatively synthesized 18 studies by meta-analysis involving 1008 ECs, 570 Barrett’s esophagus (BE, and 782 controls. Results: Our results showed higher methylation of APC in EC (OR = 23.33, P < 0.001 and BE (OR = 9.34, P < 0.001 than in normal controls. Whereas APC methylation in EC was similar to that in BE (P = 0.052, it was not associated with tumor stage (P = 0.204. Additionally, APC methylation was not significantly associated with overall survival (OS and relapse-free survival (RFS in patients with EC. The performance of APC methylation for the detection of EC and BE achieved areas under the receiver operating characteristic curves of 0.94 and 0.88, respectively. Conclusion: Our results imply that APC methylation detection is a potential diagnostic biomarker for EC and BE. Keywords: esophageal cancer, Barrett’s esophagus, methylation, APC

  1. Analysis of APC mutation in human ameloblastoma and clinical significance.

    Science.gov (United States)

    Li, Ning; Liu, Bing; Sui, Chengguang; Jiang, Youhong

    2016-01-01

    As a highly conserved signaling pathway, Wnt/β-catenin signal transduction pathway plays an important role in many processes. Either in the occurrence or development of tumor, activation of this pathway takes an important place. APC inhibits Wnt/β-catenin pathway to regulate cell proliferation and differentiation. This study aimed to investigate the function of cancer suppressor gene. PCR amplification and sequencing method was used to analyze APC mutations of human clinical specimens. The pathological specimens were collected for PCR and clear electrophoretic bands were obtained after electrophoresis. The gene sequence obtained after purification and sequencing analysis was compared with the known APC gene sequence (NM_000038.5). Base mutations at APC 1543 (T → C), APC-4564 (G → A), APC-5353 (T → G), APC-5550 (T → A) and APC-5969 (G → A) locus existed in 22 (27.5 %), 12 (15 %), 5 (6.25 %), 13 (16.25 %) and 12 patients (15 %), respectively. Gene mutations existed in ameloblastoma, and the mutation loci were 1543 locus (T → C), 4564 locus (G → A), 5353 locus (T → G), 5550 locus (T → A) and 5969 locus (G → A) 15 %, respectively. APC mutation plays a certain role in monitoring the tumor malignant degree as it may indicate the transition process of ameloblastoma malignant phenotype.

  2. Analysis of APC allelic imbalance/loss of heterozygosity and APC protein expression in cutaneous squamous cell carcinomas.

    LENUS (Irish Health Repository)

    Gray, Sarah E

    2011-05-01

    The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC).

  3. Structure of an APC3-APC16 complex: Insights into assembly of the Anaphase Promoting Complex/Cyclosome

    OpenAIRE

    Yamaguchi, Masaya; Yu, Shanshan; Qiao, Renping; Weissmann, Florian; Miller, Darcie J.; VanderLinden, Ryan; Brown, Nicholas G.; Frye, Jeremiah J.; Peters, Jan-Michael; Schulman, Brenda A.

    2014-01-01

    The Anaphase Promoting Complex/Cyclosome (APC/C) is a massive E3 ligase that controls mitosis by catalyzing ubiquitination of key cell cycle regulatory proteins. The APC/C assembly contains two subcomplexes: the “Platform” centers around a cullin-RING-like E3 ligase catalytic core; the “Arc Lamp” is a hub that mediates transient association with regulators and ubiquitination substrates. The Arc Lamp contains the small subunits APC16, CDC26, and APC13, and tetratricopeptide repeat (TPR) protei...

  4. WD40 domain of Apc1 is critical for the coactivator-induced allosteric transition that stimulates APC/C catalytic activity.

    Science.gov (United States)

    Li, Qiuhong; Chang, Leifu; Aibara, Shintaro; Yang, Jing; Zhang, Ziguo; Barford, David

    2016-09-20

    The anaphase-promoting complex/cyclosome (APC/C) is a large multimeric cullin-RING E3 ubiquitin ligase that orchestrates cell-cycle progression by targeting cell-cycle regulatory proteins for destruction via the ubiquitin proteasome system. The APC/C assembly comprises two scaffolding subcomplexes: the platform and the TPR lobe that together coordinate the juxtaposition of the catalytic and substrate-recognition modules. The platform comprises APC/C subunits Apc1, Apc4, Apc5, and Apc15. Although the role of Apc1 as an APC/C scaffolding subunit has been characterized, its specific functions in contributing toward APC/C catalytic activity are not fully understood. Here, we report the crystal structure of the N-terminal domain of human Apc1 (Apc1N) determined at 2.2-Å resolution and provide an atomic-resolution description of the architecture of its WD40 (WD40 repeat) domain (Apc1(WD40)). To understand how Apc1(WD40) contributes to APC/C activity, a mutant form of the APC/C with Apc1(WD40) deleted was generated and evaluated biochemically and structurally. We found that the deletion of Apc1(WD40) abolished the UbcH10-dependent ubiquitination of APC/C substrates without impairing the Ube2S-dependent ubiquitin chain elongation activity. A cryo-EM structure of an APC/C-Cdh1 complex with Apc1(WD40) deleted showed that the mutant APC/C is locked into an inactive conformation in which the UbcH10-binding site of the catalytic module is inaccessible. Additionally, an EM density for Apc15 is not visible. Our data show that Apc1(WD40) is required to mediate the coactivator-induced conformational change of the APC/C that is responsible for stimulating APC/C catalytic activity by promoting UbcH10 binding. In contrast, Ube2S activity toward APC/C substrates is not dependent on the initiation-competent conformation of the APC/C.

  5. APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis

    NARCIS (Netherlands)

    Giardiello, F. M.; Petersen, G. M.; Piantadosi, S.; Gruber, S. B.; Traboulsi, E. I.; Offerhaus, G. J.; Muro, K.; Krush, A. J.; Booker, S. V.; Luce, M. C.; Laken, S. J.; Kinzler, K. W.; Vogelstein, B.; Hamilton, S. R.

    1997-01-01

    Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. Mutations of the APC gene were compared with the occurrence of seven

  6. Myc deletion rescues Apc deficiency in the small intestine

    NARCIS (Netherlands)

    Sansom, O.J.; Meniel, V.S.; Muncan, V.; Phesse, T.J.; Wilkins, J.A.; Reed, K.R.; Vass, J.K.; Athineos, D.; Clevers, J.C.; Clarke, A.R.

    2007-01-01

    The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic

  7. Dietary factors and Truncating APC Mutations in Sporadic Colorectal Adenomas

    NARCIS (Netherlands)

    Diergaarde, B.; Tiemersma, E.W.; Braam, H.; Muijen, van G.N.P.; Nagengast, F.M.; Kok, F.J.; Kampman, E.

    2005-01-01

    Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control

  8. Dietary factors and truncating APC mutations in sporadic colorectal adenomas.

    NARCIS (Netherlands)

    Diergaarde, B.; Tiemersma, E.W.; Braam, H.; Muijen, G.N.P. van; Nagengast, F.M.; Kok, F.J.; Kampman, E.

    2005-01-01

    Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control

  9. Measuring APC/C-Dependent Ubiquitylation In Vitro.

    Science.gov (United States)

    Jarvis, Marc A; Brown, Nicholas G; Watson, Edmond R; VanderLinden, Ryan; Schulman, Brenda A; Peters, Jan-Michael

    2016-01-01

    The anaphase-promoting complex/cyclosome (APC/C) is a 1.2 MDa ubiquitin ligase complex with important functions in both proliferating and post-mitotic differentiated cells. In proliferating cells, APC/C controls cell cycle progression by targeting inhibitors of chromosome segregation and mitotic exit for degradation by the 26S proteasome. To understand how APC/C recruits and ubiquitylates its substrate proteins and how these processes are controlled, it is essential to analyze APC/C activity in vitro. In the past, such experiments have been limited by the fact that large quantities of purified APC/C were difficult to obtain and that mutated versions of the APC/C could not be easily generated. In this chapter we review recent advances in generating and purifying recombinant forms of the human APC/C and its co-activators, using methods that are scalable and compatible with mutagenesis. We also describe a method that allows the quantitative analysis of APC/C activity using fluorescently labeled substrate proteins.

  10. Early diagnostic potential of APC hypermethylation in esophageal cancer.

    Science.gov (United States)

    Wang, Bujiang; Song, Haojun; Jiang, Haizhong; Fu, Yangbo; Ding, Xiaoyun; Zhou, Chongchang

    2018-01-01

    The hypermethylation of APC gene is observed in various cancers, including esophageal cancer (EC). However, the association between APC methylation and the initiation and progression of EC is poorly understood. The current study systematically reviewed studies on abnormal methylation of APC in EC and quantitatively synthesized 18 studies by meta-analysis involving 1008 ECs, 570 Barrett's esophagus (BE), and 782 controls. Our results showed higher methylation of APC in EC (OR = 23.33, P APC methylation in EC was similar to that in BE ( P = 0.052), it was not associated with tumor stage ( P = 0.204). Additionally, APC methylation was not significantly associated with overall survival (OS) and relapse-free survival (RFS) in patients with EC. The performance of APC methylation for the detection of EC and BE achieved areas under the receiver operating characteristic curves of 0.94 and 0.88, respectively. Our results imply that APC methylation detection is a potential diagnostic biomarker for EC and BE.

  11. More than two decades of Apc modeling in rodents

    Science.gov (United States)

    Zeineldin, Maged; Neufeld, Kristi L.

    2013-01-01

    Mutation of tumor suppressor gene Adenomatous polyposis coli (APC) is an initiating step in most colon cancers. This review summarizes Apc models in mice and rats, with particular concentration on those most recently developed, phenotypic variation among different models, and genotype/ phenotype correlations. PMID:23333833

  12. APC selectively mediates response to chemotherapeutic agents in breast cancer

    International Nuclear Information System (INIS)

    VanKlompenberg, Monica K.; Bedalov, Claire O.; Soto, Katia Fernandez; Prosperi, Jenifer R.

    2015-01-01

    The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the Apc Min/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance independent of Wnt/β-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown. We have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment. Cells obtained from MMTV-PyMT;Apc Min/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;Apc Min/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin

  13. APC-II: an electron beam propagation code

    International Nuclear Information System (INIS)

    Iwan, D.C.; Freeman, J.R.

    1984-05-01

    The computer code APC-II simulates the propagation of a relativistic electron beam through air. APC-II is an updated version of the APC envelope model code. It incorporates an improved conductivity model which significantly extends the range of stable calculations. A number of test cases show that these new models are capable of reproducing the simulations of the original APC code. As the result of a major restructuring and reprogramming of the code, APC-II is now friendly to both the occasional user and the experienced user who wishes to make modifications. Most of the code is in standard ANS-II Fortran 77 so that it can be easily transported between machines

  14. Panta rhei: The APC/C at steady state

    Science.gov (United States)

    2013-01-01

    The anaphase-promoting complex or cyclosome (APC/C) is a conserved, multisubunit E3 ubiquitin (Ub) ligase that is active both in dividing and in postmitotic cells. Its contributions to life are especially well studied in the domain of cell division, in which the APC/C lies at the epicenter of a regulatory network that controls the directionality and timing of cell cycle events. Biochemical and structural work is shedding light on the overall organization of APC/C subunits and on the mechanism of substrate recognition and Ub chain initiation and extension as well as on the molecular mechanisms of a checkpoint that seizes control of APC/C activity during mitosis. Here, we review how these recent advancements are modifying our understanding of the APC/C. PMID:23589490

  15. Quantitative framework for ordered degradation of APC/C substrates.

    Science.gov (United States)

    Lu, Dan; Girard, Juliet R; Li, Weihan; Mizrak, Arda; Morgan, David O

    2015-11-16

    During cell-cycle progression, substrates of a single master regulatory enzyme can be modified in a specific order. Here, we used experimental and computational approaches to dissect the quantitative mechanisms underlying the ordered degradation of the substrates of the ubiquitin ligase APC/C(Cdc20), a key regulator of chromosome segregation in mitosis. We show experimentally that the rate of catalysis varies with different substrates of APC/C(Cdc20). Using a computational model based on multi-step ubiquitination, we then show how changes in the interaction between a single substrate and APC/C(Cdc20) can alter the timing of degradation onset relative to APC/C(Cdc20) activation, while ensuring a fast degradation rate. Degradation timing and dynamics depend on substrate affinity for the enzyme as well as the catalytic rate at which the substrate is modified. When two substrates share the same pool of APC/C(Cdc20), their relative enzyme affinities and rates of catalysis influence the partitioning of APC/C(Cdc20) among substrates, resulting in substrate competition. Depending on how APC/C(Cdc20) is partitioned among its substrates, competition can have minor or major effects on the degradation of certain substrates. We show experimentally that increased expression of the early APC/C(Cdc20) substrate Clb5 does not delay the degradation of the later substrate securin, arguing against a role for competition with Clb5 in establishing securin degradation timing. The degradation timing of APC/C(Cdc20) substrates depends on the multi-step nature of ubiquitination, differences in substrate-APC/C(Cdc20) interactions, and competition among substrates. Our studies provide a conceptual framework for understanding how ordered modification can be established among substrates of the same regulatory enzyme, and facilitate our understanding of how precise temporal control is achieved by a small number of master regulators to ensure a successful cell division cycle.

  16. Interaction between APC and Fen1 during breast carcinogenesis.

    Science.gov (United States)

    Narayan, Satya; Jaiswal, Aruna S; Law, Brian K; Kamal, Mohammad A; Sharma, Arun K; Hromas, Robert A

    2016-05-01

    Aberrant DNA base excision repair (BER) contributes to malignant transformation. However, inter-individual variations in DNA repair capacity plays a key role in modifying breast cancer risk. We review here emerging evidence that two proteins involved in BER - adenomatous polyposis coli (APC) and flap endonuclease 1 (Fen1) - promote the development of breast cancer through novel mechanisms. APC and Fen1 expression and interaction is increased in breast tumors versus normal cells, APC interacts with and blocks Fen1 activity in Pol-β-directed LP-BER, and abrogation of LP-BER is linked with cigarette smoke condensate-induced transformation of normal breast epithelial cells. Carcinogens increase expression of APC and Fen1 in spontaneously immortalized human breast epithelial cells, human colon cancer cells, and mouse embryonic fibroblasts. Since APC and Fen1 are tumor suppressors, an increase in their levels could protect against carcinogenesis; however, this does not seem to be the case. Elevated Fen1 levels in breast and lung cancer cells may reflect the enhanced proliferation of cancer cells or increased DNA damage in cancer cells compared to normal cells. Inactivation of the tumor suppressor functions of APC and Fen1 is due to their interaction, which may act as a susceptibility factor for breast cancer. The increased interaction of APC and Fen1 may occur due to polypmorphic and/or mutational variation in these genes. Screening of APC and Fen1 polymorphic and/or mutational variations and APC/Fen1 interaction may permit assessment of individual DNA repair capability and the risk for breast cancer development. Such individuals might lower their breast cancer risk by reducing exposure to carcinogens. Stratifying individuals according to susceptibility would greatly assist epidemiologic studies of the impact of suspected environmental carcinogens. Additionally, a mechanistic understanding of the interaction of APC and Fen1 may provide the basis for developing new and

  17. Family Perspectives on Prematurity

    Science.gov (United States)

    Zero to Three (J), 2003

    2003-01-01

    In this article, seven families describe their experiences giving birth to and raising a premature baby. Their perspectives vary, one from another, and shift over time, depending on each family's circumstances and the baby's developmental course. Experiences discussed include premature labor, medical interventions and the NICU, bringing the baby…

  18. Premature ovarian failure

    OpenAIRE

    Pacheco, José

    2011-01-01

    Premature ovarian failure is characterized by secondary amenorrhea affecting a woman before the age of 40, leading to hypoestrogenism, infertility, and consequences of premature menopause, such as osteoporosis, cardiovascular disease, neurovegetative alterations, and others. Follicular exhaustion is due to either follicles shortage or oocytes accelerated destruction. Main causes are genetic, autoimmune and iatrogenic. Among genetic causes Xq and Xp deletions, translocations, numeric aberratio...

  19. State of the APC/C: Organization, function, and structure

    Science.gov (United States)

    McLean, Janel R.; Chaix, Denis; Ohi, Melanie D.; Gould, Kathleen L.

    2016-01-01

    The ubiquitin-proteasome protein degradation system is involved in many essential cellular processes including cell cycle regulation, cell differentiation, and the unfolded protein response.The anaphase-promoting complex/cyclosome (APC/C), an evolutionary conserved E3 ubiquitin ligase, was discovered 15 years ago because of its pivotal role in cyclin degradation and mitotic progression. Since then, we have learned that the APC/C is a very large, complex E3 ligase composed of 13 subunits, yielding a molecular machine of approximately 1 MDa. The intricate regulation of the APC/C is mediated by the Cdc20 family of activators, pseudosubstrate inhibitors, protein kinases and phosphatases and the spindle assembly checkpoint. The large size, complexity, and dynamic nature of the APC/C represent significant obstacles toward high-resolution structural techniques; however, over the last decade, there have been a number of lower resolution APC/C structures determined using single particle electron microscopy. These structures, when combined with data generated from numerous genetic and biochemical studies, have begun to shed light on how APC/C activity is regulated. Here, we discuss the most recent developments in the APC/C field concerning structure, substrate recognition, and catalysis. PMID:21261459

  20. 42 CFR 419.31 - Ambulatory payment classification (APC) system and payment weights.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 3 2010-10-01 2010-10-01 false Ambulatory payment classification (APC) system and... Outpatient Services § 419.31 Ambulatory payment classification (APC) system and payment weights. (a) APC... of resource use into APC groups. Except as specified in paragraph (a)(2) of this section, items and...

  1. APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.

    Science.gov (United States)

    Saito-Diaz, Kenyi; Benchabane, Hassina; Tiwari, Ajit; Tian, Ai; Li, Bin; Thompson, Joshua J; Hyde, Annastasia S; Sawyer, Leah M; Jodoin, Jeanne N; Santos, Eduardo; Lee, Laura A; Coffey, Robert J; Beauchamp, R Daniel; Williams, Christopher S; Kenworthy, Anne K; Robbins, David J; Ahmed, Yashi; Lee, Ethan

    2018-03-12

    Adenomatous polyposis coli (APC) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting β-catenin degradation downstream of Wnt receptors. Unexpectedly, we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased β-catenin levels. In contrast, APC2 loss does not promote receptor activation. We show that APC exists in a complex with clathrin and that Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis. Finally, we demonstrate conservation of this mechanism in Drosophila intestinal stem cells. We propose a model in which APC and APC2 function to promote β-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. OpenAPC. Open-Access-Publikationskosten als Open Data

    OpenAIRE

    Tullney, Marco

    2015-01-01

    Präsentationsfolien zum Vortrag „OpenAPC. Open-Access-Publikationskosten als Open Data“ in der Session „Ausgestaltung eines wissenschaftsadäquaten APC-Marktes: Grundsätze, Finanzierungsansätze und Management“ der Open-Access-Tage 2015 in Zürich (https://www.open-access.net/community/open-access-tage/open-access-tage-2015-zuerich/programm/#c1974)

  3. Premature rupture of membranes

    Science.gov (United States)

    ... gov/ency/patientinstructions/000512.htm Premature rupture of membranes To use the sharing features on this page, ... water that surrounds your baby in the womb. Membranes or layers of tissue hold in this fluid. ...

  4. Retinopathy of Prematurity (ROP)

    Science.gov (United States)

    ... developing severe ROP, especially those in underserved or remote areas. Currently in the U.S., evaluation of premature ... files require the free Adobe® Reader® software for viewing. This website is maintained by the NEI Office ...

  5. Differential RNA-seq analysis comparing APC-defective and APC-restored SW480 colorectal cancer cells.

    Science.gov (United States)

    King, Lauren E; Love, Christopher G; Sieber, Oliver M; Faux, Maree C; Burgess, Antony W

    2016-03-01

    The adenomatous polyposis coli (APC) tumour suppressor gene is mutated in about 80% of colorectal cancers (CRC) Brannon et al. (2014) [1]. APC is a large multifunctional protein that regulates many biological functions including Wnt signalling (through the regulation of beta-catenin stability) Reya and Clevers (2005) [2], cell migration Kroboth et al. (2007), Sansom et al. (2004) [3], [4], mitosis Kaplan et al. (2001) [5], cell adhesion Faux et al. (2004), Carothers et al. (2001) [6], [7] and differentiation Sansom et al. (2004) [4]. Although the role of APC in CRC is often described as the deregulation of Wnt signalling, its other biological functions suggest that there are other factors at play that contribute to the onset of adenomas and the progression of CRC upon the truncation of APC. To identify genes and pathways that are dysregulated as a consequence of loss of function of APC, we compared the gene expression profiles of the APC mutated human CRC cell line SW480 following reintroduction of wild-type APC (SW480 + APC) or empty control vector (SW480 + vector control) Faux et al. (2004) . Here we describe the RNA-seq data derived for three biological replicates of parental SW480, SW480 + vector control and SW480 + APC cells, and present the bioinformatics pipeline used to test for differential gene expression and pathway enrichment analysis. A total of 1735 genes showed significant differential expression when APC was restored and were enriched for genes associated with cell polarity, Wnt signalling and the epithelial to mesenchymal transition. There was additional enrichment for genes involved in cell-cell adhesion, cell-matrix junctions, angiogenesis, axon morphogenesis and cell movement. The raw and analysed RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE76307. This dataset is useful for further investigations of the impact of APC mutation on the properties of colorectal cancer cells.

  6. Symbolic transfer entropy-based premature signal analysis

    International Nuclear Information System (INIS)

    Wang Jun; Yu Zheng-Feng

    2012-01-01

    In this paper, we use symbolic transfer entropy to study the coupling strength between premature signals. Numerical experiments show that three types of signal couplings are in the same direction. Among them, normal signal coupling is the strongest, followed by that of premature ventricular contractions, and that of atrial premature beats is the weakest. The T test shows that the entropies of the three signals are distinct. Symbolic transfer entropy requires less data, can distinguish the three types of signals and has very good computational efficiency. (interdisciplinary physics and related areas of science and technology)

  7. APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability.

    Science.gov (United States)

    Sansregret, Laurent; Patterson, James O; Dewhurst, Sally; López-García, Carlos; Koch, André; McGranahan, Nicholas; Chao, William Chong Hang; Barry, David J; Rowan, Andrew; Instrell, Rachael; Horswell, Stuart; Way, Michael; Howell, Michael; Singleton, Martin R; Medema, René H; Nurse, Paul; Petronczki, Mark; Swanton, Charles

    2017-02-01

    Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution. We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. Cancer Discov; 7(2); 218-33. ©2017 AACR.See related commentary by Burkard and Weaver, p. 134This article is highlighted in the In This Issue feature, p. 115. ©2017 American Association for Cancer Research.

  8. Autoimmune premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Beata Komorowska

    2017-02-01

    Full Text Available Premature ovarian failure (POF, also termed as primary ovarian insufficiency (POI, is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system.

  9. Feeding premature neonate

    DEFF Research Database (Denmark)

    Dam, Mie S.; Juhl, Sandra M.; Sangild, Per T.

    2017-01-01

    Kinship, understood as biogenetic proximity, between a chosen animal model and a human patient counterpart, is considered essential to the process of ‘translating’ research from the experimental animal laboratory to the human clinic. In the Danish research centre, NEOMUNE, premature piglets are fed...... a novel milk diet (bovine colostrum) to model the effects of this new diet in premature infants. Our ethnographic fieldwork in an experimental pig laboratory and a neonatal intensive care unit (NICU) in 2013–2014 shows that regardless of biogenetics, daily practices of feeding, housing, and clinical care...... the researchers refer to as the ‘translatability’ of the results. In the NICU, parents of premature infants likewise imagine a kind of interspecies kinship when presented with the option to supplement mother's own milk with bovine colostrum for the first weeks after birth. However, in this setting the NICU...

  10. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Persani Luca

    2006-04-01

    Full Text Available Abstract Premature ovarian failure (POF is a primary ovarian defect characterized by absent menarche (primary amenorrhea or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea. It is a heterogeneous disorder affecting approximately 1% of women e.g. Turner syndrome represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation.

  11. High performance APCS conceptual design and evaluation scoping study

    International Nuclear Information System (INIS)

    Soelberg, N.; Liekhus, K.; Chambers, A.; Anderson, G.

    1998-02-01

    This Air Pollution Control System (APCS) Conceptual Design and Evaluation study was conducted to evaluate a high-performance (APC) system for minimizing air emissions from mixed waste thermal treatment systems. Seven variations of high-performance APCS designs were conceptualized using several design objectives. One of the system designs was selected for detailed process simulation using ASPEN PLUS to determine material and energy balances and evaluate performance. Installed system capital costs were also estimated. Sensitivity studies were conducted to evaluate the incremental cost and benefit of added carbon adsorber beds for mercury control, specific catalytic reduction for NO x control, and offgas retention tanks for holding the offgas until sample analysis is conducted to verify that the offgas meets emission limits. Results show that the high-performance dry-wet APCS can easily meet all expected emission limits except for possibly mercury. The capability to achieve high levels of mercury control (potentially necessary for thermally treating some DOE mixed streams) could not be validated using current performance data for mercury control technologies. The engineering approach and ASPEN PLUS modeling tool developed and used in this study identified APC equipment and system performance, size, cost, and other issues that are not yet resolved. These issues need to be addressed in feasibility studies and conceptual designs for new facilities or for determining how to modify existing facilities to meet expected emission limits. The ASPEN PLUS process simulation with current and refined input assumptions and calculations can be used to provide system performance information for decision-making, identifying best options, estimating costs, reducing the potential for emission violations, providing information needed for waste flow analysis, incorporating new APCS technologies in existing designs, or performing facility design and permitting activities

  12. Regulated degradation of the APC coactivator Cdc20

    Directory of Open Access Journals (Sweden)

    Robbins Jonathan A

    2010-09-01

    Full Text Available Abstract Background Cdc20 is a highly conserved activator of the anaphase-promoting complex (APC, promoting cell-cycle-regulated ubiquitination and proteolysis of a number of critical cell-cycle-regulatory targets including securin and mitotic cyclins. APC-Cdc20 activity is tightly regulated, and this regulation is likely important for accurate cell cycle control. One significant component of Cdc20 regulation is thought to be Cdc20 proteolysis. However, published literature suggests different mechanisms and requirements for Cdc20 proteolysis. The degree to which Cdc20 proteolysis is cell-cycle regulated, the dependence of Cdc20 proteolysis on Cdc20 destruction boxes (recognition sequences for APC-mediated ubiqutination, either by Cdc20 or by the related Cdh1 APC activator, and the need for APC itself for Cdc20 proteolysis all have been disputed to varying extents. In animals, Cdc20 proteolysis is thought to be mediated by Cdh1, contributing an intrinsic order of APC activation by Cdc20 and then by Cdh1. One report suggests a Cdh1 requirement for Cdc20 proteolysis in budding yeast; this idea has not been tested further. Results We characterized Cdc20 proteolysis using Cdc20 expressed from its endogenous locus; previous studies generally employed strongly overexpressed Cdc20, which can cause significant artifacts. We analyzed Cdc20 proteolysis with or without mutations in previously identified destruction box sequences, using varying methods of cell cycle synchronization, and in the presence or absence of Cdh1. Cdc20 instability is only partially dependent on destruction boxes. A much stronger dependence on Cdh1 for Cdc20 proteolysis was observed, but Cdh1-independent proteolysis was also clearly observed. Cdc20 proteolysis independent of both destruction boxes and Cdh1 was especially detectable around the G1/S transition; Cdh1-dependent proteolysis was most notable in late mitosis and G1. Conclusions Cdc20 proteolysis is under complex control

  13. Your Premature Baby: Low Birthweight

    Science.gov (United States)

    ... volunteer leader Partner Spotlight Become a partner World Prematurity Day What's happening in your area Find out ... to remove damaged parts of intestine. Retinopathy of prematurity (also called ROP) . ROP affects blood vessels in ...

  14. Health Issues of Premature Babies

    Science.gov (United States)

    ... they leave the hospital for home. Retinopathy of Prematurity (ROP) What It Is: ROP is an eye ... sometimes seen in preterm babies include anemia of prematurity (a low red blood cell count) and heart ...

  15. Epigenetic regulation of APC in the molecular pathogenesis of gallbladder cancer

    Directory of Open Access Journals (Sweden)

    Dinesh Singh Tekcham

    2016-01-01

    Interpretation & conclusions: The present findings indicate epigenetic silencing of APC in advanced GBC. The methylation pattern, followed by expression analysis of APC may be suggested for diagnostic, prognostic and therapeutic purposes in GBC in future.

  16. Myopia in premature babies with and without retinopathy of prematurity.

    OpenAIRE

    Nissenkorn, I; Yassur, Y; Mashkowski, D; Sherf, I; Ben-Sira, I

    1983-01-01

    One hundred and fifty-five premature infants weighing 600-2000 g were followed up during 1974-80 for the presence of retinopathy of prematurity (ROP) and for the existence of myopia. 50% of the premature infants who had ROP were myopic, while only 16% myopic premature infants were found among those who did not have ROP. There was a positive correlation between the degree of myopia and the severity of cicatricial ROP. No difference existed in the frequency and degree of myopia between prematur...

  17. Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer

    NARCIS (Netherlands)

    Dow, Lukas E; O'Rourke, Kevin P; Simon, Janelle; Tschaharganeh, Darjus F; van Es, Johan H; Clevers, Hans; Lowe, Scott W

    2015-01-01

    The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally

  18. Retinopathy of prematurity

    International Nuclear Information System (INIS)

    Benavides Vargas, Ana Maria

    2013-01-01

    Retinopathy of prematurity has been the leading cause of childhood blindness. Early and effective screening has helped to diagnose the visual target of an infant by the difference between growing up with a disability or not. A joint effort between ophthalmologists and neonatologists is proposed to control this disease, ensuring success. An appropriate, early, effective and timely treatment has been the laser and cryotherapy like good choices for the neonate to prevent disease progression. Evaluation of screening program, to determine the incidence, compare statistics variables have been measures as other medical pathologies should be encouraged as research topics. A decrease in the incidence of retinopathy of prematurity is expected, controlling the risk factors during the child's stay in intrahospital neonatal unit [es

  19. Prematurely terminated slug tests

    International Nuclear Information System (INIS)

    Karasaki, K.

    1990-07-01

    A solution of the well response to a prematurely terminated slug test (PTST) is presented. The advantages of a PTST over conventional slug tests are discussed. A systematized procedure of a PTST is proposed, where a slug test is terminated in the midpoint of the flow point, and the subsequent shut-in data is recorded and analyzed. This method requires a downhole shut-in device and a pressure transducer, which is no more than the conventional deep-well slug testing. As opposed to slug tests, which are ineffective when a skin is present, more accurate estimate of formation permeability can be made using a PTST. Premature termination also shortens the test duration considerably. Because in most cases no more information is gained by completing a slug test to the end, the author recommends that conventional slug tests be replaced by the premature termination technique. This study is part of an investigation of the feasibility of geologic isolation of nuclear wastes being carried out by the US Department of Energy and the National Cooperative for the Storage of Radioactive Waste of Switzerland

  20. The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior in C. elegans.

    Science.gov (United States)

    Wang, Julia; Jennings, Alexandra K; Kowalski, Jennifer R

    2016-01-01

    The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation in Caenorhabditis elegans by testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted. Animals with loss of function mutations in either of two alleles (g48 and ye143) of the gene encoding the APC subunit EMB-27 APC6 showed increased chemotaxis towards diacetyl and pyrazine, odorants sensed by AWA neurons, but exhibited normal chemotaxis to isoamyl alcohol, which is sensed by AWC neurons. The statistically significant increase in chemotaxis in the emb-27 APC6 mutants suggests that the APC inhibits AWA-mediated chemosensation in C. elegans. Increased chemotaxis to pyrazine was also seen with mutants lacking another essential APC subunit, MAT-2 APC1; however, mat-2 APC1 mutants exhibited wild type responses to diacetyl. The difference in responsiveness of these two APC subunit mutants may be due to differential strength of these hypomorphic alleles or may indicate the presence of functional sub-complexes of the APC at work in this process. These findings are the first evidence for APC-mediated regulation of chemosensation and lay the groundwork for further studies aimed at identifying the expression levels, function, and targets of the APC in specific sensory neurons. Because of the similarity between human and C. elegans nervous systems, the role of the APC in sensory neurons may also advance our understanding of human sensory function and disease.

  1. Fission Yeast Apc15 Stabilizes MCC-Cdc20-APC/C Complexes, Ensuring Efficient Cdc20 Ubiquitination and Checkpoint Arrest.

    Science.gov (United States)

    May, Karen M; Paldi, Flora; Hardwick, Kevin G

    2017-04-24

    During mitosis, cells must segregate the replicated copies of their genome to their daughter cells with extremely high fidelity. Segregation errors lead to an abnormal chromosome number (aneuploidy), which typically results in disease or cell death [1]. Chromosome segregation and anaphase onset are initiated through the action of the multi-subunit E3 ubiquitin ligase known as the anaphase-promoting complex or cyclosome (APC/C [2]). The APC/C is inhibited by the spindle checkpoint in the presence of kinetochore attachment defects [3, 4]. Here we demonstrate that two non-essential APC/C subunits (Apc14 and Apc15) regulate association of spindle checkpoint proteins, in the form of the mitotic checkpoint complex (MCC), with the APC/C. apc14Δ mutants display increased MCC association with the APC/C and are unable to silence the checkpoint efficiently. Conversely, apc15Δ mutants display reduced association between the MCC and APC/C, are defective in poly-ubiquitination of Cdc20, and are checkpoint defective. In vitro reconstitution studies have shown that human MCC-APC/C can contain two molecules of Cdc20 [5-7]. Using a yeast strain expressing two Cdc20 genes with different epitope tags, we show by co-immunoprecipitation that this is true in vivo. MCC binding to the second molecule of Cdc20 is mediated via the C-terminal KEN box in Mad3. Somewhat surprisingly, complexes containing both molecules of Cdc20 accumulate in apc15Δ cells, and the implications of this observation are discussed. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  2. Banking contracts

    OpenAIRE

    Durčáková, Klára

    2010-01-01

    Resumé - Bank Contracts Bank Contracts are an integral part of our everyday lives. Citizen and bussines entities used bank contracts very often. Despite this fact we can't find legal definition in the Czech law. Banking contracts understand contracts that are signed by banks in their business activities and obligations under these contracts arise. While the banking contracts have been widely used, in Czech law there is not too much literature and judgements abou this issue. Lack of legislatio...

  3. Effects of the APC materials on c-axis correlated pinning effects in a-axis oriented Y123/2D APC multilayer films

    International Nuclear Information System (INIS)

    Takamura, M.; Mukaida, M.; Horii, S.; Ichinose, A.; Kita, R.; Namba, M.; Awaji, S.; Watanabe, K.; Matsumoto, K.; Yoshida, Y.; Teranishi, R.; Yamada, K.; Mori, N.

    2009-01-01

    For a-axis oriented and c-axis in-plane aligned YBa 2 Cu 3 O 7-δ /artificial pinning center (Y123/APC) alternately-layered thin films, effects of the APC materials on the multilayer structures are discussed. Pr123, (Y 1-x Pr x )123 and Gd 2 CuO 4 (Gd214) were used as APCs. The multilayer structure was observed for Y123/Pr123 films and Y123/Gd214 films. However, some grains are also grown in the Y123/Gd214 film. For the Y123/Pr123 multilayer film, each Pr123 layer act as two-dimensional APCs (2D APCs) in the magnetic field angular dependences of the critical current density. The growth mechanism of the multilayer structure in the Y123/2D APC films is discussed by a transmission electron microscopy and an atomic force microscope. It is found that two conditions are needed to obtain the c-axis correlated pinning effects by 2D APC in the a-axis oriented and c-axis in-plane aligned Y123/APC multilayer films: the same structure as Y123; Y-free APC materials.

  4. Retinopathy of prematurity and neurodevelopmental disabilities in premature infants.

    Science.gov (United States)

    Beligere, Nagamani; Perumalswamy, Vijayalaksmi; Tandon, Manish; Mittal, Amit; Floora, Jayasheele; Vijayakumar, B; Miller, Marilyn T

    2015-10-01

    Prematurity is a major global health issue leading to high mortality and morbidity among the survivors. Neurodevelopmental disability (NDD) and retinopathy of prematurity (ROP) are the most common complications of prematurity. In fact, ROP is the second leading cause of childhood blindness in the world. Although there is much information regarding the occurrence of ROP and of NDD in premature infants, there have been few studies on ROP and its association with NDD. The objectives of this article are to review the current literature on the subject and to publish our own findings concerning the association between ROP and NDD in premature infants. The review suggests that although NDDs are related to degree of prematurity, NDD could also be the result of visual impairments resulting from ROP. Our own study shows a close association between NDD and zonal involvement of ROP: higher NDD if zone 1 is involved and less if zone 3 is involved. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Correlation between the methylation of APC gene promoter and colon cancer.

    Science.gov (United States)

    Li, Bing-Qiang; Liu, Peng-Peng; Zhang, Cai-Hua

    2017-08-01

    The present study was planned to explore the correlation between the methylation of APC (adenomatous polyposis coli) and colon carcinogenesis. Colon cancer tissues and tumor-adjacent normal tissues of 60 colon cancer patients (who received surgical operation in our hospital from January 2012 to December 2014) were collected. SW1116 cells in human colon cancer tissues were selected for culturing. 5-aza-2c-deoxycytidine (5-aza-dC) was utilized as an inhibitor of the methylation for APC gene. Methylation specific PCR (MSP) was utilized for detection of APC methylation in SW1116 cells. The MTT and Transwell assays were performed to detect the effect of the methylation of APC gene on the proliferation and invasive abilities of SW1116 cells. The correlation between the methylation of APC gene and pathological parameters of colon cancer patients was analyzed. MSP results revealed that 41 cases (68.33%) showed methylation of APC gene in colon cancer tissues. No methylation of APC gene was found in tumor-adjacent normal tissues. 5-aza-dC was able to inhibit the methylation of APC gene in SW1116 cells. APC gene methylation was correlated with tumor size, differentiation degree, lymph node metastasis and Dukes staging. In conclusion, the levels of the methylation of APC in colon cancer tissues and SW1116 cells are relatively high. The methylation of APC promoted the proliferation and invasion abilities of SW1116 cells. Furthermore, methylation is correlated with a variety of clinicopathological features of colon cancer patients.

  6. The APC tumor suppressor is required for epithelial cell polarization and three-dimensional morphogenesis

    Science.gov (United States)

    Lesko, Alyssa C.; Goss, Kathleen H.; Yang, Frank F.; Schwertner, Adam; Hulur, Imge; Onel, Kenan; Prosperi, Jenifer R.

    2015-01-01

    The Adenomatous Polyposis Coli (APC) tumor suppressor has been previously implicated in the control of apical-basal polarity; yet, the consequence of APC loss-of-function in epithelial polarization and morphogenesis has not been characterized. To test the hypothesis that APC is required for the establishment of normal epithelial polarity and morphogenesis programs, we generated APC-knockdown epithelial cell lines. APC depletion resulted in loss of polarity and multi-layering on permeable supports, and enlarged, filled spheroids with disrupted polarity in 3D culture. Importantly, these effects of APC knockdown were independent of Wnt/β-catenin signaling, but were rescued with either full-length or a carboxy (c)-terminal segment of APC. Moreover, we identified a gene expression signature associated with APC knockdown that points to several candidates known to regulate cell-cell and cell-matrix communication. Analysis of epithelial tissues from mice and humans carrying heterozygous APC mutations further support the importance of APC as a regulator of epithelial behavior and tissue architecture. These data also suggest that the initiation of epithelial-derived tumors as a result of APC mutation or gene silencing may be driven by loss of polarity and dysmorphogenesis. PMID:25578398

  7. A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC

    Science.gov (United States)

    Schell, Michael J.; Yang, Mingli; Teer, Jamie K.; Lo, Fang Yin; Madan, Anup; Coppola, Domenico; Monteiro, Alvaro N. A.; Nebozhyn, Michael V.; Yue, Binglin; Loboda, Andrey; Bien-Willner, Gabriel A.; Greenawalt, Danielle M.; Yeatman, Timothy J.

    2016-01-01

    Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinicopathologic staging for decades. There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies. Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens, which identified a subset of 17 genes that best classify CRC, with APC playing a central role in predicting overall survival. APC may assume 0, 1 or 2 truncating mutations, each with a striking differential impact on survival. Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours; however, two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined. Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC. PMID:27302369

  8. Inhibition of CDK7 bypasses spindle assembly checkpoint via premature cyclin B degradation during oocyte meiosis.

    Science.gov (United States)

    Wang, HaiYang; Jo, Yu-Jin; Sun, Tian-Yi; Namgoong, Suk; Cui, Xiang-Shun; Oh, Jeong Su; Kim, Nam-Hyung

    2016-12-01

    To ensure accurate chromosome segregation, the spindle assembly checkpoint (SAC) delays anaphase onset by preventing the premature activation of anaphase-promoting complex/cyclosome (APC/C) until all kinetochores are attached to the spindle. Although an escape from mitosis in the presence of unsatisfied SAC has been shown in several cancer cells, it has not been reported in oocyte meiosis. Here, we show that CDK7 activity is required to prevent a bypass of SAC during meiosis I in mouse oocytes. Inhibition of CDK7 using THZ1 accelerated the first meiosis, leading to chromosome misalignment, lag of chromosomes during chromosome segregation, and a high incidence of aneuploidy. Notably, this acceleration occurred in the presence of SAC proteins including Mad2 and Bub3 at the kinetochores. However, inhibition of APC/C-mediated cyclin B degradation blocked the THZ1-induced premature polar body extrusion. Moreover, chromosomal defects mediated by THZ1 were rescued when anaphase onset was delayed. Collectively, our results show that CDK7 activity is required to prevent premature anaphase onset by suppressing the bypass of SAC, thus ensuring chromosome alignment and proper segregation. These findings reveal new roles of CDK7 in the regulation of meiosis in mammalian oocytes. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Premature emphysema in AIDS

    International Nuclear Information System (INIS)

    Kuhlman, J.E.; Fishman, E.K.; Zerhouni, E.A.; Knowles, M.

    1988-01-01

    The CT scans of 55 patients with acquired immunodeficiency syndrome (AIDS) were reviewed for evidence of pulmonary emphysema. While the average age of patients in this series was 38 years, 25 of the 55 patients, or 45%, demonstrated CT evidence of emphysema. CT findings suggestive of emphysema included areas of low-attenuation, blebs and/or vascular disruption. The authors conclude there is an increased incidence of CT-detectable pulmonary emphysema that is premature for age in patients with AIDS. Destruction of pulmonary parenchyma may represent the response of the lung to repeated pulmonary infections or may be a direct result of the human immunodeficiency virus

  10. Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention

    Science.gov (United States)

    Liskay, R.Michael

    2014-01-01

    Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitates the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells and subsequently tracks the fates of Apc-deficient intestinal cells. Our results suggest that consistent with Apc being a ‘gatekeeper’, loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. In contrast, Apc loss occurring later in life has minimal consequences, with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell-specific Lgr5-CreER mouse, we generated different sized fields of Apc-deficient crypts via independent recombination events and found that field size correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient occult crypt fission. We found that sulindac treatment started early in life inhibits the morphologically occult spread of Apc-deficient crypts and thus reduces adenoma numbers. Taken together these results suggest that: (i) earlier Apc loss promotes increased crypt fission, (ii) a field of Apc-deficient crypts, which can form via occult crypt fission or independent neighboring events, is an important intermediate between loss of Apc and adenoma formation and (iii) normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention. PMID:23996931

  11. Timing of APC/C substrate degradation is determined by fzy/fzr specificity of destruction boxes

    OpenAIRE

    Zur, Amit; Brandeis, Michael

    2002-01-01

    The anaphase promoting complex/cyclosome (APC/C), activated by fzy and fzr, degrades cell cycle proteins that carry RXXL or KEN destruction boxes (d-boxes). APC/C substrates regulate sequential events and must be degraded in the correct order during mitosis and G1. We studied how d-boxes determine APC/Cfzy/APC/Cfzr specificity and degradation timing. Cyclin B1 has an RXXL box and is degraded by both APC/Cfzy and APC/Cfzr; fzy has a KEN box and is degraded by APC/Cfzr only. We characterized th...

  12. APC: A new code for Atmospheric Polarization Computations

    International Nuclear Information System (INIS)

    Korkin, Sergey V.; Lyapustin, Alexei I.; Rozanov, Vladimir V.

    2013-01-01

    A new polarized radiative transfer code Atmospheric Polarization Computations (APC) is described. The code is based on separation of the diffuse light field into anisotropic and smooth (regular) parts. The anisotropic part is computed analytically. The smooth regular part is computed numerically using the discrete ordinates method. Vertical stratification of the atmosphere, common types of bidirectional surface reflection and scattering by spherical particles or spheroids are included. A particular consideration is given to computation of the bidirectional polarization distribution function (BPDF) of the waved ocean surface. -- Highlights: •A new code, APC, has been developed. •The code was validated against well-known codes. •The BPDF for an arbitrary Mueller matrix is computed

  13. Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis

    Science.gov (United States)

    Wood, Patricia A.; Yang, Xiaoming; Taber, Andrew; Oh, Eun-Young; Ansell, Christine; Ayers, Stacy E.; Al-Assaad, Ziad; Carnevale, Kevin; Berger, Franklin G.; Peña, Maria Marjorette O.; Hrushesky, William J.M.

    2014-01-01

    Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2m/m) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and β-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on β-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone ApcMin/+ mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases β-catenin, cyclin D, and cell proliferation. Down-regulation of β-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2m/m mice develop colonic polyps and show an increase in small intestinal mucosa β-catenin and cyclin D protein levels compared with wild-type mice. ApcMin/+Per2m/m mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with ApcMin/+ mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of β-catenin and β-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control. PMID:19010825

  14. lemmingA encodes the Apc11 subunit of the APC/C in Drosophila melanogaster that forms a ternary complex with the E2-C type ubiquitin conjugating enzyme, Vihar and Morula/Apc2

    Directory of Open Access Journals (Sweden)

    Nagy Olga

    2012-03-01

    Full Text Available Abstract Background Ubiquitin-dependent protein degradation is a critical step in key cell cycle events, such as metaphase-anaphase transition and mitotic exit. The anaphase promoting complex/cyclosome (APC/C plays a pivotal role in these transitions by recognizing and marking regulatory proteins for proteasomal degradation. Its overall structure and function has been elucidated mostly in yeasts and mammalian cell lines. The APC/C is, however, a multisubunit assembly with at least 13 subunits and their function and interaction within the complex is still relatively uncharacterized, particularly in metazoan systems. Here, lemming (lmg mutants were used to study the APC/C subunit, Apc11, and its interaction partners in Drosophila melanogaster. Results The lmg gene was initially identified through a pharate adult lethal P element insertion mutation expressing developmental abnormalities and widespread apoptosis in larval imaginal discs and pupal abdominal histoblasts. Larval neuroblasts were observed to arrest mitosis in a metaphase-like state with highly condensed, scattered chromosomes and frequent polyploidy. These neuroblasts contain high levels of both cyclin A and cyclin B. The lmg gene was cloned by virtue of the lmg03424 P element insertion which is located in the 5' untranslated region. The lemming locus is transcribed to give a 2.0 kb mRNA that contains two ORFs, lmgA and lmgB. The lmgA ORF codes for a putative protein with more than 80% sequence homology to the APC11 subunit of the human APC/C. The 85 amino acid protein also contains a RING-finger motif characteristic of known APC11 subunits. The lmgA ORF alone was sufficient to rescue the lethal and mitotic phenotypes of the lmg138 null allele and to complement the temperature sensitive lethal phenotype of the APC11-myc9 budding yeast mutant. The LmgA protein interacts with Mr/Apc2, and they together form a binding site for Vihar, the E2-C type ubiquitin conjugating enzyme. Despite

  15. Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.

    Science.gov (United States)

    Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

    2016-05-24

    Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing.

  16. Clinical application of Assessment of Parenting Competencies (APC)

    DEFF Research Database (Denmark)

    Jacobsen, Stine Lindahl

    This paper is part of a symposium on music therapy with families with Kirsi Tuomi as Chair. It revolves around the clinical application of a new music therapy assessment model on parent-child interaction and parenting competencies. APC was developed for emotional neglected children and their pare......This paper is part of a symposium on music therapy with families with Kirsi Tuomi as Chair. It revolves around the clinical application of a new music therapy assessment model on parent-child interaction and parenting competencies. APC was developed for emotional neglected children......, child somatic hospitals, centers for refuges and other populations where it would be clinical relevant to assess the parent-child interaction. APC is an observational and improvisational based assessment model evaluating dyads of parent and child (child age range is 5-12). It produces information...... (numbers, graphs, and descriptions) of parent-child interaction and parenting competencies including nonverbal communication, level of attunement in the dyad, and level of emotional support from the parent. It is based on video analysis and a fixed assessment protocol. It was developed through a completed...

  17. Human immunodeficiencies related to APC/T cell interaction

    Directory of Open Access Journals (Sweden)

    Marinos eKallikourdis

    2015-08-01

    Full Text Available The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APC in the T cell area of secondary lymphoid organs and the formation of highly organized inter-cellular junctions referred to as the immune synapses. In vivo live-cell imaging of APC-T cell interactions combined to functional studies unveiled that T cell fate is dictated, in large part, by the stability of the initial contact. Immune cell interaction is equally important during delivery of T cell help to B cells and for the killing of target cells by cytotoxic T cells and NK cells. The critical role of contact dynamics and synapse stability on the immune response is well illustrated by human immune deficiencies in which disease pathogenesis is linked to altered adhesion or defective cross-talk between the synaptic partners. Here we will discuss in details the mechanisms of defective APC-T cell communications in Wiskott-Aldrich syndrome (WAS and in warts, hypogammaglobulinemia, infections, myelokathexis syndrome (WHIM. In addition, we will summarize the evidences pointing to a compromised conjugate formation in WIP deficiency, DOCK8 deficiency and X-linked lymphoproliferative syndrome.

  18. Molecular basis of APC/C regulation by the spindle assembly checkpoint

    Science.gov (United States)

    Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-01-01

    In the dividing eukaryotic cell the spindle assembly checkpoint (SAC) ensures each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), a multimeric assembly that inhibits the APC/C, delaying chromosome segregation. Here, using cryo-electron microscopy we determined the near-atomic resolution structure of an APC/C-MCC complex (APC/CMCC). We reveal how degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit (Cdc20APC/C) responsible for substrate interactions. BubR1 also obstructs binding of UbcH10 (APC/C’s initiating E2) to repress APC/C ubiquitination activity. Conformational variability of the complex allows for UbcH10 association, and we show from a structure of APC/CMCC in complex with UbcH10 how the Cdc20 subunit intrinsic to the MCC (Cdc20MCC) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced. PMID:27509861

  19. Epigenetic regulation of APC in the molecular pathogenesis of gallbladder cancer.

    Science.gov (United States)

    Tekcham, Dinesh Singh; Poojary, Satish S; Bhunia, Shushruta; Barbhuiya, Mustafa Ahmed; Gupta, Sanjeev; Shrivastav, Braj Raj; Tiwari, Pramod Kumar

    2016-05-01

    Loss of function of adenomatous polyposis coli (APC) has been reported in cancer. The two promoters of APC, 1A and 1B also have roles in cancer. But, the epigenetic role of APC promoters is not yet clear in gallbladder cancer (GBC) and gallstone diseases (GSD). We undertook this study to determine the epigenetic role of APC in GBC and GSD. Methylation-specific (MS)-PCR was used to analyze the methylation of APC gene. The expression of APC gene was studied by semi-quantitative PCR, real-time PCR and immunohistochemistry (IHC) in GBC, GSD and adjacent normal tissues. Of the two promoters, APC 1A promoter was found methylated in 96 per cent GBC ( P=0.0155) and 80 per cent GSD (P=0.015). Exon 1 was downregulated in grade II (P=0.002) and grade III (P=0.0001) of GBC, while exon 2 was normally expressed. Scoring analysis of IHC revealed 0 or negativity in 34.48 per cent (P=0.057) and 1+ in 24.14 per cent (P=0.005) GBC cases suggesting loss of APC expression. The present findings indicate epigenetic silencing of APC in advanced GBC. The methylation pattern, followed by expression analysis of APC may be suggested for diagnostic, prognostic and therapeutic purposes in GBC in future.

  20. APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review.

    Science.gov (United States)

    Liang, Tie-Jun; Wang, Hong-Xu; Zheng, Yan-Yan; Cao, Ying-Qing; Wu, Xiaoyu; Zhou, Xin; Dong, Shu-Xiao

    2017-07-11

    Adenomatous polyposis coli (APC) promoter hypermethylation has been frequently observed in colorectal cancer (CRC). The association between APC promoter methylation and clinicopathological significance in CRC is under investigation. We performed a meta-analysis to quantitatively evaluate the significance of APC methylation in CRC. The study included a total of 24 articles and 2025 CRC patients. The frequency of APC promoter hypermethylation was significantly higher in colorectal adenoma than in normal colorectal tissue, OR was 5.76, 95% CI, 2.45-13.56; pAPC promoter more frequently hypermethylated in CRC stage I compared to normal colorectal tissue, OR was 13.42, 95% CI, 3.66-49.20; pAPC promoter hypermethylation, pooled OR was 9.80, 95%CI, 6.07-15.81; pAPC methylation was not associated with grade, stage of CRC as well as tumor location, patients' gender, and smoking behavior. The results indicate that APC promoter hypermethylation is an early event in carcinogenesis of CRC, could be a valuable diagnostic marker for early-stage CRC. APC methylation is not significantly associated with overall survival in patients with CRC. APC is a potential drug target for development of personalized treatment.

  1. Application examples of APC-03-2 and APC-03-2A airborne particle counters under various contamination conditions

    International Nuclear Information System (INIS)

    Czitrovszky, A.; Jani, P.

    1997-01-01

    Several application examples of the airborne particle counters APC-03-2 and APC-03-2A for monitoring particle size distribution and concentration in air and other gases are described. The computer controlled fast data evaluation and storage provide efficient presentation of the measured data in a variety of table- and histogram-forms, presenting of alarm levels for each size range, observation of alarm history, etc. The device can be applied not only for clean room monitoring and laminar box testing, but also for measuring contamination in health care facilities in workshops using hazardous airborne compounds (e.g. in pharmacology), and in toxicology where the concentration of the contamination may be very high. (author)

  2. Premature ejaculation. 3. Therapy.

    Science.gov (United States)

    Piediferro, Guido; Colpi, Elisabetta M; Castiglioni, Fabrizio; Scroppo, Fabrizio I

    2004-12-01

    Serotonergic drugs (SSRIs) are the most commonly used, but they are characterized by relapse some time after medication interruption as well as by sexual side effects. The efficacy of phosphodiesterase-5 inhibitors seems excellent, but the risk of tachyphylaxis has been reported. The former (fluoxetine, paroxetine, sertraline, clomipramine) should be used in young patients with hyper-orgasmic forms, while the latter (sildenafil, tadalafil, vardenafil) should be used in hypo-orgasmic forms, in old age or when PE is associated with erectile dysfunction. Topical anesthetics provide satisfactory results in premature ejaculation due to hypersensitivity of the glans, and physiotherapy of the pelvic floor muscles proves successful in cases associated with pelvic floor dysfunction. Therapeutic associations and psycho-sexual therapy techniques may improve results, particularly in the long term.

  3. [Retinopathy of prematurity].

    Science.gov (United States)

    Promelle, V; Milazzo, S

    2017-05-01

    Retinopathy of prematurity is a retinal vasoproliferative disease affecting extremely preterm infants exposed to high concentrations of oxygen therapy. Infants born before 32 post-menstrual weeks or with a birth weight of less than 1500g should systematically have a dilated fundus examination. The time of screening and schedule for follow-up are guided by the various risk factors. This disease results from immaturity of the peripheral retinal vessels at the time of premature birth. The classification of ROP depends on the anteroposterior extent of involvement (from center to periphery: zone I, II and III), its extension in 30° sectors (clock hours) and its stage (stage 1 to 5). "Plus" disease is defined as dilation and tortuosity of the retinal blood vessels in the posterior pole of the eye and represents a major risk factor for rapid unfavorable progression. A majority of patients will spontaneously recover, but patients with a high risk of progression will require treatment to prevent retinal detachment and blindness. The indications for treatment are threshold disease and type 1 pre-threshold disease. The current treatment of choice is peripheral retinal ablation with transpupillary laser, but ab externo cryotherapy may be used instead. Intravitreal injection of vascular endothelial growth factor inhibitors may be an attractive therapeutic option and is currently under investigation. After laser treatment, unfavorable outcomes occur in only 9 to 14 % of eyes, but at the price of peripheral retinal destruction. For all patients, whether treated or not, a regular fundus examination should be insured until complete retinal vascularization has occurred. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Electrodialytically treated MSWI APC residue as substitute for cement in mortar

    DEFF Research Database (Denmark)

    Kirkelund, Gunvor Marie; Geiker, Mette Rica; Jensen, Pernille Erland

    2014-01-01

    Air pollution control (APC) residues from municipal solid waste incineration (MSWI) are considered hazardous waste and need pretreatment prior to possible reuse. Here, two MSWI APC residues, from which the most mobile fraction of heavy metals and salts has been removed by carbonation and/or elect......Air pollution control (APC) residues from municipal solid waste incineration (MSWI) are considered hazardous waste and need pretreatment prior to possible reuse. Here, two MSWI APC residues, from which the most mobile fraction of heavy metals and salts has been removed by carbonation and....../or electrodialytic remediation, were used in Portland cement mortar. Mortar bars with 15 % weight replacement of cement by APC residues showed compressive strengths up to 40 MPa after 28/32 days. Heavy metal and salt leaching from both crushed and monolithic mortars with APC residues was generally similar...

  5. A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC).

    Science.gov (United States)

    Sandoval, Imelda T; Delacruz, Richard Glenn C; Miller, Braden N; Hill, Shauna; Olson, Kristofor A; Gabriel, Ana E; Boyd, Kevin; Satterfield, Christeena; Remmen, Holly Van; Rutter, Jared; Jones, David A

    2017-04-11

    Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1) , a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc .

  6. Stable MCC binding to the APC/C is required for a functional spindle assembly checkpoint

    DEFF Research Database (Denmark)

    Hein, Jamin B; Nilsson, Jakob

    2014-01-01

    stably to the APC/C. Whether MCC formation per se is sufficient for a functional SAC or MCC association with the APC/C is required remains unclear. Here, we analyze the role of two conserved motifs in Cdc20, IR and C-Box, in binding of the MCC to the APC/C. Mutants in both motifs assemble the MCC....../C is critical for a functional SAC....

  7. Detection of microsatellite instability but not truncating APC mutations in gastric adenocarcinomas in Brazilian patients

    OpenAIRE

    Bevilacqua Roberta A.U.; Corvello Cassandra M.; Duarte Ana Paula; Simpson Andrew J.G.

    2000-01-01

    A crucial role for the adenomatous polyposis colonic (APC) gene in colorectal carcinogenesis has been conclusively established, but, the role of APC in gastric tumors remains controversial. APC mutations have been detected at a relatively high frequency in gastric tumors of Japanese patients, yet such mutations have been reported to be extremely rare in British patients and patients from north-central-Italy. We here report the analysis of 40 primary sporadic gastric adenocarcinomas and 35 pri...

  8. Extensive metabolic disorders are present in APC(min) tumorigenesis mice.

    Science.gov (United States)

    Liu, Zhenzhen; Xiao, Yi; Zhou, Zhengxiang; Mao, Xiaoxiao; Cai, Jinxing; Xiong, Lu; Liao, Chaonan; Huang, Fulian; Liu, Zehao; Ali Sheikh, Md Sayed; Plutzky, Jorge; Huang, He; Yang, Tianlun; Duan, Qiong

    2016-05-15

    Wnt signaling plays essential role in mesenchymal stem cell (MSC) differentiation. Activation of Wnt signaling suppresses adipogenesis, but promotes osteogenesis in MSC. Adenomatous polyposis coli (APC) is a negative regulator of β-catenin and Wnt signaling activity. The mutation of APC gene leads to the activation of Wnt signaling and is responsible for tumorigenesis in APC(min) mouse; however, very few studies focused on its metabolic abnormalities. The present study reports a widespread metabolic disorder phenotype in APC(min) mice. The old APC(min) mice have decreased body weight and impaired adipogenesis, but severe hyperlipidemia, which mimic the phenotypes of Familial Adenomatous Polyposis (FAP), an inherited disease also caused by APC gene mutation in human. We found that the expression of lipid metabolism and free fat acids (FA) use genes in the white adipose tissue (WAT) of the APC(min) mice is much lower than those of control. The changed gene expression pattern may lead to the disability of circulatory lipid transportation and storage at WAT. Moreover, the APC(min) mice could not maintain the core body temperature in cold condition. PET-CT determination revealed that the BAT of APC(min) mice has significantly impaired ability to take up (18)FDG from the blood. Morphological studies identified that the brown adipocytes of APC(min) mice were filled with lipid droplets but fewer mitochondria. These results matched with the findings of impaired BAT function in APC(min) mice. Collectively, our study explores a new mechanism that explains abnormal metabolism in APC(min) mice and provides insights into studying the metabolic disorders of FAP patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Ablação com radiofreqüência de extra-sístoles da via de saída do ventrículo direito Radiofrequency catheter ablation of premature ventricular contractions originating in the right ventricular outflow tract

    Directory of Open Access Journals (Sweden)

    Francisco C. C. Darrieux

    2007-03-01

    Full Text Available OBJETIVOS: Avaliar se a ablação com radiofreqüência é um procedimento eficiente para o tratamento das extra-sístoles da via de saída do ventrículo direito (EVSVD, e se resulta em melhora dos sintomas. MÉTODOS: Estudo prospectivo, com 30 pacientes consecutivos (idade média de 40±13 anos, 25 do sexo feminino, sem cardiopatia estrutural aparente, com EVSVD, muito freqüentes (densidade média de 1.263±593/h, sintomáticos por mais de 1 ano (média =74 meses e refratários aos fármacos antiarrítmicos (3±1,7, incluindo os beta-bloqueadores, que foram submetidos à ablação com radiofreqüência. RESULTADOS: Após o primeiro procedimento, houve 23 sucessos iniciais (76,6% e 7 iniciais insucessos (23,4%. Quatro pacientes tiveram recorrências, sendo que dois desses não se submeteram ao segundo procedimento. O segundo procedimento foi realizado em 9 pacientes (7 insucessos iniciais e 2 recorrências, e o sucesso ocorreu em 5 pacientes adicionais, sendo 1 caso por acesso epicárdico. A taxa de sucesso final foi de 80% (24/30, e nenhuma complicação maior ocorreu. Após um seguimento médio de 14±6 meses, no grupo de sucesso final houve uma redução de mais de 90% na densidade das extra-sístoles(24/24; pOBJECTIVES: To evaluate if radiofrequency catheter ablation is an effective procedure for the treatment of right ventricular outflow tract premature ventricular contractions (RVOT-PVC and ascertain if it results in an improvement of symptoms. METHODS: A prospective study with 30 consecutive patients (mean age 40 ± 13 years, 25 females, with no apparent structural cardiopathy, with very frequent (mean density of 1,263 ± 593/h RVOT-PVC, symptomatic for more than one year (mean = 74 months and resistant to antiarrhythmic drugs (3 ± 1.7, including beta-blockers, who underwent radiofrequency catheter ablation. RESULTS: After the first procedure, there were 23 initial successful cases (76.6% and 7 initial failures (23.4%. Four patients

  10. APC/C-Cdh1-dependent anaphase and telophase progression during mitotic slippage

    Directory of Open Access Journals (Sweden)

    Toda Kazuhiro

    2012-02-01

    Full Text Available Abstract Background The spindle assembly checkpoint (SAC inhibits anaphase progression in the presence of insufficient kinetochore-microtubule attachments, but cells can eventually override mitotic arrest by a process known as mitotic slippage or adaptation. This is a problem for cancer chemotherapy using microtubule poisons. Results Here we describe mitotic slippage in yeast bub2Δ mutant cells that are defective in the repression of precocious telophase onset (mitotic exit. Precocious activation of anaphase promoting complex/cyclosome (APC/C-Cdh1 caused mitotic slippage in the presence of nocodazole, while the SAC was still active. APC/C-Cdh1, but not APC/C-Cdc20, triggered anaphase progression (securin degradation, separase-mediated cohesin cleavage, sister-chromatid separation and chromosome missegregation, in addition to telophase onset (mitotic exit, during mitotic slippage. This demonstrates that an inhibitory system not only of APC/C-Cdc20 but also of APC/C-Cdh1 is critical for accurate chromosome segregation in the presence of insufficient kinetochore-microtubule attachments. Conclusions The sequential activation of APC/C-Cdc20 to APC/C-Cdh1 during mitosis is central to accurate mitosis. Precocious activation of APC/C-Cdh1 in metaphase (pre-anaphase causes mitotic slippage in SAC-activated cells. For the prevention of mitotic slippage, concomitant inhibition of APC/C-Cdh1 may be effective for tumor therapy with mitotic spindle poisons in humans.

  11. Controlling the response to DNA damage by the APC/C-Cdh1.

    Science.gov (United States)

    de Boer, H Rudolf; Guerrero Llobet, S; van Vugt, Marcel A T M

    2016-03-01

    Proper cell cycle progression is safeguarded by the oscillating activities of cyclin/cyclin-dependent kinase complexes. An important player in the regulation of mitotic cyclins is the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase. Prior to entry into mitosis, the APC/C remains inactive, which allows the accumulation of mitotic regulators. APC/C activation requires binding to either the Cdc20 or Cdh1 adaptor protein, which sequentially bind the APC/C and facilitate targeting of multiple mitotic regulators for proteasomal destruction, including Securin and Cyclin B, to ensure proper chromosome segregation and mitotic exit. Emerging data have indicated that the APC/C, particularly in association with Cdh1, also functions prior to mitotic entry. Specifically, the APC/C-Cdh1 is activated in response to DNA damage in G2 phase cells. These observations are in line with in vitro and in vivo genetic studies, in which cells lacking Cdh1 expression display various defects, including impaired DNA repair and aberrant cell cycle checkpoints. In this review, we summarize the current literature on APC/C regulation in response to DNA damage, the functions of APC/C-Cdh1 activation upon DNA damage, and speculate how APC/C-Cdh1 can control cell fate in the context of persistent DNA damage.

  12. Apc bridges Wnt/{beta}-catenin and BMP signaling during osteoblast differentiation of KS483 cells

    Energy Technology Data Exchange (ETDEWEB)

    Miclea, Razvan L., E-mail: R.L.Miclea@lumc.nl [Department of Pediatrics, Leiden University Medical Centre (LUMC), Leiden (Netherlands); Horst, Geertje van der, E-mail: G.van_der_Horst@lumc.nl [Department of Urology, LUMC, Leiden (Netherlands); Robanus-Maandag, Els C., E-mail: E.C.Robanus@lumc.nl [Department of Human Genetics, LUMC, Leiden (Netherlands); Loewik, Clemens W.G.M., E-mail: C.W.G.M.Lowik@lumc.nl [Department of Endocrinology and Metabolic Diseases, LUMC, Leiden (Netherlands); Oostdijk, Wilma, E-mail: W.Oostdijk@lumc.nl [Department of Pediatrics, Leiden University Medical Centre (LUMC), Leiden (Netherlands); Wit, Jan M., E-mail: J.M.Wit@lumc.nl [Department of Pediatrics, Leiden University Medical Centre (LUMC), Leiden (Netherlands); Karperien, Marcel, E-mail: H.B.J.Karperien@tnw.utwente.nl [MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Zuidhorst Room ZH 144, Drienerlolaan 5, 7522 NB Enschede (Netherlands)

    2011-06-10

    The canonical Wnt signaling pathway influences the differentiation of mesenchymal cell lineages in a quantitative and qualitative fashion depending on the dose of {beta}-catenin signaling. Adenomatous polyposis coli (Apc) is the critical intracellular regulator of {beta}-catenin turnover. To better understand the molecular mechanisms underlying the role of Apc in regulating the differentiation capacity of skeletal progenitor cells, we have knocked down Apc in the murine mesenchymal stem cell-like KS483 cells by stable expression of Apc-specific small interfering RNA. In routine culture, KSFrt-Apc{sub si} cells displayed a mesenchymal-like spindle shape morphology, exhibited markedly decreased proliferation and increased apoptosis. Apc knockdown resulted in upregulation of the Wnt/{beta}-catenin and the BMP/Smad signaling pathways, but osteogenic differentiation was completely inhibited. This effect could be rescued by adding high concentrations of BMP-7 to the differentiation medium. Furthermore, KSFrt-Apc{sub si} cells showed no potential to differentiate into chondrocytes or adipocytes. These results demonstrate that Apc is essential for the proliferation, survival and differentiation of KS483 cells. Apc knockdown blocks the osteogenic differentiation of skeletal progenitor cells, a process that can be overruled by high BMP signaling.

  13. Synergistic inhibition of the APC/C by the removal of APC15 in HCT116 cells lacking UBE2C.

    Science.gov (United States)

    Garvanska, Dimitriya H; Larsen, Marie Sofie Yoo; Nilsson, Jakob

    2016-10-15

    The spindle assembly checkpoint (SAC) inhibits the anaphase-promoting complex/cyclosome (APC/C) in response to unattached kinetochores by generating a diffusible inhibitor termed the mitotic checkpoint complex (MCC). At metaphase, rapid activation of the APC/C requires removal of the MCC, a process that has been shown to depend on the APC/C E2 enzymes, UBE2C and UBE2S. Here we investigate the in vivo role of the APC/C E2 enzymes in SAC silencing using CRISPR/Cas9 genetically engineered HCT116 UBE2C or UBE2S null cell lines. Using live cell assays, we show that UBE2C and UBE2S make a minor contribution to SAC silencing in HCT116 cells. Strikingly, in cells specifically lacking UBE2C, we observe a strong synergistic inhibition of mitotic progression when we stabilize the MCC on the APC/C by depleting APC15, potentially reflecting increased competition between the MCC and the remaining initiating E2 enzyme UBE2D. In conclusion, we provide in vivo insight into the APC/C E2 module and its interplay with SAC silencing components. © 2016. Published by The Company of Biologists Ltd.

  14. Recurrent APC gene mutations in Polish FAP families

    Directory of Open Access Journals (Sweden)

    Pławski Andrzej

    2007-12-01

    Full Text Available Abstract The molecular diagnostics of genetically conditioned disorders is based on the identification of the mutations in the predisposing genes. Hereditary cancer disorders of the gastrointestinal tracts are caused by mutations of the tumour suppressor genes or the DNA repair genes. Occurrence of recurrent mutation allows improvement of molecular diagnostics. The mutation spectrum in the genes causing hereditary forms of colorectal cancers in the Polish population was previously described. In the present work an estimation of the frequency of the recurrent mutations of the APC gene was performed. Eight types of mutations occurred in 19.4% of our FAP families and these constitute 43% of all Polish diagnosed families.

  15. APC: A New Code for Atmospheric Polarization Computations

    Science.gov (United States)

    Korkin, Sergey V.; Lyapustin, Alexei I.; Rozanov, Vladimir V.

    2014-01-01

    A new polarized radiative transfer code Atmospheric Polarization Computations (APC) is described. The code is based on separation of the diffuse light field into anisotropic and smooth (regular) parts. The anisotropic part is computed analytically. The smooth regular part is computed numerically using the discrete ordinates method. Vertical stratification of the atmosphere, common types of bidirectional surface reflection and scattering by spherical particles or spheroids are included. A particular consideration is given to computation of the bidirectional polarization distribution function (BPDF) of the waved ocean surface.

  16. Detection of irradiated foods by the DEFT/APC method

    International Nuclear Information System (INIS)

    Yuecel, P. K.; Koeseoglu, T.; Halkman, H. B. D.

    2009-01-01

    Irradiation technology is used to prevent the spoilage losses and to improve the hygienic quality of foods. Appropriate techniques for the detection of irradiated foods are needed to guarantee the proper consumer information and to facilitate the trade of irradiated foods. The characteristics of the microbial population of irradiated foods have been used for developing detection methods for irradiated foods. This microbiological method is based on the comparison of an aerobic plate count (APC) with a count obtained with the direct epifluorescent filter technique (DEFT) for the detection of irradiation of foodstuffs.

  17. Apnea of Prematurity (For Parents)

    Science.gov (United States)

    ... mature enough to allow nonstop breathing. This causes large bursts of breath followed by periods of shallow breathing or stopped breathing. Apnea of prematurity usually ends on its own after a few ...

  18. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Vujović Svetlana

    2012-01-01

    Full Text Available Premature ovarian failure (POF is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc. The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone, karyotype (<30 years of age, ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc.

  19. Synergistic inhibition of the APC/C by the removal of APC15 in HCT116 cells lacking UBE2C

    DEFF Research Database (Denmark)

    Garvanska, Dimitriya H; Larsen, Marie Sofie Yoo; Nilsson, Jakob

    2016-01-01

    that has been shown to depend on the APC/C E2 enzymes, UBE2C and UBE2S. Here we investigate the in vivo role of the APC/C E2 enzymes in SAC silencing using CRISPR/Cas9 genetically engineered HCT116 UBE2C or UBE2S null cell lines. Using live cell assays, we show that UBE2C and UBE2S make a minor...... contribution to SAC silencing in HCT116 cells. Strikingly in cells specifically lacking UBE2C, we observe a strong synergistic inhibition of mitotic progression when we stabilize the MCC on the APC/C by depleting APC15, potentially reflecting increased competition between the MCC and the remaining initiating E...

  20. Premature pubarche is niet altijd onschuldig

    NARCIS (Netherlands)

    Backes, Manouk; Zwaveling-Soonawala, Nitash; Kamp, Gerdine A.

    2012-01-01

    Premature pubarche is defined as growth of pubic hair before the age of 8 years in girls and 9 years in boys. In most cases, it is caused by premature adrenarche, which is a premature increased synthesis of androgens in the adrenal gland and is considered to be relatively harmless. Premature

  1. Apc1 is required for maintenance of local brain organizers and dorsal midbrain survival.

    NARCIS (Netherlands)

    Paridaen, J.T.M.; Danesin, C.; Elas, A.T.; van de Water, S.G.P.; Houart, C.; Zivkovic, D.

    2009-01-01

    The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1

  2. Effect of drying on leaching testing of treated municipal solid waste incineration APC-residues

    DEFF Research Database (Denmark)

    Hu, Y.; Hyks, Jiri; Astrup, Thomas

    2008-01-01

    Air-pollution-control (APC) residues from waste incinerators are hazardous waste according to European legislation and must be treated prior to landfilling. Batch and column leaching data determine which type of landfill can receive the treated APC-residues. CEN standards are prescribed...

  3. REMOVAL OF ARSENIC IN DRINKING WATER: ARS CFU-50 APC ELECTROFLOCCULATION AND FILTRATION WATER TREATMENT SYSTEM

    Science.gov (United States)

    ETV testing of the ARS CFU-50 APC Electroflocculation and Filtration Water Treatment System (ARS CFU-50 APC) for arsenic removal was conducted at the Town of Bernalillo Well #3 site from April 18 through May 2, 2006. The source water was chlorinated groundwater from two supply w...

  4. Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells.

    Science.gov (United States)

    Langlands, Alistair J; Carroll, Thomas D; Chen, Yu; Näthke, Inke

    2018-02-15

    More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes that Apc mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilised intestinal organoids to compare the growth of Apc mutant and wild-type cells. Organoids derived from Apc Min/+ mice recapitulate stages of intestinal polyposis in culture. They eventually form spherical cysts that reflect the competitive growth advantage of cells that have undergone loss of heterozygosity (LOH). We discovered that this emergence of cysts was inhibited by Chiron99021 and Valproic acid, which potentiates Wnt signalling. Chiron99021 and Valproic acid restrict the growth advantage of Apc mutant cells while stimulating that of wild-type cells, suggesting that excessive Wnt signalling reduces the relative fitness of Apc mutant cells. As a proof of concept, we demonstrated that Chiron99021-treated Apc mutant organoids were rendered susceptible to TSA-induced apoptosis, while wild-type cells were protected.

  5. APC sets the Wnt tone necessary for cerebral cortical progenitor development.

    Science.gov (United States)

    Nakagawa, Naoki; Li, Jingjun; Yabuno-Nakagawa, Keiko; Eom, Tae-Yeon; Cowles, Martis; Mapp, Tavien; Taylor, Robin; Anton, E S

    2017-08-15

    Adenomatous polyposis coli (APC) regulates the activity of β-catenin, an integral component of Wnt signaling. However, the selective role of the APC-β-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated β-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-β-catenin pathway indicates that the maintenance of appropriate β-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates β-catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. β-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of β-catenin or inhibition of β-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated β-catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development. © 2017 Nakagawa et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.

    Science.gov (United States)

    Papp, Janos; Kovacs, Marietta Eva; Matrai, Zoltan; Orosz, Enikő; Kásler, Miklós; Børresen-Dale, Anne-Lise; Olah, Edith

    2016-01-01

    Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200-1400 region showing earlier age of disease onset (p APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families.

  7. Tumour Suppressor Adenomatous Polyposis Coli (APC) localisation is regulated by both Kinesin-1 and Kinesin-2

    NARCIS (Netherlands)

    Ruane, Peter T; Gumy, Laura F; Bola, Becky; Anderson, Beverley; Wozniak, Marcin J; Hoogenraad, Casper C; Allan, Victoria J

    2016-01-01

    Microtubules and their associated proteins (MAPs) underpin the polarity of specialised cells. Adenomatous polyposis coli (APC) is one such MAP with a multifunctional agenda that requires precise intracellular localisations. Although APC has been found to associate with kinesin-2 subfamily members,

  8. Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration.

    Science.gov (United States)

    Jiang, Haiming; Deng, Rong; Yang, Xiuyan; Shang, Jialin; Lu, Shaoyong; Zhao, Yanlong; Song, Kun; Liu, Xinyi; Zhang, Qiufen; Chen, Yu; Chinn, Y Eugene; Wu, Geng; Li, Jian; Chen, Guoqiang; Yu, Jianxiu; Zhang, Jian

    2017-09-01

    The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC-Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC-Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein-protein interaction inhibitors available for the development of cancer therapeutics targeting APC-Asef signaling.

  9. The aPC treatment improves microcirculation in severe sepsis/septic shock syndrome

    NARCIS (Netherlands)

    Donati, Abele; Damiani, Elisa; Botticelli, Laura; Adrario, Erica; Lombrano, Maria Rita; Domizi, Roberta; Marini, Benedetto; van Teeffelen, Jurgen W. G. E.; Carletti, Paola; Girardis, Massimo; Pelaia, Paolo; Ince, Can

    2013-01-01

    The role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the

  10. Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells

    Science.gov (United States)

    Barua, Dipak; Hlavacek, William S.

    2013-01-01

    In colorectal cancer cells, APC, a tumor suppressor protein, is commonly expressed in truncated form. Truncation of APC is believed to disrupt degradation of β—catenin, which is regulated by a multiprotein complex called the destruction complex. The destruction complex comprises APC, Axin, β—catenin, serine/threonine kinases, and other proteins. The kinases and , which are recruited by Axin, mediate phosphorylation of β—catenin, which initiates its ubiquitination and proteosomal degradation. The mechanism of regulation of β—catenin degradation by the destruction complex and the role of truncation of APC in colorectal cancer are not entirely understood. Through formulation and analysis of a rule-based computational model, we investigated the regulation of β—catenin phosphorylation and degradation by APC and the effect of APC truncation on function of the destruction complex. The model integrates available mechanistic knowledge about site-specific interactions and phosphorylation of destruction complex components and is consistent with an array of published data. We find that the phosphorylated truncated form of APC can outcompete Axin for binding to β—catenin, provided that Axin is limiting, and thereby sequester β—catenin away from Axin and the Axin-recruited kinases and . Full-length APC also competes with Axin for binding to β—catenin; however, full-length APC is able, through its SAMP repeats, which bind Axin and which are missing in truncated oncogenic forms of APC, to bring β—catenin into indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on β—catenin levels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by , we suggest that is a potential target for therapeutic intervention in colorectal cancer. Specific inhibition of is predicted to limit binding of β—catenin to truncated

  11. APC senses cell-cell contacts and moves to the nucleus upon their disruption.

    Science.gov (United States)

    Brocardo, M G; Bianchini, M; Radrizzani, M; Reyes, G B; Dugour, A V; Taminelli, G L; Gonzalez Solveyra, C; Santa-Coloma, T A

    2001-06-22

    The adenomatous polyposis coli (APC) tumor suppressor protein is involved in the Wnt/wingless pathway, modulating beta-catenin activity. We report the development of a highly specific, chemically synthesized oligobody (oligonucleotide-based synthetic antibody), directed against the N-terminal region of APC. Using this reagent, we found that within 16 h of disrupting HT-29 cell-cell contacts by harvesting cells with trypsin/EDTA treatment and replating, APC was translocated from the cytoplasm to the nucleus. Five days after plating the cells, when the cells had returned to their normal confluent phenotype and cell-cell contacts were reestablished, APC returned to the cytoplasm. These results suggest that APC functions as part of a "sensor" system, and responds to the loss of cell-cell contacts by moving to the nucleus, and returning to the cytoplasm when the contacts are fully restored. Copyright 2001 Academic Press.

  12. Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

    DEFF Research Database (Denmark)

    Bisgaard, M L; Ripa, R; Knudsen, Anne Louise

    2004-01-01

    BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein...... comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype...... in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16...

  13. Critical Current Properties in Longitudinal Magnetic Field of YBCO Superconductor with APC

    Science.gov (United States)

    Kido, R.; Kiuchi, M.; Otabe, E. S.; Matsushita, T.; Jha, A. K.; Matsumoto, K.

    The critical current density (Jc) properties of the Artificial Pinning Center (APC) introduced YBa2Cu3O7 (YBCO) films in the longitudinal magnetic field were measured. Y2O3 or Y2BaCuO5 (Y211) was introduced as APCs to YBCO, and YBCO films with APC were fabricated on SrTiO3 single crystal substrate. The sizes of Y2O3 and Y211 were 5-10 nm and 10-20 nm, respectively. As a result, Jc enhancement in the longitudinal magnetic field was observed in Y2O3 introduced YBCO films. However, it was not observed in Y211 introduced YBCO films. Therefore, it was considered that Jc properties in the longitudinal magnetic field were affected by introducing of small size APC, and it was necessary that APC does not disturb the current pathway in the superconductor.

  14. Prenatal stress, prematurity and asthma

    Science.gov (United States)

    Medsker, Brock; Forno, Erick; Simhan, Hyagriv; Celedón, Juan C.

    2016-01-01

    Asthma is the most common chronic disease of childhood, affecting millions of children in the U.S. and worldwide. Prematurity is a risk factor for asthma, and certain ethnic or racial minorities such as Puerto Ricans and non-Hispanic Blacks are disproportionately affected by both prematurity and asthma. In this review, we examine current evidence to support maternal psychosocial stress as a putative link between prematurity and asthma, while also focusing on disruption of the hypothalamic-pituitary-adrenal (HPA) axis and immune responses as potential underlying mechanisms for stress-induced “premature asthma”. Prenatal stress may not only cause abnormalities in the HPA axis but also epigenetic changes in the fetal glucocorticoid receptor gene (NR3C1), leading to impaired glucocorticoid metabolism. Moreover, maternal stress can alter fetal cytokine balance, favoring Th2 (allergic) immune responses characteristic of atopic asthma: IL-6, which has been associated with premature labor, can promote Th2 responses by stimulating production of IL-4 and IL-13. Given a link among stress, prematurity, and asthma, future research should include birth cohorts aimed at confirming and better characterizing “premature asthma”. If confirmed, clinical trials of prenatal maternal stress reduction would be warranted to reduce the burden of these common co-morbidities. While awaiting the results of such studies, sound policies to prevent domestic and community violence (e.g. from firearms) are justified, not only by public safety but also by growing evidence of detrimental effects of violence-induced stress on psychiatric and somatic health. PMID:26676148

  15. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Claudia Gaspar

    2009-07-01

    Full Text Available Germline mutations in the adenomatous polyposis coli (APC gene are responsible for familial adenomatous polyposis (FAP, an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/beta-catenin signaling. Notably, genotype-phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/beta-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/beta-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc(+/1572T mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc(+/1572T mice suggests that specific dosages of Wnt/beta-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion.

  16. The role of APC in WNT pathway activation in serrated neoplasia.

    Science.gov (United States)

    Borowsky, Jennifer; Dumenil, Troy; Bettington, Mark; Pearson, Sally-Ann; Bond, Catherine; Fennell, Lochlan; Liu, Cheng; McKeone, Diane; Rosty, Christophe; Brown, Ian; Walker, Neal; Leggett, Barbara; Whitehall, Vicki

    2018-03-01

    Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations

  17. CpG methylation of APC promoter 1A in sporadic and familial breast cancer patients.

    Science.gov (United States)

    Debouki-Joudi, Saoussen; Trifa, Fatma; Khabir, Abdelmajid; Sellami-Boudawara, Tahia; Frikha, Mounir; Daoud, Jamel; Mokdad-Gargouri, Raja

    2017-01-01

    Tumour suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer initiation. The aim of this study was to assess the extent of methylation of APC gene promoter in 91 sporadic and 44 familial cases of Tunisian patients with breast cancer (BC) in. The frequency of APC promoter methylation is somewhat similar for sporadic and familial breast cancer cases, (52.1%, and 54.5% respectively). For sporadic breast cancer patients, there was a significant correlation of APC promoter hypermethylation with TNM stage (p = 0.024) and 3-year survival (p = 0.025). Regarding the hormonal status (HR), we found significant association between negativity to PR and unmethylated APC (p= 0.005) while ER and Her2/neu are not correlated. Moreover, unmethylated APC promoter is more frequent in tumours expressing at least one out the 3 proteins compared to triple negative cases (p= 0.053). On the other hand, aberrant methylation of APC was associated with tumour size (p = 0.036), lymph node (p = 0.028), distant metastasis (p = 0.031), and 3-year survival (p = 0.046) in the group of patients with familial breast cancer. Moreover, patients with sporadic breast cancer displaying the unmethylated profile have a significant prolonged overall survival compared to those with the methylated pattern of APC promoter (p log rank = 0.008). Epigenetic change at the CpG islands in the APC promoter was associated with the silence of its transcript and the loss of protein expression suggesting that this event is the main mechanism regulating the APC expression in breast cancer. In conclusion, our data showed that the loss of APC through aberrant methylation is associated with the aggressive behavior of both sporadic and familial breast cancer in Tunisian patients.

  18. Downregulation of the anaphase-promoting complex (APC)7 in invasive ductal carcinomas of the breast and its clinicopathologic relationships

    International Nuclear Information System (INIS)

    Park, Kwang-Hwa; Choi, Sung-E; Eom, Minseob; Kang, Yup

    2005-01-01

    The anaphase-promoting complex (APC) is a multiprotein complex with E3 ubiquitin ligase activity, which is required for the ubiquitination of securin and cyclin-B. Moreover, the mitotic spindle checkpoint is activated if APC activation is prevented. In addition, several APC-targeting molecules such as securin, polo-like kinase, aurora kinase, and SnoN have been reported to be oncogenes. Therefore, dysregulation of APC may be associated with tumorigenesis. However, the clinical significance and the involvement of APC in tumorigenesis have not been investigated. The expression of APC7 was immunohistochemically investigated in 108 invasive ductal carcinomas of the breast and its relationship with clinicopathologic parameters was examined. The expression of APC7 was defined as positive when the summed scores of staining intensities (0 to 3+) and stained proportions (0 to 3+) exceeded 3+. Positive APC7 expression was less frequent than its negative expression when histologic (P = 0.009) or nuclear grade (P = 0.009), or mitotic number (P = 0.0016) was elevated. The frequency of APC7 negative expression was higher in high Ki-67 or aneuploid groups than in low Ki-67 or diploid groups. These data show that loss of APC7 expression is more common in breast carcinoma cases with poor prognostic parameters or malignant characteristics. They therefore suggest that dysregulation of APC activity, possibly through downregulation of APC7, may be associated with tumorigenesis in breast cancer

  19. 75 FR 78246 - Medicare Program; Re-Chartering of the Advisory Panel on Ambulatory Payment Classification (APC...

    Science.gov (United States)

    2010-12-15

    ...] Medicare Program; Re-Chartering of the Advisory Panel on Ambulatory Payment Classification (APC) Groups... announces the re-chartering of the Advisory Panel on Ambulatory Payment Classification (APC) Groups (the... (APC) groups and their associated weights established under the Medicare hospital Outpatient...

  20. Polymorphic Contracts

    Science.gov (United States)

    Belo, João Filipe; Greenberg, Michael; Igarashi, Atsushi; Pierce, Benjamin C.

    Manifest contracts track precise properties by refining types with predicates - e.g., {x : Int |x > 0 } denotes the positive integers. Contracts and polymorphism make a natural combination: programmers can give strong contracts to abstract types, precisely stating pre- and post-conditions while hiding implementation details - for example, an abstract type of stacks might specify that the pop operation has input type {x :α Stack |not ( empty x )} . We formalize this combination by defining FH, a polymorphic calculus with manifest contracts, and establishing fundamental properties including type soundness and relational parametricity. Our development relies on a significant technical improvement over earlier presentations of contracts: instead of introducing a denotational model to break a problematic circularity between typing, subtyping, and evaluation, we develop the metatheory of contracts in a completely syntactic fashion, omitting subtyping from the core system and recovering it post facto as a derived property.

  1. Educational paper: Retinopathy of prematurity.

    Science.gov (United States)

    Casteels, Ingele; Cassiman, Catherine; Van Calster, Joachim; Allegaert, Karel

    2012-06-01

    Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease affecting the premature infant with an incompletely vascularized retina. The spectrum of ophthalmological findings in ROP exists from minimal sequelae, which do not affect vision, to bilateral retinal detachment and total blindness. With the increased survival of very small infants, retinopathy of prematurity has become one of the leading causes of childhood blindness. Over the past two decades, major advances have been made in understanding the pathogenesis of ROP, to a large extent as a result of changes in clinical risk factors (oxygen and non-oxygen related) and characteristics observed in ROP cases. This article provides a literature review on the evolution in clinical characteristics, classification and treatment modalities and indications of ROP. Special attention is hereby paid to the neonatal factors influencing the development of ROP and to the necessity for everyone caring for premature babies to have a well-defined screening and treatment protocol for ROP. Such screening protocol needs to be based on a unit-specific ROP risk profile and, consequently, may vary between different European regions. Retinopathy of prematurity is an important cause of ocular morbidity and blindness in children. With better understanding of the pathogenesis, screening and treatment guidelines have changed over time and are unit specific.

  2. Administrative contracts

    Directory of Open Access Journals (Sweden)

    Vukićević-Petković Milica

    2015-01-01

    Full Text Available Administrative contracts are a special type of contract where usually one of the contracting parties is a public law body and which is concluded for the performance of public service and the realization of a public interest. They go a long way since its inception to its eventual final acceptance of all the legal systems. One of the enduring characteristics of this type of contract is their disquised or unnoticed existence. This is why only monitoring their development may lead to a complete understanding of the importance and essence of this institution as well as the need for its complete legal regulation.

  3. Electrical contracting

    CERN Document Server

    Neidle, Michael

    2013-01-01

    Electrical Contracting, Second Edition is a nine-chapter text guide for the greater efficiency in planning and completing installations for the design, installation and control of electrical contracts. This book starts with a general overview of the efficient cabling and techniques that must be employed for safe wiring design, as well as the cost estimation of the complete electrical contract. The subsequent chapters are devoted to other electrical contracting requirements, including electronic motor control, lighting, and electricity tariffs. A chapter focuses on the IEE Wiring Regulations an

  4. Administrative contracts

    OpenAIRE

    Vukićević-Petković Milica

    2015-01-01

    Administrative contracts are a special type of contract where usually one of the contracting parties is a public law body and which is concluded for the performance of public service and the realization of a public interest. They go a long way since its inception to its eventual final acceptance of all the legal systems. One of the enduring characteristics of this type of contract is their disquised or unnoticed existence. This is why only monitoring their development may lead to a complete u...

  5. OSD1 promotes meiotic progression via APC/C inhibition and forms a regulatory network with TDM and CYCA1;2/TAM.

    Science.gov (United States)

    Cromer, Laurence; Heyman, Jefri; Touati, Sandra; Harashima, Hirofumi; Araou, Emilie; Girard, Chloe; Horlow, Christine; Wassmann, Katja; Schnittger, Arp; De Veylder, Lieven; Mercier, Raphael

    2012-01-01

    Cell cycle control is modified at meiosis compared to mitosis, because two divisions follow a single DNA replication event. Cyclin-dependent kinases (CDKs) promote progression through both meiosis and mitosis, and a central regulator of their activity is the APC/C (Anaphase Promoting Complex/Cyclosome) that is especially required for exit from mitosis. We have shown previously that OSD1 is involved in entry into both meiosis I and meiosis II in Arabidopsis thaliana; however, the molecular mechanism by which OSD1 controls these transitions has remained unclear. Here we show that OSD1 promotes meiotic progression through APC/C inhibition. Next, we explored the functional relationships between OSD1 and the genes known to control meiotic cell cycle transitions in Arabidopsis. Like osd1, cyca1;2/tam mutation leads to a premature exit from meiosis after the first division, while tdm mutants perform an aberrant third meiotic division after normal meiosis I and II. Remarkably, while tdm is epistatic to tam, osd1 is epistatic to tdm. We further show that the expression of a non-destructible CYCA1;2/TAM provokes, like tdm, the entry into a third meiotic division. Finally, we show that CYCA1;2/TAM forms an active complex with CDKA;1 that can phosphorylate OSD1 in vitro. We thus propose that a functional network composed of OSD1, CYCA1;2/TAM, and TDM controls three key steps of meiotic progression, in which OSD1 is a meiotic APC/C inhibitor.

  6. Apc1 is required for maintenance of local brain organizers and dorsal midbrain survival.

    Science.gov (United States)

    Paridaen, Judith T M L; Danesin, Catherine; Elas, Abu Tufayal; van de Water, Sandra; Houart, Corinne; Zivkovic, Danica

    2009-07-15

    The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1 zygotic-effect mutation on late brain development in zebrafish. Apc1 is required for maintenance of established brain subdivisions and control of local organizers such as the isthmic organizer (IsO). Caudal expansion of Fgf8 from IsO into the cerebellum is accompanied by hyperproliferation and abnormal cerebellar morphogenesis. Loss of apc1 results in reduced proliferation and apoptosis in the dorsal midbrain. Mosaic analysis shows that Apc is required cell-autonomously for maintenance of dorsal midbrain cell fate. The tectal phenotype occurs independently of Fgf8-mediated IsO function and is predominantly caused by stabilization of beta-catenin and subsequent hyperactivation of Wnt/beta-catenin signalling, which is mainly mediated through LEF1 activity. Chemical activation of the Wnt/beta-catenin in wild-type embryos during late brain maintenance stages phenocopies the IsO and tectal phenotypes of the apc mutants. These data demonstrate that Apc1-mediated restriction of Wnt/beta-catenin signalling is required for maintenance of local organizers and tectal integrity.

  7. PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.

    Science.gov (United States)

    Raab, Monika; Sanhaji, Mourad; Matthess, Yves; Hörlin, Albrecht; Lorenz, Ioana; Dötsch, Christina; Habbe, Nils; Waidmann, Oliver; Kurunci-Csacsko, Elisabeth; Firestein, Ron; Becker, Sven; Strebhardt, Klaus

    2018-03-16

    The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

  8. Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc Min/+ mice.

    Science.gov (United States)

    He, Zhengxiang; Chen, Lili; Souto, Fabricio O; Canasto-Chibuque, Claudia; Bongers, Gerold; Deshpande, Madhura; Harpaz, Noam; Ko, Huaibin M; Kelley, Kevin; Furtado, Glaucia C; Lira, Sergio A

    2017-07-14

    Increased expression of Interleukin (IL)-33 has been detected in intestinal samples of patients with ulcerative colitis, a condition associated with increased risk for colon cancer, but its role in the development of colorectal cancer has yet to be fully examined. Here, we investigated the role of epithelial expressed IL-33 during development of intestinal tumors. IL-33 expression was detected in epithelial cells in colorectal cancer specimens and in the Apc Min/+ mice. To better understand the role of epithelial-derived IL-33 in the intestinal tumorigenesis, we generated transgenic mice expressing IL-33 in intestinal epithelial cells (V33 mice). V33 Apc Min/+ mice, resulting from the cross of V33 with Apc Min/+ mice, had increased intestinal tumor burden compared with littermate Apc Min/+ mice. Consistently, Apc Min/+ mice deficient for IL-33 receptor (ST2), had reduced polyp burden. Mechanistically, overexpression of IL-33 promoted expansion of ST2 + regulatory T cells, increased Th2 cytokine milieu, and induced alternatively activated macrophages in the gut. IL-33 promoted marked changes in the expression of antimicrobial peptides, and antibiotic treatment of V33 Apc Min/+ mice abrogated the tumor promoting-effects of IL-33 in the colon. In conclusion, elevated IL-33 signaling increases tumor development in the Apc Min/+ mice.

  9. APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

    Science.gov (United States)

    VanKlompenberg, Monica K; Leyden, Emily; Arnason, Anne H; Zhang, Jian-Ting; Stefanski, Casey D; Prosperi, Jenifer R

    2017-11-28

    Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT; Apc Min/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT; Apc Min/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT; Apc Min/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.

  10. Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.

    Science.gov (United States)

    Ciavarella, Michele; Miccoli, Sara; Prossomariti, Anna; Pippucci, Tommaso; Bonora, Elena; Buscherini, Francesco; Palombo, Flavia; Zuntini, Roberta; Balbi, Tiziana; Ceccarelli, Claudio; Bazzoli, Franco; Ricciardiello, Luigi; Turchetti, Daniela; Piazzi, Giulia

    2018-03-01

    Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

  11. The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.

    Science.gov (United States)

    Wan, Lixin; Chen, Ming; Cao, Juxiang; Dai, Xiangpeng; Yin, Qing; Zhang, Jinfang; Song, Su-Jung; Lu, Ying; Liu, Jing; Inuzuka, Hiroyuki; Katon, Jesse M; Berry, Kelsey; Fung, Jacqueline; Ng, Christopher; Liu, Pengda; Song, Min Sup; Xue, Lian; Bronson, Roderick T; Kirschner, Marc W; Cui, Rutao; Pandolfi, Pier Paolo; Wei, Wenyi

    2017-04-01

    BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APC FZR1 , APC FZR1 earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APC FZR1 , leading to elevation of a cohort of oncogenic APC FZR1 substrates to facilitate melanomagenesis. Importantly, CDK4 and/or BRAF/MEK inhibitors restore APC FZR1 E3 ligase activity, which might be critical for their clinical effects. Furthermore, FZR1 depletion cooperates with AKT hyperactivation to transform primary melanocytes, whereas genetic ablation of Fzr1 synergizes with Pten loss, leading to aberrant coactivation of BRAF/ERK and AKT signaling in mice. Our findings therefore reveal a reciprocal suppression mechanism between FZR1 and BRAF in controlling tumorigenesis. Significance: FZR1 inhibits BRAF oncogenic functions via both APC-dependent proteolysis and APC-independent disruption of BRAF dimers, whereas hyperactivated ERK and CDK4 reciprocally suppress APC FZR1 E3 ligase activity. Aberrancies in this newly defined signaling network might account for BRAF hyperactivation in human cancers, suggesting that targeting CYCLIN D1/CDK4, alone or in combination with BRAF/MEK inhibition, can be an effective anti-melanoma therapy. Cancer Discov; 7(4); 424-41. ©2017 AACR. See related commentary by Zhang and Bollag, p. 356 This article is highlighted in the In This Issue feature, p. 339 . ©2017 American Association for Cancer Research.

  12. Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in Apc(Min/+) mice.

    Science.gov (United States)

    Pierre, Christina C; Longo, Joseph; Mavor, Meaghan; Milosavljevic, Snezana B; Chaudhary, Roopali; Gilbreath, Ebony; Yates, Clayton; Daniel, Juliet M

    2015-09-01

    Constitutive Wnt/β-catenin signaling is a key contributor to colorectal cancer (CRC). Although inactivation of the tumor suppressor adenomatous polyposis coli (APC) is recognized as an early event in CRC development, it is the accumulation of multiple subsequent oncogenic insults facilitates malignant transformation. One potential contributor to colorectal carcinogenesis is the POZ-ZF transcription factor Kaiso, whose depletion extends lifespan and delays polyp onset in the widely used Apc(Min/+) mouse model of intestinal cancer. These findings suggested that Kaiso potentiates intestinal tumorigenesis, but this was paradoxical as Kaiso was previously implicated as a negative regulator of Wnt/β-catenin signaling. To resolve Kaiso's role in intestinal tumorigenesis and canonical Wnt signaling, we generated a transgenic mouse model (Kaiso(Tg/+)) expressing an intestinal-specific myc-tagged Kaiso transgene. We then mated Kaiso(Tg/+) and Apc(Min/+) mice to generate Kaiso(Tg/+):Apc(Min/+) mice for further characterization. Kaiso(Tg/+):Apc(Min/+) mice exhibited reduced lifespan and increased polyp multiplicity compared to Apc(Min/+) mice. Consistent with this murine phenotype, we found increased Kaiso expression in human CRC tissue, supporting a role for Kaiso in human CRC. Interestingly, Wnt target gene expression was increased in Kaiso(Tg/+):Apc(Min/+) mice, suggesting that Kaiso's function as a negative regulator of canonical Wnt signaling, as seen in Xenopus, is not maintained in this context. Notably, Kaiso(Tg/+):Apc(Min/+) mice exhibited increased inflammation and activation of NFκB signaling compared to their Apc(Min/+) counterparts. This phenotype was consistent with our previous report that Kaiso(Tg/+) mice exhibit chronic intestinal inflammation. Together our findings highlight a role for Kaiso in promoting Wnt signaling, inflammation and tumorigenesis in the mammalian intestine. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji, E-mail: tmntt08@gmail.com [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Mori, Takayuki [Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502 (Japan); Watanabe, Naoki [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Naiki, Takafumi [Department of Clinical Laboratory, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513 (Japan); Moriwaki, Hisataka [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi [The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501 (Japan)

    2014-07-21

    Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation.

  14. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    International Nuclear Information System (INIS)

    Tanaka, Takuji; Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei; Mori, Takayuki; Watanabe, Naoki; Naiki, Takafumi; Moriwaki, Hisataka; Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi

    2014-01-01

    Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation

  15. Stabilization of APC residues from waste incineration with ferrous sulfate on a semi-industrial scale

    DEFF Research Database (Denmark)

    Lundtorp, Kasper; Jensen, Dorthe Lærke; Christensen, Thomas Højlund

    2002-01-01

    A stabilization method for air pollution control (APC) residues from municipal solid waste incineration (MSWI) involving mixing of the residue with water and FeSO4 has been demonstrated on a semi-industrial scale on three types of APC residues: a semidy (SD) APC residue, a fly ash (FA), and an FA...... mixed with sludge (FAS) from a wet flue gas cleaning system. The process was performed in batches of 165-175 kg residue. It generates a wastewater that is highly saline but has a low content of heavy metals such as Cd, Cr, and Pb. The stabilized and raw residues have been subject to a range of leaching...

  16. β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

    Science.gov (United States)

    Cai, Jing; Maitra, Anirban; Anders, Robert A.; Taketo, Makoto M.; Pan, Duojia

    2015-01-01

    Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo–YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex. PMID:26193883

  17. PREMATURE RUPTURE OF THE MEMBRANES*

    African Journals Online (AJOL)

    In patients presenting with premature rupture of the membranes there are two factors which influence the foetal morbidity and mortality. These factors are prema- turity and intra-uterine infection. The purpose of this analysis was to elucidate which factor carried the greater risk to the foetus. Recently there has been a spate of.

  18. Mothers' Retrospections of Premature Childbirth.

    Science.gov (United States)

    Kalmar, Magda; And Others

    This study examined Hungarian mothers' recollections, 8 years after the birth of their premature baby, of their stress at the time of the baby's birth. Interviews were conducted with 30 mothers whose babies had been born between 30 and 37 weeks gestational age. At the time of the follow-up, all children had normal IQs and were attending normal…

  19. Noninvasive Ventilation in Premature Neonates.

    Science.gov (United States)

    Flanagan, Keri Ann

    2016-04-01

    The use of noninvasive ventilation is a constantly evolving treatment option for respiratory disease in the premature infant. The goals of these noninvasive ventilation techniques are to improve gas exchange in the premature infant's lungs and to minimize the need for intubation and invasive mechanical ventilation. The goals of this article are to consider various uses of nasal interfaces, discuss skin care and developmental positioning concerns faced by the bedside nurse, and discuss the medical management aimed to reduce morbidity and mortality. This article explores the nursing role, the advances in medical strategies for noninvasive ventilation, and the team approach to noninvasive ventilation use in this population. Search strategy included a literature review on medical databases, such as EBSCOhost, CINAHL, PubMed, and NeoReviews. Innovative products, nursing research on developmental positioning and skin care, and advanced medical management have led to better and safer outcomes for premature infants requiring noninvasive ventilation. The medical focus of avoiding long-term mechanical ventilation would not be possible without the technology to provide noninvasive ventilation to these premature infants and the watchful eye of the nurse in terms of careful positioning, preventing skin breakdown and facial scarring, and a proper seal to maximize ventilation accuracy. This article encourages nursing-based research to quantify some of the knowledge about skin care and positioning as well as research into most appropriate uses for noninvasive ventilation devices.

  20. Music Therapy with Premature Infants

    Science.gov (United States)

    Standley, Jayne

    2003-01-01

    Over 20 years of research and clinical practice in music therapy with premature infants has been compiled into this text designed for Board Certified Music Therapists specializing in Neonatal Intensive Care clinical services, for NICU medical staff incorporating research-based music therapy into developmental care plans, and for parents of…

  1. Complications of Prematurity - An Infographic

    Science.gov (United States)

    Chandrasekharan, Praveen; Rawat, Munmun; Lakshminrusimha, Satyan

    2017-01-01

    Infographics or information graphics are easy-to-understand visual representation of knowledge. An infographic outlining the course of an extremely preterm infant and various potential complications encountered during a neonatal intensive care unit (NICU) stay was developed. This infographic can be used to discuss outcomes of prematurity during prenatal counseling and while the infant is in the NICU. PMID:29138522

  2. Aggressive Posterior Retinopathy of Prematurity in a Premature Male Infant

    Directory of Open Access Journals (Sweden)

    Jun Zhou

    2017-07-01

    Full Text Available A premature male infant was born at 30 weeks’ gestation with a birth weight of 1,700 g in a rural hospital. He was diagnosed with respiratory distress syndrome and received continuous positive airway pressure treatment for 26 days. At 26 days after birth, the patient was transferred to our hospital for further evaluation and management. A comprehensive eye examination revealed a stage 3 retinopathy of prematurity (ROP involving zone 2 in both eyes. The patient was recommended to a provincial-level eye hospital for emergency laser therapy. Five months after birth, the feedback from the eye hospital showed that the patient had a high risk of blindness in both eyes. Our case report shows that delaying first screening examination increases the possibility of developing aggressive posterior ROP in infants with ROP. Doctors in rural hospitals should be aware of this possibility and trained for early screening and treatment in high-risk infants.

  3. Apoptosis in neural crest cells by functional loss of APC tumor suppressor gene

    Science.gov (United States)

    Hasegawa, Sumitaka; Sato, Tomoyuki; Akazawa, Hiroshi; Okada, Hitoshi; Maeno, Akiteru; Ito, Masaki; Sugitani, Yoshinobu; Shibata, Hiroyuki; Miyazaki, Jun-ichi; Katsuki, Motoya; Yamauchi, Yasutaka; Yamamura, Ken-ichi; Katamine, Shigeru; Noda, Tetsuo

    2002-01-01

    Apc is a gene associated with familial adenomatous polyposis coli (FAP) and its inactivation is a critical step in colorectal tumor formation. The protein product, adenomatous polyposis coli (APC), acts to down-regulate intracellular levels of β-catenin, a key signal transducer in the Wnt signaling. Conditional targeting of Apc in the neural crest of mice caused massive apoptosis of cephalic and cardiac neural crest cells at about 11.5 days post coitum, resulting in craniofacial and cardiac anomalies at birth. Notably, the apoptotic cells localized in the regions where β-catenin had accumulated. In contrast to its role in colorectal epithelial cells, inactivation of APC leads to dysregulation of β-catenin/Wnt signaling with resultant apoptosis in certain tissues including neural crest cells. PMID:11756652

  4. Visualizing the complex functions and mechanisms of the anaphase promoting complex/cyclosome (APC/C)

    Science.gov (United States)

    Alfieri, Claudio; Zhang, Suyang

    2017-01-01

    The anaphase promoting complex or cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that orchestrates cell cycle progression by mediating the degradation of important cell cycle regulators. During the two decades since its discovery, much has been learnt concerning its role in recognizing and ubiquitinating specific proteins in a cell-cycle-dependent manner, the mechanisms governing substrate specificity, the catalytic process of assembling polyubiquitin chains on its target proteins, and its regulation by phosphorylation and the spindle assembly checkpoint. The past few years have witnessed significant progress in understanding the quantitative mechanisms underlying these varied APC/C functions. This review integrates the overall functions and properties of the APC/C with mechanistic insights gained from recent cryo-electron microscopy (cryo-EM) studies of reconstituted human APC/C complexes. PMID:29167309

  5. Novel APC gene mutations associated with protein alteration in diffuse type gastric cancer.

    Science.gov (United States)

    Ghatak, Souvik; Chakraborty, Payel; Sarkar, Sandeep Roy; Chowdhury, Biswajit; Bhaumik, Arup; Kumar, Nachimuthu Senthil

    2017-06-02

    The role of adenomatous polyposis coli (APC) gene in mitosis might be critical for regulation of genomic stability and chromosome segregation. APC gene mutations have been associated to have a role in colon cancer and since gastric and colon tumors share some common genetic lesions, it is relevant to investigate the role of APC tumor suppressor gene in gastric cancer. We investigated for somatic mutations in the Exons 14 and 15 of APC gene from 40 diffuse type gastric cancersamples. Rabbit polyclonal anti-APC antibody was used, which detects the wild-type APC protein and was recommended for detection of the respective protein in human tissues. Cell cycle analysis was done from tumor and adjacent normal tissue. APC immunoreactivity showed positive expression of the protein in stages I, II, III and negative expression in Stages III and IV. Two novel deleterious variations (g.127576C > A, g.127583C > T) in exon 14 sequence were found to generate stop codon (Y622* and Q625*)in the tumor samples. Due to the generation of stop codon, the APC protein might be truncated and all the regulatory features could be lost which has led to the down-regulation of protein expression. Our results indicate that aneuploidy might occurdue to the codon 622 and 625 APC-driven gastric tumorigenesis, in agreement with our cell cycle analysis. The APC gene function in mitosis and chromosomal stability might be lost and G1 might be arrested with high quantity of DNA in the S phase. Six missense somatic mutations in tumor samples were detected in exon 15 A-B, twoof which showed pathological and disease causing effects based on SIFT, Polyphen2 and SNPs & GO score and were not previously reported in the literature or the public mutation databases. The two novel pathological somatic mutations (g.127576C > A, g.127583C > T) in exon 14 might be altering the protein expression leading to development of gastric cancer in the study population. Our study showed that mutations in the APC

  6. FOETOMATERNAL AND NEONATAL OUTCOME OF PRETERM PREMATURE RUPTURE OF MEMBRANES

    Directory of Open Access Journals (Sweden)

    Kusumam Vilangot Nhalil

    2017-10-01

    Full Text Available BACKGROUND Preterm premature rupture of membrane is defined as rupture of foetal membrane before onset of labour at less than 37 completed weeks of gestation. Incidence of PPROM is around 3-10% of all deliveries. Primary complication for mother is infection and for foetus and neonate is prematurity, foetal distress, cord compression, deformation, pulmonary hypoplasia, necrotising enterocolitis and neurologic disorders. Most likely outcome is preterm delivery within 1 week. The aim of the study is to study the foetomaternal and neonatal outcome in PPROM patients and the common prevalent organism in PPROM. MATERIALS AND METHODS This is a cohort study of pregnant women from 24-37 weeks with PPROM admitted to IMCH for a period of 1 year, January 2016 to December 2016. 100 patients with PPROM were taken up for the study. The data was collected using the following inclusion and exclusion criteria. Inclusion criteria are gestational age 24-37 weeks confirmed by dates, clinical examination and ultrasound with lack of uterine contractions for at least 1 hour from PPROM; single live pregnancy in vertex presentation; PPROM confirmed by direct visualisation, neonates admitted in NICU soon after delivery. RESULTS 49% of patients with preterm premature rupture of membranes were from 18-24 years.68% of patients had a latency period of 3 weeks.15% of patients had maternal tachycardia, 4% had tenderness of uterus and 4% had leucocytosis and 14% had an elevated CRP. Thus, clinical chorioamnionitis was seen in 14% of patients, 38% of babies born had prematurity and 2% had sepsis and 19% had respiratory distress syndrome and hyperbilirubinaemia, 2% had perinatal asphyxia, 2% had anomalies, 1% had necrotising enterocolitis and 5% were NND. Common organisms were normal flora, E. coli, Streptococci and Enterococci. CONCLUSION PPROM increases the incidence of maternal morbidity with longer hospital stay due to chorioamnionitis. Neonatal morbidity is increased due to

  7. Outcomes for Extremely Premature Infants

    Science.gov (United States)

    Glass, Hannah C.; Costarino, Andrew T.; Stayer, Stephen A.; Brett, Claire; Cladis, Franklyn; Davis, Peter J.

    2015-01-01

    Premature birth is a significant cause of infant and child morbidity and mortality. In the United States, the premature birth rate, which had steadily increased during the 1990s and early 2000s, has decreased annually for four years and is now approximately 11.5%. Human viability, defined as gestational age at which the chance of survival is 50%, is currently approximately 23–24 weeks in developed countries. Infant girls, on average, have better outcomes than infant boys. A relatively uncomplicated course in the intensive care nursery for an extremely premature infant results in a discharge date close to the prenatal EDC. Despite technological advances and efforts of child health experts during the last generation, the extremely premature infant (less than 28 weeks gestation) and extremely low birth weight infant (ELBW) (CPAP, mechanical ventilation, and exogenous surfactant increased survival and spurred the development of neonatal intensive care in the 1970s through the early 1990s. Routine administration of antenatal steroids during premature labor improved neonatal mortality and morbidity in the late 1990s. The recognition that chronic postnatal administration of steroids to infants should be avoided may have improved outcomes in the early 2000s. Evidence from recent trials attempting to define the appropriate target for oxygen saturation in preterm infants suggests arterial oxygen saturation between 91–95% (compared to 85–89%) avoids excess mortality. However, final analyses of data from these trials have not been published, so definitive recommendations are still pending The development of neonatal neurocognitive care visits may improve neurocognitive outcomes in this high-risk group. Long-term follow up to detect and address developmental, learning, behavioral, and social problems is critical for children born at these early gestational ages. The striking similarities in response to extreme prematurity in the lung and brain imply that agents and

  8. APC fly ashes stabilized with Portland cement for further development of road sub-base aggregates

    Science.gov (United States)

    Formosa, J.; Giro-Paloma, J.; Maldonado-Alameda, A.; Huete-Hernández, S.; Chimenos, J. M.

    2017-10-01

    Although waste-to-energy plants allow reducing the mass and volume of municipal solid waste (MSW) incinerated, an average around 30 % of the total content remains as bottom ash (BA) and air pollution control (APC) ashes at the end of combustion process. While weathered bottom ash (WBA) is considered a non-hazardous residue that can be revalorized as a secondary aggregate, APC fly ashes generated during the flue gas treatment are classified as hazardous waste and are handled in landfill disposal after stabilization, usually with Portland cement (OPC). However, taking into account the amount of APC residues produced and the disposing cost in landfill, their revalorization is an important issue that could be effectively addressed. As MSW can be incinerated producing bottom ashes (BA) or air pollutant control (APC) residues, the development of a mortar formulated with APC fly ash as secondary building material is a significant risk to the environment for their content of heavy metals. In this way, Design of Experiment (DoE) was used for the improvement of granular material (GM) formulation composed by APC and OPC for further uses as road sub-base aggregate. DoE analysis was successful in the modelling and optimization the formulation as function of the mechanical properties and APC amount. Consequently, an optimal mortar formulation (OMF) of around 50 wt.% APC and 50 wt.% OPC was considered. The OMF leachates and abrasion resistance have been analyzed. These results have demonstrated the viability of OMF as non-hazardous material feasible to be used as secondary aggregate. Moreover, it would be possible to consider the environmental assessment of a GM composed by ≈20 wt.% of OMF and ≈80 wt.% of WBA in order to improve mechanical properties and heavy metals stabilization.

  9. Use of operator training and simulating complexes for development of NPP APCS

    International Nuclear Information System (INIS)

    Malkin, S.D.; Rakitin, I.D.; Sivokon', V.P.

    2002-01-01

    The evolution of NPP educational facilities - from systems of training of personnel to power simulating systems for the development of Automatic Process Control System (APCS) and safety analysis is followed. High efficiency of simulating systems application for the development of NPP APCS including optimization of man-machine system interface was shown by experiments of USA, France, Japan, United Kingdom, conforming examples were given [ru

  10. Irradiated Foods Detection by Thermoluminescence (TL) and DEFT/APC Analysis

    International Nuclear Information System (INIS)

    Choi, I.D.; Kang, E.K.; Yang, J.S.

    2004-01-01

    Irradiated food detection methods such as Thermoluminescence (TL) and Direct Epifluorescent Filter Technique and Aerobic Plate Count (DEFT/APC) methods were evaluated. Fresh green-onion, onion, and ginger were irradiated at 0, 0.3, 0.6, and 0.9 kGy. Difference in log DEFT/APC units between irradiated and un-irradiated samples was less than 2 long units, below the average threshold value (3-4 long units) of international researches

  11. Prevalence of Resistence to Activated Protein C (Apc-Resistance in Blood Donors in Kosovo

    Directory of Open Access Journals (Sweden)

    Ymer Mekaj

    2009-11-01

    Full Text Available AbstractOne of the most frequent hereditary causes of thrombophilia is, without a doubt, resistance to Activated Protein C (APC-resistance, which is a consequence of point mutation in gene coding for coagulation Factor V (Factor V Leiden in 90-95% of cases.The aim of this paper was to determine prevalence of APC-resistance in a group of healthy blood donors. The size of the group is quite representative of Kosovo Albanians.A total of 944 blood donors were examined (537 males and 407 females, for whom APC-resistance was determined by functional methods of coagulation using the kit ACTICLOT® Protein C Resistance. Method is based on the test of APTT determined twice: first in the presence and second in the absence of activated Protein C (APC. The ratio of these two values constitutes is called Activated Protein C - Sensitivity Ratio (APC-SR.From 944 examined donors, pathologic values of APC-SR (1,3-1,9 were found in 32 persons (3,4% of the total number. The distribution among sexes was 3,35% (18/537 in male and 3,43% (14/407 in female subjects. The mean values of APC-SR (1,64 in male and 1,71 in female subjects were not significantly different (P = 0,22.Based on these results, we conclude that the prevalence of APC resistance in Albanian population of Kosovo is within the lower limit of prevalence in general population in different countries of European countries, which, according to some authors ranges is from 3 to 7%.

  12. Ubiquitination of Cdc20 by the APC occurs through an intramolecular mechanism

    Science.gov (United States)

    Foe, Ian T.; Foster, Scott A.; Cheung, Stephanie K.; DeLuca, Steven Z.; Morgan, David O.; Toczyski, David P.

    2012-01-01

    SUMMARY Background Cells control progression through late mitosis by regulating Cdc20 and Cdh1, the two mitotic activators of the Anaphase Promoting Complex (APC). The control of Cdc20 protein levels during the cell cycle is not well understood. Results Here, we demonstrate that Cdc20 is degraded in budding yeast by multiple APC-dependent mechanisms. We find that the majority of Cdc20 turnover does not involve a second activator molecule, but instead depends on in cis Cdc20 autoubiquitination while it is bound to its activator-binding site on the APC core. Unlike in trans ubiquitination of Cdc20 substrates, the APC ubiquitinates Cdc20 independent of APC activation by Cdc20’s C-box. Cdc20 turnover by this intramolecular mechanism is cell cycle-regulated, contributing to the decline in Cdc20 levels that occurs after anaphase. Interestingly, high substrate levels in vitro significantly reduce Cdc20 autoubiquitination. Conclusion We show here that Cdc20 fluctuates through the cell cycle via a distinct form of APC-mediated ubiquitination. This in cis autoubiquitination may preferentially occur in early anaphase, following depletion of Cdc20 substrates. This suggests that distinct mechanisms are able to target Cdc20 for ubiquitination at different points during the cell cycle. PMID:22079111

  13. The APC/C Ubiquitin Ligase: From Cell Biology to Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Penas, Clara; Ramachandran, Vimal [John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL (United States); Ayad, Nagi George, E-mail: nayad@med.miami.edu [John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL (United States); Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL (United States)

    2012-01-09

    The ubiquitin proteasome system (UPS) is required for normal cell proliferation, vertebrate development, and cancer cell transformation. The UPS consists of multiple proteins that work in concert to target a protein for degradation via the 26S proteasome. Chains of an 8.5-kDa protein called ubiquitin are attached to substrates, thus allowing recognition by the 26S proteasome. Enzymes called ubiquitin ligases or E3s mediate specific attachment to substrates. Although there are over 600 different ubiquitin ligases, the Skp1–Cullin–F-box (SCF) complexes and the anaphase promoting complex/cyclosome (APC/C) are the most studied. SCF involvement in cancer has been known for some time while APC/C’s cancer role has recently emerged. In this review we will discuss the importance of APC/C to normal cell proliferation and development, underscoring its possible contribution to transformation. We will also examine the hypothesis that modulating a specific interaction of the APC/C may be therapeutically attractive in specific cancer subtypes. Finally, given that the APC/C pathway is relatively new as a cancer target, therapeutic interventions affecting APC/C activity may be beneficial in cancers that are resistant to classical chemotherapy.

  14. Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ mice

    Science.gov (United States)

    Cleveland, Alicia G.; Oikarinen, Seija I.; Bynoté, Kimberly K.; Marttinen, Maija; Rafter, Joseph J.; Gustafsson, Jan-Åke; Roy, Shyamal K.; Pitot, Henry C.; Korach, Kenneth S.; Lubahn, Dennis B.; Mutanen, Marja; Gould, Karen A.

    2009-01-01

    Estrogen receptors (ERs) [ERα (Esr1) and ERβ (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ERα and ERβ is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ERα knockout and ApcMin mouse strains, we demonstrate that ERα deficiency is associated with a significant increase in intestinal tumor multiplicity, size and burden in ApcMin/+ mice. Within the normal intestinal epithelium of ApcMin/+ mice, ERα deficiency is associated with an accumulation of nuclear β-catenin, an indicator of activation of the Wnt–β-catenin-signaling pathway, which is known to play a critical role in intestinal cancers. Consistent with the hypothesis that ERα deficiency is associated with activation of Wnt–β-catenin signaling, ERα deficiency in the intestinal epithelium of ApcMin/+ mice also correlated with increased expression of Wnt–β-catenin target genes. Through crosses between an ERβ knockout and ApcMin mouse strains, we observed some evidence that ERβ deficiency is associated with an increased incidence of colon tumors in ApcMin/+ mice. This effect of ERβ deficiency does not involve modulation of Wnt–β-catenin signaling. Our studies suggest that ERα and ERβ signaling modulate colorectal carcinogenesis, and ERα does so, at least in part, by regulating the activity of the Wnt–β-catenin pathway. PMID:19520794

  15. Upregulation of miR-3607 promotes lung adenocarcinoma proliferation by suppressing APC expression.

    Science.gov (United States)

    Lin, Yong; Gu, Qiangye; Sun, Zongwen; Sheng, Baowei; Qi, Congcong; Liu, Bing; Fu, Tian; Liu, Cun; Zhang, Yan

    2017-11-01

    Lung cancer is the leading cause of worldwide cancer-related deaths, although many drugs and new therapeutic approaches have been used, the 5-years survival rate is still low for lung cancer patients. microRNAs have been shown to regulate lung cancer initiation and development, here we studied the role of miR-3607 in lung cancer cell proliferation. We found miR-3607 was upregulated in lung cancer tissues and cells, miR-3607 overexpression promoted lung cancer cell A549 proliferation determined by MTT assay, colony formation assay, anchorage-independent growth ability assay and bromodeoxyuridine incorporation assay, while the opposite phenotypes were shown when miR-3607 was knocked down. Predicted analysis suggested a Wnt signaling pathway regulator adenomatous polyposis coli (APC) was the target of miR-3607, miR-3607 could directly bind to the 3'UTR of APC, and promoted Cyclin D1 and c-Myc expression which can be suppressed by APC. Double knockdown of miR-3607 and APC copied the phenotypes of miR-3607 overexpression, suggesting miR-3607 promoted lung cancer cell A549 proliferation by targeting APC. In conclusion, our study suggested miR-3607 contributes to lung cancer cell proliferation by inhibiting APC. Copyright © 2017. Published by Elsevier Masson SAS.

  16. The APC/C Ubiquitin Ligase: From Cell Biology to Tumorigenesis

    International Nuclear Information System (INIS)

    Penas, Clara; Ramachandran, Vimal; Ayad, Nagi George

    2012-01-01

    The ubiquitin proteasome system (UPS) is required for normal cell proliferation, vertebrate development, and cancer cell transformation. The UPS consists of multiple proteins that work in concert to target a protein for degradation via the 26S proteasome. Chains of an 8.5-kDa protein called ubiquitin are attached to substrates, thus allowing recognition by the 26S proteasome. Enzymes called ubiquitin ligases or E3s mediate specific attachment to substrates. Although there are over 600 different ubiquitin ligases, the Skp1–Cullin–F-box (SCF) complexes and the anaphase promoting complex/cyclosome (APC/C) are the most studied. SCF involvement in cancer has been known for some time while APC/C’s cancer role has recently emerged. In this review we will discuss the importance of APC/C to normal cell proliferation and development, underscoring its possible contribution to transformation. We will also examine the hypothesis that modulating a specific interaction of the APC/C may be therapeutically attractive in specific cancer subtypes. Finally, given that the APC/C pathway is relatively new as a cancer target, therapeutic interventions affecting APC/C activity may be beneficial in cancers that are resistant to classical chemotherapy.

  17. Atomic structure of the APC/C and its mechanism of protein ubiquitination

    Science.gov (United States)

    Yang, Jing; McLaughlin, Stephen H.; Barford, David

    2015-01-01

    The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit. Its regulation by coactivator subunits, phosphorylation, the mitotic checkpoint complex, and interphase inhibitor Emi1 ensures the correct order and timing of distinct cell cycle transitions. Here, we used cryo-electron microscopy to determine atomic structures of APC/C-coactivator complexes with either Emi1 or a UbcH10-ubiquitin conjugate. These structures define the architecture of all APC/C subunits, the position of the catalytic module, and explain how Emi1 mediates inhibition of the two E2s UbcH10 and Ube2S. Definition of Cdh1 interactions with the APC/C indicates how they are antagonized by Cdh1 phosphorylation. The structure of the APC/C with UbcH10-ubiquitin reveals insights into the initiating ubiquitination reaction. Our results provide a quantitative framework for the design of experiments to further investigate APC/C functions in vivo. PMID:26083744

  18. The APC/C Ubiquitin Ligase: From Cell Biology to Tumorigenesis

    Science.gov (United States)

    Penas, Clara; Ramachandran, Vimal; Ayad, Nagi George

    2011-01-01

    The ubiquitin proteasome system (UPS) is required for normal cell proliferation, vertebrate development, and cancer cell transformation. The UPS consists of multiple proteins that work in concert to target a protein for degradation via the 26S proteasome. Chains of an 8.5-kDa protein called ubiquitin are attached to substrates, thus allowing recognition by the 26S proteasome. Enzymes called ubiquitin ligases or E3s mediate specific attachment to substrates. Although there are over 600 different ubiquitin ligases, the Skp1–Cullin–F-box (SCF) complexes and the anaphase promoting complex/cyclosome (APC/C) are the most studied. SCF involvement in cancer has been known for some time while APC/C’s cancer role has recently emerged. In this review we will discuss the importance of APC/C to normal cell proliferation and development, underscoring its possible contribution to transformation. We will also examine the hypothesis that modulating a specific interaction of the APC/C may be therapeutically attractive in specific cancer subtypes. Finally, given that the APC/C pathway is relatively new as a cancer target, therapeutic interventions affecting APC/C activity may be beneficial in cancers that are resistant to classical chemotherapy. PMID:22655255

  19. APC binds the Miro/Milton motor complex to stimulate transport of mitochondria to the plasma membrane.

    Science.gov (United States)

    Mills, Kate M; Brocardo, Mariana G; Henderson, Beric R

    2016-02-01

    Mutations in adenomatous polyposis coli (APC) disrupt regulation of Wnt signaling, mitosis, and the cytoskeleton. We describe a new role for APC in the transport of mitochondria. Silencing of wild-type APC by small interfering RNA caused mitochondria to redistribute from the cell periphery to the perinuclear region. We identified novel APC interactions with the mitochondrial kinesin-motor complex Miro/Milton that were mediated by the APC C-terminus. Truncating mutations in APC abolished its ability to bind Miro/Milton and reduced formation of the Miro/Milton complex, correlating with disrupted mitochondrial distribution in colorectal cancer cells that could be recovered by reconstitution of wild-type APC. Using proximity ligation assays, we identified endogenous APC-Miro/Milton complexes at mitochondria, and live-cell imaging showed that loss of APC slowed the frequency of anterograde mitochondrial transport to the membrane. We propose that APC helps drive mitochondria to the membrane to supply energy for cellular processes such as directed cell migration, a process disrupted by cancer mutations. © 2016 Mills et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  20. The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc Min/+ mice.

    Science.gov (United States)

    Ono, Junya; Shime, Hiroaki; Takaki, Hiromi; Takashima, Ken; Funami, Kenji; Yoshida, Sumito; Takeda, Yohei; Matsumoto, Misako; Kasahara, Masanori; Seya, Tsukasa

    2017-10-17

    Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc Min/+ mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway. We established Apc Min/+ Ticam1 -/- mice and their survival was compared to survival of Apc Min/+ Myd88 -/- and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis. We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc Min/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc Min/+ background. Polyps were more frequently formed in the distal intestine of Apc Min/+ Ticam1 -/- mice than in Apc Min/+ mice. Infiltration of immune cells such as CD11b + and CD8α + cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc Min/+ Ticam1 -/- mice compared to Apc Min/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Min/+ Ticam1 -/- mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Min/+ Ticam1 -/- mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc Min/+ mice. These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc Min/+ mice.

  1. Contract Renewal Information - all Contracts

    Data.gov (United States)

    Department of Housing and Urban Development — Multifamily Portfolio datasets (section 8 contracts) - The information has been compiled from multiple data sources within FHA or its contractors. HUD oversees more...

  2. Contract theory and EU Contract Law

    OpenAIRE

    Hesselink, M.W.; Twigg-Flesner, C.

    2016-01-01

    This paper explores the relationship between contract theory and European contract law. In particular, it confronts the leading contract law theories with the main characteristics of EU contract law. The conclusion is that the two do not match well. In particular, monist normative contract theories are largely irreconcilable with the contract law of the EU. The paper further addresses the main implications of this mismatch, both for contract theory and for EU contract law. It suggests that in...

  3. Living with uncertainty: a Swedish qualitative interview study of women at home on sick leave due to premature labour.

    Science.gov (United States)

    Höglund, Eva; Dykes, Anna-Karin

    2013-05-01

    to highlight the experiences of pregnant women, experiencing preterm labour, being on sick leave at home and how they handled their daily life. qualitative, descriptive using open interviews. 10 antenatal clinics in the south of Sweden. 15 pregnant women who were on sick leave for premature labour. four categories were identified: how to interpret unpredictable contractions in the uterus? Having concern regarding premature labour of their child, handling the new situation and finding a balance, and from work to sick leave. to be on sick leave for premature contractions can be compared with enduring a situation of inactivity. The woman finds herself in a stressful situation which she must learn to handle this and find a balance. it appears that supportive information offers the women in premature labour the opportunity of increased participation and responsibility which thereby positively affects her well-being. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas

    International Nuclear Information System (INIS)

    Sæbø, Mona; Skjelbred, Camilla F; Breistein, Rebecca; Lothe, Inger Marie B; Hagen, Per Chr; Bock, Gunter; Hansteen, Inger-Lise; Kure, Elin H

    2006-01-01

    The association between colorectal cancer (CRC) and smoking has not been consistent. Incomplete smoking history and association to a specific subset of CRC tumors have been proposed as explanations. The adenomatous polyposis coli (APC) gene has been reported to have a 'gatekeeper' function in the colonic mucosa. To evaluate the hypothesis that cigarette smoking is associated with adenoma and carcinoma development and further to investigate whether this association is due to mutations in the APC gene, we used a study population consisting of 133 cases (45 adenomas and 88 carcinomas) and 334 controls. All tumors were sequenced in the mutation cluster region (MCR) of the APC gene. Cases and controls were drawn from a homogeneous cohort of Norwegian origin. The mutational spectra of the APC gene revealed no difference in frequencies of mutations in cases based on ever and never smoking status. An overall case-control association was detected for adenomas and 'ever smoking' OR = 1.73 (95% CI 0.83–3.58). For CRC cases several smoking parameters for dose and duration were used. We detected an association for all smoking parameters and 'duration of smoking > 30 years', yielded a statistically significant OR = 2.86 (1.06–7.7). When cases were divided based on APC truncation mutation status, an association was detected in adenomas without APC mutation in relation to 'ever smoking', with an OR = 3.97 (1.26–12.51). For CRC cases without APC mutation 'duration of smoking > 30 years', yielded a statistically significant OR = 4.06 (1.20–13.7). The smoking parameter 'starting smoking ≥ 40 years ago' was only associated with CRC cases with APC mutations, OR = 2.0 (0.34–11.95). A case-case comparison revealed similar findings for this parameter, OR = 2.24 (0.73–6.86). Our data suggest an association between smoking and adenoma and CRC development. This association was strongest for cases without APC truncation

  5. α2-Macroglobulin Is a Significant In Vivo Inhibitor of Activated Protein C and Low APC:α2M Levels Are Associated with Venous Thromboembolism.

    Science.gov (United States)

    Martos, Laura; Ramón, Luis Andrés; Oto, Julia; Fernández-Pardo, Álvaro; Bonanad, Santiago; Cid, Ana Rosa; Gruber, Andras; Griffin, John H; España, Francisco; Navarro, Silvia; Medina, Pilar

    2018-04-01

     Activated protein C (APC) is a major regulator of thrombin formation. Two major plasma inhibitors form complexes with APC, protein C inhibitor (PCI) and α 1 -antitrypsin (α 1 AT), and these complexes have been quantified by specific enzyme-linked immunosorbent assays (ELISAs). Also, complexes of APC with α 2 -macroglobulin (α 2 M) have been observed by immunoblotting. Here, we report an ELISA for APC:α 2 M complexes in plasma.  Plasma samples were pre-treated with dithiothreitol and then with iodoacetamide. The detection range of the newly developed APC:α 2 M assay was 0.031 to 8.0 ng/mL of complexed APC. Following infusions of APC in humans and baboons, complexes of APC with α 2 M, PCI and α 1 AT were quantified. These complexes as well as circulating APC were also measured in 121 patients with a history of venous thromboembolism (VTE) and 119 matched controls.  In all the in vivo experiments, α 2 M was a significant APC inhibitor. The VTE case-control study showed that VTE patients had significantly lower APC:α 2 M and APC levels than the controls ( p  APC:α 2 M or the lowest quartile of APC had approximately four times more VTE risk than those in the highest quartile of APC:α 2 M or of APC. The risk increased for individuals with low levels of both parameters.  The APC:α 2 M assay reported here may be useful to help monitor the in vivo fate of APC in plasma. In addition, our results show that a low APC:α 2 M level is associated with increased VTE risk. Schattauer GmbH Stuttgart.

  6. Agile Contracts

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Pries-Heje, Lene

    2014-01-01

    with “endless” re-negotiation of the requirements; you need a more flexible way to develop IS. A new way of coping with many changes is to use an agile development approach and a fixed budget and resources contract. This paper presents an example case. We analyse the case and design a guideline for how......When you have stable and non-ambiguous requirements then a classic contract for IS between a supplier and a public sector institution based on a requirements specification may be well suited. However, if you have to accept many changes or have ambiguous requirements then you may end up...... to implement a fixed budget and resources contract in the public sector. The guideline includes elements to cope with challenges in a tender process such as transparency, criteria for supplier selection, and live assessment of resource skills and capabilities, as well as achieving the flexibility for change...

  7. Turnkey contracts

    International Nuclear Information System (INIS)

    Langetepe, G.

    1977-01-01

    To make energy available economically and in sufficient quantity is a main point for the future of an industrial and more for a developing country. The investment costs and the availability of a power plant and in particular for a nuclear power plant are the most significant factors in the economic operation of the plant. In the phase before signing the contract the essential decisions are made with high influence in the economic operation and the availability of the plant. A turn-key contract offers good possibilities to minimize the risks referring a) the plant quality and functionality, b) the plant investment cost, c) the plant completion date, d) the handling of the licensing procedures, e) the availability of the operation. The lecture mentions the points which are of high influence for a successful erection and operation period and which must be clarified before signing the contract between the buyer and supplier of the plant. (orig./HP) [de

  8. Human APC sequesters beta-catenin even in the absence of GSK-3beta in a Drosophila model.

    Science.gov (United States)

    Rao, P R; Makhijani, K; Shashidhara, L S

    2008-04-10

    There have been conflicting reports on the requirement of GSK-3beta-mediated phosphorylation of the tumor suppressor adenomatous polyposis coli (APC) vis-à-vis its ability to bind and degrade beta-catenin. Using a unique combination of loss of function for Shaggy/GSK-3beta and a gain of function for human APC in Drosophila, we show that misexpressed human APC (hAPC) can still sequester Armadillo/beta-catenin. In addition, human APC could suppress gain of Wnt/Wingless phenotypes associated with loss of Shaggy/GSK-3beta activity, suggesting that sequestered Armadillo/beta-catenin is non-functional. Based on these studies, we propose that binding per se of beta-catenin by APC does not require phosphorylation by GSK-3beta.

  9. Detection and Analysis of Cell Cycle-Associated APC/C-Mediated Cellular Ubiquitylation In Vitro and In Vivo.

    Science.gov (United States)

    Cedeño, Cesyen; La Monaca, Esther; Esposito, Mara; Gutierrez, Gustavo J

    2016-01-01

    The anaphase-promoting complex or cyclosome (APC/C) is one of the major orchestrators of the cell division cycle in mammalian cells. The APC/C acts as a ubiquitin ligase that triggers sequential ubiquitylation of a significant number of substrates which will be eventually degraded by proteasomes during major transitions of the cell cycle. In this chapter, we present accessible methodologies to assess both in in vitro conditions and in cellular systems ubiquitylation reactions mediated by the APC/C. In addition, we also describe techniques to evidence the changes in protein stability provoked by modulation of the activity of the APC/C. Finally, specific methods to analyze interactors or posttranslational modifications of particular APC/C subunits are also discussed. Given the crucial role played by the APC/C in the regulation of the cell cycle, this review only focuses on its action and effects in actively proliferating cells.

  10. Meta-analysis of the association between APC promoter methylation and colorectal cancer.

    Science.gov (United States)

    Ding, Zhenyu; Jiang, Tong; Piao, Ying; Han, Tao; Han, Yaling; Xie, Xiaodong

    2015-01-01

    Previous studies investigating the association between adenomatous polyposis coli (APC) gene promoter methylation and colorectal cancer (CRC) have yielded conflicting results. The aim of this study was to comprehensively evaluate the potential application of the detection of APC promoter methylation to the prevention and treatment of CRC. PubMed, Embase, and MEDLINE (results updated to October 2014) were searched for relevant studies. The effect size was defined as the weighted odds ratio (OR), which was calculated using either the fixed-effects or random-effects model. Prespecified subgroup and sensitivity analyses were conducted to evaluate potential heterogeneity among the included studies. Nineteen studies comprising 2,426 participants were selected for our meta-analysis. The pooled results of nine studies comprising a total of 740 subjects indicated that APC promoter methylation was significantly associated with CRC risk (pooled OR 5.53; 95% confidence interval [CI] 3.50-8.76; PAPC promoter methylation and the presence of CRC metastasis, and the pooled OR was 0.80 (95% CI 0.44-1.46; P=0.47). A meta-analysis conducted with four studies with a total of 467 patients found no significant correlation between APC promoter methylation and the presence of colorectal adenoma (pooled OR 1.85; 95% CI 0.67-5.10; P=0.23). No significant correlation between APC promoter methylation and patients' Dukes' stage, TNM stage, differentiation grade, age, or sex was identified. In conclusion, APC promoter methylation was found to be significantly associated with a higher risk of developing CRC. The findings indicate that APC promoter methylation may be a potential biomarker for the carcinogenesis of CRC.

  11. Efficacy and safety of Hybrid-APC for the ablation of Barrett's esophagus.

    Science.gov (United States)

    Manner, Hendrik; May, Andrea; Kouti, Ioanna; Pech, Oliver; Vieth, Michael; Ell, Christian

    2016-04-01

    After thermal ablation of Barrett's esophagus (BE), stricture formation is reported in 5 to over 10% of patients. The question arises whether submucosal fluid injection prior to ablation may lower the risk of stricture formation. The aim of the present study was to evaluate the efficacy and safety of the new technique of Hybrid-APC which combines submucosal injection with APC. Patients who had a residual BE segment of at least 1 cm after endoscopic resection of early Barrett's neoplasia underwent thermal ablation of BE by Hybrid-APC. Prior to thermal ablation, submucosal injection of sodium chloride 0.9% was carried out using a flexible water-jet probe (Erbejet 2; Erbe Elektromedizin, Tuebingen, Germany). Check-up upper GI endoscopy was carried out 3 months after macroscopically complete ablation including biopsies from the neo-Z-line and the former BE segment, and recording of stricture formation. From May 2011 to November 2012, a total of 60 patients (pt) were included in the study [55 pt male (92%); mean age 62 ± 9 years, range 42-79]. Ten patients were excluded from the study. In the remaining 50 pt, Hybrid-APC ablation and check-up endoscopy at 3 months were carried out. Forty-eight out of 50 pt (96%; ITT: 49/60, 82%) achieved macroscopically complete remission after a median of 3.5 APC sessions [SD 2.4; range 1-10]. Freedom from BE was histopathologically observed in 39/50 patients (78%). There was one treatment-related stricture (2%). Minor adverse events of Hybrid-APC were observed in 11 patients (22%). According to this pilot series, Hybrid-APC was effective and safe for BE ablation in a tertiary referral center. The rate of stricture formation was only 2%. Further studies are required to confirm the present results. DRKS00003369.

  12. APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors.

    Science.gov (United States)

    Ginesta, Mireia M; Diaz-Riascos, Zamira Vanessa; Busquets, Juli; Pelaez, Núria; Serrano, Teresa; Peinado, Miquel Àngel; Jorba, Rosa; García-Borobia, Francisco Javier; Capella, Gabriel; Fabregat, Joan

    2016-09-01

    Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71-80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms.

  13. The Spindle Assembly Checkpoint Is Not Essential for Viability of Human Cells with Genetically Lowered APC/C Activity.

    Science.gov (United States)

    Wild, Thomas; Larsen, Marie Sofie Yoo; Narita, Takeo; Schou, Julie; Nilsson, Jakob; Choudhary, Chunaram

    2016-03-01

    The anaphase-promoting complex/cyclosome (APC/C) and the spindle assembly checkpoint (SAC), which inhibits the APC/C, are essential determinants of mitotic timing and faithful division of genetic material. Activation of the APC/C is known to depend on two APC/C-interacting E2 ubiquitin-conjugating enzymes-UBE2C and UBE2S. We show that APC/C activity in human cells is tuned by the combinatorial use of three E2s, namely UBE2C, UBE2S, and UBE2D. Genetic deletion of UBE2C and UBE2S, individually or in combination, leads to discriminative reduction in APC/C function and sensitizes cells to UBE2D depletion. Reduction of APC/C activity results in loss of switch-like metaphase-to-anaphase transition and, strikingly, renders cells insensitive to chemical inhibition of MPS1 and genetic ablation of MAD2, both of which are essential for the SAC. These results provide insights into the regulation of APC/C activity and demonstrate that the essentiality of the SAC is imposed by the strength of the APC/C. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Detection of irradiated food by using direct epifluorescent filter technique/aerobic plate count method (DEFT/APC)

    International Nuclear Information System (INIS)

    Zhao Yongfu; Li Lili; Wang Changbao; Ji Ping; Wang Chao; Wang Zhidong

    2010-01-01

    The Direct Epifluorescent Filter Technique/Aerobic Plate Count technique(DEFT/APC) can be used to identify the irradiated food by comparing the DEFT and APC counts of the samples prior to the irradiation and after. This technology was tested by using spice and dried marine fish as testing materials in this study. The results shows that the index, log (DEFT/APC) > 4.0, can indicate that the samples have been irradiated at a dose level higher than 1.0 kGy. It also indicates that the detecting sensitivity was affected by the initial value of APC and D 10 value of the samples. (authors)

  15. Proteomic analysis reveals APC-dependent post-translational modifications and identifies a novel regulator of β-catenin.

    Science.gov (United States)

    Blundon, Malachi A; Schlesinger, Danielle R; Parthasarathy, Amritha; Smith, Samantha L; Kolev, Hannah M; Vinson, David A; Kunttas-Tatli, Ezgi; McCartney, Brooke M; Minden, Jonathan S

    2016-07-15

    Wnt signaling generates patterns in all embryos, from flies to humans, and controls cell fate, proliferation and metabolic homeostasis. Inappropriate Wnt pathway activation results in diseases, including colorectal cancer. The adenomatous polyposis coli (APC) tumor suppressor gene encodes a multifunctional protein that is an essential regulator of Wnt signaling and cytoskeletal organization. Although progress has been made in defining the role of APC in a normal cellular context, there are still significant gaps in our understanding of APC-dependent cellular function and dysfunction. We expanded the APC-associated protein network using a combination of genetics and a proteomic technique called two-dimensional difference gel electrophoresis (2D-DIGE). We show that loss of Drosophila Apc2 causes protein isoform changes reflecting misregulation of post-translational modifications (PTMs), which are not dependent on β-catenin transcriptional activity. Mass spectrometry revealed that proteins involved in metabolic and biosynthetic pathways, protein synthesis and degradation, and cell signaling are affected by Apc2 loss. We demonstrate that changes in phosphorylation partially account for the altered PTMs in APC mutants, suggesting that APC mutants affect other types of PTM. Finally, through this approach Aminopeptidase P was identified as a new regulator of β-catenin abundance in Drosophila embryos. This study provides new perspectives on the cellular effects of APC that might lead to a deeper understanding of its role in development. © 2016. Published by The Company of Biologists Ltd.

  16. Adenomatous polyposis coli (APC) regulates miR17-92 cluster through β-catenin pathway in colorectal cancer.

    Science.gov (United States)

    Li, Yajuan; Lauriola, Mattia; Kim, Donghwa; Francesconi, Mirko; D'Uva, Gabriele; Shibata, Dave; Malafa, Mokenge P; Yeatman, Timothy J; Coppola, Domenico; Solmi, Rossella; Cheng, Jin Q

    2016-09-01

    Adenomatous polyposis coli (APC) mutation is the most common genetic change in sporadic colorectal cancer (CRC). Although deregulations of miRNAs have been frequently reported in this malignancy, APC-regulated miRNAs have not been extensively documented. Here, by using an APC-inducible cell line and array analysis, we identified a total of 26 deregulated miRNAs. Among them, members of miR-17-92 cluster were dramatically inhibited by APC and induced by enforced expression of β-catenin. Furthermore, we demonstrate that activated β-catenin resulted from APC loss binds to and activates the miR-17-92 promoter. Notably, enforced expression of miR-19a overrides APC tumor suppressor activity, and knockdown of miR-19a in cancer cells with compromised APC function reduced their aggressive features in vitro. Finally, we observed that expression of miR-19a significantly correlates with β-catenin levels in colorectal cancer specimens, and it is associated to the aggressive stage of tumor progression. Thus, our study reveals that miR-17-92 cluster is directly regulated by APC/β-catenin pathway and could be a potential therapeutic target in colon cancers with aberrant APC/β-catenin signaling.

  17. Hypermethylated APC in serous carcinoma based on a meta-analysis of ovarian cancer.

    Science.gov (United States)

    Shen, Chunyan; Sheng, Qifang; Zhang, Xiaojie; Fu, Yuling; Zhu, Kemiao

    2016-09-26

    The reduced expression of the Adenomatous polyposis coli (APC) gene, a tumor suppressor gene, through promoter hypermethylation has been reported to play a key role in the carcinogenesis. However, the correlation between APC promoter hypermethylation and ovarian cancer (OC) remains to be clarified. A comprehensive literature search was carried out in related research databases. The overall odds ratio (OR) and corresponding 95 % confidence interval (CI) were used to evaluate the effects of APC promoter hypermethylation on OC and clinicopathological characteristics. Ultimately, 12 eligible studies were used in our study, including 806 OC samples, 429 normal controls, 109 benign lesions and 75 LMP samples. The pooled OR showed that APC promoter hypermethylation was significantly higher in OC than in normal and benign controls (OR = 6.18 and OR = 3.26, respectively). No significant correlation was observed between OC and low malignant potential (LMP) tumors (P = 0.436). In the comparison of OC and normal controls, subgroup analysis based on race showed that the overall OR of APC promoter hypermethylation was significant and similar in Asians and Caucasians (OR = 8.34 and OR = 5.39, respectively). A subgroup analysis based on sample type found that the pooled OR was significantly higher in blood than in tissue (OR = 18.71 and OR = 5.74, respectively). A significant association was not observed between APC promoter hypermethylation and tumor grade or tumor stage. The pooled OR indicated that APC promoter hypermethylation was significantly lower in serous carcinoma than in non-serous carcinoma (OR = 0.56, P = 0.02). No obvious publication bias was detected by Egger's test (all P > 0.05). APC promoter hypermethylation may be linked to the increased risk of OC. It was associated with histological type, but not with tumor grade or tumor stage. Moreover, hypermethylated APC may be a noninvasive biomarker using blood samples. Future

  18. Function of the activated protein C (APC) autolysis loop in activated FVIII inactivation.

    Science.gov (United States)

    Cramer, Thomas J; Gale, Andrew J

    2011-06-01

    Activated protein C (APC) binds to its substrates activated factor V (FVa) and activated factor VIII (FVIIIa) with a basic exosite that consists of loops 37, 60, 70 and the autolysis loop. These loops have a high density of basic residues, resulting in a positive charge on the surface of APC. Many of these residues are important in the interaction of APC with FVa and FVIIIa. The current study focused on the function of the autolysis loop in the interaction with FVIIIa. This loop was previously shown to interact with FVa, and it inhibits APC inactivation by plasma serpins. Charged residues of the autolysis loop were individually mutated to alanine and the activity of these mutants was assessed in functional FVIIIa inactivation assays. The autolysis loop was functionally important for FVIIIa inactivation. Mutation of R306, K311 and R314 each resulted in significantly reduced FVIIIa inactivation. The inactivating cleavages of FVIIIa at R336 and R562 were affected equally by the mutations. Protein S and FV stimulated cleavage at R562 more than cleavage at R336, independent of mutations in the autolysis loop. Together, these results confirmed that the autolysis loop plays a significant role as part of the basic exosite on APC in the interaction with FVIIIa. © 2011 Blackwell Publishing Ltd.

  19. APC-PCI complex levels for screening of AAA in patients with peripheral atherosclerosis.

    Science.gov (United States)

    Zarrouk, Moncef; Keshavarz, Kave; Lindblad, Bengt; Gottsäter, Anders

    2013-11-01

    To evaluate the use of activated protein C-protein C inhibitor (APC-PCI) complex levels for detection of abdominal aortic aneurysm (AAA) in patients with peripheral atherosclerotic disease (PAD). APC-PCI levels and aortic diameter evaluated in 511 PAD patients without previously known AAA followed-up concerning survival for 4.8(0.5) years. AAA was found in 13% of patients. Aortic diameter correlated (r = 0.138; p = 0.002) with APC-PCI levels which were higher (0.40[0.45] vs. 0.30[0.49] μg/l; p = 0.004) in patients with AAA. This difference persisted in multivariate analysis (p = 0.029). A threshold value of APC-PCI ≥0.15 μg/L showed a specificity of 11%, a sensitivity of 97% and a negative predictive value of 96% for an AAA diagnosis. APC-PCI levels were higher in patients with AAA, and showed high sensitivity but low specificity for the diagnosis and can therefore not be considered as a screening tool in PAD patients. An AAA prevalence of 13% in patients with PAD indicates a need for AAA screening within this population.

  20. Naringin, a natural dietary compound, prevents intestinal tumorigenesis in Apc (Min/+) mouse model.

    Science.gov (United States)

    Zhang, Yu-Sheng; Li, Ye; Wang, Yan; Sun, Shi-Yue; Jiang, Tao; Li, Cong; Cui, Shu-Xiang; Qu, Xian-Jun

    2016-05-01

    Naringin is a natural dietary flavonoid compound. We aimed to evaluate the effects of naringin on intestinal tumorigenesis in the adenomatous polyposis coli multiple intestinal neoplasia (Apc (Min/+)) mouse model. Apc (Min/+) mice were given either naringin (150 mg/kg) or vehicle by p.o. gavage daily for 12 consecutive weeks. Mice were killed with ether, and blood samples were collected to assess the concentrations of IL-6 and PGE2. Total intestines were removed, and the number of polyps was examined. Tissue samples of intestinal polyps were subjected to the assays of histopathology, immunohistochemical analysis and Western blotting analysis. Apc (Min/+) mice fed with naringin developed less and smaller polyps in total intestines. Naringin prevented intestinal tumorigenesis without adverse effects. Histopathologic analysis revealed the reduction of dysplastic cells and dysplasia in the adenomatous polyps. The treatments' effects might arise from its anti-proliferation, induction of apoptosis and modulation of GSK-3β and APC/β-catenin signaling pathways. Naringin also exerted its effects on tumorigenesis through anti-chronic inflammation. Naringin prevented intestinal tumorigenesis likely through a collection of activities including anti-proliferation, induction of apoptosis, modulation of GSK-3β and APC/β-catenin pathways and anti-inflammation. Naringin is a potential chemopreventive agent for reducing the risk of colonic cancers.

  1. APC-PC Combined Scheme in Gilbert Two State Model: Proposal and Study

    Science.gov (United States)

    Bulo, Yaka; Saring, Yang; Bhunia, Chandan Tilak

    2017-04-01

    In an automatic repeat request (ARQ) scheme, a packet is retransmitted if it gets corrupted due to transmission errors caused by the channel. However, an erroneous packet may contain both erroneous bits and correct bits and hence it may still contain useful information. The receiver may be able to combine this information from multiple erroneous copies to recover the correct packet. Packet combining (PC) is a simple and elegant scheme of error correction in transmitted packet, in which two received copies are XORed to obtain the bit location of erroneous bits. Thereafter, the packet is corrected by bit inversion of bit located as erroneous. Aggressive packet combining (APC) is a logic extension of PC primarily designed for wireless communication with objective of correcting error with low latency. PC offers higher throughput than APC, but PC does not correct double bit errors if occur in same bit location of erroneous copies of the packet. A hybrid technique is proposed to utilize the advantages of both APC and PC while attempting to remove the limitation of both. In the proposed technique, applications of APC-PC on Gilbert two state model has been studied. The simulation results show that the proposed technique offers better throughput than the conventional APC and lesser packet error rate than PC scheme.

  2. APC promoter 1B deletion in seven American families with familial adenomatous polyposis.

    Science.gov (United States)

    Snow, A K; Tuohy, T M F; Sargent, N R; Smith, L J; Burt, R W; Neklason, D W

    2015-10-01

    Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation-dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele-specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42-98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. xidative Stress and Retinopathy of Prematurity

    OpenAIRE

    Ümeyye Taka Aydın; Hatip Aydın; Osman Çekiç

    2014-01-01

    Oxidative stress plays an important role in the etiology of retinopathy of prematurity. Insufficient antioxidant system and increased oxidative stress in premature infants lead to the development of the disease. Understanding the mechanism of oxidative stress and antioxidant system and the related signaling pathways contribute to the development of novel options for diagnosis and treatment of retinopathy of prematurity. The current review aimed to evaluate the relationship between ox...

  4. Contract theory and EU Contract Law

    NARCIS (Netherlands)

    Hesselink, M.W.; Twigg-Flesner, C.

    2016-01-01

    This paper explores the relationship between contract theory and European contract law. In particular, it confronts the leading contract law theories with the main characteristics of EU contract law. The conclusion is that the two do not match well. In particular, monist normative contract theories

  5. Muscle Contraction.

    Science.gov (United States)

    Sweeney, H Lee; Hammers, David W

    2018-02-01

    SUMMARYMuscle cells are designed to generate force and movement. There are three types of mammalian muscles-skeletal, cardiac, and smooth. Skeletal muscles are attached to bones and move them relative to each other. Cardiac muscle comprises the heart, which pumps blood through the vasculature. Skeletal and cardiac muscles are known as striated muscles, because the filaments of actin and myosin that power their contraction are organized into repeating arrays, called sarcomeres, that have a striated microscopic appearance. Smooth muscle does not contain sarcomeres but uses the contraction of filaments of actin and myosin to constrict blood vessels and move the contents of hollow organs in the body. Here, we review the principal molecular organization of the three types of muscle and their contractile regulation through signaling mechanisms and discuss their major structural and functional similarities that hint at the possible evolutionary relationships between the cell types. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

  6. AGILE integration into APC for high mix logic fab

    Science.gov (United States)

    Gatefait, M.; Lam, A.; Le Gratiet, B.; Mikolajczak, M.; Morin, V.; Chojnowski, N.; Kocsis, Z.; Smith, I.; Decaunes, J.; Ostrovsky, A.; Monget, C.

    2015-09-01

    mix logic Fab) in term of product and technology portfolio AGILE corrects for up to 120nm of product topography error on process layer with less than 50nm depth of focus Based on tool functionalities delivered by ASML and on high volume manufacturing requirement, AGILE integration is a real challenge. Regarding ST requirements "Automatic AGILE" functionality developed by ASML was not a turnkey solution and a dedicated functionality was needed. A "ST homemade AGILE integration" has been fully developed and implemented within ASML and ST constraints. This paper describes this integration in our Advanced Process Control platform (APC).

  7. Contract design

    International Nuclear Information System (INIS)

    Bradley, P.

    2006-01-01

    The current state of the electric power industry in Ontario was discussed with particular reference to the procurement of contracts and why the Ontario Power Authority (OPA) must be contracting to resolve many of Ontario's electricity issues. As Ontario increasingly relies on imports and natural gas-fired generation, the price of electricity continues to rise given that supply is at a low level. In addition to the generation gap, there are also several transmission constrained areas in Ontario, particularly in the Greater Toronto Area (GTA). The OPA announced 2 projects totalling 1900 MW to relieve congestion. According to the Independent Electricity System Operator (IESO), the total potential opportunity for new generation by 2015 is about 5,000 to 7,000 megawatts. OPA is expected to launch procurement processes for up to 1000 MW of cogeneration, 250 MW of province-wide conservation initiatives, 1900 MW of generation in the western part of the GTA, and 600 MW of generation in downtown Toronto. New nuclear capacity is also anticipated in addition to renewables and conservation/demand management (CDM) initiatives. The OPA's competitive procurement processes will include requests for expressions of interest, requests for qualifications and requests for proposals. The challenge of balancing the technical complexities and realities of procuring generation assets with the need for a fair procurement process was discussed. Contracts will be designed to react to market signals and will include 3 styles: tariff style, tolling style and standard offer contract. OPA will make every effort to balance generator and ratepayer interests. 6 figs

  8. [Laser treatment for retinopathy of prematurity in neonatal intensive care units. Premature Eye Rescue Program].

    Science.gov (United States)

    Maka, Erika; Imre, László; Somogyvári, Zsolt; Németh, János

    2015-02-01

    Retinopathy of prematurity is a leading cause of childhood blindness around the world. The Department of Ophthalmology at the Semmelweis University and the Peter Cerny Neonatal Emergency and Ambulance Service started an innovative Premature Eye Rescue Program to reduce the non-essential transport of premature babies suffering from retinopathy of prematurity. During the first 5 years 186 eyes of 93 premature babies were treated at the bedside with stage 3 retinopathy of prematurity in the primary hospitals. In this first 5-years period the authors reduced the number of transports of premature babies for laser treatment; 93 children avoided the unnecessary transport, saving altogether a distance of 21,930 kilometers for children, as well as the ambulance service. The Premature Eye Rescue Program offers a good and effective alternative for treatment of retinopathy in the primary hospitals. The authors propose the national extension of this program.

  9. A kinetic model to study the regulation of β-catenin, APC, and Axin in the human colonic crypt.

    Science.gov (United States)

    Emerick, Brooks; Schleiniger, Gilberto; Boman, Bruce M

    2017-11-01

    The Wnt/[Formula: see text]-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between [Formula: see text]-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of [Formula: see text]-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, [Formula: see text]-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between [Formula: see text]-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of [Formula: see text]-catenin within the cell while raising the levels of APC.

  10. Thermally induced transformations of iron oxide stabilised APC residues from waste incineration

    DEFF Research Database (Denmark)

    Sørensen, Mette Abildgaard; Koch, C.B.

    2001-01-01

    Air pollution control (APC) facilities at waste incinerator plants produce large quantities of solid residues rich in salts and heavy metals. Heavy metals are readily released to water from the residues and it has, therefore, been found suitable to apply a rapid co-precipitation/adsorption process...... as a means to immobilize the toxic elements. In the 'Ferrox process', this immobilization is based on co-precipitation with an Fe(III) oxide formed by oxidation of Fe(II) by air in an aqueous slurry with the APC residue at alkaline pH. In this work we have undertaken a Mossbauer spectroscopy study of the Fe...

  11. Test of electrodialytic upgrading of MSWI APC residue in pilot scale: focus on reduced metal and salt leaching

    DEFF Research Database (Denmark)

    Kirkelund, Gunvor Marie; Jensen, Pernille Erland; Villumsen, Arne

    2010-01-01

    that is adapted from conventional electrodialysis, e.g. used in desalination of solutions. The APC residue was treated in a suspension (8 kg APC residue and 80 L tap water) and circulated through an electrodialytic (ED) stack consisting of 50 cell pairs separated by ion exchange membranes. A direct current...

  12. The role of S100a4 (Mts1) in Apc- and Smad4-driven tumour onset and progression

    DEFF Research Database (Denmark)

    Atlasi, Yaser; Noori, Rubina; Marolin, Ivana

    2016-01-01

    burden characteristic of the Apc1638N model. In agreement with these results, S100a4 appears to be co-expressed together with mesenchymal stem cell (MSC) markers in desmoid tumours from Apc1638N/+ mice, as well as from sporadic and hereditary human desmoids. Conclusion Our data provide the first report...

  13. Different effection of p.1125Val>Ala and rs11954856 in APC on Wnt signaling pathway.

    Science.gov (United States)

    Li, Fei-Feng; Zhao, Zhi-Xun; Yan, Peng; Wang, Song; Liu, Zheng; Zhang, Qiong; Zhang, Xiao-Ning; Sun, Chang-Hao; Wang, Xi-Shan; Wang, Gui-Yu; Liu, Shu-Lin

    2017-09-19

    Colorectal cancer (CRC) is among the most common and fatal forms of solid tumors worldwide and more than two thirds of CRC and adenomas patients have APC gene mutations. APC is a key regulator in the Wnt/β-catenin signaling pathway but its roles in CRC remains to be elucidated. In this study, we compared APC genes between CRC patients and controls to determine possible associations of nucleotide changes in the APC gene with the pathways involved in CRC pathogenesis. All participants received physical and enteroscopic examinations. The APC gene was sequenced for 300 Chinese Han CRC patients and 411 normal controls, and the expression levels of genes in the signaling pathway were analyzed using Western Blotting. Statistical analyses were conducted using SPSS (version 19.0) software. We found that rs11954856 in the APC gene was associated with colorectal cancer and could increase the expression levels of APC , β-catenin , TCF7L1 , TCF7L2 and LEF1 genes in the pathway in the CRC patients, demonstrating the involvement of APC in the pathological processes leading to CRC.

  14. 77 FR 34455 - In the Matter of Aegis Assessments, Inc., APC Group, Inc., Aurelio Resource Corp., BioAuthorize...

    Science.gov (United States)

    2012-06-11

    ... SECURITIES AND EXCHANGE COMMISSION [File No. 500-1] In the Matter of Aegis Assessments, Inc., APC Group, Inc., Aurelio Resource Corp., BioAuthorize Holdings, Inc., and Fonix Corporation; Order of... securities of APC Group, Inc. because it has not filed any periodic reports since the period ended August 31...

  15. The Spindle Assembly Checkpoint Is Not Essential for Viability of Human Cells with Genetically Lowered APC/C Activity

    DEFF Research Database (Denmark)

    Wild, Thomas; Larsen, Marie Sofie Yoo; Narita, Takeo

    2016-01-01

    The anaphase-promoting complex/cyclosome (APC/C) and the spindle assembly checkpoint (SAC), which inhibits the APC/C, are essential determinants of mitotic timing and faithful division of genetic material. Activation of the APC/C is known to depend on two APC/C-interacting E2 ubiquitin......-conjugating enzymes-UBE2C and UBE2S. We show that APC/C activity in human cells is tuned by the combinatorial use of three E2s, namely UBE2C, UBE2S, and UBE2D. Genetic deletion of UBE2C and UBE2S, individually or in combination, leads to discriminative reduction in APC/C function and sensitizes cells to UBE2D...... depletion. Reduction of APC/C activity results in loss of switch-like metaphase-to-anaphase transition and, strikingly, renders cells insensitive to chemical inhibition of MPS1 and genetic ablation of MAD2, both of which are essential for the SAC. These results provide insights into the regulation of APC...

  16. An APC/C-Cdh1 Biosensor Reveals the Dynamics of Cdh1 Inactivation at the G1/S Transition.

    Science.gov (United States)

    Ondracka, Andrej; Robbins, Jonathan A; Cross, Frederick R

    2016-01-01

    B-type cyclin-dependent kinase activity must be turned off for mitotic exit and G1 stabilization. B-type cyclin degradation is mediated by the anaphase-promoting complex/cyclosome (APC/C); during and after mitotic exit, APC/C is dependent on Cdh1. Cdh1 is in turn phosphorylated and inactivated by cyclin-CDK at the Start transition of the new cell cycle. We developed a biosensor to assess the cell cycle dynamics of APC/C-Cdh1. Nuclear exit of the G1 transcriptional repressor Whi5 is a known marker of Start; APC/C-Cdh1 is inactivated 12 min after Whi5 nuclear exit with little measurable cell-to-cell timing variability. Multiple phosphorylation sites on Cdh1 act in a redundant manner to repress its activity. Reducing the number of phosphorylation sites on Cdh1 can to some extent be tolerated for cell viability, but it increases variability in timing of APC/C-Cdh1 inactivation. Mutants with minimal subsets of phosphorylation sites required for viability exhibit striking stochasticity in multiple responses including budding, nuclear division, and APC/C-Cdh1 activity itself. Multiple cyclin-CDK complexes, as well as the stoichiometric inhibitor Acm1, contribute to APC/C-Cdh1 inactivation; this redundant control is likely to promote rapid and reliable APC/C-Cdh1 inactivation immediately following the Start transition.

  17. New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer's Disease.

    Science.gov (United States)

    Fuchsberger, Tanja; Lloret, Ana; Viña, Jose

    2017-05-14

    The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer's disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation of APC/C in AD. It has been shown that oligomers of the AD-related peptide, Aβ, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Furthermore, in the AD mouse model APP/PS1, lower cdh1 levels were observed in pyramidal neurons in CA1 when compared to age-matched wildtype mice. In this review, we provide a complete list of APC/C substrates that are involved in the nervous system and we discuss their functions. We also summarize recent studies that show neurobiological effects in cdh1 knockout mouse models. Finally, we discuss the role of APC/C in the pathophysiology of AD.

  18. Nuclear renaissance or premature try

    International Nuclear Information System (INIS)

    Coderch, M.

    2008-01-01

    After the economic failure of the 70's and not having been able to solve for decades its multiple problems, the nuclear industry was suffering a slow but inescapable agony. However, the need to reduce CO 2 emissions and the likely arrival of the worldwide peak of oil production have infused new life to the nuclear option, and it has again become one of the main topics of discussion in the worldwide energy debate. But in this debate we tend to forget that the causes of the abrupt end of the first nuclear era have not disappeared, and that for this reason it may well be that we are lead to a repetition of the events that induced its first demise. The much talked nuclear renaissance is thus likely to end up as a premature miscarriage. (Author)

  19. 4-Hydroxy-2(E)-nonenal metabolism differs in Apc(+/+) cells and in Apc(Min/+) cells: it may explain colon cancer promotion by heme iron.

    Science.gov (United States)

    Baradat, Maryse; Jouanin, Isabelle; Dalleau, Sabine; Taché, Sylviane; Gieules, Mathilde; Debrauwer, Laurent; Canlet, Cécile; Huc, Laurence; Dupuy, Jacques; Pierre, Fabrice H F; Guéraud, Françoise

    2011-11-21

    Animal and epidemiological studies suggest that dietary heme iron would promote colorectal cancer. Oxidative properties of heme could lead to the formation of cytotoxic and genotoxic secondary lipid oxidation products, such as 4-hydroxy-2(E)-nonenal (HNE). This compound is more cytotoxic to mouse wild-type colon cells than to isogenic cells with a mutation on the adenomatous polyposis coli (APC) gene. The latter thus have a selective advantage, possibly leading to cancer promotion. This mutation is an early and frequent event in human colorectal cancer. To explain this difference, the HNE biotransformation capacities of the two cell types have been studied using radiolabeled and stable isotope-labeled HNE. Apc-mutated cells showed better biotransformation capacities than nonmutated cells did. Thiol compound conjugation capacities were higher for mutated cells, with an important advantage for the extracellular conjugation to cysteine. Both cells types were able to reduce HNE to 4-hydroxynonanal, a biotransformation pathway that has not been reported for other intestinal cells. Mutated cells showed higher capacities to oxidize 4-hydroxynonanal into 4-hydroxynonanoic acid. The mRNA expression of different enzymes involved in HNE metabolism such as aldehyde dehydrogenase 1A1, 2 and 3A1, glutathione transferase A4-4, or cystine transporter xCT was upregulated in mutated cells compared with wild-type cells. In conclusion, this study suggests that Apc-mutated cells are more efficient than wild-type cells in metabolizing HNE into thiol conjugates and 4-hydroxynonanoic acid due to the higher expression of key biotransformation enzymes. These differential biotransformation capacities would explain the differences of susceptibility between normal and Apc-mutated cells regarding secondary lipid oxidation products.

  20. Retinopathy of Prematurity in Triplets

    Directory of Open Access Journals (Sweden)

    Mehmet Ali Şekeroğlu

    2016-06-01

    Full Text Available Objectives: To investigate the incidence, severity and risk factors of retinopathy of prematurity (ROP in triplets. Materials and Methods: The medical records of consecutive premature triplets who had been screened for ROP in a single maternity hospital were analyzed and presence and severity of ROP; birth weight, gender, gestational age of the infant; route of delivery and the mode of conception were recorded. Results: A total of 54 triplets (40 males, 14 females who were screened for ROP between March 2010 and February 2013 were recruited for the study. All triplets were delivered by Caesarean section and 36 (66.7% were born following an assisted conception. During follow-up, seven (13% of the infants developed ROP of any stage and two (3.7% required laser photocoagulation. The mean gestational age of triplets with ROP was 27.6±1.5 (27-31 weeks whereas it was 32.0±1.5 (30-34 weeks in those without ROP (p=0.002. The mean birth weights of triplets with and without ROP were 1290.0±295.2 (970-1600 g and 1667.5±222.2 (1130-1960 g, respectively (p<0.001. The presence of ROP was not associated with gender (p=0.358 or mode of conception (p=0.674. Conclusion: ROP in triplets seems to be mainly related to low gestational age and low birth weight. Further prospective randomized studies are necessary to demonstrate risk factors of ROP in triplets and to determine if and how gemelarity plays a role in the development of ROP.

  1. Human cytomegalovirus infections in premature infants by ...

    African Journals Online (AJOL)

    Freezing breast milk may be protective for the preterm infant until the titer of CMV antibody increases. However clinical importance of CMV infection in premature infants by breast-feeding is still unclear. This minireview focuses on recent advances in the study of CMV infection in premature infants by breastfeeding.

  2. 7 CFR 29.1050 - Prematurity.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Prematurity. 29.1050 Section 29.1050 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... Type 92) § 29.1050 Prematurity. A condition of growth and development characteristic of the lower...

  3. Premature infants' health at multiple induced pregnancy.

    Directory of Open Access Journals (Sweden)

    Chernenkov Yu.V.

    2015-09-01

    Full Text Available Objective: to define the risk factors adversely influencing prenatal development at premature birth at use of methods of assisted reproductive technology (ART; to estimate premature' infants health from multiple induced pregnancy according to Perinatal Center of Saratov for last 3 years. Material and Methods. Under supervision there were 139 pregnant women with application ART. 202 children (51 twins were born and 5 triplet babies, from them 83 premature infants born from multiple induced pregnancy have been analyzed. Results. The newborns examined by method ART, were distributed as follows: 22-28 weeks — 19 children; 29-32 weeks — 23; 33-36 weeks — 41. Asphyxia at birth was marked at all premature infants. Respiratory insufficiency at birth is revealed in 87,3% of cases. The most frequent pathologies in premature infants are revealed: neurologic infringements and bronchopulmonary pathology occured at all children, developmental anomaly — 33, 8%, retinopathies in premature infants — 26,5%. The mortality causes include: extreme immaturity, cerebral leukomalacia, IVN 3 degrees. Conclusion. The risk factors, premature birth at application of methods ART are revealed: aged primiparas, pharmacological influence, absence of physiological conditions of prenatal development; multifetation. The high percent of birth of children with ELBW and ULBW is revealed. RDCN with further BPD development, retinopathies in premature infants and CNS defeat is more often occured.

  4. Retractable Contracts

    Directory of Open Access Journals (Sweden)

    Franco Barbanera

    2016-02-01

    Full Text Available In calculi for modelling communication protocols, internal and external choices play dual roles. Two external choices can be viewed naturally as dual too, as they represent an agreement between the communicating parties. If the interaction fails, the past agreements are good candidates as points where to roll back, in order to take a different agreement. We propose a variant of contracts with synchronous rollbacks to agreement points in case of deadlock. The new calculus is equipped with a compliance relation which is shown to be decidable.

  5. The Regulation of the Angiogenic Factor FGF Binding Protein (FGF-BP) by the APC/Beta-Catenin Signaling Pathway in the Progression of Breast Cancer

    National Research Council Canada - National Science Library

    Stylianou, Dora

    2004-01-01

    ...) to study the expression of FGF-BP in mammary tumorigenesis progression of the APC/+ mouse and 2) to determine the mechanism of regulation of FGF-BP b the APC/beta-catenin signaling pathway in breast cancer...

  6. The Regulation of the Angiogenic Factor FGF Binding Protein (FGF-BP) by the APC/Beta-Catenin Signaling Pathway in the Progression of Breast Cancer

    National Research Council Canada - National Science Library

    Stylianou, Dora

    2003-01-01

    ...) to study the expression of FGF-BP in mammary tumorigenesis% progression of the APC/+ mouse and 2) to determine the mechanism of regulation of FGF-BP by the APC/beta- catenin signaling pathway in breast cancer...

  7. Human milk for the premature infant

    Science.gov (United States)

    Underwood, Mark A.

    2012-01-01

    Synopsis Premature infants are a heterogeneous group with widely differing needs for nutrition and immune protection with risk of growth failure, developmental delays, necrotizing enterocolitis, and late-onset sepsis increasing with decreasing gestational age and birth weight. Human milk from women delivering prematurely has more protein and higher levels of many bioactive molecules compared to milk from women delivering at term. Human milk must be fortified for small premature infants to achieve adequate growth. Mother’s own milk improves growth and neurodevelopment and decreases the risk of necrotizing enterocolitis and late-onset sepsis and should therefore be the primary enteral diet of premature infants. Donor milk is a valuable resource for premature infants whose mothers are unable to provide an adequate supply of milk, but presents significant challenges including the need for pasteurization, nutritional and biochemical deficiencies and a limited supply. PMID:23178065

  8. Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis

    Science.gov (United States)

    Zhang, Jinfang; Wan, Lixin; Dai, Xiangpeng; Sun, Yi; Wei, Wenyi

    2014-01-01

    The Anaphase Promoting Complex/Cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase that primarily governs cell cycle progression. APC/C is composed of at least 14 core subunits and recruits its substrates for ubiquitination via one of the two adaptor proteins, Cdc20 or Cdh1, in M or M/early G1 phase, respectively. Furthermore, recent studies have shed light on crucial functions for APC/C in maintaining genomic integrity, neuronal differentiation, cellular metabolism and tumorigenesis. To gain better insight into the in vivo physiological functions of APC/C in regulating various cellular processes, particularly development and tumorigenesis, a number of mouse models of APC/C core subunits, coactivators or inhibitors have been established and characterized. However, due to their essential role in cell cycle regulation, most of the germline knockout mice targeting the APC/C pathway are embryonic lethal, indicating the need for generating conditional knockout mouse models to assess the role in tumorigenesis for each APC/C signaling component in specific tissues. In this review, we will first provide a brief introduction of the ubiquitin-proteasome system (UPS) and the biochemical activities and cellular functions of the APC/C E3 ligase. We will then focus primarily on characterizing genetic mouse models used to understand the physiological roles of each APC/C signaling component in embryogenesis, cell proliferation, development and carcinogenesis. Finally, we discuss future research directions to further elucidate the physiological contributions of APC/C components during tumorigenesis and validate their potentials as a novel class of anti-cancer targets. PMID:24569229

  9. Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners.

    Science.gov (United States)

    Zhang, Zhenyi; Akyildiz, Senem; Xiao, Yafei; Gai, Zhongchao; An, Ying; Behrens, Jürgen; Wu, Geng

    2015-01-01

    The tumor suppressor APC employs its conserved armadillo repeat (ARM) domain to recognize many of its binding partners, including Amer1/WTX, which is mutated in Wilms' tumor and bone overgrowth syndrome. The APC-Amer1 complex has important roles in regulating Wnt signaling and cell adhesion. Three sites A1, A2, and A3 of Amer1 have been reported to mediate its interaction with APC-ARM. In this study, crystal structures of APC-ARM in complexes with Amer1-A1, -A2, and -A4, which is newly identified in this work, were determined. Combined with our GST pull-down, yeast two-hybrid, and isothermal titration calorimetry (ITC) assay results using mutants of APC and Amer1 interface residues, our structures demonstrate that Amer1-A1, -A2, and -A4, as well as other APC-binding proteins such as Asef and Sam68, all employ a common recognition pattern to associate with APC-ARM. In contrast, Amer1-A3 binds to the C-terminal side of APC-ARM through a bipartite interaction mode. Composite mutations on either APC or Amer1 disrupting all four interfaces abrogated their association in cultured cells and impaired the membrane recruitment of APC by Amer1. Our study thus comprehensively elucidated the recognition mechanism between APC and Amer1, and revealed a consensus recognition sequence employed by various APC-ARM binding partners.

  10. APC/C-Cdh1 coordinates neurogenesis and cortical size during development

    Science.gov (United States)

    Delgado-Esteban, Maria; García-Higuera, Irene; Maestre, Carolina; Moreno, Sergio; Almeida, Angeles

    2013-12-01

    The morphology of the adult brain is the result of a delicate balance between neural progenitor proliferation and the initiation of neurogenesis in the embryonic period. Here we assessed whether the anaphase-promoting complex/cyclosome (APC/C) cofactor, Cdh1—which regulates mitosis exit and G1-phase length in dividing cells—regulates neurogenesis in vivo. We use an embryo-restricted Cdh1 knockout mouse model and show that functional APC/C-Cdh1 ubiquitin ligase activity is required for both terminal differentiation of cortical neurons in vitro and neurogenesis in vivo. Further, genetic ablation of Cdh1 impairs the ability of APC/C to promote neurogenesis by delaying the exit of the progenitor cells from the cell cycle. This causes replicative stress and p53-mediated apoptotic death resulting in decreased number of cortical neurons and cortex size. These results demonstrate that APC/C-Cdh1 coordinates cortical neurogenesis and size, thus posing Cdh1 in the molecular pathogenesis of congenital neurodevelopmental disorders, such as microcephaly.

  11. Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa.

    Science.gov (United States)

    Saada, Jamal I; Pinchuk, Irina V; Barrera, Carlos A; Adegboyega, Patrick A; Suarez, Giovanni; Mifflin, Randy C; Di Mari, John F; Reyes, Victor E; Powell, Don W

    2006-11-01

    The human gastrointestinal mucosa is exposed to a diverse normal microflora and dietary Ags and is a common site of entry for pathogens. The mucosal immune system must respond to these diverse signals with either the initiation of immunity or tolerance. APCs are important accessory cells that modulate T cell responses which initiate and maintain adaptive immunity. The ability of APCs to communicate with CD4+ T cells is largely dependent on the expression of class II MHC molecules by the APCs. Using immunohistochemistry, confocal microscopy, and flow cytometry, we demonstrate that alpha-smooth muscle actin(+), CD90+ subepithelial myofibroblasts (stromal cells) constitutively express class II MHC molecules in normal colonic mucosa and that they are distinct from professional APCs such as macrophages and dendritic cells. Primary isolates of human colonic myofibroblasts (CMFs) cultured in vitro were able to stimulate allogeneic CD4+ T cell proliferation. This process was dependent on class II MHC and CD80/86 costimulatory molecule expression by the myofibroblasts. We also demonstrate that CMFs, engineered to express a specific DR4 allele, can process and present human serum albumin to a human serum albumin-specific and DR4 allele-restricted T cell hybridoma. These studies characterize a novel cell phenotype which, due to its strategic location and class II MHC expression, may be involved in capture of Ags that cross the epithelial barrier and present them to lamina propria CD4+ T cells. Thus, human CMFs may be important in regulating local immunity in the colon.

  12. Microbiological Method (DEFT/APC) For The Detection Of Irradiated Foods In Egypt

    International Nuclear Information System (INIS)

    Osman, M.E.; Abo El-Nasr, A.; Abo El Nour, S.A.; Hammad, A.; Ibrahim, H.M.A.

    2013-01-01

    The applicability of a microbiological screening method based on the comparison of the count obtained by the direct epi fluorescent filter technique (DEFT) with the count obtained by the conventional aerobic plate count (APC) for the detection of three kinds of irradiated foodstuffs (black pepper, strawberry, de-boned chicken meat) in Egypt was evaluated. The detection method was carried out immediately after irradiation and during subsequent storage. The results revealed that for irradiation doses of 5 kGy or higher, the DEFT/APC difference of around 2 log units or more could be a suitable criterion for judging black pepper samples as irradiated. DEFT/APC difference of around 2 log units or more could be used as a criterion for irradiation processing of strawberry at dose level of 2 kGy or higher. The DEFT/APC difference of around 2.5 log units or more could be indicated that fresh and frozen de-boned chicken meat samples had been irradiated at least at 3 and 6 kGy or higher, respectively. In general, the results showed that this method had the potential to detect irradiated food samples either immediately after irradiation or throughout the storage period.

  13. Opposite effects of modifiers of the Apc(Min) mutation in intestine and mammary gland

    Czech Academy of Sciences Publication Activity Database

    Czarnomska, A.; Krysiak, E.; Piskorowska, J.; Sitarz, M.; Pilčík, Tomáš; Demant, P.

    2003-01-01

    Roč. 2003, č. 63 (2003), s. 4533-4537 ISSN 0008-5472 Institutional research plan: CEZ:AV0Z5052915 Keywords : Recombinant congenic strains * primary breast cancers * APC gene Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.649, year: 2003

  14. Filtration Algorithms of Untrustworthy Analogous Information in APCS at TPP and NPP

    Directory of Open Access Journals (Sweden)

    V. I. Nazarov

    2012-01-01

    Full Text Available The paper considers filtration algorithms of untrustworthy analogous information in APCS at TTP and NPP that make it possible to identify credibility of information transmitted through communication channels in the form of signals and which are continuously changeable in the regime of real time.

  15. Psychosocial interventions for premature ejaculation

    Directory of Open Access Journals (Sweden)

    Tamara Melnik

    Full Text Available BACKGROUND: Premature ejaculation (PE is a very common sexual dysfunction among patients, and with varying prevalence estimates ranging from 3% to 20%. Although psychological issues are present in most patients with premature PE, as a cause or as a consequence, research on the effects of psychological approaches for PE has in general not been controlled or randomised and is lacking in long-term follow up. OBJECTIVE: To assess the efficacy of psychosocial interventions for PE. CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW: Trials were searched in computerized general and specialized databases, such as: MEDLINE by PubMed (1966 to 2010; PsycINFO (1974 to 2010; EMBASE (1980 to 2010; LILACS (1982 to 2010; the Cochrane Central Register of Controlled Trials (Cochrane Library, 2010; and by checking bibliographies, and contacting manufacturers and researchers. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials evaluating psychosocial interventions compared with different psychosocial interventions, pharmacological interventions, waiting list, or no treatment for PE. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, and outcomes was extracted by at least two independent reviewers using a standard form. The primary outcome measure for comparing the effects of psychosocial interventions to waiting list and standard medications was improvement in IELT (i.e., time from vaginal penetration to ejaculation. The secondary outcome was change in validated PE questionnaires. MAIN RESULTS: In one study behavioral therapy (BT was significantly better than waiting list for duration of intercourse (MD (mean difference 407.90 seconds, 95% CI 302.42 to 513.38, and couples' sexual satisfaction (MD -26.10, CI -50.48 to -1.72. BT was also significantly better for a new functional-sexological treatment (FS (MD 412.00 seconds, 95% CI 305.88 to 518.12, change over time in subjective perception of duration of intercourse (Women: MD 2

  16. Types of contracts and contracting procedures

    International Nuclear Information System (INIS)

    Zijl, N.A. van

    1977-01-01

    Contracting for a nuclear power plant can be carried out in many different ways, from a bilateral agreement between two countries to an international open bidding competition. Also the kind of contracts (turnkey, split-package or multi-contract type) are discussed with their pros and cons as well as the contracting procedures which can be followed to come to the conclusion of a contract. (orig.) [de

  17. Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet

    Directory of Open Access Journals (Sweden)

    Christina Pettan-Brewer

    2011-06-01

    Full Text Available Colorectal cancer (CRC is a leading cause of cancer deaths in the United States. Various risk factors have been associated with CRC including increasing age and diet. Epidemiological and experimental studies have implicated a diet high in fat as an important risk factor for colon cancer. High fat diets can promote obesity resulting in insulin resistance and inflammation and the development of oxidative stress, increased cell proliferation, and suppression of apoptosis. Because of the high consumption of dietary fats, especially saturated fats, by Western countries, it is of interest to see if non-nutrient food factors might be effective in preventing or delaying CRC in the presence of high saturated fat intake. Curcumin (Curcuma longa, the main yellow pigment in turmeric, was selected to test because of its reported anti-tumor activity. APC Min mice, which develop intestinal polyps and have many molecular features of CRC, were fed a diet containing 35% pork fat, 33% sucrose, and a protein and vitamin mineral mixture (HFD with or without 0.5% curcumin. These cohorts were compared to APC Min mice receiving standard rodent chow (RC with 8% fat. APC Min mice fed the HFD for 3 months had a 23% increase in total number of polyps compared to APC Min mice on RC. Curcumin was able to significantly reverse the accelerated polyp development associated with the HFD suggesting it may be effective clinically in helping prevent colon cancer even when ingesting high amounts of fatty foods. The anti-tumor effect of curcumin was shown to be associated with enhanced apoptosis and increased efficiency of DNA repair. Since curcumin prevented the gain in body weight seen in APC Min mice ingesting the HFD, modulation of energy metabolism may also be a factor.

  18. Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression.

    Science.gov (United States)

    Xu, Jinfei; Cortellino, Salvatore; Tricarico, Rossella; Chang, Wen-Chi; Scher, Gabrielle; Devarajan, Karthik; Slifker, Michael; Moore, Robert; Bassi, Maria Rosaria; Caretti, Elena; Clapper, Margie; Cooper, Harry; Bellacosa, Alfonso

    2017-10-27

    Thymine DNA Glycosylase (TDG) is a base excision repair enzyme that acts as a thymine and uracil DNA N-glycosylase on G:T and G:U mismatches, thus protecting CpG sites in the genome from mutagenesis by deamination. In addition, TDG has an epigenomic function by removing the novel cytosine derivatives 5-formylcytosine and 5-carboxylcytosine (5caC) generated by Ten-Eleven Translocation (TET) enzymes during active DNA demethylation. We and others previously reported that TDG is essential for mammalian development. However, its involvement in tumor formation is unknown. To study the role of TDG in tumorigenesis, we analyzed the effects of its inactivation in a well-characterized model of tumor predisposition, the Apc Min mouse strain. Mice bearing a conditional Tdg flox allele were crossed with Fabpl ::Cre transgenic mice, in the context of the Apc Min mutation, in order to inactivate Tdg in the small intestinal and colonic epithelium. We observed an approximately 2-fold increase in the number of small intestinal adenomas in the test Tdg -mutant Apc Min mice in comparison to control genotypes (p=0.0001). This increase occurred in female mice, and is similar to the known increase in intestinal adenoma formation due to oophorectomy. In the human colorectal cancer (CRC) TCGA database, the subset of patients with TDG and APC expression in the lowest quartile exhibits an excess of female cases. We conclude that TDG inactivation plays a role in intestinal tumorigenesis initiated by mutation/underexpression of APC . Our results also indicate that TDG may be involved in sex-specific protection from CRC.

  19. Disruption of the APC gene by t(5;7) translocation in a Turcot family.

    Science.gov (United States)

    Sahnane, Nora; Bernasconi, Barbara; Carnevali, Ileana; Furlan, Daniela; Viel, Alessandra; Sessa, Fausto; Tibiletti, Maria Grazia

    2016-03-01

    Turcot syndrome (TS) refers to the combination of colorectal polyps and primary tumours of the central nervous system. TS is a heterogeneous genetic condition due to APC and/or mismatch repair germline mutations. When APC is involved the vast majority of mutations are truncating, but in approximately 20%-30% of patients with familial polyposis no germline mutation can be found. A 30-year-old Caucasian woman with a positive pedigree for TS was referred to our Genetic Counselling Service. She was negative for APC and MUTYH but showed a reciprocal balanced translocation t(5;7)(q22;p15) at chromosome analysis. FISH analysis using specific BAC probes demonstrated that 5q22 breakpoint disrupted the APC gene. Transcript analysis by MLPA and digital PCR revealed that the cytogenetic rearrangement involving the 3' end of the APC gene caused a defective expression of a truncated transcript. This result allowed cytogenetic analysis to be offered to all the other family members and segregation analysis clearly demonstrated that all the carriers were affected, whereas non-carriers did not have the polyposis. A cytogenetic approach permitted the identification of the mutation-causing disease in this family, and the segregation analysis together with the transcript study supported the pathogenetic role of this mutation. Karyotype analysis was used as a predictive test in all members of this family. This family suggests that clinically positive TS and FAP cases, which test negative with standard molecular analysis, could be easily and cost-effectively resolved by a classical and molecular cytogenetic approach. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. A novel mutation of adenomatous polyposis coli (APC) gene results in the formation of supernumerary teeth.

    Science.gov (United States)

    Yu, Fang; Cai, Wenping; Jiang, Beizhan; Xu, Laijun; Liu, Shangfeng; Zhao, Shouliang

    2018-01-01

    Supernumerary teeth are teeth that are present in addition to normal teeth. Although several hypotheses and some molecular signalling pathways explain the formation of supernumerary teeth, but their exact disease pathogenesis is unknown. To study the molecular mechanisms of supernumerary tooth-related syndrome (Gardner syndrome), a deeper understanding of the aetiology of supernumerary teeth and the associated syndrome is needed, with the goal of inhibiting disease inheritance via prenatal diagnosis. We recruited a Chinese family with Gardner syndrome. Haematoxylin and eosin staining of supernumerary teeth and colonic polyp lesion biopsies revealed that these patients exhibited significant pathological characteristics. APC gene mutations were detected by PCR and direct sequencing. We revealed the pathological pathway involved in human supernumerary tooth development and the mouse tooth germ development expression profile by RNA sequencing (RNA-seq). Sequencing analysis revealed that an APC gene mutation in exon 15, namely 4292-4293-Del GA, caused Gardner syndrome in this family. This mutation not only initiated the various manifestations typical of Gardner syndrome but also resulted in odontoma and supernumerary teeth in this case. Furthermore, RNA-seq analysis of human supernumerary teeth suggests that the APC gene is the key gene involved in the development of supernumerary teeth in humans. The mouse tooth germ development expression profile shows that the APC gene plays an important role in tooth germ development. We identified a new mutation in the APC gene that results in supernumerary teeth in association with Gardner syndrome. This information may shed light on the molecular pathogenesis of supernumerary teeth. Gene-based diagnosis and gene therapy for supernumerary teeth may become available in the future, and our study provides a high-resolution reference for treating other syndromes associated with supernumerary teeth. © 2017 The Authors. Journal of

  1. Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR

    International Nuclear Information System (INIS)

    Tippin, Brigette L; Kwong, Alan M; Inadomi, Michael J; Lee, Oliver J; Park, Jae Man; Materi, Alicia M; Buslon, Virgilio S; Lin, Amy M; Kudo, Lili C; Karsten, Stanislav L; French, Samuel W; Narumiya, Shuh; Urade, Yoshihiro; Salido, Eduardo; Lin, Henry J

    2014-01-01

    Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D 2 ) caused more adenomas in Apc Min/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D 2 (PGD 2 ) binds to the prostaglandin D 2 receptor known as PTGDR (or DP1). PGD 2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD 2 . To assess, we produced Apc Min/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc Min/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc Min/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc Min/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD 2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD 2 signals acting through PTGDR in suppression of intestinal tumors

  2. An APC:WNT counter-current-like mechanism regulates cell division along the colonic crypt axis: a mechanism that explains how APC mutations induce proliferative abnormalities that drive colon cancer development.

    Directory of Open Access Journals (Sweden)

    Bruce M Boman

    2013-11-01

    Full Text Available APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside. WNT signaling, in contrast, is high at the bottom (where SCs reside and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g. survivin are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric. APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly-proliferating cells during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes.

  3. An APC:WNT Counter-Current-Like Mechanism Regulates Cell Division Along the Human Colonic Crypt Axis: A Mechanism That Explains How APC Mutations Induce Proliferative Abnormalities That Drive Colon Cancer Development

    Science.gov (United States)

    Boman, Bruce M.; Fields, Jeremy Z.

    2013-01-01

    APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT) that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs) at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside). WNT signaling, in contrast, is high at the bottom (where SCs reside) and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g., survivin) are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric). APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly proliferating cells) during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes. PMID:24224156

  4. Acute appendicitis in a premature baby

    International Nuclear Information System (INIS)

    Beluffi, Giampiero; Alberici, Elisa

    2002-01-01

    A case of acute appendicitis in a premature baby in whom diagnosis was suggested on plain films of the abdomen is presented. In this baby air in a hollow viscus suspected of being an enlarged appendix was the clue to diagnosis. The diagnostic dilemma of this rare and life-threatening condition in premature babies and newborns is underlined. The relevance of different imaging modalities and of different findings in this age group is discussed. Awareness of this rare condition and possible differential diagnosis in newborns and premature babies is stressed. (orig.)

  5. Social support for parents of premature infants

    Directory of Open Access Journals (Sweden)

    Agnieszka Skurzak

    2018-03-01

    Full Text Available Prematurity is still an actual medical problem. Significant increase in the survival rate of premature babies is observed due to the progress in perinatal care .Usually, parents are not prepared for a premature birth, for the majority of them the hospitalization of a child in neonatal intensive care unit is a source of fear,  moreover parents often blame themselves for the situation. Appearing emotions and questions require a compatible response from the therapeutic team. The most important activity in the practice of the team is emotional, informative, evaluative support.

  6. The epidemiology of premature ejaculation.

    Science.gov (United States)

    Saitz, Theodore Robert; Serefoglu, Ege Can

    2016-08-01

    Vast advances have occurred over the past decade with regards to understanding the epidemiology, pathophysiology and management of premature ejaculation (PE); however, we still have much to learn about this common sexual problem. As a standardized evidence-based definition of PE has only recently been established, the reported prevalence rates of PE prior to this definition have been difficult to interpret. As a result, a large range of conflicting prevalence rates have been reported. In addition to the lack of a standardized definition and operational criteria, the method of recruitment for study participation and method of data collection have obviously contributed to the broad range of reported prevalence rates. The new criteria and classification of PE will allow for continued research into the diverse phenomenology, etiology and pathogenesis of the disease to be conducted. While the absolute pathophysiology and true prevalence of PE remains unclear, developing a better understanding of the true prevalence of the disease will allow for the completion of more accurate analysis and treatment of the disease.

  7. [Psychologic management of extreme prematurity].

    Science.gov (United States)

    Granboulan, V; Danan, C; Dassieu, G; Janaud, J C; Durand, B

    1995-05-01

    The ongoing progress in neonatal intensive care is modifying the psychic context of prematurity for all the partners, infants as well as parents and physicians. Comfort and prognosis of preterm infants have much improved. Since newborns under 24 weeks of gestational age are now surviving, they spend approximately half the duration of pregnancy out of the maternal uterus. All the psychological issues of such an early separation have to be considered, including the developmental outcome of a sensorial environment which is quite different from the intra-uterine one. Research has been developing in this field. The cooperation between neonatalogists and psychologists has been profitable to parents. Problems linked to the separation, such as difficulty in representing the infant, are no more frequent owing to the attention paid to the mother-child bond and subsequent early contacts. What is forward now is the impact of an hyper technical world of intensive care on the parents, and of the strange aspect of the tiny baby surrounded by engines and tubes. Such an overpresence of reality often results in a reaction of traumatic daziness among parents. The cooperation of the whole staff is necessary for the resumption of an imaginary process of psychic functioning. Finally, the survival of very-low-birth-weight infants confronts the neonatalogists with some delicate ethical questions. Psychiatrists and psychologists might have an important part to play in aiding the profession in its sorting out of these ethical issues.

  8. Role of heterozygous APC mutation in niche succession and initiation of colorectal cancer--a computational study.

    Directory of Open Access Journals (Sweden)

    Roschen Sasikumar

    Full Text Available Mutations in the adenomatous polyposis coli (APC gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC(+/- stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking.

  9. The combination of heteroduplex analysis and protein truncation test for exact detection of the APC gene mutations

    International Nuclear Information System (INIS)

    Tomka, M.; Kirchhoff, T.; Stefurkova, V.; Zajac, V.; Kulcsar, L.

    1998-01-01

    Familial adenomatous polyposis (FAP) is usually associated with mutation in the adenomatous polyposis coli (APC) gene. To examine the occurrence of these mutations in the number of FAP suspected families from the whole Slovakia effectively, we have applied heteroduplex analysis (HDA) and protein truncation test (PTT) for the analyses of 2-5 base pair deletions and point mutations of the APC gene. In the analyzed exon 15 of the APC gene determined by the primers 15Efor-15Grev for HDA and 15ET7-15J3 for PTT more than 70% of mutations should be deletions [3, 12], which are detectable by HDA. In our collection of 5 FAP families mutations in the APC gene were found in families 10, 27 and 41 using HDA. By PTT test the formation of truncated APC protein in FAP families 2, 10, 16 and 27 were revealed. The necessity of combination of at least HDA and PTT techniques for exact detection of APC mutations in analyzed APC region is discussed. (authors)

  10. Activated protein C (APC) can increase bone anabolism via a protease-activated receptor (PAR)1/2 dependent mechanism.

    Science.gov (United States)

    Shen, Kaitlin; Murphy, Ciara M; Chan, Ben; Kolind, Mille; Cheng, Tegan L; Mikulec, Kathy; Peacock, Lauren; Xue, Meilang; Park, Sang-Youel; Little, David G; Jackson, Chris J; Schindeler, Aaron

    2014-12-01

    Activated Protein C (APC) is an anticoagulant with strong cytoprotective properties that has been shown to promote wound healing. In this study APC was investigated for its potential orthopedic application using a Bone Morphogenetic Protein 2 (rhBMP-2) induced ectopic bone formation model. Local co-administration of 10 µg rhBMP-2 with 10 µg or 25 µg APC increased bone volume at 3 weeks by 32% (N.S.) and 74% (pAPC are largely mediated by its receptors endothelial protein C receptor (EPCR) and protease-activated receptors (PARs). Cultured pre-osteoblasts and bone nodule tissue sections were shown to express PAR1/2 and EPCR. When pre-osteoblasts were treated with APC, cell viability and phosphorylation of ERK1/2, Akt, and p38 were increased. Inhibition with PAR1 and sometimes PAR2 antagonists, but not with EPCR blocking antibodies, ameliorated the effects of APC on cell viability and kinase phosphorylation. These data indicate that APC can affect osteoblast viability and signaling, and may have in vivo applications with rhBMP-2 for bone repair. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  11. High-resolution Melting Analysis for Gene Scanning of Adenomatous Polyposis Coli (APC) Gene With Oral Squamous Cell Carcinoma Samples.

    Science.gov (United States)

    Chang, Ya-Sian; Lin, Chien-Yu; Yang, Shu-Fen; Ho, Cheng Mao; Chang, Jan-Gowth

    2016-02-01

    There have been many different mutations reported for the large adenomatous polyposis coli (APC) tumor suppressor gene. APC mutations result in inactivation of APC tumor suppressor action, allowing the progression of tumorigenesis. The present study utilized a highly efficient method to identify APC mutations and investigated the association between the APC genetic variants Y486Y, A545A, T1493T, and D1822V and susceptibility to oral squamous cell carcinoma (OSCC). High-resolution melting (HRM) analysis was used to characterize APC mutations. Genomic DNA was extracted from 83 patient specimens of OSCC and 50 blood samples from healthy control subjects. The 14 exons and mutation cluster region of exon 15 were screened by HRM analysis. All mutations were confirmed by direct DNA sequencing. Three mutations and 4 single nucleotide polymorphisms (SNPs) were found in this study. The mutations were c.573T>C (Y191Y) in exon 5, c.1005A>G (L335L) in exon 9, and c.1488A>T (T496T) in exon 11. Two SNPs, c.4479G>A (T1493T) and c.5465A>T (D1822V), were located in exon 15, whereas c.1458T>C (Y486Y) and c.1635G>A (A545A) were located in exon 11 and 13, respectively. There was no observed association between OSCC risk and genotype for any of the 4 APC SNPs. The mutation of APC is rare in Taiwanese patients with OSCC. HRM analysis is a reliable, accurate, and fast screening method for APC mutations.

  12. Trends of premature mortality in Swietokrzyskie Province (Poland), years 2002-2010.

    Science.gov (United States)

    Gózdz, Stanislaw; Krzyzak, Michalina; Maślach, Dominik; Wróbel, Monika; Bielska-Lasota, Magdalena

    2013-01-01

    Premature mortality in younger age groups influences the society as far as social and economic aspects are concerned. Therefore, it is important to come up with a tool which will allow to assess them, and will enable to implement only these health care measures that bring tangible benefits. That is the reason for introducing PYLL rate (PYLL - potential years of life lost), which is an addition to the analysis of premature mortality as it includes the number of deaths due to a particular cause and the age at death. The purpose of this study was to analyse the level and trends of PYLL rate according to death causes in years 2002 -2010 in Swietokrzyskie Province. The material for the analysis was the information from the Central Statistical Office on the number of deaths due to all causes registered among the inhabitants of Swiytokrzyskie Province in years 2002-2010. Causes of death were coded according to the 10th revision of the International Classification of Diseases. The analysis of premature mortality was carried out with the use of PYLL rate. PYLL rate was calculated according to the method proposed by Romeder, according to which the premature mortality was defined as death before the age of 70. The analysis of time trends of PYLL rate and the APC (annual percent change) of the PYLL rate were calculated using jointpoint model as well as the Jointpoint Regression Program (Version 4.0.1 - January 2013). In men, in years 2002 - 2007 PYLL rate increased by 1.5% per year (paverage by 3.1% per year till year 2010. External causes of death, cardiovascular diseases and cancers in years 2002 - 2010 were the reason for almost 74.0% PYLL in men. In year 2010 PYLL rate due to all death causes amounted to 8913.8/105 and was three times higher than in women (2975.5/10(5)). In women, however, during the analysed period PYLL rate did not change significantly, and was dominated by cancers, cardiovascular diseases and external death causes. Similarly to men, those three groups

  13. Maternal assessment of pain in premature infants

    Directory of Open Access Journals (Sweden)

    Maria Carolina Correia dos Santos

    2015-12-01

    Full Text Available Objective: to identify mothers' perceptions about the pain in their premature babies in the Neonatal Intensive Care Unit. Methods: evaluative, quantitative study with investigative nature conducted with 19 mothers of hospitalized premature newborns. Data were obtained from closed questions, answered by mothers. Results: from the participants, two (10.5% reported that newborns are unable to feel pain. From the 17 mothers who said that premature babies can feel pain, the majority (94.1% identified crying as a characteristic of pain sensation. Eleven (64.7% stated that uneasiness is a sign of pain in newborns. Conclusion: for the proper management of neonatal pain it is essential that mothers know the signs of pain in premature newborns, and that health professionals instruct this recognition, through the enhancement of the maternal presence and practice of effective communication between professionals and newborns’ families.

  14. APC/β-catenin-rich complexes at membrane protrusions regulate mammary tumor cell migration and mesenchymal morphology

    International Nuclear Information System (INIS)

    Odenwald, Matthew A; Prosperi, Jenifer R; Goss, Kathleen H

    2013-01-01

    The APC tumor suppressor is mutated or downregulated in many tumor types, and is prominently localized to punctate clusters at protrusion tips in migratory cells, such as in astrocytes where it has been implicated in directed cell motility. Although APC loss is considered an initiating event in colorectal cancer, for example, it is less clear what role APC plays in tumor cell motility and whether loss of APC might be an important promoter of tumor progression in addition to initiation. The localization of APC and β-catenin was analyzed in multiple cell lines, including non-transformed epithelial lines treated with a proteasome inhibitor or TGFβ to induce an epithelial-to-mesenchymal transition (EMT), as well as several breast cancer lines, by immunofluorescence. APC expression was knocked down in 4T07 mammary tumor cells using lentiviral-mediated delivery of APC-specific short-hairpin (sh) RNAs, and assessed using quantitative (q) reverse-transcriptase (RT)-PCR and western blotting. Tumor cell motility was analyzed by performing wound-filling assays, and morphology via immunofluorescence (IF) and phase-contrast microscopy. Additionally, proliferation was measured using BrdU incorporation, and TCF reporter assays were performed to determine β-catenin/TCF-mediated transcriptional activity. APC/β-catenin-rich complexes were observed at protrusion ends of migratory epithelial cells treated with a proteasome inhibitor or when EMT has been induced and in tumor cells with a mesenchymal, spindle-like morphology. 4T07 tumor cells with reduced APC levels were significantly less motile and had a more rounded morphology; yet, they did not differ significantly in proliferation or β-catenin/TCF transcriptional activity. Furthermore, we found that APC/β-catenin-rich complexes at protrusion ends were dependent upon an intact microtubule cytoskeleton. These findings indicate that membrane protrusions with APC/β-catenin-containing puncta control the migratory potential and

  15. APC/β-catenin-rich complexes at membrane protrusions regulate mammary tumor cell migration and mesenchymal morphology

    Science.gov (United States)

    2013-01-01

    Background The APC tumor suppressor is mutated or downregulated in many tumor types, and is prominently localized to punctate clusters at protrusion tips in migratory cells, such as in astrocytes where it has been implicated in directed cell motility. Although APC loss is considered an initiating event in colorectal cancer, for example, it is less clear what role APC plays in tumor cell motility and whether loss of APC might be an important promoter of tumor progression in addition to initiation. Methods The localization of APC and β-catenin was analyzed in multiple cell lines, including non-transformed epithelial lines treated with a proteasome inhibitor or TGFβ to induce an epithelial-to-mesenchymal transition (EMT), as well as several breast cancer lines, by immunofluorescence. APC expression was knocked down in 4T07 mammary tumor cells using lentiviral-mediated delivery of APC-specific short-hairpin (sh) RNAs, and assessed using quantitative (q) reverse-transcriptase (RT)-PCR and western blotting. Tumor cell motility was analyzed by performing wound-filling assays, and morphology via immunofluorescence (IF) and phase-contrast microscopy. Additionally, proliferation was measured using BrdU incorporation, and TCF reporter assays were performed to determine β-catenin/TCF-mediated transcriptional activity. Results APC/β-catenin-rich complexes were observed at protrusion ends of migratory epithelial cells treated with a proteasome inhibitor or when EMT has been induced and in tumor cells with a mesenchymal, spindle-like morphology. 4T07 tumor cells with reduced APC levels were significantly less motile and had a more rounded morphology; yet, they did not differ significantly in proliferation or β-catenin/TCF transcriptional activity. Furthermore, we found that APC/β-catenin-rich complexes at protrusion ends were dependent upon an intact microtubule cytoskeleton. Conclusions These findings indicate that membrane protrusions with APC/β-catenin-containing puncta

  16. Mutation analysis of the adenomatous polyposis coli (APC) gene in Danish patients with familial adenomatous polyposis (FAP)

    DEFF Research Database (Denmark)

    Bisgaard, Marie Luise; Ripa, Rasmus S; Bülow, Steffen

    2004-01-01

    Development of one hundred or more adenomas in the colon and rectum is diagnostic for the dominantly inherited, autosomal disease Familial Adenomatous Polyposis (FAP). It is possible to identify a mutation in the Adenomatous Polyposis Coli (APC) gene in approximately 80% of the patients, and almost...... 1,000 different pathogenic mutations have been identified in the APC gene up till now. We report 12 novel and 24' previously described germline APC mutations from 48 unrelated Danish families. Four families with the mutation localized in the 3' region of the gene showed great variance in phenotypic...

  17. High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats.

    Science.gov (United States)

    Brückner, Melanie; Lasarzik, Irina; Jahn-Eimermacher, Antje; Peetz, Dirk; Werner, Christian; Engelhard, Kristin; Thal, Serge C

    2013-09-13

    Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol. Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mm Hg for 14 min and a subsequent 5h-infusion of rhAPC (2mg/kg bolus+6 mg/kg/h continuous IV) or vehicle (0.9% NaCl). The dosage was calculated to maintain plasma hAPC activity at 150%. Cerebral inflammation, apoptosis and neuronal survival was determined at day 10. rhAPC infusion did not influence cortical cerebral perfusion during reperfusion and failed to reduce neuronal cell loss, microglia activation, and caspase 3 activity. Even an optimized rhAPC infusion protocol designed to maintain a high level of APC plasma activity failed to improve the sequels following GI. Despite positive reports about protective effects of APC following, e.g., ischemic stroke, the present study supports the notion that infusion of APC during the early reperfusion phase does not result in sustained neuroprotection and fails to improve outcome after global cerebral ischemia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Reversible Modification of Adenomatous Polyposis Coli (APC) with K63-linked Polyubiquitin Regulates the Assembly and Activity of the β-Catenin Destruction Complex

    Science.gov (United States)

    Tran, Hoanh; Polakis, Paul

    2012-01-01

    The adenomatous polyposis coli (APC) tumor suppressor forms a complex with Axin and GSK3β to promote the phosphorylation and degradation of β-catenin, a key co-activator of Wnt-induced transcription. Here, we establish that APC is modified predominantly with K63-linked ubiquitin chains when it is bound to Axin in unstimulated HEK293 cells. Wnt3a stimulation induced a time-dependent loss of K63-polyubiquitin adducts from APC, an effect synchronous with the dissociation of Axin from APC and the stabilization of cytosolic β-catenin. RNAi-mediated depletion of Axin or β-catenin, which negated the association between APC and Axin, resulted in the absence of K63-adducts on APC. Overexpression of wild-type and phosphodegron-mutant β-catenin, combined with analysis of thirteen human cancer cell lines that harbor oncogenic mutations in APC, Axin, or β-catenin, support the hypothesis that a fully assembled APC-Axin-GSK3β-phospho-β-catenin complex is necessary for the K63-polyubiquitylation of APC. Intriguingly, the degree of this modification on APC appears to correlate inversely with the levels of β-catenin in cells. Together, our results indicate that K63-linked polyubiquitin adducts on APC regulate the assembly and/or efficiency of the β-catenin destruction complex. PMID:22761442

  19. Retinal vascular speed prematurity requiring treatment.

    Science.gov (United States)

    Solans Pérez de Larraya, Ana M; Ortega Molina, José M; Fernández, José Uberos; Escudero Gómez, Júlia; Salgado Miranda, Andrés D; Chaves Samaniego, Maria J; García Serrano, José L

    2018-03-01

    To analyse the speed of temporal retinal vascularisation in preterm infants included in the screening programme for retinopathy of prematurity. A total of 185 premature infants were studied retrospectively between 2000 and 2017 in San Cecilio University Hospital of Granada, Spain. The method of binocular indirect ophthalmoscopy with indentation was used for the examination. The horizontal disc diameter was used as a unit of length. Speed of temporal retinal vascularisation (disc diameter/week) was calculated as the ratio between the extent of temporal retinal vascularisation (disc diameter) and the time in weeks. The weekly temporal retinal vascularisation (0-1.25 disc diameter/week, confidence interval) was significantly higher in no retinopathy of prematurity (0.73 ± 0.22 disc diameter/week) than in stage 1 retinopathy of prematurity (0.58 ± 0.22 disc diameter/week). It was also higher in stage 1 than in stages 2 (0.46 ± 0.14 disc diameter/week) and 3 of retinopathy of prematurity (0.36 ± 0.18 disc diameter/week). The rate of temporal retinal vascularisation (disc diameter/week) decreases when retinopathy of prematurity stage increases. The area under the receiver operating characteristic curve was 0.85 (95% confidence interval: 0.79-0.91) for retinopathy of prematurity requiring treatment versus not requiring treatment. The best discriminative cut-off point was a speed of retinal vascularisation prematurity may be required. However, before becoming a new standard of care for treatment, it requires careful documentation, with agreement between several ophthalmologists.

  20. Premature dental eruption: report of case.

    LENUS (Irish Health Repository)

    McNamara, C M

    2011-08-05

    This case report reviews the variability of dental eruption and the possible sequelae. Dental eruption of the permanent teeth in cleft palate children may be variable, with delayed eruption the most common phenomenon. A case of premature dental eruption of a maxillary left first premolar is demonstrated, however, in a five-year-old male. This localized premature dental eruption anomaly was attributed to early extraction of the primary dentition, due to caries.

  1. USP7 Is a Tumor-Specific WNT Activator for APC-Mutated Colorectal Cancer by Mediating β-Catenin Deubiquitination

    Directory of Open Access Journals (Sweden)

    Laura Novellasdemunt

    2017-10-01

    Full Text Available The tumor suppressor gene adenomatous polyposis coli (APC is mutated in most colorectal cancers (CRCs, resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation, and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations; thus, it can be used as a tumor-specific therapeutic target for most CRCs.

  2. USP7 Is a Tumor-Specific WNT Activator for APC-Mutated Colorectal Cancer by Mediating β-Catenin Deubiquitination.

    Science.gov (United States)

    Novellasdemunt, Laura; Foglizzo, Valentina; Cuadrado, Laura; Antas, Pedro; Kucharska, Anna; Encheva, Vesela; Snijders, Ambrosius P; Li, Vivian S W

    2017-10-17

    The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRCs), resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation, and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations; thus, it can be used as a tumor-specific therapeutic target for most CRCs. Copyright © 2017 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

  3. Frequency of neonatal complications after premature delivery

    Directory of Open Access Journals (Sweden)

    Gordana Grgić

    2013-04-01

    Full Text Available Introduction: Preterm delivery is the delivery before 37 weeks of gestation are completed. The incidence of preterm birth ranges from 5 to 15%. Aims of the study were to determine the average body weight, Apgar score after one and five minutes, and the frequency of the most common complications in preterminfants.Methods: The study involved a total of 631 newborns, of whom 331 were born prematurely Aims of this study were to (24th-37th gestational weeks-experimental group, while 300 infants were born in time (37-42 weeks of gestation-control group.Results: Average body weight of prematurely born infants was 2382 grams, while the average Apgar score in this group after the fi rst minute was 7.32 and 7.79 after the fifth minute. The incidence of respiratory distress syndrome was 50%, intracranial hemorrhage, 28.1% and 4.8% of sepsis. Respiratory distresssyndrome was more common in infants born before 32 weeks of gestation. Mortality of premature infants is present in 9.1% and is higher than that of infants born at term.Conclusions: Birth body weight and Apgar scores was lower in preterm infants. Respiratory distress syndrome is the most common fetal complication of prematurity. Intracranial hemorrhage is the second most common complication of prematurity. Mortality of premature infants is higher than the mortality of infants born at term birth.

  4. Drosophila homologues of adenomatous polyposis coli (APC) and the formin diaphanous collaborate by a conserved mechanism to stimulate actin filament assembly.

    Science.gov (United States)

    Jaiswal, Richa; Stepanik, Vince; Rankova, Aneliya; Molinar, Olivia; Goode, Bruce L; McCartney, Brooke M

    2013-05-10

    Vertebrate APC collaborates with Dia through its Basic domain to assemble actin filaments. Despite limited sequence homology between the vertebrate and Drosophila APC Basic domains, Drosophila APC1 collaborates with Dia to stimulate actin assembly in vitro. The mechanism of actin assembly is highly conserved over evolution. APC-Dia collaborations may be crucial in a wide range of animal cells. Adenomatous polyposis coli (APC) is a large multidomain protein that regulates the cytoskeleton. Recently, it was shown that vertebrate APC through its Basic domain directly collaborates with the formin mDia1 to stimulate actin filament assembly in the presence of nucleation barriers. However, it has been unclear whether these activities extend to homologues of APC and Dia in other organisms. Drosophila APC and Dia are each required to promote actin furrow formation in the syncytial embryo, suggesting a potential collaboration in actin assembly, but low sequence homology between the Basic domains of Drosophila and vertebrate APC has left their functional and mechanistic parallels uncertain. To address this question, we purified Drosophila APC1 and Dia and determined their individual and combined effects on actin assembly using both bulk fluorescence assays and total internal reflection fluorescence microscopy. Our data show that APC1, similar to its vertebrate homologue, bound to actin monomers and nucleated and bundled filaments. Further, Drosophila Dia nucleated actin assembly and protected growing filament barbed ends from capping protein. Drosophila APC1 and Dia directly interacted and collaborated to promote actin assembly in the combined presence of profilin and capping protein. Thus, despite limited sequence homology, Drosophila and vertebrate APCs exhibit highly related activities and mechanisms and directly collaborate with formins. These results suggest that APC-Dia interactions in actin assembly are conserved and may underlie important in vivo functions in a broad

  5. Termination of T cell priming relies on a phase of unresponsiveness promoting disengagement from APCs and T cell division.

    Science.gov (United States)

    Bohineust, Armelle; Garcia, Zacarias; Beuneu, Hélène; Lemaître, Fabrice; Bousso, Philippe

    2018-05-07

    T cells are primed in secondary lymphoid organs by establishing stable interactions with antigen-presenting cells (APCs). However, the cellular mechanisms underlying the termination of T cell priming and the initiation of clonal expansion remain largely unknown. Using intravital imaging, we observed that T cells typically divide without being associated to APCs. Supporting these findings, we demonstrate that recently activated T cells have an intrinsic defect in establishing stable contacts with APCs, a feature that was reflected by a blunted capacity to stop upon T cell receptor (TCR) engagement. T cell unresponsiveness was caused, in part, by a general block in extracellular calcium entry. Forcing TCR signals in activated T cells antagonized cell division, suggesting that T cell hyporesponsiveness acts as a safeguard mechanism against signals detrimental to mitosis. We propose that transient unresponsiveness represents an essential phase of T cell priming that promotes T cell disengagement from APCs and favors effective clonal expansion. © 2018 Bohineust et al.

  6. Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1

    DEFF Research Database (Denmark)

    Petersen, B O; Wagener, C; Marinoni, F

    2000-01-01

    is targeted for ubiquitin-mediated proteolysis by the anaphase promoting complex (APC)/cyclosome in G(1). A combination of point mutations in the destruction box and KEN-box motifs in CDC6 stabilizes the protein in G(1) and in quiescent cells. Furthermore, APC, in association with CDH1, ubiquitinates CDC6...... in vitro, and both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo. Although a stable mutant of CDC6 is biologically active, overexpression of this mutant or wild-type CDC6 is not sufficient to induce multiple rounds of DNA replication in the same cell cycle. The APC-CDH1-dependent...

  7. Prematures with and without Regressed Retinopathy of Prematurity: Comparison of Long-Term (6-10 Years) Ophthalmological Morbidity.

    Science.gov (United States)

    Cats, Bernard P.; Tan, Karel E. W. P.

    Reporting long-term ophthalmologic sequelae among ex-prematures at 6 to 10 years of age, this study compares 42 ex-premature infants who had had regressed forms of retinopathy of prematurity (ROP) during the neonatal period with 42 matched non-ROP ex-premature controls at 6 to 10 years of age. Subjects were subdivided into four groups: (1) ROP…

  8. Role of APC and DNA mismatch repair genes in the development of colorectal cancers

    Directory of Open Access Journals (Sweden)

    Roy Deodutta

    2003-12-01

    Full Text Available Abstract Colorectal cancer is the third most common cause of cancer-related death in both men and women in the western hemisphere. According to the American Cancer Society, an estimated 105,500 new cases of colon cancer with 57,100 deaths will occur in the U.S. in 2003, accounting for about 10% of cancer deaths. Among the colon cancer patients, hereditary risk contributes approximately 20%. The main inherited colorectal cancers are the familial adenomatous polyposis (FAP and the hereditary nonpolyposis colorectal cancers (HNPCC. The FAP and HNPCC are caused due to mutations in the adenomatous polyposis coli (APC and DNA mismatch repair (MMR genes. The focus of this review is to summarize the functions of APC and MMR gene products in the development of colorectal cancers.

  9. IFN-beta inhibits T cell activation capacity of central nervous system APCs

    DEFF Research Database (Denmark)

    Teige, Ingrid; Liu, Yawei; Issazadeh-Navikas, Shohreh

    2006-01-01

    We have previously investigated the physiological effects of IFN-beta on chronic CNS inflammation and shown that IFN-beta(-/-) mice develop a more severe experimental autoimmune encephalomyelitis than their IFN-beta(+/-) littermates. This result was shown to be associated with a higher activation...... state of the glial cells and a higher T cell cytokine production in the CNS. Because this state suggested a down-regulatory effect of IFN-beta on CNS-specific APCs, these results were investigated further. We report that IFN-beta pretreatment of astrocytes and microglia (glial cells) indeed down......-modulate their capacity to activate autoreactive Th1 cells. First, we investigated the intrinsic ability of glial cells as APCs and report that glial cells prevent autoreactive Th1 cells expansion while maintaining Ag-specific T cell effector functions. However, when the glial cells are treated with IFN-beta before...

  10. Differential regulation of microtubule severing by APC underlies distinct patterns of projection neuron and interneuron migration

    Science.gov (United States)

    Eom, Tae-Yeon; Stanco, Amelia; Guo, Jiami; Wilkins, Gary; Deslauriers, Danielle; Yan, Jessica; Monckton, Chase; Blair, Josh; Oon, Eesim; Perez, Abby; Salas, Eduardo; Oh, Adrianna; Ghukasyan, Vladimir; Snider, William D.; Rubenstein, John L. R.; Anton, E. S.

    2014-01-01

    Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. Two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial vs. tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex. PMID:25535916

  11. ABERRANT METHYLATION OF THE PROMOTER OF APC, CDH13 AND MGMT GENES IN COLORECTAL CANCER PATIENTS

    Directory of Open Access Journals (Sweden)

    O. I. Kit

    2016-01-01

    Full Text Available Aberrant methylation of gene promoter regions is the main epigenetic change characterizing colorectal cancer. Methylation levels of 42 CpG-sites of promoter regions of the MGMT, APC and CDH13 genes in colorectal cancer were studied in comparison with methylation levels of the adjacent normal tissue in 25 patients. Pyrosequencing showed an increase in methylation levels of promoter regions of the MGMT, APC and CDH13 genes in tumor samples by 3 to 5 times. These tumor samples were screened for activating SNP-mutations in the KRAS (40 %, NRAS (0 % and BRAF (0 % oncogenes. SNP-mutations in the KRAS gene were accompanied by hypermethylation of one or more promoters of the studied genes. Association of this epigenetic index with tumor metastasis was proved. The data on an increase in methylation of the promoter regions of oncosupressor genes can be used as sensitive prognostic markers of progression and metastasis of colorectal cancer.

  12. Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice.

    Science.gov (United States)

    Sasada, Tatsunari; Hinoi, Takao; Saito, Yasufumi; Adachi, Tomohiro; Takakura, Yuji; Kawaguchi, Yasuo; Sotomaru, Yusuke; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Ohdan, Hideki

    2015-01-01

    The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli (Apc) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma--caused by either chromosomal (CDX2P 9.5-NLS Cre;Apc(+/flox), abbreviated to CPC;Apc) or microsatellite (CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox)) instability, respectively--were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In CPC;Apc mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox) mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the Apc gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes Clostridium perfringens and C. difficile, as well as species belonging to the Atopobium cluster, including Enterobacteriaceae and Staphylococcus sp., which was associated with colon tumorigenesis in CPC;Apc mice. These results suggest that differences in tumorigenesis among CPC;Apc mice consuming chlorinated versus tap water may be due to differences

  13. APC/C-mediated degradation of dsRNA-binding protein 4 (DRB4 involved in RNA silencing.

    Directory of Open Access Journals (Sweden)

    Katia Marrocco

    Full Text Available Selective protein degradation via the ubiquitin-26S proteasome is a major mechanism underlying DNA replication and cell division in all Eukaryotes. In particular, the APC/C (Anaphase Promoting Complex or Cyclosome is a master ubiquitin protein ligase (E3 that targets regulatory proteins for degradation allowing sister chromatid separation and exit from mitosis. Interestingly, recent work also indicates that the APC/C remains active in differentiated animal and plant cells. However, its role in post-mitotic cells remains elusive and only a few substrates have been characterized.In order to identify novel APC/C substrates, we performed a yeast two-hybrid screen using as the bait Arabidopsis APC10/DOC1, one core subunit of the APC/C, which is required for substrate recruitment. This screen identified DRB4, a double-stranded RNA binding protein involved in the biogenesis of different classes of small RNA (sRNA. This protein interaction was further confirmed in vitro and in plant cells. Moreover, APC10 interacts with DRB4 through the second dsRNA binding motif (dsRBD2 of DRB4, which is also required for its homodimerization and binding to its Dicer partner DCL4. We further showed that DRB4 protein accumulates when the proteasome is inactivated and, most importantly, we found that DRB4 stability depends on APC/C activity. Hence, depletion of Arabidopsis APC/C activity by RNAi leads to a strong accumulation of endogenous DRB4, far beyond its normal level of accumulation. However, we could not detect any defects in sRNA production in lines where DRB4 was overexpressed.Our work identified a first plant substrate of the APC/C, which is not a regulator of the cell cycle. Though we cannot exclude that APC/C-dependent degradation of DRB4 has some regulatory roles under specific growth conditions, our work rather points to a housekeeping function of APC/C in maintaining precise cellular-protein concentrations and homeostasis of DRB4.

  14. The PP2AB56 phosphatase promotes the association of Cdc20 with APC/C in mitosis.

    Science.gov (United States)

    Lee, Sun Joo; Rodriguez-Bravo, Veronica; Kim, Hyunjung; Datta, Sutirtha; Foley, Emily A

    2017-05-15

    PP2A comprising B56 regulatory subunit isoforms (PP2A B56 ) is a serine/threonine phosphatase essential for mitosis. At the kinetochore, PP2A B56 both stabilizes microtubule binding and promotes silencing of the spindle assembly checkpoint (SAC) through its association with the SAC protein BubR1. Cells depleted of the B56 regulatory subunits of PP2A are delayed in activation of Cdc20-containing APC/C (APC/C Cdc20 ), which is an essential step for mitotic exit. It has been hypothesized that this delay arises from increased production of the mitotic checkpoint complex (MCC), an APC/C Cdc20 inhibitor formed at unattached kinetochores through SAC signaling. In contrast to this prediction, we show that depletion of B56 subunits does not increase the amount or stability of the MCC. Rather, delays in APC/C Cdc20 activation in B56-depleted cells correlate with impaired Cdc20 binding to APC/C. Stimulation of APC/C Cdc20 assembly does not require binding between PP2A B56 and BubR1, and thus this contribution of PP2A B56 towards mitotic exit is distinct from its functions at kinetochores. PP2A B56 associates with APC/C constitutively in a BubR1-independent manner. A mitotic phosphorylation site on Cdc20, known to be a substrate of PP2A B56 , modulates APC/C Cdc20 assembly. These results elucidate the contributions of PP2A B56 towards completion of mitosis. © 2017. Published by The Company of Biologists Ltd.

  15. Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia.

    Science.gov (United States)

    Sumner, E T; Chawla, A T; Cororaton, A D; Koblinski, J E; Kovi, R C; Love, I M; Szomju, B B; Korwar, S; Ellis, K C; Grossman, S R

    2017-08-17

    Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP1 and 2) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with this oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP's contribution to in vivo tumorigenesis, Apc min/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2 +/- mice. CtBP interacts with adenomatous polyposis coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apc min/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apc min/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2 +/- polyps exhibiting reduced levels of β-catenin and its oncogenic transcriptional target, cyclin D1. CtBP's potential as a therapeutic target was studied by treating Apc min/+ mice with the CtBP small-molecule inhibitors 4-methylthio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner β-catenin, and the effects of the inhibitors on CtBP and β-catenin levels could be modeled in an APC-mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

  16. Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.

    Science.gov (United States)

    Spier, Isabel; Drichel, Dmitriy; Kerick, Martin; Kirfel, Jutta; Horpaopan, Sukanya; Laner, Andreas; Holzapfel, Stefanie; Peters, Sophia; Adam, Ronja; Zhao, Bixiao; Becker, Tim; Lifton, Richard P; Perner, Sven; Hoffmann, Per; Kristiansen, Glen; Timmermann, Bernd; Nöthen, Markus M; Holinski-Feder, Elke; Schweiger, Michal R; Aretz, Stefan

    2016-03-01

    In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ≥ 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  17. Multi-scale modeling of APC and [Formula: see text]-catenin regulation in the human colonic crypt.

    Science.gov (United States)

    Emerick, Brooks; Schleiniger, Gilberto; Boman, Bruce M

    2018-06-01

    Stem cell renewal and differentiation in the human colonic crypt are linked to the [Formula: see text]-catenin pathway. The spatial balance of Wnt factors in proliferative cells within the crypt maintain an appropriate level of cellular reproduction needed for normal crypt homeostasis. Mutational events at the gene level are responsible for deregulating the balance of Wnt factors along the crypt, causing an overpopulation of proliferative cells, a loss of structure of the crypt domain, and the initiation of colorectal carcinomas. We formulate a PDE model describing cell movement and reproduction in a static crypt domain. We consider a single cell population whose proliferative capabilities are determined by stemness, a quantity defined by intracellular levels of adenomatous polyposis coli (APC) scaffold protein and [Formula: see text]-catenin. We fit APC regulation parameters to biological data that describe normal protein gradients in the crypt. We also fit cell movement and protein flux parameters to normal crypt characteristics such as renewal time, total cell count, and proportion of proliferating cells. The model is used to investigate abnormal crypt dynamics when subjected to a diminished APC gradient, a scenario synonymous to mutations in the APC gene. We find that a 25% decrease in APC synthesis leads to a fraction of 0.88 proliferative, which is reflective of normal-appearing FAP crypts. A 50% drop in APC activity yields a fully proliferative crypt showing a doubling of the level of stemness, which characterizes the initial stages of colorectal cancer development. A sensitivity analysis of APC regulation parameters shows the perturbation of factors that is required to restore crypt dynamics to normal in the case of APC mutations.

  18. Association of APC I1307K and E1317Q polymorphisms with colorectal cancer among Egyptian subjects.

    Science.gov (United States)

    Abdel-Malak, Camelia; Darwish, Hossam; Elsaid, Afaf; El-Tarapely, Fatma; Elshazli, Rami

    2016-01-01

    Colorectal cancer is a multifactorial disease that involves both environmental and genetic factors. The gene encoding adenomatous polyposis coli (APC) has been reported to be associated with colorectal cancer (CRC) risk in several ethnic populations. The aim of this work is to assess the association of the APC I1307K and E1317Q polymorphisms with CRC risk among Egyptian subjects. This study included 120 unrelated CRC Egyptian patients who were compared to 100 healthy controls from the same locality. For all subjects, DNA was genotyped for APC I1307K and E1317Q polymorphisms using the PCR-ARMS technique. The frequency of APC I1307K carrier (TA+AA genotypes) was noted to be significantly higher among cases with CRC compared to controls (18.3 vs. 9.0 %, OR 2.58, 95 % CI 1.09-6.09, p = 0.03). Also the frequency of the APC I1307K A allele was significantly higher among cases compared to controls (10.4 vs. 4.5 %, OR 2.47; 95 % CI 1.12-5.42, p = 0.03). On the contrast, the frequencies of APC E1317Q GC genotype and C allele showed no significant difference among CRC patients compared to controls (3.3 vs. 2.0 %, OR 1.69; 95 % CI 0.30-9.42, p = 0.69 and 2.1 vs. 1.0 %, OR 2.11; 95 % CI 0.40-10.97, p = 0.46, respectively). Cases of the APC I1307K and E1317Q carriers (TA+AA and GC) showed no significant difference compared to those with I1307K and E1317Q non-carriers (TT and GG) regarding their clinical and laboratory markers. APC I1307K variant was associated with an increased risk of CRC among Egyptian subjects.

  19. Complete Genome Sequence of the Gamma-Aminobutyric Acid-Producing Strain Streptococcus thermophilus APC151.

    Science.gov (United States)

    Linares, Daniel M; Arboleya, Silvia; Ross, R Paul; Stanton, Catherine

    2017-04-27

    Here is presented the whole-genome sequence of Streptococcus thermophilus APC151, isolated from a marine fish. This bacterium produces gamma-aminobutyric acid (GABA) in high yields and is biotechnologically suitable to produce naturally GABA-enriched biofunctional yogurt. Its complete genome comprises 2,097 genes and 1,839,134 nucleotides, with an average G+C content of 39.1%. Copyright © 2017 Linares et al.

  20. PLK1 regulates spindle formation kinetics and APC/C activation in mouse zygote

    Czech Academy of Sciences Publication Activity Database

    Baran, V.; Brzáková, Adéla; Rehák, P.; Kovaříková, V.; Šolc, Petr

    2016-01-01

    Roč. 24, č. 3 (2016), s. 338-345 ISSN 0967-1994 R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk LH12057 Institutional support: RVO:67985904 Keywords : APC/C * BI2536 * live cell imaging * mouse zygote * PLK1 * securin * spindle assembly Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.053, year: 2016

  1. INTERVIEW: Quick, Social and Collaborative - wiki-based user documentation at APC by Schneider Electric

    DEFF Research Database (Denmark)

    Møller, Margrethe H.; Pernille Bagger Nielsen, Pernille; Kalianov, Stanislav

    2013-01-01

    In the software documentation department at APC by Schneider Electric in Kolding, Denmark, Technical Writer Pernille Bagger Nielsen writes user documentation for the software developed by the company. In cooperation with Localization Manager Stanislav Kalianov she reorganised the user documentation...... for publication as wiki-based documentation on the internet. The new platform supports their strategy of using agile and iterative, topic-based, collaborative writing when developing user documentation. Their experience will interest readers who consider introducing a similar new strategy....

  2. Development of two distinct dendritic-like APCs in the context of splenic stroma

    Directory of Open Access Journals (Sweden)

    Pravin ePeriasamy

    2013-03-01

    Full Text Available Murine splenic stroma has been found to provide an in vitro niche for hematopoiesis of dendritic-like APCs (APC. Two distinct cell types have been characterised. The novel ‘L-DC’ subset, has cross presenting capacity leading to activation of CD8+ T cells, but do not activate CD4+ T cells consistent with their CD11cloCD11bhiMHC-II- phenotype. For L-DC, an equivalent tissue-specific APC has been found only in spleen. A second population of CD11chiCD11bloMHC-II+ cells resembling conventional dendritic cells (cDC can activate both CD4 and CD8 T cells. Production of L-DC but not cDC-like cells is now shown to be dependent on contact between the L-DC progenitor and stroma such that the presence of a Transwell membrane can prevent L-DC development. Since L-DC can be produced continuously in vitro in stromal co-cultures overlaid with bone marrow (BM progenitors, it was hypothesised that L-DC progenitors are self-renewing. The L-DC progenitor is shown here to be defined by the Flt3-c-kit+Lin-Sca-1+ (F-KLS subset of adult BM which contains primitive HSC. Since the less primitive F+KLS HSC subset also contains L-DC progenitors, Flt3 does not appear to be a defining marker for this progenitor. Precursors of the cDC-like subset are found only within the F+KLS subset and seed production of a transient population of APC. All data identify differentiation of L-DC from HSC, and of cDC-like cells from DC precursors, which occurs independently of inflammatory signals and is dependent on a splenic stromal microenvironment.

  3. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

    Science.gov (United States)

    Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojevic, Ivan; Vandeusen, Jeffrey B; Hsu, David; Clary, Bryan M; Clay, Timothy M; Chen, Wei; Morse, Michael A; Lyerly, H Kim

    2011-06-15

    Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.

  4. Cdh1-APC/C, cyclin B-Cdc2, and Alzheimer's disease pathology

    International Nuclear Information System (INIS)

    Aulia, Selina; Tang, Bor Luen

    2006-01-01

    The anaphase-promoting complex/cyclosome (APC/C) is a key E3 ubiquitin ligase complex that functions in regulating cell cycle transitions in proliferating cells and has, as revealed recently, novel roles in postmitotic neurons. Regulated by its activator Cdh1 (or Hct1), whose level is high in postmitotic neurons, APC/C seems to have multiple functions at different cellular locations, modulating diverse processes such as synaptic development and axonal growth. These processes do not, however, appear to be directly connected to cell cycle regulation. It is now shown that Cdh1-APC/C activity may also have a basic role in suppressing cyclin B levels, thus preventing terminally differentiated neurons from aberrantly re-entering the cell cycle. The result of an aberrant cyclin B-induced S-phase entry, at least for some of these neurons, would be death via apoptosis. Cdh1 thus play an active role in maintaining the terminally differentiated, non-cycling state of postmitotic neurons-a function that could become impaired in Alzheimer's and other neurodegenerative diseases

  5. Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.

    Science.gov (United States)

    Brown, Nicholas G; VanderLinden, Ryan; Watson, Edmond R; Weissmann, Florian; Ordureau, Alban; Wu, Kuen-Phon; Zhang, Wei; Yu, Shanshan; Mercredi, Peter Y; Harrison, Joseph S; Davidson, Iain F; Qiao, Renping; Lu, Ying; Dube, Prakash; Brunner, Michael R; Grace, Christy R R; Miller, Darcie J; Haselbach, David; Jarvis, Marc A; Yamaguchi, Masaya; Yanishevski, David; Petzold, Georg; Sidhu, Sachdev S; Kuhlman, Brian; Kirschner, Marc W; Harper, J Wade; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A

    2016-06-02

    Protein ubiquitination involves E1, E2, and E3 trienzyme cascades. E2 and RING E3 enzymes often collaborate to first prime a substrate with a single ubiquitin (UB) and then achieve different forms of polyubiquitination: multiubiquitination of several sites and elongation of linkage-specific UB chains. Here, cryo-EM and biochemistry show that the human E3 anaphase-promoting complex/cyclosome (APC/C) and its two partner E2s, UBE2C (aka UBCH10) and UBE2S, adopt specialized catalytic architectures for these two distinct forms of polyubiquitination. The APC/C RING constrains UBE2C proximal to a substrate and simultaneously binds a substrate-linked UB to drive processive multiubiquitination. Alternatively, during UB chain elongation, the RING does not bind UBE2S but rather lures an evolving substrate-linked UB to UBE2S positioned through a cullin interaction to generate a Lys11-linked chain. Our findings define mechanisms of APC/C regulation, and establish principles by which specialized E3-E2-substrate-UB architectures control different forms of polyubiquitination. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. The specificity of targeted vaccines for APC surface molecules influences the immune response phenotype.

    Directory of Open Access Journals (Sweden)

    Gunnveig Grødeland

    Full Text Available Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA to different surface molecules on antigen presenting cells (APC. We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8(+/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m delivery as compared to intradermal (i.d. vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs.

  7. A novel approach to assess the spontaneous gastrointestinal bleeding risk of antithrombotic agents using Apc(min/+) mice.

    Science.gov (United States)

    Wei, Huijun; Shang, Jin; Keohane, CarolAnn; Wang, Min; Li, Qiu; Ni, Weihua; O'Neill, Kim; Chintala, Madhu

    2014-06-01

    Assessment of the bleeding risk of antithrombotic agents is usually performed in healthy animals with some form of vascular injury to peripheral organs to induce bleeding. However, bleeding observed in patients with currently marketed antithrombotic drugs is typically spontaneous in nature such as intracranial haemorrhage (ICH) and gastrointestinal (GI) bleeding, which happens most frequently on top of preexisting pathologies such as GI ulcerations and polyps. Apc(min/+) mice are reported to develop multiple adenomas through the entire intestinal tract and display progressive anaemia.In this study, we evaluated the potential utility of Apc(min/+) mice as a model for assessing spontaneous GI bleeding with antithrombotic agents. Apc(min/+) mice exhibited progressive blood loss starting at the age of nine weeks. Despite the increase in bleeding, Apc(min/+) mice were in a hypercoagulable state and displayed an age-dependent increase in thrombin generation and circulating fibrinogen as well as a significant decrease in clotting times. We evaluated the effect of warfarin, dabigatran etexilate, apixaban and clopidogrel in this model by administering them in diet or in the drinking water to mice for 1-4 weeks. All of these marketed drugs significantly increased GI bleeding in Apc(min/+) mice, but not in wild-type mice. Although different exposure profiles of these antithrombotic agents make it challenging to compare the bleeding risk of compounds, our results indicate that the Apc(min/+) mouse may be a sensitive preclinical model for assessing the spontaneous GI bleeding risk of novel antithrombotic agents.

  8. Association between aberrant APC promoter methylation and breast cancer pathogenesis: a meta-analysis of 35 observational studies.

    Science.gov (United States)

    Zhou, Dan; Tang, Weiwei; Wang, Wenyi; Pan, Xiaoyan; An, Han-Xiang; Zhang, Yun

    2016-01-01

    Background. Adenomatous polyposis coli (APC) is widely known as an antagonist of the Wnt signaling pathway via the inactivation of β-catenin. An increasing number of studies have reported that APC methylation contributes to the predisposition to breast cancer (BC). However, recent studies have yielded conflicting results. Methods. Herein, we systematically carried out a meta-analysis to assess the correlation between APC methylation and BC risk. Based on searches of the Cochrane Library, PubMed, Web of Science and Embase databases, the odds ratio (OR) with 95% confidence interval (CI) values were pooled and summarized. Results. A total of 31 articles involving 35 observational studies with 2,483 cases and 1,218 controls met the inclusion criteria. The results demonstrated that the frequency of APC methylation was significantly higher in BC cases than controls under a random effect model (OR = 8.92, 95% CI [5.12-15.52]). Subgroup analysis further confirmed the reliable results, regardless of the sample types detected, methylation detection methods applied and different regions included. Interestingly, our results also showed that the frequency of APC methylation was significantly lower in early-stage BC patients than late-stage ones (OR = 0.62, 95% CI [0.42-0.93]). Conclusion. APC methylation might play an indispensable role in the pathogenesis of BC and could be regarded as a potential biomarker for the diagnosis of BC.

  9. The APC/C Coordinates Retinal Differentiation with G1 Arrest through the Nek2-Dependent Modulation of Wingless Signaling.

    Science.gov (United States)

    Martins, Torcato; Meghini, Francesco; Florio, Francesca; Kimata, Yuu

    2017-01-09

    The cell cycle is coordinated with differentiation during animal development. Here we report a cell-cycle-independent developmental role for a master cell-cycle regulator, the anaphase-promoting complex or cyclosome (APC/C), in the regulation of cell fate through modulation of Wingless (Wg) signaling. The APC/C controls both cell-cycle progression and postmitotic processes through ubiquitin-dependent proteolysis. Through an RNAi screen in the developing Drosophila eye, we found that partial APC/C inactivation severely inhibits retinal differentiation independently of cell-cycle defects. The differentiation inhibition coincides with hyperactivation of Wg signaling caused by the accumulation of a Wg modulator, Drosophila Nek2 (dNek2). The APC/C degrades dNek2 upon synchronous G1 arrest prior to differentiation, which allows retinal differentiation through local suppression of Wg signaling. We also provide evidence that decapentaplegic signaling may posttranslationally regulate this APC/C function. Thus, the APC/C coordinates cell-fate determination with the cell cycle through the modulation of developmental signaling pathways. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration

    Science.gov (United States)

    Ekman, Maria; Mu, Yabing; Lee, So Young; Edlund, Sofia; Kozakai, Takaharu; Thakur, Noopur; Tran, Hoanh; Qian, Jiang; Groeden, Joanna; Heldin, Carl-Henrik; Landström, Maréne

    2012-01-01

    Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3β (GSK-3β). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-β (TGFβ) and is known to inhibit various TGFβ-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen–activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGFβ stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3β kinases to facilitate local TGFβ/p38–dependent inactivation of GSK-3β, accumulation of β-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7–APC complex links the TGFβ type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGFβ. PMID:22496417

  11. Premature Ejaculation and Utilization of Cognitive Techniques

    Directory of Open Access Journals (Sweden)

    Serkan AKKOYUNLU

    2013-03-01

    Full Text Available Introduction: Premature ejaculation is the most common male sexual dysfunction leading to distress in many couples. Master and Johnson emphasized the concept of early learned experiences and Kaplan emphasized lack of sensory awareness. For treatment sex therapists mainly utilize start-stop and squeeze techniques as homework. Couples enter sex therapy with some cognitive distortions and beliefs about sex and sexuality. These beliefs are also named sexual myths. For some couples using techniques to challenge cognitive distortions and maladaptive beliefs about sex and sexuality can be used. In this paper by presenting a case we discussed how cognitive techniques can be used along with behaviour techniques with couples. Case: Presenting clients are five years married couple who are thirty and twenty nine years old respectively. They attended to the outpatient clinic with the request of the female client. Their main complaint was premature ejaculation. They were diagnosed premature ejaculation using clinical interview. In treatment besides start and stop technique, cognitive techniques were utilized to address dysfunctional beliefs about sexuality. Discussion: Premature ejaculation is a male sexual dysfunction that causes distress and intimacy problems between couples. Stop start and squeeze techniques were accepted as the choice of treatment but their effectiveness is questioned recently. Also cognitive distortions and maladaptive beliefs may hamper therapy progress. Besides that, behavioral techniques utilizing cognitive techniques to lessen the degree of dysfunctional beliefs about sex and sexuality may help the couple to overcome premature ejaculation and enhance sexual satisfaction and intimacy.

  12. Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects

    Directory of Open Access Journals (Sweden)

    Vesela Kamila

    2007-04-01

    Full Text Available Abstract Background Germline mutations in the adenomatous polyposis gene (APC result in familial adenomatous polyposis (FAP. FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP is characterized by less than 100 adenomas and later onset of the disease. Methods Here, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346. Results In the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5% and 9 mutations in 25 patients with attenuated FAP (36%. We report 20 novel germline APC mutations and 3 large deletions (6% encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease. Conclusion The results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically

  13. Radiation-induced premature menopause: a misconception

    International Nuclear Information System (INIS)

    Madsen, Berit L.; Giudice, Linda; Donaldson, Sarah S.

    1995-01-01

    Purpose: To disprove the common view that women who have undergone irradiation to fields excluding the pelvis are at risk for radiation-induced premature menopause, we reviewed menstrual function and fertility among women treated with subtotal lymphoid irradiation for Hodgkin's Disease. Methods and Materials: Treatment and follow-up records of all women less than age 50 at the time of diagnosis of Stage I or II supradiaphragmatic Hodgkin's Disease, treated with subtotal lymphoid irradiation alone and enrolled in radiotherapy trials from 1967 to 1985, were reviewed. In addition, patients were surveyed regarding their menstrual status and fertility history. Results: Thirty-six women, aged 10 to 40 years, with normal menstrual function at the time of Hodgkin's diagnosis, were identified. Mean follow-up was 14 years, with a range of 1.25-22.75 years. The average radiation dose to mantle and paraaortic fields was 40-44 Gy; the calculated scatter radiation dose to the pelvis at the ovaries was 3.2 Gy. There were 38 pregnancies in 18 women; all offspring are normal. One of 36 women (2.7%) experienced premature menopause. The reported rate of premature menopause in women who have not undergone irradiation is 1-3%; not significantly different than the rate in our study. There is a syndrome whereby antibodies to several endocrine organs occur (including the ovary), which is associated with premature ovarian failure. This syndrome may be associated with prior radiation to the thyroid, such as that given by mantle-irradiation for Hodgkin's Disease. We report such a case. Conclusion: There is little risk of premature menopause in women treated with radiation fields that exclude the pelvis. Women with presumed radiation-induced premature menopause warrant an evaluation to exclude other causes of ovarian failure, such as autoimmune disorders

  14. Premature Ejaculation and Utilization of Cognitive Techniques

    Directory of Open Access Journals (Sweden)

    Serkan AKKOYUNLU

    2013-04-01

    Discussion: Premature ejaculation is a male sexual dysfunction that causes distress and intimacy problems between couples. Stop start and squeeze techniques were accepted as the choice of treatment but their effectiveness is questioned recently. Also cognitive distortions and maladaptive beliefs may hamper therapy progress. Besides that, behavioral techniques utilizing cognitive techniques to lessen the degree of dysfunctional beliefs about sex and sexuality may help the couple to overcome premature ejaculation and enhance sexual satisfaction and intimacy. [JCBPR 2013; 2(1.000: 47-52

  15. Follow-up study on premature infants with and without retinopathy of prematurity.

    OpenAIRE

    Robinson, R; O'Keefe, M

    1993-01-01

    The ocular complications in population of 131 premature infants, with and without retinopathy of prematurity (ROP) are reported. An increased incidence of strabismus (20% with ROP and 25% without ROP) and myopia (27.5% with ROP and 8.8% without ROP) was shown. Significant visual loss occurred in 10.7% overall, increasing to 35% with stage 3 disease and 100% with stage 4. With the increased survival rate of premature infants, the relevance to future management of this expanding group of young ...

  16. Induction of endoplasmic reticulum stress by deletion of Grp78 depletes Apc mutant intestinal epithelial stem cells.

    Science.gov (United States)

    van Lidth de Jeude, J F; Meijer, B J; Wielenga, M C B; Spaan, C N; Baan, B; Rosekrans, S L; Meisner, S; Shen, Y H; Lee, A S; Paton, J C; Paton, A W; Muncan, V; van den Brink, G R; Heijmans, J

    2017-06-15

    Intestinal epithelial stem cells are highly sensitive to differentiation induced by endoplasmic reticulum (ER) stress. Colorectal cancer develops from mutated intestinal epithelial stem cells. The most frequent initiating mutation occurs in Apc, which results in hyperactivated Wnt signalling. This causes hyperproliferation and reduced sensitivity to chemotherapy, but whether these mutated stem cells are sensitive to ER stress induced differentiation remains unknown. Here we examined this by generating mice in which both Apc and ER stress repressor chaperone Grp78 can be conditionally deleted from the intestinal epithelium. For molecular studies, we used intestinal organoids derived from these mice. Homozygous loss of Apc alone resulted in crypt elongation, activation of the Wnt signature and accumulation of intestinal epithelial stem cells, as expected. This phenotype was however completely rescued on activation of ER stress by additional deletion of Grp78. In these Apc-Grp78 double mutant animals, stem cells were rapidly lost and repopulation occurred by non-mutant cells that had escaped recombination, suggesting that Apc-Grp78 double mutant stem cells had lost self-renewal capacity. Although in Apc-Grp78 double mutant mice the Wnt signature was lost, these intestines exhibited ubiquitous epithelial presence of nuclear β-catenin. This suggests that ER stress interferes with Wnt signalling downstream of nuclear β-catenin. In conclusion, our findings indicate that ER stress signalling results in loss of Apc mutated intestinal epithelial stem cells by interference with the Wnt signature. In contrast to many known inhibitors of Wnt signalling, ER stress acts downstream of β-catenin. Therefore, ER stress poses a promising target in colorectal cancers, which develop as a result of Wnt activating mutations.

  17. Identification of the APC/C co-factor FZR1 as a novel therapeutic target for multiple myeloma.

    Science.gov (United States)

    Crawford, Lisa J; Anderson, Gordon; Johnston, Cliona K; Irvine, Alexandra E

    2016-10-25

    Multiple Myeloma (MM) is a haematological neoplasm characterised by the clonal proliferation of malignant plasma cells in the bone marrow. The success of proteasome inhibitors in the treatment of MM has highlighted the importance of the ubiquitin proteasome system (UPS) in the pathogenesis of this disease. In this study, we analysed gene expression of UPS components to identify novel therapeutic targets within this pathway in MM. Here we demonstrate how this approach identified previously validated and novel therapeutic targets. In addition we show that FZR1 (Fzr), a cofactor of the multi-subunit E3 ligase complex anaphase-promoting complex/cyclosome (APC/C), represents a novel therapeutic target in myeloma. The APC/C associates independently with two cofactors, Fzr and Cdc20, to control cell cycle progression. We found high levels of FZR1 in MM primary cells and cell lines and demonstrate that expression is further increased on adhesion to bone marrow stromal cells (BMSCs). Specific knockdown of either FZR1 or CDC20 reduced viability and induced growth arrest of MM cell lines, and resulted in accumulation of APC/CFzr substrate Topoisomerase IIα (TOPIIα) or APC/CCdc20 substrate Cyclin B. Similar effects were observed following treatment with proTAME, an inhibitor of both APC/CFzr and APC/CCdc20. Combinations of proTAME with topoisomerase inhibitors, etoposide and doxorubicin, significantly increased cell death in MM cell lines and primary cells, particularly if TOPIIα levels were first increased through pre-treatment with proTAME. Similarly, combinations of proTAME with the microtubule inhibitor vincristine resulted in enhanced cell death. This study demonstrates the potential of targeting the APC/C and its cofactors as a therapeutic approach in MM.

  18. A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine

    International Nuclear Information System (INIS)

    Reed, Karen R; Meniel, Valerie S; Marsh, Victoria; Cole, Alicia; Sansom, Owen J; Clarke, Alan R

    2008-01-01

    p53 is an important tumour suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of β-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development

  19. Promoter methylation of APC and RAR-β genes as prognostic markers in non-small cell lung cancer (NSCLC).

    Science.gov (United States)

    Feng, Hongxiang; Zhang, Zhenrong; Qing, Xin; Wang, Xiaowei; Liang, Chaoyang; Liu, Deruo

    2016-02-01

    Aberrant promoter hypermethylations of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine methylation status at APC and RAR-β promoters in primary NSCLC, and whether they have any relationship with survival. APC and RAR-β promoter methylation status were determined in 41 NSCLC patients using methylation specific PCR. APC promoter methylation was detectable in 9 (22.0%) tumor samples and 6 (14.6%) corresponding non-tumor samples (P=0.391). RAR-β promoter methylation was detectable in 13 (31.7%) tumor samples and 4 (9.8%) corresponding non-tumor samples (P=0.049) in the NSCLC patients. APC promoter methylation was found to be associated with T stage (P=0.046) and nodal status (P=0.019) in non-tumor samples, and with smoking (P=0.004) in tumor samples. RAR-β promoter methylation was found associated with age (P=0.031) in non-tumor samples and with primary tumor site in tumor samples. Patients with APC promoter methylation in tumor samples showed significantly longer survival than patients without it (Log-rank P=0.014). In a multivariate analysis of prognostic factors, APC methylation in tumor samples was an independent prognostic factor (P=0.012), as were N1 positive lymph node number (P=0.025) and N2 positive lymph node number (P=0.06). Our study shows that RAR-β methylation detected in lung tissue may be used as a predictive marker for NSCLC diagnosis and that APC methylation in tumor sample may be a useful marker for superior survival in NSCLC patients. Copyright © 2015. Published by Elsevier Inc.

  20. Premature ovarian failure and ovarian autoimmunity

    NARCIS (Netherlands)

    J.A. Schoemaker (Joop); H.A. Drexhage (Hemmo); A. Hoek (Annemieke)

    1997-01-01

    textabstractPremature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a

  1. Optimal oxygen saturation in premature infants

    Directory of Open Access Journals (Sweden)

    Meayoung Chang

    2011-09-01

    Full Text Available There is a delicate balance between too little and too much supplemental oxygen exposure in premature infants. Since underuse and overuse of supplemental oxygen can harm premature infants, oxygen saturation levels must be monitored and kept at less than 95% to prevent reactive oxygen species-related diseases, such as retinopathy of prematurity and bronchopulmonary dysplasia. At the same time, desaturation below 80 to 85% must be avoided to prevent adverse consequences, such as cerebral palsy. It is still unclear what range of oxygen saturation is appropriate for premature infants; however, until the results of further studies are available, a reasonable target for pulse oxygen saturation (SpO2 is 90 to 93% with an intermittent review of the correlation between SpO2 and the partial pressure of arterial oxygen tension (PaO2. Because optimal oxygenation depends on individuals at the bedside making ongoing adjustments, each unit must define an optimal target range and set alarm limits according to their own equipment or conditions. All staff must be aware of these values and adjust the concentration of supplemental oxygen frequently.

  2. Osteopenia (metabolic bone disease) of prematurity

    Science.gov (United States)

    Osteopenia is defined as postnatal bone mineralization that is inadequate to fully mineralize bones. Osteopenia occurs commonly in very low birth weight (VLBW) infants. Prior to the use of high-mineral containing diets for premature infants, which is the current practice, significant radiographic ch...

  3. Psychological and Educational Sequelae of Prematurity

    Science.gov (United States)

    Rubin, Rosalyn A.; And Others

    1973-01-01

    Psychological and educational correlates of prematurity in children during four periods, the last at 7 years of age, were assessed as part of a prospective longitudinal study of 241 infants classified by birth weight, gestational age, and sex to determine later functioning in school. (Author/MC)

  4. AMH as Predictor of Premature Ovarian Insufficiency

    DEFF Research Database (Denmark)

    Lunding, Stine Aa; Aksglæde, Lise; Anderson, Richard A

    2015-01-01

    CONTEXT: The majority of Turner syndrome (TS) patients suffer from accelerated loss of primordial follicles. Low circulating levels of anti-Müllerian hormone (AMH) may predict the lack of spontaneous puberty in prepubertal girls and imminent premature ovarian insufficiency (POI) in TS women...

  5. Morbidities, concordance, and predictors of preterm premature ...

    African Journals Online (AJOL)

    2015-12-05

    Dec 5, 2015 ... Background: Preterm premature rupture of membranes (PPROM) is a challenging complication of ... PROM (P < 0.000), latency period (P < 0.000), and birth weight (P < 0.001). ..... J Obstet Gynecol 2000;183:271‑6. 25. Mercer ...

  6. RESEARCH ON REDUCING PREMATURITY RUPTURE OF MEMBRANE

    Directory of Open Access Journals (Sweden)

    Maria URSACHI (BOLOTA

    2016-12-01

    Full Text Available The membranes surrounding the amniotic cavity are composed from amnion and chorion, tightly adherent layers which are composed of several cell types, including epithelial cells, trophoblasts cells and mesenchyme cells, embedded in a collagenous matrix. They retain amniotic fluid, secret substances into the amniotic fluid, as well as to the uterus and protect the fetus against upward infections from urogenital tract. Normally, the membranes it breaks during labor. Premature rupture of the amniotic sac (PRAS is defined as rupture of membranes before the onset of labor. Premature rupture of the fetal membrane, which occurs before 37 weeks of gestation, usually, refers to preterm premature rupture of membranes. Despite advances in the care period, premature rupture of membranes and premature rupture of membranes preterm continue to be regarded as serious obstetric complications. On the term 8% - 10% of pregnant women have premature rupture of membranes; these women are at increased risk of intrauterine infections, where the interval between membrane rupture and expulsion is rolled-over. Premature rupture of membranes preterm occurs in approximately 1% of all pregnancies and is associated with 30% -40% of preterm births. Thus, it is important to identify the cause of pre-term birth (after less than 37 completed weeks of "gestation" and its complications, including respiratory distress syndrome, neonatal infection and intraventricular hemorrhage. Objectives: the development of the protocol of the clinical trial on patients with impending preterm birth, study clinical and statistical on the socio-demographic characteristics of patients with imminent preterm birth; clinical condition of patients and selection of cases that could benefit from the application of interventional therapy; preclinical investigation (biological and imaging of patients with imminent preterm birth; the modality therapy; clinical investigation of the effectiveness of short

  7. Reviving Ulysses contracts.

    Science.gov (United States)

    Spellecy, Ryan

    2003-12-01

    Ulysses contracts have faced paternalism objections since they first were proposed. Since the contracts are designed to override a present request from a legally competent patient in favor of a past request made by that patient, enforcement of these contracts was argued to be unjustifiable strong paternalism. Recent legal developments and new theories of practical reasoning suggest that the discussion of Ulysses contracts should be revived. This paper argues that with a proper understanding of the future-directed planning embodied in Ulysses contracts, the charge of strong paternalism can be answered, and the enforcement of some Ulysses contracts may be justified under the rubric of weak paternalism.

  8. ADMINISTRATIVE CONTRACTS. DELIMITATIONS

    Directory of Open Access Journals (Sweden)

    Liana Teodora PASCARIU

    2016-12-01

    Full Text Available Article examines whether all contracts of public persons are administrative contracts; in other words, if the administration may conclude contracts that, according to their legal nature, are not administrative. If we start from the definition of administrative contracts as it appears in Law no. 554/2004, these include contracts by public authorities which concern the enhancement of public property execution of works of public interest, public services, public procurement and other administrative contracts provided by special laws and subject to the jurisdiction of the administrative courts.

  9. Risk Factors for premature birth in a hospital 1

    OpenAIRE

    Ahumada-Barrios, Margarita E.; Alvarado, German F.

    2016-01-01

    Abstract Objective: to determine the risk factors for premature birth. Methods: retrospective case-control study of 600 pregnant women assisted in a hospital, with 298 pregnant women in the case group (who gave birth prematurely

  10. T cell reactivity with allergoids: influence of the type of APC.

    Science.gov (United States)

    Kahlert, H; Grage-Griebenow, E; Stüwe, H T; Cromwell, O; Fiebig, H

    2000-08-15

    The use of allergoids for allergen-specific immunotherapy has been established for many years. The characteristic features of these chemically modified allergens are their strongly reduced IgE binding activity compared with the native form and the retained immunogenicity. T cell reactivity of chemically modified allergens is documented in animals, but in humans indirect evidence of reactivity has been concluded from the induction of allergen-specific IgG during immunotherapy. Direct evidence of T cell reactivity was obtained recently using isolated human T cells. To obtain further insight into the mechanism of action of allergoids, we compared the Ag-presenting capacity of different APC types, including DC and macrophages, generated from CD14+ precursor cells from the blood of grass pollen allergic subjects, autologous PBMC, and B cells. These APC were used in experiments together with Phl p 5-specific T cell clones under stimulation with grass pollen allergen extract, rPhl p 5b, and the respective allergoids. Using DC and macrophages, allergoids exhibited a pronounced and reproducible T cell-stimulating capacity. Responses were superior to those with PBMC, and isolated B cells failed to present allergoids. Considerable IL-12 production was observed only when using the DC for Ag presentation of both allergens and allergoids. The amount of IL-10 in supernatants was dependent on the phenotype of the respective T cell clone. High IL-10 production was associated with suppressed IL-12 production from the DC in most cases. In conclusion, the reactivity of Th cells with allergoids is dependent on the type of the APC.

  11. B lymphocytes as natural antigen-presenting cells (APC) of their own Ig receptor determinants

    International Nuclear Information System (INIS)

    Yurin, V.L.; Rudensky, A.Yu.; Rabinovich, O.R.; Kulakova, O.G.; Bobreneva, R.A.

    1986-01-01

    The authors use Igk-lb allotype-specific rat T cell proliferation(Pr) in vitro as a model of natural Ig determinants B cell presentation in Ig-specific T-B cell interactions. As shown before Igk-lb-specific responsiveness of AUG(RT-l/sup c/, Igk-la) and WAG (RT-l, Igk-la) rats is controlled by dominant Ir gene, linked to RT-l/sup c/. Only IgG(Igk-lb)-pulsed splenic APC of AUG(responder) but not WAG(non-responder) origin induce specific F 1 (WAGxAUG) T cell Pr. The same restriction was observed if purified B cells from Igk-l congeneic AUG-lb and WAG-lb rats were used as APC. B cell presentation was found to be sensitive to high irradiation dose(2000 rad). Anti-RT-l monoclonal antibody inhibition studies suggested RT-lB(I-A) molecule as a main restricting element of Igk-lb T cell recognition. B cell and splenic APC presentation of Igk-lb allotype was not inhibited by poly- and monoclonal anti-Igk-lb antibodies. Allelic exclusion of Igk-lb presentation by B cells from heterozygous F 1 (WAG-lbx AUG) rats was demonstrated by panning with antiallotypic reagents. Important, that irradiated anti-Igk-lb T cells induce specific Pr of normal Igk-lb-positive B cells. The data demonstrate MHC-restricted B cell presentation of their own receptor determinants, distinct from serologically-defined epitopes. T cell recognition of these determinants induce specific Pr of Ig-recognizing T cells and Ig-presenting B lymphocytes

  12. Different modes of APC/C activation control growth and neuron-glia interaction in the developing Drosophila eye.

    Science.gov (United States)

    Neuert, Helen; Yuva-Aydemir, Yeliz; Silies, Marion; Klämbt, Christian

    2017-12-15

    The development of the nervous system requires tight control of cell division, fate specification and migration. The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that affects different steps of cell cycle progression, as well as having postmitotic functions in nervous system development. It can therefore link different developmental stages in one tissue. The two adaptor proteins, Fizzy/Cdc20 and Fizzy-related/Cdh1, confer APC/C substrate specificity. Here, we show that two distinct modes of APC/C function act during Drosophila eye development. Fizzy/Cdc20 controls the early growth of the eye disc anlage and the concomitant entry of glial cells onto the disc. In contrast, fzr/cdh1 acts during neuronal patterning and photoreceptor axon growth, and subsequently affects neuron-glia interaction. To further address the postmitotic role of Fzr/Cdh1 in controlling neuron-glia interaction, we identified a series of novel APC/C candidate substrates. Four of our candidate genes are required for fzr/cdh1 -dependent neuron-glia interaction, including the dynein light chain Dlc90F Taken together, our data show how different modes of APC/C activation can couple early growth and neuron-glia interaction during eye disc development. © 2017. Published by The Company of Biologists Ltd.

  13. Intestinal APCs of the endogenous nanomineral pathway fail to express PD-L1 in Crohn’s disease

    Science.gov (United States)

    Robertson, Jack; Haas, Carolin T.; Pele, Laetitia C.; Monie, Tom P.; Charalambos, Charles; Parkes, Miles; Hewitt, Rachel E.; Powell, Jonathan J.

    2016-01-01

    Crohn’s disease is a chronic inflammatory condition most commonly affecting the ileum and colon. The aetiology of Crohn’s disease is complex and may include defects in peptidoglycan recognition, and/or failures in the establishment of intestinal tolerance. We have recently described a novel constitutive endogenous delivery system for the translocation of nanomineral-antigen-peptidoglycan (NAP) conjugates to antigen presenting cells (APCs) in intestinal lymphoid patches. In mice NAP conjugate delivery to APCs results in high surface expression of the immuno-modulatory molecule programmed death receptor ligand 1 (PD-L1). Here we report that NAP conjugate positive APCs in human ileal tissues from individuals with ulcerative colitis and intestinal carcinomas, also have high expression of PD-L1. However, NAP-conjugate positive APCs in intestinal tissue from patients with Crohn’s disease show selective failure in PD-L1 expression. Therefore, in Crohn’s disease intestinal antigen taken up by lymphoid patch APCs will be presented without PD-L1 induced tolerogenic signalling, perhaps initiating disease. PMID:27226337

  14. Intestinal APCs of the endogenous nanomineral pathway fail to express PD-L1 in Crohn's disease.

    Science.gov (United States)

    Robertson, Jack; Haas, Carolin T; Pele, Laetitia C; Monie, Tom P; Charalambos, Charles; Parkes, Miles; Hewitt, Rachel E; Powell, Jonathan J

    2016-05-26

    Crohn's disease is a chronic inflammatory condition most commonly affecting the ileum and colon. The aetiology of Crohn's disease is complex and may include defects in peptidoglycan recognition, and/or failures in the establishment of intestinal tolerance. We have recently described a novel constitutive endogenous delivery system for the translocation of nanomineral-antigen-peptidoglycan (NAP) conjugates to antigen presenting cells (APCs) in intestinal lymphoid patches. In mice NAP conjugate delivery to APCs results in high surface expression of the immuno-modulatory molecule programmed death receptor ligand 1 (PD-L1). Here we report that NAP conjugate positive APCs in human ileal tissues from individuals with ulcerative colitis and intestinal carcinomas, also have high expression of PD-L1. However, NAP-conjugate positive APCs in intestinal tissue from patients with Crohn's disease show selective failure in PD-L1 expression. Therefore, in Crohn's disease intestinal antigen taken up by lymphoid patch APCs will be presented without PD-L1 induced tolerogenic signalling, perhaps initiating disease.

  15. The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

    Science.gov (United States)

    Halberg, Richard B.; Chen, Xiaodi; Amos-Landgraf, James M.; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri; Sullivan, Ruth; Pitot, Henry C.; Dove, William F.

    2008-01-01

    Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes. PMID:18723878

  16. Aggregate material formulated with MSWI bottom ash and APC fly ash for use as secondary building material

    International Nuclear Information System (INIS)

    Valle-Zermeño, R. del; Formosa, J.; Chimenos, J.M.; Martínez, M.; Fernández, A.I.

    2013-01-01

    Highlights: ► A concrete formulation was optimized using Bottom Ash and APC ash. ► 10% of APC ash achieves good compromise between economic and performance aspects. ► The crushed concrete was evaluated as secondary building granular material. ► The environmental behavior allows its use as secondary material. ► The abrasion resistance is not good enough for its use as a road sub-base material. - Abstract: The main goal of this paper is to obtain a granular material formulated with Municipal Solid Waste Incineration (MSWI) bottom ash (BA) and air pollution control (APC) fly ash to be used as secondary building material. Previously, an optimum concrete mixture using both MSWI residues as aggregates was formulated. A compromise between the environmental behavior whilst maximizing the reuse of APC fly ash was considered and assessed. Unconfined compressive strength and abrasion resistance values were measured in order to evaluate the mechanical properties. From these results, the granular mixture was not suited for certain applications owing to the high BA/APC fly ash content and low cement percentages used to reduce the costs of the final product. Nevertheless, the leaching test performed showed that the concentrations of all heavy metals were below the limits established by the current Catalan legislation for their reutilization. Therefore, the material studied might be mainly used in embankments, where high mechanical properties are not needed and environmental safety is assured

  17. Liver Inflammation and Metabolic Signaling in ApcMin/+ Mice: The Role of Cachexia Progression

    Science.gov (United States)

    Narsale, Aditi A.; Enos, Reilly T.; Puppa, Melissa J.; Chatterjee, Saurabh; Murphy, E. Angela; Fayad, Raja; Pena, Majorette O’; Durstine, J. Larry; Carson, James A.

    2015-01-01

    The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer

  18. Electrodialytic upgrading of MSWI APC residue from hazardous waste to secondary resource

    DEFF Research Database (Denmark)

    Jensen, Pernille Erland; Kirkelund, Gunvor Marie; Parés Viader, Raimon

    .g. for substitution of cement or fillers in concrete. In general leaching could not be reduced by optimizing current density and treatment time in the pilot scale stack treatment unit, as hypothesized, even though there was evidence of dependency on current density for e.g. zinc, this was not true for most elements......The aim of this project was to contribute to the development of electrodialytic treatment technology of air pollution control residues (APC) from municipal solid waste incineration (MSWI) to obtain maximal leaching reduction by optimization of treatment time and current density for different types...

  19. Sistem Monitoring Pendeteksi Kebocoran LPG berbasis Mikrokontroller ATmega16 menggunakan RF APC220

    Directory of Open Access Journals (Sweden)

    RATNA SUSANA

    2016-02-01

    Full Text Available Abstrak Penggunaan LPG sebagai bahan bakar alternatif pengganti bahan bakar minyak dirasakan lebih efektif dan praktis. Namun kandungan senyawa di dalamnya memiliki efek yang negatif jika menguap di udara bebas. Sistem detektor gas LPG dapat menjadi salah satu solusi untuk mengetahui lebih dini terjadinya kebocoran gas. Implementasi sistem detektor gas LPG pada penelitian ini berupa sistem monitoring nirkabel yang dilengkapi alarm sebagai indikasi jika terjadi kebocoran gas. Sistem terdiri dari bagian Remote Controller dan Master Controller. Remote Controller menggunakan mikrokontroler ATMega16 yang terintegrasi dengan sensor MQ5, LCD dan transceiver RF APC220. Sedangkan Master Controller berupa komputer (PC yang dapat menampilkan kondisi ruangan yang dideteksi oleh bagian Remote Controller. Sistem berhasil mendeteksi gas LPG dan menampilkan kadar konsentrasinya dalam rentang 200 sampai dengan 1000 ppm. Ketika kadar konsentrasi gas mencapai 5000 ppm, alarm aktif secara otomatis dan memberikan status waspada. Pengiriman data secara nirkabel dengan adanya sejumlah penghalang berhasil dilakukan sampai jarak 200 m. Kata kunci: Sistem Monitoring, Remote Controller, Master Controller, LPG, RF APC220   Abstract The use of LPG as a fuel alternative to fossil fuels may be more effective and practical. Neverfluless its compound has a negative effect if it evaporates to the air. LPG gas detector system may be one solution to determine the early occurrence of gas leak. The detector system implementation in this study was a wireless monitoring system that had alarm to indicate if there was the gas leak. The system consisted of the Remote Controller and the Master Controller. Remote Controller used ATmega16 microcontroller integrated with MQ5 sensor, LCD and RF transceiver APC220. While the Master Controller in the form of a computer (PC that could display a room condition was detected by the Remote Controller section. LPG gas system successfully detected

  20. Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression.

    Directory of Open Access Journals (Sweden)

    Aditi A Narsale

    Full Text Available The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein, IRE-1α (endoplasmic reticulum to nucleus signaling 1, and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3. While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3. Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin, despite a suppression of Akt (thymoma viral proto-oncogene 1 and S6 (ribosomal protein S6 phosphorylation. Thus

  1. Premature graying of hair: An independent risk marker for coronary ...

    African Journals Online (AJOL)

    The presence of premature graying of hair was associated with 3.24 times the risk of CAD on multiple logistic regression analysis. CONCLUSION: The presence of premature graying of hair was associated with an increased risk of CAD in young smokers. Premature graying of hair can be used as preliminary evidence by ...

  2. Contractibility of curves

    Directory of Open Access Journals (Sweden)

    Janusz Charatonik

    1991-11-01

    Full Text Available Results concerning contractibility of curves (equivalently: of dendroids are collected and discussed in the paper. Interrelations tetween various conditions which are either sufficient or necessary for a curve to be contractible are studied.

  3. Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis.

    Science.gov (United States)

    Lorthe, Elsa; Goffinet, François; Marret, Stéphane; Vayssiere, Christophe; Flamant, Cyril; Quere, Mathilde; Benhammou, Valérie; Ancel, Pierre-Yves; Kayem, Gilles

    2017-08-01

    There are conflicting results regarding tocolysis in cases of preterm premature rupture of membranes. Delaying delivery may reduce neonatal morbidity because of prematurity and allow for prenatal corticosteroids and, if necessary, in utero transfer. However, that may increase the risks of maternofetal infection and its adverse consequences. The objective of the study was to investigate whether tocolytic therapy in cases of preterm premature rupture of membranes is associated with improved neonatal or obstetric outcomes. Etude Epidémiologique sur les Petits Ages Gestationnels 2 is a French national prospective, population-based cohort study of preterm births that occurred in 546 maternity units in 2011. Inclusion criteria in this analysis were women with preterm premature rupture of membranes at 24-32 weeks' gestation and singleton gestations. Outcomes were survival to discharge without severe morbidity, latency prolonged by ≥48 hours and histological chorioamnionitis. Uterine contractions at admission, individual and obstetric characteristics, and neonatal outcomes were compared by tocolytic treatment or not. Propensity scores and inverse probability of treatment weighting for each woman were used to minimize indication bias in estimating the association of tocolytic therapy with outcomes. The study population consisted of 803 women; 596 (73.4%) received tocolysis. Women with and without tocolysis did not differ in neonatal survival without severe morbidity (86.7% vs 83.9%, P = .39), latency prolonged by ≥48 hours (75.1% vs 77.4%, P = .59), or histological chorioamnionitis (50.0% vs 47.6%, P = .73). After applying propensity scores and assigning inverse probability of treatment weighting, tocolysis was not associated with improved survival without severe morbidity as compared with no tocolysis (odds ratio, 1.01 [95% confidence interval, 0.94-1.09], latency prolonged by ≥48 hours (1.03 [95% confidence interval, 0.95-1.11]), or histological chorioamnionitis

  4. Concept of contracting authority

    OpenAIRE

    Kasiliauskaitė, Vitalija

    2016-01-01

    Concept of Contracting Authority Law on Public Procurement the procurement concept implies the conclusion that public procurement be declared only such purchases are carried out by the contracting authority. The contracting authorities can be a subject of state and municipal management institutes, whose assignment authority is determined by a functional approach. Also, contracting authorities may be public and legal entities, but that the public interest and operates non-commercial activities...

  5. Inflation Forecast Contracts

    OpenAIRE

    Gersbach, Hans; Hahn, Volker

    2012-01-01

    We introduce a new type of incentive contract for central bankers: inflation forecast contracts, which make central bankers’ remunerations contingent on the precision of their inflation forecasts. We show that such contracts enable central bankers to influence inflation expectations more effectively, thus facilitating more successful stabilization of current inflation. Inflation forecast contracts improve the accuracy of inflation forecasts, but have adverse consequences for output. On balanc...

  6. Teaching about Contracts.

    Science.gov (United States)

    Froman, Michael; Kosnoff, Kathy

    1978-01-01

    Presents teaching strategies for introducing high school students to contract law. Offers as a case study a contract agreement between pro football players and team owners. Stresses basic elements of contracts (offer, acceptance, consideration, and understanding the bargaining process). Journal available from the American Bar Association, 1155…

  7. Contract law as fairness

    NARCIS (Netherlands)

    Klijnsma, J.

    2015-01-01

    This article examines the implications for contract law of Rawls' theory of justice as fairness. It argues that contract law as an institution is part of the basic structure of society and as such subject to the principles of justice. Discussing the basic structure in relation to contract law is

  8. 3 CFR - Government Contracting

    Science.gov (United States)

    2010-01-01

    ... contract oversight could reduce such sums significantly. Government outsourcing for services also raises... a risk that taxpayer funds will be spent on contracts that are wasteful, inefficient, subject to... mission. In such cases, the agency must ensure that the risks associated with noncompetitive contracts are...

  9. Contracting for nuclear fuels

    International Nuclear Information System (INIS)

    Schuessler, C.M.

    1981-10-01

    This paper deals with uranium sales contracts, i.e. with contractual arrangements in the first steps of the fuel cycle, which cover uranium production and conversion. The various types of contract are described and, where appropriate, their underlying business philosophy and their main terms and conditions. Finally, the specific common features of such contracts are reviewed. (NEA) [fr

  10. Other enrichment related contracts

    International Nuclear Information System (INIS)

    Hall, J.C.

    1978-01-01

    In addition to long-term enrichment contracts, DOE has other types of contracts: (1) short-term, fixed-commitment enrichment contract; (2) emergency sales agreement for enriched uranium; (3) feed material lease agreement; (4) enriched uranium storage agreement; and (5) feed material usage agreement

  11. ATP depletion during mitotic arrest induces mitotic slippage and APC/CCdh1-dependent cyclin B1 degradation.

    Science.gov (United States)

    Park, Yun Yeon; Ahn, Ju-Hyun; Cho, Min-Guk; Lee, Jae-Ho

    2018-04-27

    ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN 3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole-induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly. Additionally, cells successfully progressed through the cell cycle after mitotic slippage, as indicated by EdU incorporation and time-lapse imaging. Although degradation of cyclin B during normal mitotic progression is primarily regulated by APC/C Cdc20 , we observed an unexpected decrease in Cdc20 prior to degradation of cyclin B during mitotic slippage. This decrease in Cdc20 was followed by a change in the binding partner preference of APC/C from Cdc20 to Cdh1; consequently, APC/C Cdh1 , but not APC/C Cdc20 , facilitated cyclin B degradation following ATP depletion. Pulse-chase analysis revealed that ATP depletion significantly abrogated global translation, including the translation of Cdc20 and Cdh1. Additionally, the half-life of Cdh1 was much longer than that of Cdc20. These data suggest that ATP depletion during mitotic arrest induces mitotic slippage facilitated by APC/C Cdh1 -dependent cyclin B degradation, which follows a decrease in Cdc20 resulting from reduced global translation and the differences in the half-lives of the Cdc20 and Cdh1 proteins.

  12. Hsa-miR-11181 regulates Wnt signaling pathway through targeting of APC2 transcripts in SW480 cell line.

    Science.gov (United States)

    Dokanehiifard, Sadat; Soltani, Bahram M

    2018-01-30

    Wnt signaling plays important roles in differentiation, morphogenesis and development. This signaling pathway is highly regulated at all levels and microRNAs are small noncoding RNAs regulating Wnt signaling. Here, we intended to investigate hsa-miR-11181 (a novel miRNA located in TrkC gene) effect on Wnt signaling pathway in SW480 cell line. TOP/FOP flash assay indicated up-regulation of Wnt signaling, following the overexpression of hsa-miR-11181, verified through RT-qPCR. Bioinformatics analysis predicted APC1, APC2 and Axin1 might be targeted by hsa-miR-11181. Then, RT-qPCR analysis indicated that APC2 and Axin1 have been significantly down-regulated following the hsa-miR-11181 overexpression. However dual luciferase assay analysis supported only APC2 3'-UTR is directly targeted by this miRNA. Then, treatment of SW480 cells with Wnt-inhibitory small molecules supported the effect of hsa-miR-11181 at the inhibitory complex level containing APC2 protein. Consistently, viability of SW480 cells overexpressing hsa-miR-11181 was significantly elevated, measured through MTT assay. Overall, these results suggest that hsa-miR-11181 may play a crucial role in Wnt signaling regulation and confirmed that APC2 3'-UTR is targeted by hsa-miR-11181 and propose the presence of its recognition sites in the promoter or coding regions of Axin1 gene. Copyright © 2017. Published by Elsevier B.V.

  13. The effect of EBV on WIF1, NLK, and APC gene methylation and expression in gastric carcinoma and nasopharyngeal cancer.

    Science.gov (United States)

    Zhao, Zhenzhen; Liu, Wen; Liu, Jincheng; Wang, Jiayi; Luo, Bing

    2017-10-01

    Epstein-Barr virus (EBV) is an important DNA tumor virus that is associated with approximately 10% of gastric carcinomas and 99% of nasopharyngeal cancers (NPC). DNA methylation and microRNAs (miRNAs) are the most studied epigenetic mechanisms that can prompt disease susceptibility. This study aimed to detect the effect of EBV on Wnt inhibitory factor 1 (WIF1), Nemo-like kinase (NLK), and adenomatous polyposis coli (APC) gene methylation, and expression in gastric carcinoma and NPC. The WIF1, NLK, and APC gene mRNA expression levels were measured by real-time quantitative RT-PCR in four EBV-positive cell lines and four EBV-negative cell lines. Bisulfite genomic sequencing or methylation-specific PCR was used to detect the methylation status of the WIF1, NLK, and APC promoters. All cell lines were treated with 5-azacytidine (5-aza-dC), miR-BART19-3p mimics or an inhibitor, and analyzed by flow cytometry and MTT cell proliferation assays. The WIF1, NLK, and APC promoters were hypermethylated in all eight cell lines. 5-Aza-dC displayed a growth inhibitory effect on cells . After transfection with miR-BART19-3p mimics, the expression of WIF1, and APC decreased, and the cellular proliferation rate increased. After transfection with the miR-BART19-3p inhibitor, the expression levels were higher, and the cell growth was inhibited. In the NPC and GC cell lines, the promoters of WIF1, NLK, and APC are highly methylated, and the expression of these three genes is regulated by miR-BART19-3p. The activity of the Wnt pathway in EBV-associated tumors may be enhanced by miR-BART19-3p. © 2017 Wiley Periodicals, Inc.

  14. Intestinal microbiota: a potential diet-responsive prevention target in ApcMin mice.

    Science.gov (United States)

    Mai, Volker; Colbert, Lisa H; Perkins, Susan N; Schatzkin, Arthur; Hursting, Stephen D

    2007-01-01

    We previously reported that two dietary regimens, calorie restriction (CR) and a high olive oil-containing diet supplemented with a freeze-dried fruit and vegetable extract (OFV), reduced the development of intestinal adenomas in Apc(Min) mice by 57% and 33%, respectively, compared to control mice fed a defined diet ad libitum. The OFV diet was designed to have a strong effect on the composition of the intestinal microbiota through its high content of fiber, which represents a major source of fermentable substrate for the gut bacteria. We hypothesized that some of the observed effects of diet on intestinal carcinogenesis might be mediated by diet-related changes in the bacterial species that thrive in the gut. Therefore, we determined by fluorescent in situ hybridization (FISH) and denaturing gradient gel electrophoresis (DGGE) how the dietary interventions affected the composition of the intestinal microbiota, and we characterized specific microbiota changes that were associated with diet and reduced intestinal carcinogenesis. The OFV diet changed the overall composition of the intestinal microbiota, smaller changes were observed for the CR diet. Furthermore, we detected a 16S rDNA fragment associated with mice that did not develop polyps. Sequence analysis suggested that hitherto unidentified bacteria belonging to the family Lachnospiraceae (order Clostridiales) were its source. Thus, these bacteria may be an indicator of intestinal conditions associated with reduced intestinal carcinogenesis in Apc(Min) mice. Copyright 2006 Wiley-Liss, Inc.

  15. Evaluation of APC NbTi superconductor in a model dipole magnet

    International Nuclear Information System (INIS)

    Scanlan, R.M.; Lietzke, A.; Royet, J.; Wandesforde, A.; Taylor, C.E.; Wong, J.; Rudziak, M.K.

    1993-01-01

    The artificial pinning center (APC) approach to NbTi superconductor fabrication offers the potential benefits of higher current density and lower cost than the conventional process for NbTi. We have been evaluating several approaches for fabricating NbTi via the APC approach to determine whether these advantages can be realized in a practical conductor. The study began with the fabrication by several vendors of 10kg size samples which were evaluated as short samples. This was followed by the scale-up of one process to 150mm diameter billets. This material was evaluated first in a solenoid configuration and recently in a one-meter long dipole. We will report here on the results of these coil tests and other characterization results for this new material. We will also describe the plans to continue the scale-up to full size billets and we will discuss the potential cost savings of this approach compared with conventional NbTi fabrication

  16. Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

    Science.gov (United States)

    Afulani, Patience A; Altman, Molly; Musana, Joseph; Sudhinaraset, May

    2017-11-08

    Globally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity. The key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors. There is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving

  17. Premature ovarian failure and ovarian autoimmunity

    OpenAIRE

    Schoemaker, Joop; Drexhage, Hemmo; Hoek, Annemieke

    1997-01-01

    textabstractPremature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic...

  18. RESEARCH ON REDUCING PREMATURITY RUPTURE OF MEMBRANE

    OpenAIRE

    Maria URSACHI (BOLOTA); Emil ANTON; Sorana Caterina ANTON

    2016-01-01

    The membranes surrounding the amniotic cavity are composed from amnion and chorion, tightly adherent layers which are composed of several cell types, including epithelial cells, trophoblasts cells and mesenchyme cells, embedded in a collagenous matrix. They retain amniotic fluid, secret substances into the amniotic fluid, as well as to the uterus and protect the fetus against upward infections from urogenital tract. Normally, the membranes it breaks during labor. Premature rupture of the amn...

  19. Duration in Production Contracts

    OpenAIRE

    MacDonald, James M.; Korb, Penelope J.

    2006-01-01

    We use 2003 and 2004 ARMS data to analyze variations in contract duration among growers of broilers who hold production contracts. Most contracts cover just a single flock, but many extend for 1-2 years, and a significant minority of broiler contracts specify lengths of 5, 10, and even 15 years. We find that grower debt and production volume are inversely related to the choice of a short term (a year or less) contract, while lengthy prior experience with the contractor promotes short term con...

  20. Retinopathy of prematurity: the need for prevention

    Science.gov (United States)

    Liegl, Raffael; Hellström, Ann; Smith, Lois EH

    2016-01-01

    More than 450,000 babies are born prematurely in the USA every year. The improved survival of even the most vulnerable low body weight preterm infants has, despite improving health outcomes, led to the resurgence in preterm complications including one of the major causes for blindness in children, retinopathy of prematurity (ROP). The current mainstay in ROP therapy is laser photocoagulation and the injection of vascular endothelial growth factor (VEGF) antibodies in the late stages of the disease after the onset of neovascularization. Both are proven options for ophthalmologists to treat the severe forms of late ROP. However, laser photocoagulation destroys major parts of the retina, and the injection of VEGF antibodies, although rather simple to administer, may cause a systemic suppression of normal vascularization, which has not been studied in sufficient depth. However, the use of neither VEGF antibody nor laser treatment prevents ROP, which should be the long-term goal. It should be possible to prevent ROP by more closely mimicking the intrauterine environment after preterm birth. Such preventive measures include preventing the toxic postbirth influences (eg, oxygen excess) as well as providing the missing intrauterine factors (eg, insulin growth factor 1) and are likely to also reduce other complications of premature birth as well as ROP. This review is meant to summarize the current knowledge on the prevention of ROP with a particular emphasize on the use of insulin growth factor 1 supplementation. PMID:28539804

  1. Patent Ductus Arteriosus in Premature Neonates

    Science.gov (United States)

    Mezu-Ndubuisi, Olachi J.; Agarwal, Ghanshyam; Raghavan, Aarti; Pham, Jennifer T.; Ohler, Kirsten H.; Maheshwari, Akhil

    2015-01-01

    Persistent patency of the ductus arteriosus is a major cause of morbidity and mortality in premature infants. In infants born prior to 28 weeks of gestation, a hemodynamically-significant patent ductus arteriosus (PDA) can cause cardiovascular instability, exacerbate respiratory distress syndrome, prolong the need for assisted ventilation, and increase the risk of bronchopulmonary dysplasia, intraventricular hemorrhage, renal dysfunction, intraventricular hemorrhage, cerebral palsy, and mortality. In this article, we review the pathophysiology, clinical features, and assessment of hemodynamic significance, and provide a rigorous appraisal of the quality of evidence to support current medical and surgical management of PDA of prematurity. Cyclo-oxygenase inhibitors such as indomethacin and ibuprofen remain the mainstay of medical therapy for PDA, and can be used both for prophylaxis as well as rescue therapy to achieve PDA closure. Surgical ligation is also effective and is used in infants who do not respond to medical management. Although both medical and surgical treatment have proven efficacy in closing the ductus, both modalities are associated with significant adverse effects. Because the ductus does undergo spontaneous closure in some premature infants, improved and early identification of infants most likely to develop a symptomatic PDA could help in directing treatment to the at-risk infants and allow others to receive expectant management. PMID:22564132

  2. Open bite in prematurely born children.

    Science.gov (United States)

    Harila, V; Heikkinen, T; Grön, M; Alvesalo, L

    2007-01-01

    The aims of this study were to: examine the expression of open bite in prematurely born children and discuss the etiological factors that may lead to bite it. The subjects were 328 prematurely born (cross-sectional study of the Collaborative Perinatal Project in the 1960s and 1970s. Dental documents, including casts and photographs, were taken once at the age of 6-12 years in the mixed dentition. The occlusion was recorded by examining and measuring the hard stone casts. Vertical open bite was recorded only for full erupted teeth. The statistical method used was chi-square analysis. Significant differences in the incidence of anterior open bite (from left to right canine) was found between the preterm and control groups and between gender and ethnic groups. The prevalence of anterior open bite was nearly 9% in the preterm group and almost 7% in the control group. African Americans (9%) had a significantly greater incidence of open bite than Caucasians (3%; Pbite than boys (8% vs 6%; Pbite was increased--especially in preterm African American boys compared to controls (11% vs 8%). The results show differences in the development of anterior open bite between ethnic and gender groups. Premature birth may also influence dental occlusal development. Of importance are the patient's: general health condition; respiratory infections; inadequate nasal- and mouth-breathing; oral habits; and other medical problems. Preterm children may be relatively more predisposed to etiological factors for the development of anterior open bite.

  3. High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations.

    Science.gov (United States)

    Out, Astrid A; van Minderhout, Ivonne J H M; van der Stoep, Nienke; van Bommel, Lysette S R; Kluijt, Irma; Aalfs, Cora; Voorendt, Marsha; Vossen, Rolf H A M; Nielsen, Maartje; Vasen, Hans F A; Morreau, Hans; Devilee, Peter; Tops, Carli M J; Hes, Frederik J

    2015-06-01

    Familial adenomatous polyposis is most frequently caused by pathogenic variants in either the APC gene or the MUTYH gene. The detection rate of pathogenic variants depends on the severity of the phenotype and sensitivity of the screening method, including sensitivity for mosaic variants. For 171 patients with multiple colorectal polyps without previously detectable pathogenic variant, APC was reanalyzed in leukocyte DNA by one uniform technique: high-resolution melting (HRM) analysis. Serial dilution of heterozygous DNA resulted in a lowest detectable allelic fraction of 6% for the majority of variants. HRM analysis and subsequent sequencing detected pathogenic fully heterozygous APC variants in 10 (6%) of the patients and pathogenic mosaic variants in 2 (1%). All these variants were previously missed by various conventional scanning methods. In parallel, HRM APC scanning was applied to DNA isolated from polyp tissue of two additional patients with apparently sporadic polyposis and without detectable pathogenic APC variant in leukocyte DNA. In both patients a pathogenic mosaic APC variant was present in multiple polyps. The detection of pathogenic APC variants in 7% of the patients, including mosaics, illustrates the usefulness of a complete APC gene reanalysis of previously tested patients, by a supplementary scanning method. HRM is a sensitive and fast pre-screening method for reliable detection of heterozygous and mosaic variants, which can be applied to leukocyte and polyp derived DNA.

  4. The World's Approach toward Publishing in Springer and Elsevier's APC-Funded Open Access Journals

    Science.gov (United States)

    Sotudeh, Hajar; Ghasempour, Zahra

    2018-01-01

    Purpose: The present study explored tendencies of the world's countries--at individual and scientific development levels--toward publishing in APC-funded open access journals. Design/Methodology/Approach: Using a bibliometric method, it studied OA and NOA articles issued in Springer and Elsevier's APC journals? during 2007-2011. The data were…

  5. IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo.

    Science.gov (United States)

    Brahmakshatriya, Vinayak; Kuang, Yi; Devarajan, Priyadharshini; Xia, Jingya; Zhang, Wenliang; Vong, Allen Minh; Swain, Susan L

    2017-04-01

    Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6-independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses. Copyright © 2017 by The American Association of Immunologists, Inc.

  6. Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort.

    Science.gov (United States)

    Khan, Nikhat; Lipsa, Anuja; Arunachal, Gautham; Ramadwar, Mukta; Sarin, Rajiv

    2017-05-22

    Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.

  7. Negotiating Efficient PPP Contracts

    DEFF Research Database (Denmark)

    Tvarnø, Christina D.

    . An opportunity the member states should consider using when procuring a PPP. This paper looks at the negotiation and contracting of a PPP in an economic theoretical and EU public procurement perspective and discusses how to establish an efficient PPP contract under a strong public law doctrine. Governments......This paper concerns Public Private Partnership (PPP) contracts in concern to the coming new 2014/24IEU public procurement directive. The new EU public procurement directive gives the public authority the opportunity to negotiate PPPs much more when they are implemented in national law...... procurement law. Furthermore, the paper seeks to establish a connection between public law, private law and the efficient PPP contract by drawing upon economic theory and empirical contract data from UK, US and Danish partnering contracts from the construction industry and the aim of contracting joint utility...

  8. Prematurity Affects Age of Presentation of Pyloric Stenosis.

    Science.gov (United States)

    Costanzo, Caitlyn M; Vinocur, Charles; Berman, Loren

    2017-02-01

    Term infants with hypertrophic pyloric stenosis (HPS) typically present between 4 and 6 weeks. There is limited consensus, however, regarding age of presentation of premature infants. We aim to determine if there is an association between the degree of prematurity and chronological age of presentation of HPS. A total of 2988 infants who had undergone a pyloromyotomy for HPS were identified from the 2012 and 2013 NSQIP-P Participant Use Files. Two hundred seventeen infants (7.3%) were born prematurely. A greater degree of prematurity was associated with an older chronological age of presentation ( P Prematurity was significantly associated with an increase in overall postoperative morbidity, reintubation, readmission, and postoperative length of stay. When clinicians evaluate an infant with nonbilious emesis with a history of prematurity, they should consider pyloric stenosis if the calculated postconceptional age is between 44 and 50 weeks. When counseling families of premature infants, surgeons should discuss the increased incidence of postpyloromyotomy morbidity.

  9. DETERMINATION OF PHASE COMPOSITION OF SEALING COATING BASED ON APC (ALUMINOPHOSPHATE COMPOUNDS

    Directory of Open Access Journals (Sweden)

    BOLSHAKOV V. I.

    2017-02-01

    Full Text Available Summary. Goal. To investigate the phase composition of the obtained sealing coatings based on aluminophosphate compound (APC and the impact of temperature rise on it. Methods. Qualitative X-ray phase analysis (XRPA and differential thermal analysis (DTA are used as the methods of research. Roentgenograms for structural analysis were obtained on a DRON-4-07 using filtered copper radiation in the secondary beam. Registration and initial processing of diffraction patterns was performed using the software package PDOS with the output of the diffraction patterns on the screen. Using the "loupe" option allowed to identify weak interference lines, which increased the accuracy of the method of qualitative XRPA. The thermograms for DTA received on the device type Termoskan-2. The results. It is revealed that base of coating is X-ray amorphous phase. There are following crystalline phases: Al, AlPO4, Al (PO3 3, BN found in the coating. It is revealed that annealing doesn’t make a significant influence on the phase composition of the crystalline phases and the coating doesn’t lose properties after annealing during repeated thermal stress. Scientific novelty. The phase composition of the proposed sealing coatings based on APC and produced by plasma spraying, and the effect of annealing on the phase composition of the coating are investigated. The reaction of synthesis of primary material forming on the basis of APC for coating is offered. Practical significance. The results can be used in aviation technology in the development of gas turbine engines (GTE and the design of the compressors. The sealing coating may be used to improve the reliability of the compressor and to increase the efficiency ratio of turbine engine. During the operation the compressor’s blades touch the sealing coating of compressor’s stator and grooves it without causing locking and destruction of the rotor. Therefore, the development of new sealing coating compositions that

  10. Assessment of hormonal activity in patients with premature ejaculation

    Directory of Open Access Journals (Sweden)

    Lütfi Canat

    Full Text Available ABSTRACT Purpose Premature ejaculation is considered the most common type of male sexual dysfunction. Hormonal controls of ejaculation have not been exactly elucidated. The aim of our study is to investigate the role of hormonal factors in patients with premature ejaculation. Materials and Methods Sixty-three participants who consulted our outpatient clinics with complaints of premature ejaculation and 39 healthy men as a control group selected from volunteers were included in the study. A total of 102 sexual active men aged between 21 and 76 years were included. Premature ejaculation diagnostic tool questionnaires were used to assessment of premature ejaculation. Serum levels of follicle stimulating hormone, luteinizing hormone, prolactin, total and free testosterone, thyroid-stimulating hormone, free triiodothyronine and thyroxine were measured. Results Thyroid-stimulating hormone, luteinizing hormone, and prolactin levels were significantly lower in men with premature ejaculation according to premature ejaculation diagnostic tool (p=0.017, 0.007 and 0.007, respectively. Luteinizing hormone level (OR, 1.293; p=0.014 was found to be an independent risk factor for premature ejaculation. Conclusions Luteinizing hormone, prolactin, and thyroid-stimulating hormone levels are associated with premature ejaculation which was diagnosed by premature ejaculation diagnostic tool questionnaires. The relationship between these findings have to be determined by more extensive studies.

  11. A new way of thinking about complications of prematurity.

    Science.gov (United States)

    Moore, Tiffany A; Berger, Ann M; Wilson, Margaret E

    2014-01-01

    The morbidity and mortality of preterm infants are impacted by their ability to maintain physiologic homeostasis using metabolic, endocrine, and immunologic mechanisms independent of the mother's placenta. Exploring McEwen's allostatic load model in preterm infants provides a new way to understand the altered physiologic processes associated with frequently occurring complications of prematurity such as bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity. The purpose of this article is to present a new model to enhance understanding of the altered physiologic processes associated with complications of prematurity. The model of allostatic load and complications of prematurity was derived to explore the relationship between general stress of prematurity and complications of prematurity. The proposed model uses the concepts of general stress of prematurity, allostasis, physiologic response patterns (adaptive-maladaptive), allostatic load, and complications of prematurity. These concepts are defined and theoretical relationships in the proposed model are interpreted using the four maladaptive response patterns of repeated hits, lack of adaptation, prolonged response, and inadequate response. Empirical evidence for cortisol, inflammation, and oxidative stress responses are used to support the theoretical relationships. The proposed model provides a new way of thinking about physiologic dysregulation in preterm infants. The ability to describe and understand complex physiologic mechanisms involved in complications of prematurity is essential for research. Advancing the knowledge of complications of prematurity will advance clinical practice and research and lead to testing of interventions to reduce negative outcomes in preterm infants.

  12. New staff contract policy

    CERN Document Server

    HR Department

    2006-01-01

    Following discussion at TREF and on the recommendation of the Finance Committee, Council approved a new staff contract policy, which became effective on 1 January 2006. Its application is covered by a new Administrative Circular No. 2 (Rev. 3) 'Recruitment, appointment and possible developments regarding the contractual position of staff members'. The revised circular replaces the previous Circulars No. 9 (Rev. 3) 'Staff contracts' and No. 2 (Rev. 2) 'Guidelines and procedures concerning recruitment and probation period for staff members'. The main features of the new contract policy are as follows: The new policy provides chances for long-term employment for all staff recruits staying for four years without distinguishing between those assigned to long-term or short-term activities when joining CERN. In addition, it presents a number of simplifications for the award of ICs. There are henceforth only 2 types of contract: Limited Duration (LD) contracts for all recruitment and Indefinite Contracts (IC) for...

  13. Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

    Directory of Open Access Journals (Sweden)

    Clara Penas

    2015-04-01

    Full Text Available Although casein kinase 1δ (CK1δ is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1 ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

  14. Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells

    DEFF Research Database (Denmark)

    Olsen, Anders Krüger; Coskun, Mehmet; Bzorek, Michael

    2013-01-01

    was associated with endogenous downregulation of APC and AXIN2 expression in Caco-2 cells but did not affect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results......Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling......-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analyzed for gene regulatory activity...

  15. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

    NARCIS (Netherlands)

    Weijenberg, M.P.; Luchtenborg, M.; Goeij, A.F. de; Brink, M.; Muijen, G.N.P. van; Bruine, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den

    2007-01-01

    OBJECTIVE: To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat

  16. Application of the microbiological method DEFT/APC to detect minimally processed vegetables treated with gamma radiation

    Science.gov (United States)

    Araújo, M. M.; Duarte, R. C.; Silva, P. V.; Marchioni, E.; Villavicencio, A. L. C. H.

    2009-07-01

    Marketing of minimally processed vegetables (MPV) are gaining impetus due to its convenience, freshness and apparent health effect. However, minimal processing does not reduce pathogenic microorganisms to safe levels. Food irradiation is used to extend the shelf life and to inactivate food-borne pathogens. In combination with minimal processing it could improve safety and quality of MPV. A microbiological screening method based on the use of direct epifluorescent filter technique (DEFT) and aerobic plate count (APC) has been established for the detection of irradiated foodstuffs. The aim of this study was to evaluate the applicability of this technique in detecting MPV irradiation. Samples from retail markets were irradiated with 0.5 and 1.0 kGy using a 60Co facility. In general, with a dose increment, DEFT counts remained similar independent of the irradiation while APC counts decreased gradually. The difference of the two counts gradually increased with dose increment in all samples. It could be suggested that a DEFT/APC difference over 2.0 log would be a criteria to judge if a MPV was treated by irradiation. The DEFT/APC method could be used satisfactorily as a screening method for indicating irradiation processing.

  17. Application of the microbiological method DEFT/APC to detect minimally processed vegetables treated with gamma radiation

    International Nuclear Information System (INIS)

    Araujo, M.M.; Duarte, R.C.; Silva, P.V.; Marchioni, E.; Villavicencio, A.L.C.H.

    2009-01-01

    Marketing of minimally processed vegetables (MPV) are gaining impetus due to its convenience, freshness and apparent health effect. However, minimal processing does not reduce pathogenic microorganisms to safe levels. Food irradiation is used to extend the shelf life and to inactivate food-borne pathogens. In combination with minimal processing it could improve safety and quality of MPV. A microbiological screening method based on the use of direct epifluorescent filter technique (DEFT) and aerobic plate count (APC) has been established for the detection of irradiated foodstuffs. The aim of this study was to evaluate the applicability of this technique in detecting MPV irradiation. Samples from retail markets were irradiated with 0.5 and 1.0 kGy using a 60 Co facility. In general, with a dose increment, DEFT counts remained similar independent of the irradiation while APC counts decreased gradually. The difference of the two counts gradually increased with dose increment in all samples. It could be suggested that a DEFT/APC difference over 2.0 log would be a criteria to judge if a MPV was treated by irradiation. The DEFT/APC method could be used satisfactorily as a screening method for indicating irradiation processing.

  18. Application of the microbiological method DEFT/APC to detect minimally processed vegetables treated with gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Araujo, M.M.; Duarte, R.C.; Silva, P.V. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Centro de Tecnologia das Radiacoes, Laboratorio de Deteccao de Alimentos Irradiados, Cidade Universitaria, Av. Prof. Lineu Prestes 2242, Butanta Zip Code 05508-000 Sao Paulo (Brazil); Marchioni, E. [Laboratoire de Chimie Analytique et Sciences de l' Aliment (UMR 7512), Faculte de Pharmacie, Universite Louis Pasteur, 74, route du Rhin, F-67400 Illkirch (France); Villavicencio, A.L.C.H. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Centro de Tecnologia das Radiacoes, Laboratorio de Deteccao de Alimentos Irradiados, Cidade Universitaria, Av. Prof. Lineu Prestes 2242, Butanta Zip Code 05508-000 Sao Paulo (Brazil)], E-mail: villavic@ipen.br

    2009-07-15

    Marketing of minimally processed vegetables (MPV) are gaining impetus due to its convenience, freshness and apparent health effect. However, minimal processing does not reduce pathogenic microorganisms to safe levels. Food irradiation is used to extend the shelf life and to inactivate food-borne pathogens. In combination with minimal processing it could improve safety and quality of MPV. A microbiological screening method based on the use of direct epifluorescent filter technique (DEFT) and aerobic plate count (APC) has been established for the detection of irradiated foodstuffs. The aim of this study was to evaluate the applicability of this technique in detecting MPV irradiation. Samples from retail markets were irradiated with 0.5 and 1.0 kGy using a {sup 60}Co facility. In general, with a dose increment, DEFT counts remained similar independent of the irradiation while APC counts decreased gradually. The difference of the two counts gradually increased with dose increment in all samples. It could be suggested that a DEFT/APC difference over 2.0 log would be a criteria to judge if a MPV was treated by irradiation. The DEFT/APC method could be used satisfactorily as a screening method for indicating irradiation processing.

  19. Thermal Treatment of Iron Oxide Stabilized APC Residues from Waste Incineration and the Effect on Heavy Metal Binding

    DEFF Research Database (Denmark)

    Sørensen, Mette Abildgaard; Stackpoole, M.; Bender-Koch, C.

    2000-01-01

    Iron oxide stabilized APC residues from MSWI were heat treated at 600°C and 900°C. The thermal treatments resulted in a change in product stability by forcing a transformation in the mineralogical structures of the products. The treatments, moreover, simulated somewhat the natural aging processes...

  20. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

    Science.gov (United States)

    Weijenberg, Matty P; Lüchtenborg, Margreet; de Goeij, Anton F P M; Brink, Mirian; van Muijen, Goos N P; de Bruïne, Adriaan P; Goldbohm, R Alexandra; van den Brandt, Piet A

    2007-10-01

    To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) oncogene. After 7.3 years of follow-up of the Netherlands Cohort Study (n = 120,852), adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed, based on 401 colon and 130 rectal cancer patients. Total, saturated and monounsaturated fat were not associated with the risk of colon or rectal cancer, or different molecular subgroups. There was also no association between polyunsaturated fat and the risk of overall or subgroups of rectal cancer. Linoleic acid, the most abundant polyunsaturated fatty acid in the diet, was associated with increased risk of colon tumors with only a KRAS mutation and no additional truncating APC mutation or lack of MLH1 expression (RR = 1.41, 95% CI 1.18-1.69 for one standard deviation (i.e., 7.5 g/day) increase in intake, p-trend over the quartiles of intake colon tumors without any of the gene defects, or with tumors harboring aberrations in either MLH1 or APC. Linoleic acid intake is associated with colon tumors with an aberrant KRAS gene, but an intact APC gene and MLH1 expression, suggesting a unique etiology of tumors with specific genetic aberrations.

  1. Copyright Preemption of Contracts

    OpenAIRE

    Bohannan, Christina

    2008-01-01

    This Article argues that both courts and scholars are wrong in their categorical approaches to preemption of contracts under the Copyright Act, and proposes an intermediate approach that recognizes the importance of both contract rights and federal policy in preemption analysis. First, it argues that both courts and scholars have misapplied preemption law to breach of contract claims. Although the two sides tend to favor opposite results, they take equally categorical approaches. Categori...

  2. The pathophysiology of lifelong premature ejaculation

    Science.gov (United States)

    2016-01-01

    For many decades it has been thought that lifelong premature ejaculation (PE) is only characterized by persistent early ejaculations. Despite enormous progress of in vivo animal research, and neurobiological, genetic and pharmacological research in men with lifelong PE, our current understanding of the mechanisms behind early ejaculations is far from complete. The new classification of PE into four PE subtypes has shown that the symptomatology of lifelong PE strongly differs from acquired PE, subjective PE and variable PE. The phenotype of lifelong PE and therefore also the pathophysiology of lifelong PE is much more complex. A substantial number of men with lifelong PE not only have PE, but also premature erection and premature penile detumescence as part of an acute hypertonic or hypererotic state when engaged in an erotic situation or when making love. As both erectio praecox, ejaculatio praecox, detumescentia praecox, and the hypererotic state are part of the phenotype lifelong PE, it is argued that lifelong PE is not only a disturbance of the timing of ejaculation but also a disturbance of the timing of erection, detumescence and arousal. Since 1998, the pathophysiology of lifelong PE was thought to be mainly mediated by the central serotonergic system in line with genetic polymorphisms of specific serotonergic genes. However, by accepting that lifelong PE is characterized by the reversible hypertonic state the hypothesis of mainly serotonergic dysfunction is no longer tenable. Instead, it has been postulated that the pathophysiology of lifelong PE is mediated by a very complex interplay of central and peripheral serotonergic, dopaminergic, oxytocinergic, endocrinological, genetic and probably also epigenetic factors. Progress in research of lifelong PE can only be accomplished when a stopwatch is used to measure the IELT and the cut-off point of 1 minute for the definition of lifelong PE is maintained. Current use of validated questionnaires, neglect of

  3. Premature menopause linked to CVD and osteoporosis.

    Science.gov (United States)

    Park, Claire; Overton, Caroline

    2010-03-01

    Premature menopause affects 1% of women under the age of 40, the usual age of the menopause is 51. Most women will present with irregular periods or no periods at all with or without climacteric symptoms. Around 10% of women present with primary amenorrhoea. A careful history and examination are required. It is important to ask specifically about previous chemotherapy or radiotherapy and to look for signs of androgen excess e.g. polycystic ovarian syndrome, adrenal problems e.g. galactorrhoea and thyroid goitres. Once pregnancy has been excluded, a progestagen challenge test can be performed in primary care. Norethisterone 5 mg tds po for ten days or alternatively medroxyprogesterone acetate 10 mg daily for ten days is prescribed. A withdrawal bleed within a few days of stopping the norethisterone indicates the presence of oestrogen and bleeding more than a few drops is considered a positive withdrawal bleed. The absence of a bleed indicates low levels of oestrogen, putting the woman at risk of CVD and osteoporosis. FSH levels above 30 IU/l are an indicator that the ovaries are failing and the menopause is approaching or has occurred. It should be remembered that FSH levels fluctuate during the month and from one month to the next, so a minimum of two measurements should be made at least four to six weeks apart. The presence of a bleed should not exclude premature menopause as part of the differential diagnosis as there can be varying and unpredictable ovarian function remaining. The progestagen challenge test should not be used alone, but in conjunction with FSH, LH and oestradiol. There is no treatment for premature menopause. Women desiring pregnancy should be referred to a fertility clinic and discussion of egg donation. Women not wishing to become pregnant should be prescribed HRT until the age of 50 to control symptoms of oestrogen deficiency and reduce the risks of osteoporosis and CVD.

  4. Contracting for Public Services

    DEFF Research Database (Denmark)

    Greve, Carsten

    strategic purchasing understanding markets communicating the contracting decision designing and drafting the contract the role of the consumer the regulation of service provision Illustrated throughout with practitioner case-studies from a range of OECD countries, this book presents an important new......Insightful and comprehensive and covering new subjects like globalization and IT, this text, international in its approach, provides a thorough introduction to the key phases of the contracting process and the skills required by managers in its implementation. These include: policy for contracting...

  5. Smart contracts sobre Bitcoin

    OpenAIRE

    Andreu Alemany, Josep Miquel

    2016-01-01

    El present treball final de màster realitza una introducció als smart contracts. El treball introdueix el concepte de contracte intel·ligent, els seus usos i alguns exemples existents. Seguidament proporciona les nocions necessàries de les transaccions del protocol Bitcoin per poder implementar un contracte intel·ligent, usant la blockchain que ofereix el protocol. Per últim, s'explica la implementació d'un contracte intel·ligent usant bitcoin: un canal de micropagaments. El presente traba...

  6. Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice

    Directory of Open Access Journals (Sweden)

    Bi Xiuli

    2013-01-01

    Full Text Available Abstract Background Both selenium and non-steroidal anti-inflammatory drug (NSAID sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. Results We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p Conclusions The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.

  7. The effect of soy isoflavones on the development of intestinal neoplasia in Apc(Min) mouse

    DEFF Research Database (Denmark)

    Sørensen, Ilona Kryspin; Kristiansen, Eva; Mortensen, Alicja

    1998-01-01

    Data from epidemiological studies suggest that isoflavones in soy may have a protective effect on the development of colon cancer in humans. Therefore, we have investigated whether soy isoflavones will inhibit intestinal tumour development in Apc(Min) mice. The mice were fed a Western-type high...... risk diet (high fat, low fibre and calcium) containing two different isolates of soy protein as a protein source. For the control and test groups this resulted in the administration of about 16 and 475 mg of total isoflavones per kg diet, respectively. As a positive control, a third group of mice...... was administered a low isoflavone diet supplemented with 300 ppm sulindac. No significant differences in the incidence, multiplicity, size and distribution of intestinal tumours were observed between Min mice fed low and high isoflavone-containing diets. However, a clear reduction in the number of small intestinal...

  8. Premature closure of the Trojan Nuclear Plant

    International Nuclear Information System (INIS)

    Kononetz, B.P.

    1995-01-01

    The premature closure of the Trojan Nuclear Plant is discussed in outline form. The topics discussed include: an overview of Trojan; events leading to shutdown decision; Trojan's lifetime O ampersand M performance; Trojan's Regulatory performance; historical Trojan regulatory versus economic performance; applicable Oregon law; least-cost planning process; 1992 least cost plan; 1993 LCP update; LCP limitations; comparative performance analysis; management assessments; Trojan O ampersand M analysis; steam generator issues; quantification of deficiencies; quantification of impact of steam generator degradation; 'net benefits' test; conclusions from net benefits analysis; total disallowances; and conclusions and ramifications

  9. Human milk: medicine for premature babies.

    Science.gov (United States)

    Hilton, Sioned

    2011-12-01

    Following years of research there have been some significant developments in the understanding and subsequent support being offered to Neonatal Intensive Care Unit (NICU) families. In addition, ground breaking advances in the treatment of premature infants, with specific interest in the role of human milk, are now available. New information was presented by leading international researcher, Professor Meier, at an international symposium earlier this year. This article seeks to share this insightful information and provide support to those working in or around the NICU.

  10. The economic burden of prematurity in Canada.

    Science.gov (United States)

    Johnston, Karissa M; Gooch, Katherine; Korol, Ellen; Vo, Pamela; Eyawo, Oghenowede; Bradt, Pamela; Levy, Adrian

    2014-04-05

    Preterm birth is a major risk factor for morbidity and mortality among infants worldwide, and imposes considerable burden on health, education and social services, as well as on families and caregivers. Morbidity and mortality resulting from preterm birth is highest among early (prematurity due to the larger number of late preterm infants relative to early and moderate preterm infants. The aim in this study was to characterize the burden of premature birth in Canada for early, moderate, and late premature infants, including resource utilization, direct medical costs, parental out-of-pocket costs, education costs, and mortality, using a validated and published decision model from the UK, and adapting it to a Canadian setting based on analysis of administrative, population-based data from Québec. Two-year survival was estimated at 56.0% for early preterm infants, 92.8% for moderate preterm infants, and 98.4% for late preterm infants. Per infant resource utilization consistently decreased with age. For moderately preterm infants, hospital days ranged from 1.6 at age two to 0.09 at age ten. Cost per infant over the first ten years of life was estimated to be $67,467 for early preterm infants, $52,796 for moderate preterm infants, and $10,010 for late preterm infants. Based on population sizes this corresponds to total national costs of $123.3 million for early preterm infants, $255.6 million for moderate preterm infants, $208.2 million for late preterm infants, and $587.1 million for all infants. Premature birth results in significant infant morbidity, mortality, healthcare utilization and costs in Canada. A comprehensive decision-model based on analysis of a Canadian population-based administrative data source suggested that the greatest national-level burden is associated with moderate preterm infants due to both a large cost per infant and population size while the highest individual-level burden is in early preterm infants and the largest total population size is

  11. Lactoferrin and prematurity: a promising milk protein?

    Science.gov (United States)

    Ochoa, Theresa J; Sizonenko, Stéphane V

    2017-02-01

    Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and iron homeostasis. Oral Lf supplementation in human preterm infants has been shown to reduce the incidence of sepsis and necrotizing enterocolitis. In preclinical models of antenatal stress and perinatal brain injury, bovine Lf protected the developing brain from neuronal loss, improved connectivity, increased neurotrophic factors, and decreased inflammation. It also supported brain development and cognition. Further, Lf can prevent preterm delivery by reducing proinflammatory factors and inhibiting premature cervix maturation. We review here the latest research on Lf in the field of neonatology.

  12. Chemopreventive Effects of RXR-Selective Rexinoid Bexarotene on Intestinal Neoplasia of ApcMin/+ Mice

    Directory of Open Access Journals (Sweden)

    Naveena B. Janakiram

    2012-02-01

    Full Text Available Retinoid X receptor (RXR has been implicated in several neoplastic diseases. Previously, we have shown that RXR-α is downregulated in human and rodent colonic tumors, suggesting a potential target for colon cancer prevention (http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics. Experiments were designed to assess the chemopreventive efficacy of the selective RXR agonist bexarotene for the suppression of intestinal tumorigenesis in ApcMin/+ mice. Before the efficacy studies, we determined that the maximal tolerated dose in C57BL/6J mice was less than 400 ppm. For the efficacy study, 6-week-old male and female C57BL/6J-ApcMin/+ mice (nine mice per group were fed diets containing 0, 30, and 60 ppm of bexarotene or 200 ppm of bexarotene for 80 days before intestinal tumors were evaluated. Dietary administration of 30 and 60 ppm of bexarotene suppressed the intestinal polyp formation by 38% (P < .015 and 60% (P < .0001 in males, respectively, and by 8.5% and 37% (P < .007 in females, respectively. Also, significant inhibition (50%–100% of colonic tumor formation was observed in both male and female mice with bexarotene treatment. Administration of 200 ppm of bexarotene showed significant suppression of tumor formation (66%, P < .0001; however, it had significant toxicity. Intestinal tumors of bexarotene-fed mice showed significantly reduced expression of proliferating cell nuclear antigen (60%, P < .0001, cyclin D1, and cyclooxygenase 2 and increased RXR-α messenger RNA and uptake of oleate (34%, P < .01. Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%–72%, P < .0001 and inflammatory cytokines.

  13. Voluntary exercise inhibits intestinal tumorigenesis in ApcMin/+ mice and azoxymethane/dextran sulfate sodium-treated mice

    International Nuclear Information System (INIS)

    Ju, Jihyeung; Nolan, Bonnie; Cheh, Michelle; Bose, Mousumi; Lin, Yong; Wagner, George C; Yang, Chung S

    2008-01-01

    Epidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, Apc Min/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice. In Experiments 1 and 2, five-week old female Apc Min/+ mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks. In the Apc Min/+ mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In Apc Min/+ mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E 2 and nuclear β-catenin levels, but increased E-cadherin levels in the tumors. These results indicate hat voluntary exercise inhibited intestinal tumorigenesis in Apc Min/+ mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism

  14. Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis.

    Science.gov (United States)

    Tabrizian, Tahmineh; Wang, Donghai; Guan, Fangxia; Hu, Zunju; Beck, Amanda P; Delahaye, Fabien; Huffman, Derek M

    2017-06-01

    Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of Apc However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP- Pten flox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, Apc- and Pten -deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU-positive cells in the small intestine ( P  Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion ( P  Apc deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis. © 2017 Society for Endocrinology.

  15. Antibiotic Therapy for Premature Rupture of Membranes and Preterm Labor and Effect on Fetal Outcome

    Science.gov (United States)

    Seelbach-Goebel, B.

    2013-01-01

    In Germany almost 10 % of children are born before the end of 37th week of gestation. In at least one quarter of these cases, ascending infection of the vagina plays a causative role, particularly during the early weeks of gestation. If, in addition to the decidua, the amniotic membrane, amniotic fluid and the umbilical cord are also affected, infection not only triggers uterine contractions and premature rupture of membranes but also initiates a systemic inflammatory reaction on the part of the fetus, which can increase neonatal morbidity. Numerous studies and meta-analyses have found that antibiotic therapy prolongs pregnancy and reduces neonatal morbidity. No general benefit of antibiotic treatment was found for premature uterine contractions. But it is conceivable that a subgroup of pregnant women would benefit from antibiotic treatment. It is important to identify this subgroup of women and offer them targeted treatment. This overview summarizes the current body of evidence on antibiotic treatment for impending preterm birth and the effect on neonatal outcomes. PMID:24771902

  16. Path analysis of risk factors leading to premature birth.

    Science.gov (United States)

    Fields, S J; Livshits, G; Sirotta, L; Merlob, P

    1996-01-01

    The present study tested whether various sociodemographic, anthropometric, behavioral, and medical/physiological factors act in a direct or indirect manner on the risk of prematurity using path analysis on a sample of Israeli births. The path model shows that medical complications, primarily toxemia, chorioammionitis, and a previous low birth weight delivery directly and significantly act on the risk of prematurity as do low maternal pregnancy weight gain and ethnicity. Other medical complications, including chronic hypertension, preclampsia, and placental abruption, although significantly correlated with prematurity, act indirectly on prematurity through toxemia. The model further shows that the commonly accepted sociodemographic, anthropometric, and behavioral risk factors act by modifying the development of medical complications that lead to prematurity as opposed to having a direct effect on premature delivery. © 1996 Wiley-Liss, Inc. Copyright © 1996 Wiley-Liss, Inc.

  17. RESEARCHES RELATED TO THE REDUCTION OF PREMATURITY THROUGH PREMATURE RUPTURE OF MEMBRANES IN 2017

    Directory of Open Access Journals (Sweden)

    Maria BOLOTA

    2017-06-01

    Full Text Available Data from literature, especially from the US, has provided data on prediction, prevention and treatment of premature membrane rupture (RPM. RPM is a significant cause of premature birth and can cause complications of a term task. Considerable research on RPM has led to a better understanding of the mechanism of spontaneous breakage of membranes, risk factors, and good results for newborns resulting from such obstetrical events. Spontaneous rupture of the membranes increases the risk of intrauterine infection and umbilical cord compression as well as the risk of premature detachment of placenta. Newborn babies resulting from RPM have an increased risk of morbidity compared to gestational age, and the risk of infection is increased compared with other premature babies due to ancillary causes. If RPM occurs in the second trimester, there is an additional risk of pulmonary hypoplasia and hip dysplasia. Pre-term conservative treatment prolongs latency to birth. Antibiotics reduce the risk of infection while corticosteroid treatment (dexamethasone reduces respiratory complications and interventricular haemorrhage without increasing the risk of infection. Birth is necessary or unavoidable in many cases by RPMs and because conservative treatment often results in no results; That is why studies are needed to identify all risk factors and the need to treat pregnant women at risk of RPM; 17-hydroxy-progesterone is a specific treatment for preventing recurrent membrane rupture. (http://www.ginecologultau.ro/ruptura-prematura-a-membranelor, 2013.

  18. Ichthyosis prematurity syndrome: a well-defined congenital ichthyosis subtype

    DEFF Research Database (Denmark)

    Bygum, Anette; Westermark, Per; Brandrup, Flemming

    2008-01-01

    Ichthyosis prematurity syndrome is a rare syndrome characterized by the clinical triad of premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. We describe two siblings with ichthyosis prematurity syndrome. The index patient was born at gestational week 34. Immediately aft...... in the stratum corneum and stratum granulosum. Diagnosing this syndrome is important to reassure parents, obstetricians, and pediatricians about its benign course after complications in the perinatal period....

  19. 'Rush' type retinopathy of prematurity: report of three cases.

    OpenAIRE

    Nissenkorn, I; Kremer, I; Gilad, E; Cohen, S; Ben-Sira, I

    1987-01-01

    Three premature infants observed to develop severe stage III retinopathy of prematurity (ROP) at 3 to 5 weeks of age received immediate treatment by cryoablation and photocoagulation, with good results. The critical importance of the ophthalmic examination of premature babies from the age of 2 weeks, so as not to overlook such cases of 'rush' type ROP is stressed and the difficulty involved in treating such small neonates is discussed.

  20. Regulation of nuclear envelope dynamics via APC/C is necessary for the progression of semi-open mitosis in Schizosaccharomyces japonicus.

    Science.gov (United States)

    Aoki, Keita; Shiwa, Yuh; Takada, Hiraku; Yoshikawa, Hirofumi; Niki, Hironori

    2013-09-01

    Three types of mitosis, which are open, closed or semi-open mitosis, function in eukaryotic cells, respectively. The open mitosis involves breakage of the nuclear envelope before nuclear division, whereas the closed mitosis proceeds with an intact nuclear envelope. To understand the mechanism and significance of three types of mitotic division in eukaryotes, we investigated the process of semi-open mitosis, in which the nuclear envelope is only partially broken, in the fission yeast Schizosaccharomyces japonicus. In anaphase-promoting complex/cyclosome (APC/C) mutants of Sz. japonicus, the nuclear envelope remained relatively intact during anaphase, resulting in impaired semi-open mitosis. As a suppressor of apc2 mutant, a mutation of Oar2, which was a 3-oxoacyl-[acyl carrier protein] reductase, was obtained. The level of the Oar2, which had two destruction-box motifs recognized by APC/C, was increased in APC/C mutants. Furthermore, the defective semi-open mitosis observed in an apc2 mutant was restored by mutated oar2+. Based on these findings, we propose that APC/C regulates the dynamics of the nuclear envelope through degradation of Oar2 dependent on APC/C during the metaphase-to-anaphase transition of semi-open mitosis in Sz. japonicus. © 2013 The Authors Genes to Cells © 2013 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  1. Definition of APC presentation of phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate to Vgamma2Vdelta 2 TCR.

    Science.gov (United States)

    Wei, Huiyong; Huang, Dan; Lai, Xiaomin; Chen, Meiling; Zhong, Weihua; Wang, Richard; Chen, Zheng W

    2008-10-01

    Although microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) can activate primate Vgamma2Vdelta2 T cells, molecular mechanisms by which HMBPP interacts with Vgamma2Vdelta2 T cells remain poorly characterized. Here, we developed soluble, tetrameric Vgamma2Vdelta2 TCR of rhesus macaques to define HMBPP/APC interaction with Vgamma2Vdelta2 TCR. While exogenous HMBPP was associated with APC membrane in an appreciable affinity, the membrane-associated HMBPP readily bound to the Vgamma2Vdelta2 TCR tetramer. The Vgamma2Vdelta2 TCR tetramer was shown to bind stably to HMBPP presented on membrane by various APC cell lines from humans and nonhuman primates but not those from mouse, rat, or pig. The Vgamma2Vdelta2 TCR tetramer also bound to the membrane-associated HMBPP on primary monocytes, B cells and T cells. Consistently, endogenous phosphoantigen produced in Mycobacterium-infected dendritic cells was transported and presented on membrane, and bound stably to the Vgamma2Vdelta2 TCR tetramer. The capability of APC to present HMBPP for recognition by Vgamma2Vdelta2 TCR was diminished after protease treatment of APC. Thus, our studies elucidated an affinity HMBPP-APC association conferring stable binding to the Vgamma2Vdelta2 TCR tetramer and the protease-sensitive nature of phosphoantigen presentation. The findings defined APC presentation of phosphoantigen HMBPP to Vgamma2Vdelta2 TCR.

  2. Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint-restricted Cdc20.

    Science.gov (United States)

    Boekhout, Michiel; Wolthuis, Rob

    2015-04-15

    Nek2 isoform A (Nek2A) is a presumed substrate of the anaphase-promoting complex/cyclosome containing Cdc20 (APC/C(Cdc20)). Nek2A, like cyclin A, is degraded in mitosis while the spindle checkpoint is active. Cyclin A prevents spindle checkpoint proteins from binding to Cdc20 and is recruited to the APC/C in prometaphase. We found that Nek2A and cyclin A avoid being stabilized by the spindle checkpoint in different ways. First, enhancing mitotic checkpoint complex (MCC) formation by nocodazole treatment inhibited the degradation of geminin and cyclin A, whereas Nek2A disappeared at a normal rate. Second, depleting Cdc20 effectively stabilized cyclin A but not Nek2A. Nevertheless, Nek2A destruction crucially depended on Cdc20 binding to the APC/C. Third, in contrast to cyclin A, Nek2A was recruited to the APC/C before the start of mitosis. Interestingly, the spindle checkpoint very effectively stabilized an APC/C-binding mutant of Nek2A, which required the Nek2A KEN box. Apparently, in cells, the spindle checkpoint primarily prevents Cdc20 from binding destruction motifs. Nek2A disappearance marks the prophase-to-prometaphase transition, when Cdc20, regardless of the spindle checkpoint, activates the APC/C. However, Mad2 depletion accelerated Nek2A destruction, showing that spindle checkpoint release further increases APC/C(Cdc20) catalytic activity. © 2015. Published by The Company of Biologists Ltd.

  3. Mechanisms controlling the temporal degradation of Nek2A and Kif18A by the APC/C-Cdc20 complex

    DEFF Research Database (Denmark)

    Sedgwick, G.G.; Hayward, D.G.; Nilsson, J.

    2013-01-01

    The Anaphase Promoting Complex/Cyclosome (APC/C) in complex with its co-activator Cdc20 is responsible for targeting proteins for ubiquitin-mediated degradation during mitosis. The activity of APC/C-Cdc20 is inhibited during prometaphase by the Spindle Assembly Checkpoint (SAC) yet certain...... substrates escape this inhibition. Nek2A degradation during prometaphase depends on direct binding of Nek2A to the APC/C via a C-terminal MR dipeptide but whether this motif alone is sufficient is not clear. Here, we identify Kif18A as a novel APC/C-Cdc20 substrate and show that Kif18A degradation depends...... by the APC/C. Nek2A and the mitotic checkpoint complex (MCC) have an overlap in APC/C subunit requirements for binding and we propose that Nek2A binds with high affinity to apo-APC/C and is degraded by the pool of Cdc20 that avoids inhibition by the SAC....

  4. Neuro-ophthalmic manifestations of prematurity

    Directory of Open Access Journals (Sweden)

    Preeti Patil Chhablani

    2014-01-01

    Full Text Available Increasing rates of preterm births coupled with better survival of these infants have resulted in higher prevalence of systemic and ocular complications associated with prematurity. In addition to retinopathy of prematurity, infants who are born preterm may suffer from severe visual impairment as a result of hypoxic ischemic encephalopathy, hypoglycemia, and other metabolic imbalances. The effect of these processes on the anterior visual pathway may result in optic atrophy, optic nerve hypoplasia or optic disc cupping and affection of the posterior visual pathway leads to cortical visual impairment (CVI. Other ocular associations include strabismus, nystagmus, and ocular motor abnormalities such as tonic down gaze and defective saccades and pursuits. Cortical and subcortical involvement also manifests as defects in functional vision and these have not yet been completely understood. Children with CVI may have visual field defects, photophobia, defective visual processing, and deficient color vision. Since most of these children also suffer from additional systemic disabilities, evaluation, and management remains a challenge. However, early diagnosis and initiation of rehabilitation therapy can prove to be of significant benefit in these children.

  5. Premature ovarian insufficiency: Pathogenesis and management

    Directory of Open Access Journals (Sweden)

    Anna J Fenton

    2015-01-01

    Full Text Available The term premature ovarian insufficiency (POI describes a continuum of declining ovarian function in a young woman, resulting in an earlier than average menopause. It is a term that reflects the variable nature of the condition and is substantially less emotive than the formerly used "premature ovarian failure" which signaled a single event in time. Contrary to the decline in the age of menarche seen over the last 3-4 decades there has been no similar change in the age of menopause. In developed nations, the average age for cessation of menstrual cycles is 50-52 years. The age is younger among women from developing nations. Much has been written about POI despite a lack of good data on the incidence of this condition. It is believed that 1% of women under the age of 40 years and 0.1% under the age of 30 years will develop POI. Research is increasingly providing information about the pathogenesis and treatments are being developed to better preserve ovarian function during cancer treatment and to improve fertility options. This narrative review summarizes the current literature to provide an approach to best practice management of POI.

  6. Treatment of threshold retinopathy of prematurity

    Directory of Open Access Journals (Sweden)

    Deshpande Dhanashree

    1998-01-01

    Full Text Available This report deals with our experience in the management of threshold retinopathy of prematurity (ROP. A total of 45 eyes of 23 infants were subjected to treatment of threshold ROP. 26.1% of these infants had a birth weight of >l,500 gm. The preferred modality of treatment was laser indirect photocoagulation, which was facilitated by scleral depression. Cryopexy was done in cases with nondilating pupils or medial haze and was always under general anaesthesia. Retreatment with either modality was needed in 42.2% eyes; in this the skip areas were covered. Total regression of diseases was achieved in 91.1% eyes with no sequelae. All the 4 eyes that progressed to stage 5 despite treatment had zone 1 disease. Major treatment-induced complications did not occur in this series. This study underscores the importance of routine screening of infants upto 2,000 gm birth weight for ROP and the excellent response that is achieved with laser photocoagulation in inducing regression of threshold ROP. Laser is the preferred method of treatment in view of the absence of treatment-related morbidity to the premature infants.

  7. The Neural Retina in Retinopathy of Prematurity

    Science.gov (United States)

    Hansen, Ronald M.; Moskowitz, Anne; Akula, James D.; Fulton, Anne B.

    2016-01-01

    Retinopathy of prematurity (ROP) is a neurovascular disease that affects prematurely born infants and is known to have significant long term effects on vision. We conducted the studies described herein not only to learn more about vision but also about the pathogenesis of ROP. The coincidence of ROP onset and rapid developmental elongation of the rod photoreceptor outer segments motivated us to consider the role of the rods in this disease. We used noninvasive electroretinographic (ERG), psychophysical, and retinal imaging procedures to study the function and structure of the neurosensory retina. Rod photoreceptor and post-receptor responses are significantly altered years after the preterm days during which ROP is an active disease. The alterations include persistent rod dysfunction, and evidence of compensatory remodeling of the post-receptor retina is found in ERG responses to full-field stimuli and in psychophysical thresholds that probe small retinal regions. In the central retina, both Mild and Severe ROP delay maturation of parafoveal scotopic thresholds and are associated with attenuation of cone mediated multifocal ERG responses, significant thickening of post-receptor retinal laminae, and dysmorphic cone photoreceptors. These results have implications for vision and control of eye growth and refractive development and suggest future research directions. These results also lead to a proposal for noninvasive management using light that may add to the currently invasive therapeutic armamentarium against ROP. PMID:27671171

  8. Computed tomography of the head of new born premature infants

    International Nuclear Information System (INIS)

    Ohno, Tsutomu; Mizobe, Naoki; Takehiro, Hideo

    1983-01-01

    Evaluation of the extracerebral space on CT resulted as follows: The existence of the etracerebral space in the parieto-occipital region (PO-ECS) was physiological findings characteristic to premature infants. Its incidence was higher and the width of the space was greater, in those of premature infants. Generally PO-ECS disappeared around 40 weeks of gestation, while it tended to remaine beyond 40 weeks in premature infants born after less than 30 weeks of pregnancy. The appearance and disappearance of the PO-ECS may present some approach to learning the development of the brain in premature infants. (Ueda, J.)

  9. Association between human breast milk and retinopathy of prematurity.

    Science.gov (United States)

    Fonseca, Luciana Teixeira; Senna, Denise C; Eckert, Gabriela Unchalo; Silveira, Rita de Cássia; Procianoy, Renato Soibelmann

    2018-04-01

    To evaluate the possible protective effect of breast milk against retinopathy of prematurity by comparing the amount of breast milk received by patients who developed retinopathy of prematurity and those who did not and to determine both the required minimum amount of breast milk and the time of life during which neonates need to receive breast milk for this effect to be significant. Cohort study of newborns with a birth weight of prematurity of any degree was 31% (100 of 323 patients) and that of severe retinopathy of prematurity was of 9% (29 of 323 patients). The median amounts of breast milk received daily by patients with and without retinopathy of prematurity were 4.9 mL/kg (interquartile range, 0.3-15.4) and 10.2 mL/kg (1.5-25.5), respectively. The amount of breast milk received in the first 6 weeks of life was inversely associated with the incidence of both retinopathy of prematurity of any degree and severe retinopathy of prematurity in the univariate analyses. However, the statistical significance was maintained only during the sixth week of life in a per-period multivariate analysis controlling for confounding factors. Small amounts of breast milk are inadequate to prevent retinopathy of prematurity in premature newborns at risk for the disease.

  10. Democratic contract law

    NARCIS (Netherlands)

    Hesselink, M.W.

    2015-01-01

    This article discusses the normative relationship between contract law and democracy. In particular, it argues that in order to be legitimate contract law needs to have a democratic basis. Private law is not different in this respect from public law. Thus, the first claim made in this article will

  11. Contract Teachers in India

    Science.gov (United States)

    Goyal, Sangeeta; Pandey, Priyanka

    2013-01-01

    In this paper, we use non-experimental data from government schools in Uttar Pradesh and Madhya Pradesh, two of the largest Indian states, to present average school outcomes by contract status of teachers. We find that contract teachers are associated with higher effort than civil service teachers with permanent tenures, before as well as after…

  12. Whither Performance Contracting?

    Science.gov (United States)

    Green, Norman S.

    This report describes briefly performance contracts; discusses their shortcomings, pitfalls, and advantages; and gives some insight into the future development of this new concept. Two shortcomings of performance contracting include (1) teaching to the test and (2) board abdication of its responsibility for making final decisions about educational…

  13. Comparing contracting performance

    DEFF Research Database (Denmark)

    Lindholst, Andrej Christian

    . Hypotheses are suggested for the role of culture, competition, contracts, capabilities and collaboration for contracting performance between and across the countries. Arguments are tested against data from on four comparable national surveys of private delivery of park and road maintenance services in local...

  14. BOT Outsourcing Contracts

    DEFF Research Database (Denmark)

    Ørberg Jensen, Peter D.; Petersen, Bent

    2012-01-01

    Build-operate-transfer (BOT) contracting has been widely usen in the engineering and construction industry, but has only recently been introduced in services industry domains. Notably, service provider firms from emerging markets have recently started offering BOT outsourcing contracts. In this p...

  15. Increase in a distinct pulmonary macrophage subset possessing an antigen-presenting cell phenotype and in vitro APC activity following silica exposure

    International Nuclear Information System (INIS)

    Migliaccio, Christopher T.; Hamilton, Raymond F.; Holian, Andrij

    2005-01-01

    Silica inhalation results in chronic lung inflammation and fibrosis. While the role of the alveolar macrophage (AM) is considered key to the effects of silica on lung pathology, the etiology is not completely understood. Evidence suggests an increase in antigen presenting cell (APC) activity as a contributing factor to this process, as well as potential roles for both AM and interstitial macrophages (IM) in silicosis. In order to study the effects of crystalline silica on the APC activity of pulmonary macrophages, mice were exposed intranasally and changes in pulmonary macrophage populations were assessed using flow cytometry. Following intranasal instillation of silica, a significant increase in the APC activity of AM was observed, as well as a significant increase in a subset of IM expressing classic APC markers (MHC class II, CD11c). In addition, an in vitro system using bone marrow-derived macrophages (BMDM) was generated to assess the effects of silica on the APC activity of macrophages in vitro. Data using BMDM in the in vitro APC assay demonstrated a significant increase in APC activity following silica exposure, but not following exposure to saline or a control particle (TiO 2 ). Using a combination of in vivo and in vitro experiments, the current study describes a significant increase in an interstitial macrophage subset with an APC phenotype, as well as an increase in the APC activity of both AM and BMDM, as a direct result of exposure to crystalline silica. These studies suggest a specific mechanism, macrophage subset activation, by which crystalline silica exposure results in chronic pulmonary inflammation and, eventually, fibrosis

  16. Refractive status and optical components of premature babies with or without retinopathy of prematurity at 3-4 years old.

    Science.gov (United States)

    Ouyang, Li-Juan; Yin, Zheng-Qin; Ke, Ning; Chen, Xin-Ke; Liu, Qin; Fang, Jing; Chen, Lin; Chen, Xiu-Rong; Shi, Hui; Tang, Ling; Pi, Lian-Hong

    2015-01-01

    To investigate the refractive status and optical components of premature babies with or without retinopathy of prematurity (ROP) at 3-4 years old, and to explore the influence of prematurity and ROP on the refractive status and optical components. Premature babies receiving fundus examination were recruited into ROP group and non-ROP group, with age-matched full-term babies as controls. The incidence of myopia was the highest in ROP (3/59, 5.08%). The incidence of astigmatism was significantly different between ROP (37.29%, 22/59) and controls (17.86%, 15/84). The corneal refractive power in ROP and non-ROP was more potent compared with controls (PPremature babies with or without ROP are susceptible to myopia and astigmatism. ROP, prematurity and low birth-weight synergistically influence the development of refractive status and optical components, of which the prematurity and low birth-weight are more important.

  17. Drilling contracts and incentives

    International Nuclear Information System (INIS)

    Osmundsen, Petter; Sorenes, Terje; Toft, Anders

    2008-01-01

    Shortages of rigs and personnel have encouraged discussion of designing incentive contracts in the drilling sector. However, for the drilling contracts, there are not a large variety of contract types in use. This article describes and analyses incentives for drilling contractors. These are directly represented by the compensation formats utilised in the present and in the consecutive drilling contracts. Indirectly, incentives are also provided by the evaluation criteria that oil companies use for awarding drilling assignments. Changes in contract format pose a number of relevant questions relating to resource management, and the article takes an in-depth look at some of these. Do evaluation criteria for awarding drilling assignments encourage the development of new technology and solutions? How will a stronger focus on drilling efficiency influence reservoir utilisation?

  18. Drilling contract issues

    International Nuclear Information System (INIS)

    Davison, G.B.; Worden, D.R.; Borbridge, G.K.D.

    1997-01-01

    Some selected issues which are facing both operators and contractors in drilling for oil and gas, such as the allocation of risk by contract and by statute and the implementation of new technologies, were discussed. There are three varieties of written drilling contracts used in Canada: (1) day work and meterage contracts, (2) master drilling agreements, and (3) contracts that are used in construction projects that do not specifically relate to drilling. Issues relevant to the contractual allocation of risk, to implementing new drilling technologies, to reconciling contract and statute liability, and the formation of strategic alliances for mutual benefit, and the factors contributing to the success of such alliances were explored. 12 refs

  19. THE PSYCHOLOGICAL CONTRACT

    Directory of Open Access Journals (Sweden)

    Blanca Giorgiana GRAMA

    2015-04-01

    Full Text Available The psychological contract became known as a research paradigm within corporate research, providing a broad framework which explains the employee-company relations. Despite all this, there are still many debates on the concept and a series of criticism were expressed that led to the necessity of some more rigorous theoretical and empirical analysis. The psychological contract refers to the unwritten, implicit expectations that employees have from the company and vice versa; it is that which defines the things the employee expects from the employer. Consequently, each of the parties involved in the contract may have different perceptions on these commitments and obligations. Thus the psychological contract may be regarded as an exchange relation between the employer and the employee. Breaking the psychological contract affects the performance, the morale, and the motivation of the staff in a negative manner. The information presented in this paper is intended to contribute to the theoretical and methodological development of the concept.

  20. ATR-Chk1-APC/C-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

    DEFF Research Database (Denmark)

    Yamada, M.; Watanabe, K.; Mistrik, M.

    2013-01-01

    replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosomeCdh1 (APC/C) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C through...... degradation of Cdh1 upon replication block, thereby stabilizing APC/C substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4...

  1. Contract Award Decisions Resulting in Contract Termination for Default

    National Research Council Canada - National Science Library

    1996-01-01

    .... Specifically, the audit focused on contracts terminated either for default or convenience and determined whether the contract terminations could have been averted based on information available before contract award...

  2. Prematurity, atopy, and childhood asthma in Puerto Ricans.

    Science.gov (United States)

    Rosas-Salazar, Christian; Ramratnam, Sima K; Brehm, John M; Han, Yueh-Ying; Boutaoui, Nadia; Forno, Erick; Acosta-Pérez, Edna; Alvarez, María; Colón-Semidey, Angel; Canino, Glorisa; Celedón, Juan C

    2014-02-01

    Puerto Rican children share a disproportionate burden of prematurity and asthma in the United States. Little is known about prematurity and childhood asthma in Puerto Rican subjects. We sought to examine whether prematurity is associated with asthma in Puerto Rican children. We performed a case-control study of 678 children aged 6 to 14 years with (n = 351) and without (n = 327) asthma living in San Juan, Puerto Rico. Prematurity was defined by parental report for our primary analysis. In a secondary analysis, we only included children whose parents reported prematurity that required admission to the neonatal intensive care unit. Asthma was defined as physician-diagnosed asthma and wheeze in the prior year. We used logistic regression for analysis. All multivariate models were adjusted for age, sex, household income, atopy (≥1 positive IgE level to common allergens), maternal history of asthma, and early-life exposure to environmental tobacco smoke. In a multivariate analysis there was a significant interaction between prematurity and atopy on asthma (P = .006). In an analysis stratified by atopy, prematurity was associated with a nearly 5-fold increased odds of asthma in atopic children (adjusted odds ratio, 4.7; 95% CI, 1.5-14.3; P = .007). In contrast, there was no significant association between prematurity and asthma in nonatopic children. Similar results were obtained in our analysis of prematurity requiring admission to the neonatal intensive care unit and asthma. Our results suggest that atopy modifies the estimated effect of prematurity on asthma in Puerto Rican children. Prematurity might explain, in part, the high prevalence of atopic asthma in this ethnic group. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  3. NEONATAL COMPLICATIONS OF PREMATURE RUPTURE OF MEMBRANES

    Directory of Open Access Journals (Sweden)

    F. Nili AA. Shams Ansari

    2003-07-01

    Full Text Available Premature rupture of membranes (PROM is one of the most common complications of pregnancy that has a major impact on neonatal outcomes. With respect to racial, nutritional and cultural differences between developed and developing countries, this study was conducted to detect the prevalence of neonatal complications following PROM and the role of the duration of rupture of membranes in producing morbidities and mortalities in these neonates in our hospital. Among 2357 pregnant women, we found 163 (6.91% cases of premature rupture of the fetal membranes in Tehran Vali-e-Asr Hospital during April 2001 to April 2002. Route of delivery was cesarean section in 65.6% of women. Urinary tract infection occured in 1.8%, maternal leukocytosis and fever in 20.2% and 5.5%, chorioamnionitis in 6.1%, fetal tachycardia in 1.2% and olygohydramnios in 4.9%. Gestational age in 138 (86% of neonates was less than 37 completed weeks. Thirty five infants (21.47% had respiratory distress syndrome and 33 (20.245% had clinical sepsis. Pneumonia in 6 (3.7% and skeletal deformity in 7 (4.294% were seen. Rupture of membrane of more than 24 hours duration occurred in 71 (43.6% of the patients. Comparison of morbidities between two groups of neonates and their mothers according to the duration of PROM (less and more than 24 hours showed significant differences in NICU admission, olygohydramnios, maternal fever, leukocytosis and chorioamnionitis rates (p24 hr of PROM with an odds ratio of 2.68 and 2.73, respectively. Positive blood and eye cultures were detected in 16 cases during 72 hours of age. Staphylococcus species, klebsiella, E.coli and streptococcus were the predominant organisms among positive blood cultures. Mortality was seen in 18 (11% of neonates because of respiratory failure, disseminated intravascular coagulation, septic shock, and a single case of congenital toxoplasmosis. In this study, the prevalence of prematurity, sepsis and prolonged rupture of membrane

  4. ENFORCEMENT OF MORTGAGE CONTRACT

    Directory of Open Access Journals (Sweden)

    Alisa A. BELU

    2016-07-01

    Full Text Available A chattel mortgage contract is the expression of a real guarantee that gives the creditor precedence over other creditors, in addition to the general pledge upon the belongings of the debtor. It refers to the sale of mortgaged movable assets, exclusively or prioritized in favor of the mortgaging creditor, in case the debtor does not comply with his / her commitments, under the signed mortgage contract. Beginning from this purpose, shared by both sides (as the chattel mortgage contract is synallagmatic, in case the debtor is unable to fulfill his / her commitments, the sides reach a situation of enforcement of the signed chattel mortgage contract. Given the legal status of the chattel mortgage contract [Art. 2387-2477 Noul Cod Civil , Universul Juridic, Bucureşti, 2016, ISBN 978-606-673-792-0], the principle of binding force of the contract and the principle according to which signed legal conventions will entail legal effects, the Romanian law maker developed the proper legal framework for the enforcement of the chattel mortgage contract. [art. 622 si urm. Noul Cod de Procedură Civilă, ed. Hamangiu, Bucureşti, 2016, ISBN 978-606-27-0459-9].

  5. JURIDICAL WILL IN CONTRACTS

    Directory of Open Access Journals (Sweden)

    Emilian CIONGARU

    2015-07-01

    Full Text Available In the business law, almost all judicial relationships of private law are obligational juridical relationships which are made up of legal acts and facts. The most important legal act is the contract since it is the basis of the social life in any community meaning that it represents the most important economic and juridical instrument for the participants to a contract. The persons are free and equal in society and, consequently, no power is valid and fundamental unless it relies on their consent, namely on a contract. So, the existence of a civil contract relies on the principles of consensualism, a perception based on moral rules to observe one’s promises, to have good faith and to observe the interests of your fellow creature. The exterior manifestation, the expression or declaration of the juridical will constitutes the consent of such person in making the structure of contract. The declared will must correspond to the person’s real will and the adoption and declaration of the juridical will must take place consciously. Any contract that does not derive from juridical will is null and the civilizing character is inexistent. The principles giving sense to consensualism is the one of agreement between parties so as to produce legal effects by itself and it is enough for the conclusion of a contract, regardless of the form in which it is exteriorized, a principle expressed by the Latin adagio pacta sunt servanda.

  6. Bottlenecks and contracts

    International Nuclear Information System (INIS)

    2001-01-01

    The report surveys the central points in the literature about contracts on geographical price differences and transmission rights in the power market. It is commonly believed that such contracts may reduce market power and contribute to better network investments. The theoretical debate is in part unfinished and largely based on very stylised assumptions. There is some indication that such contracts may not be very useful in practice. But they may be useful in some cases, perhaps in particular when power is transported outside limited surplus areas and for certain investment decisions where there is no systems operator with a natural responsibility

  7. Contract management survey 2002.

    Science.gov (United States)

    Hoppszallern, Suzanna

    2002-10-01

    Spending on clinical contracts continues to outpace spending on business services, but may be leveling off. The 12th annual Contract Management Survey shows that the performance of clinical vendors is now comparable to business service vendors in meeting savings targets. Both business and clinical vendors are receiving higher marks from hospital leaders, but execs quickly respond to low marks by bringing the service back in-house of changing vendors. This report examines trends in outsourcing, satisfaction levels, the decision-making process, contract features and performance, and spending.

  8. 2001 contract management survey.

    Science.gov (United States)

    2001-10-01

    For the second year running, hospitals are spending more on clinical outsourcing than on business services. The Eleventh Annual Contract Services Survey shows that, in clinical areas, executives use outsourcing to acquire specialized expertise with cost savings secondary. Reducing costs and FTEs are the primary reasons for outsourcing business operations. Business service contracts are more likely to meet expectations for cost savings. Overall, satisfaction levels are up, but in some areas there's still a lot of room for improvement. This report examines current trends in outsourcing, strategies for the future, satisfaction levels, the decisionmaking process, contract features, and costs.

  9. The contract - introduction

    International Nuclear Information System (INIS)

    Loeffler, G.

    1975-01-01

    The contract is the last and final step of project planning and the first step of project implementation. The contract has to specify in detail and to the point, as concisely as possible, the complete scope of supplies and work, define all technical particulars and requirements, put forward the conditions of legal, regulatory, administrative and financial procedure, prepare for operating and maintenance instructions to be issued after commissioning. In short, the contract is expected to be a reliable instrument during the manufacturing and construction period as well as a guide-book to assist the owner afterwards in the operation and maintenance of the plant. (orig./FW) [de

  10. [Genetic aspects of premature ovarian failure].

    Science.gov (United States)

    Warenik-Szymankiewicz, Alina; Słopień, Radosław

    2005-01-01

    Among the causes of premature ovarian failure (POF) two groups of factors are reported: factors which lead to decrease of follicular number and factors which stimulate follicular atresia. In the first group genetic factors are the most important whereas in the second: enzymatic autoimmunological, iatrogenic, toxins and infections are reported. In 1986 familiar POF on the background of long arm of chromosome X deletion was reported. Other chromosomes which are important for normal ovarian function are: chromosome 21 (AIRE gene), chromosome 11 (gene of beta FSH, ATM gene), chromosome 3 (gene responsible for BEPS syndrome) and chromosome 2 (genes of FSH and LH receptors). In this review the role of these genes and results of several epidemiological studies are reported.

  11. Lung function and exercise capacity in young adults born prematurely

    NARCIS (Netherlands)

    Vrijlandt, EJLE; Gerritsen, J; Boezen, HM; Grevink, RG; Duiverman, EJ

    2006-01-01

    Rationale: Limited information is available about the long-term outcome of lung function and exercise capacity in young adults born prematurely. Objective: To determine long-term effects of prematurity on lung function (volumes, diffusing capacity) and exercise capacity in expreterms compared with

  12. Prematurity Stereotype: Effects of Labeling on Adults' Perceptions of Infants.

    Science.gov (United States)

    Stern, Marilyn; Hildebrandt, Katherine A.

    1984-01-01

    Two studies were conducted in which college students and mothers were asked to rate unfamiliar infants shown on videotapes. Infants were described as either full-term or premature and as either male or female. Infants labeled premature were rated more negatively than those labeled full-term, but infants labeled male and female were rated…

  13. Histological Chorioamnionitis: Effects on Premature Delivery and Neonatal Prognosis

    Directory of Open Access Journals (Sweden)

    Gulin Erdemir

    2013-08-01

    Conclusion: Chorioamnionitis not only causes premature deliveries, but is also associated with neonatal complications and increased mortality. Clinical findings and infectious markers in mother or infant do not predict the diagnosis of histological chorioamnionitis. Therefore, placental histopathology may have a role in predicting neonatal outcome in premature deliveries, especially those below 30 weeks.

  14. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

    Anderson, Brian J; van Lingen, Richard A; Hansen, Tom G

    2002-01-01

    The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens.......The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens....

  15. Impact of Prematurity on Language Skills at School Age

    Science.gov (United States)

    Smith, Jamie Mahurin; DeThorne, Laura Segebart; Logan, Jessica A. R.; Channell, Ron W.; Petrill, Stephen A.

    2014-01-01

    Purpose: The existing literature on language outcomes in children born prematurely focuses almost exclusively on standardized test scores rather than discourse-level abilities. The authors of this study looked longitudinally at school-age language outcomes and potential moderating variables for a group of twins born prematurely versus a control…

  16. Anemia of prematurity : time for a change in transfusion management?

    NARCIS (Netherlands)

    Khodabux, Chantal Muriel

    2013-01-01

    In this thesis we investigated clinical effects of allogeneic red blood cell (RBC) transfusions in premature infants, different transfusion volumes in relation to neonatal outcome in premature infants and the use of autologous cord blood (CB) as an alternative for allogeneic transfusions. Despite

  17. Bartter syndrome: presentation in an extremely premature neonate.

    Science.gov (United States)

    Flores, F X; Ojeda, F J; Calhoun, D A

    2013-08-01

    Reports of Bartter syndrome in premature neonates are rare. We describe the presentation and clinical course of a neonate born at 25.6 weeks estimated gestational age with polyuria, hyponatremia, hypokalemia and hypercalciuria ,who was diagnosed with neonatal Bartter syndrome. The evaluation, diagnosis and management of neonatal Bartter syndrome in this premature neonate are discussed.

  18. Antibiotics after preterm premature rupture of the membranes.

    Science.gov (United States)

    Singh, Katherine; Mercer, Brian

    2011-06-01

    Preterm premature rupture of the membranes remains a common cause of preterm deliveries and neonatal morbidities. The goal of this study is to review the evidence with regard to the antibiotic treatment after preterm premature rupture of the membranes, long-term outcomes related to antibiotic treatment, and possible complications with treatment. Future research goals are also discussed.

  19. Premature ejaculation: A clinical review for the general physician.

    Science.gov (United States)

    Chung, Eric; Gilbert, Brent; Perera, Marlon; Roberts, Matthew J

    2015-10-01

    Premature ejaculation is one of the most common sexual dysfunctions in men. Recent epidemiological studies suggest its prevalence in Australia may range from 21-31% This article will discuss the current definition of premature ejaculation from a urological perspective. It will provide an understanding of the pathogenesis of premature ejaculation, as well as assessment and management options. Premature ejaculation can have a significant adverse effect on the quality of life for the patient and his sexual partners. It can potentially lead to psychological distress, diminished self- esteem, anxiety, erectile dysfunction, reduced libido and poor interpersonal relationships. Most men feel reluctant to discuss premature ejaculation with their general practitioner despite its psychological, emotional and relational effects. Effective, evidence-based treatment options are available and physicians should feel confident when exploring ways to improve the quality of life for men with sexual dysfunction.

  20. Adequacy of published screening criteria for retinopathy of prematurity.

    Science.gov (United States)

    Taranath, Deepa A; Oh, Dickson D-S; Keane, Miriam C; Fabel, Helen; Marshall, Peter

    2016-03-01

    Criteria for screening preterm infants for retinopathy of prematurity vary around the world. We aimed to analyse the efficacy of alternative screening criteria. We collected retrospective data at a tertiary level neonatal nursery. Our participants were 1007 babies, born between 1997 and 2011, at prematurity. We determined whether disease would be detected using an alternative Australian screening model (gestational age prematurity is our main outcome. Using several of the alternative criteria, two neonates with clinically significant retinopathy of prematurity, one of whom required laser treatment to preserve sight, would not have been screened, and their disease may have gone undetected. Use of prematurity may risk clinically significant cases being missed and others may screen babies unnecessarily. Alternative criteria should be considered and '<30 weeks gestational age and/or <1500 g birth weight' appears a viable option. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

  1. Long-term impact of prematurity on postnatal neurohormonal regulation

    Directory of Open Access Journals (Sweden)

    M. I. Ziborova

    2016-01-01

    Full Text Available This article considers the psychophysiological and neuroendocrine differences characteristic of premature children, which are as a result of long-term perinatal consequences. Particular emphasis is laid on the effects of the hypothalamic-pituitary-adrenocortical stress system, the performance of which is reprogramed during complicated pregnancy, labor, and postnatal period under pain stress due to medical manipulations. Being extremely sensitive to all these exposures, the brain of a premature infant develops during activation of the stress system and takes on a few distinctive properties in addition to independent neuroanatomical distinctions due to premature birth. The altered neurohormonal patterns revealed in very prematurely born children and adolescents involve the regulation of mental processes, behavior, metabolism, and circadian rhythms (sleep-wake regulation, which differ from those in their maturely born peers. These cases allow learning and behavior problems and lower cognitive estimates to be considered in normally developing children born extremely prematurely who have also hormonal dysregulation.

  2. Establishing contract periods

    International Nuclear Information System (INIS)

    Huffman, F.C.

    1978-01-01

    The lead time for executing the Adjustable Fixed-Commitment (AFC) contract and exceptions which may be considered are discussed. The initial delivery period is also discussed. Delays, deferrals, and schedule adjustment charges are finally considered

  3. Industrial Services Contracts

    CERN Document Server

    2006-01-01

    This document gives an overview of Industrial Services contracts at CERN, including the probable expenditure in 2006 and the estimated expenditure for 2007. The Finance Committee is invited: - to take note of the revised amount in 2006 for Industrial Services contracts referred to in this document of 138.02 MCHF at 2006 prices compared to the previously anticipated amount of 122.67 MCHF at 2005 prices; - to take note that the estimated amount in 2007 for the contracts referred to in this document will be 112.54 MCHF at 2006 prices; - for the reasons set out in this document, the Finance Committee is also invited to approve the requests for the contracts presented and highlighted in the Annexes.

  4. Temporary labour contracts

    CERN Document Server

    2001-01-01

    At its September 2000 meeting, the Finance Committee approved a second one-year extension of the four existing temporary labour contracts (L020/PE, L021/PE, L022/PE, L023/PE) until 31 December 2001 for a total amount not exceeding 6 000 000 Swiss francs at 2000 prices. The Finance Committee is invited: - to take note that the estimated annual expenditure on temporary labour in 2001 will amount to approximately 4 500 000 Swiss francs against the previously estimated 6 000 000 Swiss francs; - to approve the extension of the four existing contracts by six months to 30 June 2002 for an overall amount not exceeding 1 500 000 Swiss francs; - to take note that new contracts for the Swiss part of the CERN site will be submitted for adjudication in December 2001 and that new contracts for the French part of the CERN site will be submitted for adjudication in the course of 2002.

  5. Temporary labour contracts

    CERN Document Server

    1999-01-01

    The five contracts for Temporary Labour assignments on the CERN site (L020/PE, L021/PE, L022/PE, L023/PE and L024/PE) approved by the Finance Committee in March 1996 (CERN/FC/3857) will reach the end of their initial three-year contractual period at the end of December 1999. Following the satisfactory execution of these contracts during this period, CERN requests approval to extend them from January 2000 for the first of the two years foreseen in the original adjudication. The Finance Committee is invited: - to take note that the three-year expenditure for Temporary Labour contracts from 1997 to 1999 will not exceed 19 100 000 Swiss francs, compared to the 18 900 000 Swiss francs estimated at the time of the adjudication in March 1996; - to approve an extension of the present Temporary Labour contracts for the year 2000 for a total amount not exceeding 6 000 000 Swiss francs.

  6. Association of Maternal Preeclampsia With Infant Risk of Premature Birth and Retinopathy of Prematurity.

    Science.gov (United States)

    Shulman, Julia P; Weng, Cindy; Wilkes, Jacob; Greene, Tom; Hartnett, M Elizabeth

    2017-09-01

    Studies report conflicting associations between preeclampsia and retinopathy of prematurity (ROP). This study provides explanations for the discrepancies to clarify the relationship between preeclampsia and ROP. To evaluate the association of maternal preeclampsia and risk of ROP among infants in an unrestricted birth cohort and a restricted subcohort of preterm, very low birth weight (P-VLBW) infants. A retrospective review of 290 992 live births within the Intermountain Healthcare System in Utah from January 1, 2001, through December 31, 2010, was performed. Generalized estimating equations for logistic regressions with covariate adjustment were applied to relate ROP to preeclampsia among the full cohort and in a subcohort of P-VLBW infants born at younger than 31 weeks' gestation and weighing less than 1500 g. The occurrence of ROP was related to maternal preeclampsia in the full cohort and in a subcohort of P-VLBW infants. In the full cohort, 51% of the infants were male and the mean (SD) gestational age was 38.38 (1.87) weeks. In the P-VLBW cohort, 55% were male and the mean (SD) gestational age was 26.87 (2.40) weeks. In the full cohort, preeclampsia was associated with an increased risk of all ROP (adjusted odds ratio [aOR], 2.46; 95% CI, 2.17-2.79; P prematurity, because prematurity is an outcome of preeclampsia.

  7. Premature Calcifications of Costal Cartilages: A New Perspective Premature Calcifications of Costal Cartilages: A New Perspective

    International Nuclear Information System (INIS)

    Rhomberg, W.; Schuster, A.

    2014-01-01

    Calcifications of the costal cartilages occur, as a rule, not until the age of 30 years. The knowledge of the clinical significance of early and extensive calcifications is still incomplete. Materials and Methods. A search was made to find patients below the age of 30 years who showed distinct calcifications of their lower costal cartilages by viewing 360 random samples of intravenous pyelograms and abdominal plain films. The histories, and clinical and laboratory findings of these patients were analyzed. Results. Nineteen patients fulfilled the criteria of premature calcifications of costal cartilages (CCCs). The patients had in common that they were frequently referred to a hospital and were treated by several medical disciplines. Nevertheless many complaints of the patients remained unsolved. Premature CCCs were often associated with rare endocrine disorders, inborn errors of metabolism, and abnormal hematologic findings. Among the metabolic disorders there were 2 proven porphyrias and 7 patients with a suspected porphyria but with inconclusive laboratory findings. Conclusion. Premature CCCs are unlikely to be a normal variant in skeletal radiology. The findings in this small group of patients call for more intensive studies, especially in regard to the putative role of a porphyria

  8. Fission yeast APC/C activators Slp1 and Fzr1 sequentially trigger two consecutive nuclear divisions during meiosis.

    Science.gov (United States)

    Chikashige, Yuji; Yamane, Miho; Okamasa, Kasumi; Osakada, Hiroko; Tsutsumi, Chihiro; Nagahama, Yuki; Fukuta, Noriko; Haraguchi, Tokuko; Hiraoka, Yasushi

    2017-04-01

    In meiosis, two rounds of nuclear division occur consecutively without DNA replication between the divisions. We isolated a fission yeast mutant in which the nucleus divides only once to generate two spores, as opposed to four, in meiosis. In this mutant, we found that the initiation codon of the slp1 + gene is converted to ATA, producing a reduced amount of Slp1. As a member of the Fizzy family of anaphase-promoting complex/cyclosome (APC/C) activators, Slp1 is essential for vegetative growth; however, the mutant allele shows a phenotype only in meiosis. Slp1 insufficiency delays degradation of maturation-promoting factor at the first meiotic division, and another APC/C activator, Fzr1, which acts late in meiosis, terminates meiosis immediately after the delayed first division to produce two viable spores. © 2017 Federation of European Biochemical Societies.

  9. An automated Pearson's correlation change classification (APC3) approach for GC/MS metabonomic data using total ion chromatograms (TICs).

    Science.gov (United States)

    Prakash, Bhaskaran David; Esuvaranathan, Kesavan; Ho, Paul C; Pasikanti, Kishore Kumar; Chan, Eric Chun Yong; Yap, Chun Wei

    2013-05-21

    A fully automated and computationally efficient Pearson's correlation change classification (APC3) approach is proposed and shown to have overall comparable performance with both an average accuracy and an average AUC of 0.89 ± 0.08 but is 3.9 to 7 times faster, easier to use and have low outlier susceptibility in contrast to other dimensional reduction and classification combinations using only the total ion chromatogram (TIC) intensities of GC/MS data. The use of only the TIC permits the possible application of APC3 to other metabonomic data such as LC/MS TICs or NMR spectra. A RapidMiner implementation is available for download at http://padel.nus.edu.sg/software/padelapc3.

  10. Corrupt Relational Contracting

    OpenAIRE

    Johann Graf Lambsdorff; Sitki Utku Teksoz

    2002-01-01

    Because corruption must be hidden from the public and is not enforced by courts it entails transaction costs, which are larger than those from legal exchange. This suggests that corrupt contracts are primarily relational contracts where legal exchange serves as a basis for sealing and enforcing corrupt agreements. Legal exchange not only provides for corrupt opportunities, but for the necessary enforcement mechanisms. Examples of such legal exchange are long-term business exchange, belonging ...

  11. Contracting as a Science

    Science.gov (United States)

    2012-04-30

    disconfirmation of expectations theory to examine customer satisfaction in the procuring contracting officer (PCO)–program manager (PM) relationship in...marketing terms, finding that disconfirmed expectations lead to consumer satisfaction or dissatisfaction. The former approach presents the idea that if an...individual exerts effort, the expectation is that successful performance will occur leading to a desired result. In contracting, the theory might be

  12. Expansionary fiscal contractions

    DEFF Research Database (Denmark)

    Bergman, Ulf Michael; Hutchison, Michael

    2010-01-01

    The Expansionary Fiscal Contraction (EFC) hypothesis predicts that a major fiscal consolidation leads to an economic expansion under certain circumstances. We test this hypothesis, and the implied non-linear responses of the economy to large and small changes in fiscal policy, using data from...... that the exogenous fiscal contraction in Denmark was a credible regime shift and, together with other reforms undertaken at the time, increased both private consumption and aggregate output....

  13. An unsatisfactory contract policy

    CERN Multimedia

    Association du personnel

    2012-01-01

    For the last 15 years contract policy has been one of the top priorities of CERN staff, as expressed in successive surveys initiated by the Staff Association. In one’s professional life, having some forward vision of one’s career prospects is the key to loyalty and motivation. On the contrary, instability about the future is always at the root of anxiety, conflicts, or even health problems. A good employer must therefore balance the needs of the Company and those of its employees. CERN’s current contract policy, as described in the Administrative Circular No 2, states that staff members should first obtain a limited duration (LD) contract of up to five years. Then, if they want to stay in the Organization, staff members must apply, usually once a year, and before the end of their LD contract, for an indefinite contract (IC) post. All candidates for an IC post are considered by the Review Board for the award of indefinite contracts (Review Board) which will choose the most suita...

  14. Proteomic profiling of a mouse model of acute intestinal Apc deletion leads to identification of potential novel biomarkers of human colorectal cancer (CRC).

    Science.gov (United States)

    Hammoudi, Abeer; Song, Fei; Reed, Karen R; Jenkins, Rosalind E; Meniel, Valerie S; Watson, Alastair J M; Pritchard, D Mark; Clarke, Alan R; Jenkins, John R

    2013-10-25

    Colorectal cancer (CRC) is the fourth most common cause of cancer-related death worldwide. Accurate non-invasive screening for CRC would greatly enhance a population's health. Adenomatous polyposis coli (Apc) gene mutations commonly occur in human colorectal adenomas and carcinomas, leading to Wnt signalling pathway activation. Acute conditional transgenic deletion of Apc in murine intestinal epithelium (AhCre(+)Apc(fl)(/)(fl)) causes phenotypic changes similar to those found during colorectal tumourigenesis. This study comprised a proteomic analysis of murine small intestinal epithelial cells following acute Apc deletion to identify proteins that show altered expression during human colorectal carcinogenesis, thus identifying proteins that may prove clinically useful as blood/serum biomarkers of colorectal neoplasia. Eighty-one proteins showed significantly increased expression following iTRAQ analysis, and validation of nine of these by Ingenuity Pathaway Analysis showed they could be detected in blood or serum. Expression was assessed in AhCre(+)Apc(fl)(/)(fl) small intestinal epithelium by immunohistochemistry, western blot and quantitative real-time PCR; increased nucelolin concentrations were also detected in the serum of AhCre(+)Apc(fl)(/)(fl) and Apc(Min)(/)(+) mice by ELISA. Six proteins; heat shock 60kDa protein 1, Nucleolin, Prohibitin, Cytokeratin 18, Ribosomal protein L6 and DEAD (Asp-Glu-Ala-Asp) box polypeptide 5,were selected for further investigation. Increased expression of 4 of these was confirmed in human CRC by qPCR. In conclusion, several novel candidate biomarkers have been identified from analysis of transgenic mice in which the Apc gene was deleted in the intestinal epithelium that also showed increased expression in human CRC. Some of these warrant further investigation as potential serum-based biomarkers of human CRC. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras

    OpenAIRE

    Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R.; Sauer, Martin G.

    2009-01-01

    Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cel...

  16. The E3 Ligase APC/C-Cdh1 Is Required for Associative Fear Memory and Long-Term Potentiation in the Amygdala of Adult Mice

    Science.gov (United States)

    Pick, Joseph E.; Malumbres, Marcos; Klann, Eric

    2013-01-01

    The anaphase promoting complex/cyclosome (APC/C) is an E3 ligase regulated by Cdh1. Beyond its role in controlling cell cycle progression, APC/C-Cdh1 has been detected in neurons and plays a role in long-lasting synaptic plasticity and long-term memory. Herein, we further examined the role of Cdh1 in synaptic plasticity and memory by generating…

  17. Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras.

    Science.gov (United States)

    Kawaguchi, Yasuo; Hinoi, Takao; Saito, Yasufumi; Adachi, Tomohiro; Miguchi, Masashi; Niitsu, Hiroaki; Sasada, Tatsunari; Shimomura, Manabu; Egi, Hiroyuki; Oka, Shiro; Tanaka, Shinji; Chayama, Kazuaki; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Ohdan, Hideki

    2016-05-01

    KRAS gene mutations are found in 40-50% of colorectal cancer cases, but their functional contribution is not fully understood. To address this issue, we generated genetically engineered mice with colon tumors expressing an oncogenic Kras(G12D) allele in the context of the Adenomatous polyposis coli (Apc) deficiency to compare them to tumors harboring Apc deficiency alone. CDX2P9.5-G22Cre (referred to as G22Cre) mice showing inducible Cre recombinase transgene expression in the proximal colon controlled under the CDX2 gene promoter were intercrossed with Apc (flox/flox) mice and LSL-Kras (G12D) mice carrying loxP-flanked Apc and Lox-Stop-Lox oncogenic Kras(G12D) alleles, respectively, to generate G22Cre; Apc(flox/flox); Kras(G12D) and G22Cre; Apc(flox/flox); KrasWT mice. Gene expression profiles of the tumors were analyzed using high-density oligonucleotide arrays. Morphologically, minimal difference in proximal colon tumor was observed between the two mouse models. Consistent with previous findings in vitro, Glut1 transcript and protein expression was up-regulated in the tumors of G22Cre;Apc (flox/flox) ; Kras(G12D) mice. Immunohistochemical staining analysis revealed that GLUT1 protein expression correlated with KRAS mutations in human colorectal cancer. Microarray analysis identified 11 candidate genes upregulated more than fivefold and quantitative PCR analysis confirmed that Aqp8, Ttr, Qpct, and Slc26a3 genes were upregulated 3.7- to 30.2-fold in tumors with mutant Kras. These results demonstrated the validity of the G22Cre; Apc(flox/flox) ;Kras (G12D) mice as a new mouse model with oncogenic Kras activation. We believe that this model can facilitate efforts to define novel factors that contribute to the pathogenesis of human colorectal cancer with KRAS mutations.

  18. Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients.

    Science.gov (United States)

    Balgkouranidou, I; Matthaios, D; Karayiannakis, A; Bolanaki, H; Michailidis, P; Xenidis, N; Amarantidis, K; Chelis, L; Trypsianis, G; Chatzaki, E; Lianidou, E S; Kakolyris, S

    2015-08-01

    Gastric carcinogenesis is a multistep process including not only genetic mutations but also epigenetic alterations. The best known and more frequent epigenetic alteration is DNA methylation affecting tumor suppressor genes that may be involved in various carcinogenetic pathways. The aim of the present study was to investigate the methylation status of APC promoter 1A and RASSF1A promoter in cell free DNA of operable gastric cancer patients. Using methylation specific PCR, we examined the methylation status of APC promoter 1A and RASSF1A promoter in 73 blood samples obtained from patients with gastric cancer. APC and RASSF1A promoters were found to be methylated in 61 (83.6%) and 50 (68.5%) of the 73 gastric cancer samples examined, but in none of the healthy control samples (p APC promoter and elevated CEA (p = 0.033) as well as CA-19.9 (p = 0.032) levels, was noticed. The Kaplan-Meier estimates of survival, significantly favored patients with a non-methylated APC promoter status (p = 0.008). No other significant correlations between APC and RASSF1A methylation status and different tumor variables examined was observed. Serum RASSF1A and APC promoter hypermethylation is a frequent epigenetic event in patients with early operable gastric cancer. The observed correlations between APC promoter methylation status and survival as well as between a hypermethylated RASSF1A promoter and nodal positivity may be indicative of a prognostic role for those genes in early operable gastric cancer. Additional studies, in a larger cohort of patients are required to further explore whether these findings could serve as potential molecular biomarkers of survival and/or response to specific treatments. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

    Science.gov (United States)

    Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

    2016-10-01

    Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

  20. Problems of collaborative work of the automated process control system (APCS) and the its information security and solutions.

    Science.gov (United States)

    Arakelyan, E. K.; Andryushin, A. V.; Mezin, S. V.; Kosoy, A. A.; Kalinina, Ya V.; Khokhlov, I. S.

    2017-11-01

    The principle of interaction of the specified systems of technological protections by the Automated process control system (APCS) and information safety in case of incorrect execution of the algorithm of technological protection is offered. - checking the correctness of the operation of technological protection in each specific situation using the functional relationship between the monitored parameters. The methodology for assessing the economic feasibility of developing and implementing an information security system.

  1. Environmental impact of APC residues from municipal solid waste incineration: reuse assessment based on soil and surface water protection criteria.

    Science.gov (United States)

    Quina, Margarida J; Bordado, João C M; Quinta-Ferreira, Rosa M

    2011-01-01

    Waste management and environmental protection are mandatory requirements of modern society. In our study, air pollution control (APC) residues from municipal solid waste incinerators (MSWI) were considered as a mixture of fly ash and fine particulate solids collected in scrubbers and fabric filters. These are hazardous wastes and require treatment before landfill. Although there are a number of treatment options, it is highly recommended to find practical applications rather than just dump them in landfill sites. In general, for using a construction material, beyond technical specifications also soil and surface water criteria may be used to ensure environmental protection. The Dutch Building Materials Decree (BMD) is a valuable tool in this respect and it was used to investigate which properties do not meet the threshold criteria so that APC residues can be further used as secondary building material. To this end, some scenarios were evaluated by considering release of inorganic species from unmoulded and moulded applications. The main conclusion is that the high amount of soluble salts makes the APC residues a building material prohibited in any of the conditions tested. In case of moulding materials, the limits of heavy metals are complied, and their use in Category 1 would be allowed. However, also in this case, the soluble salts lead to the classification of "building material not allowed". The treatments with phosphates or silicates are able to solve the problem of heavy metals, but difficulties with the soluble salts are still observed. This analysis suggests that for APC residues to comply with soil and surface water protection criteria to be further used as building material at least a pre-treating for removing soluble salts is absolutely required. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity.

    Science.gov (United States)

    Niku, Mikael; Pajari, Anne-Maria; Sarantaus, Laura; Päivärinta, Essi; Storvik, Markus; Heiman-Lindh, Anu; Suokas, Santeri; Nyström, Minna; Mutanen, Marja

    2017-01-01

    Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of Apc Min/+ (Min/+) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε + T lymphocytes and of mucosal FoxP3 + regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Sildenafil and retinopathy of prematurity risk in very low birth weight infants

    NARCIS (Netherlands)

    S. Samiee-Zafarghandy; J.N. van den Anker (John); M. Laughon (Matthew); R.H. Clark; P.B. Smith; C.P. Hornik

    2016-01-01

    textabstractObjective: To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants. Study Design: We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care

  4. Leaching of APC residues from secondary Pb metallurgy using single extraction tests: the mineralogical and the geochemical approach.

    Science.gov (United States)

    Ettler, Vojtech; Mihaljevic, Martin; Sebek, Ondrej; Strnad, Ladislav

    2005-05-20

    Two air-pollution-control (APC) residues--one from flue gas cooling with alkaline water and one from deionized water cooling--from secondary lead metallurgy were submitted to two different standardized short-term leaching protocols: US EPA toxicity characteristic leaching procedure (TCLP) and static leaching according to Czech/European norm EN 12457-2. The experimental procedure was coupled with detailed mineralogical investigation of the solid material (SEM, XRPD) and speciation-solubility calculations using the PHREEQC-2 geochemical code. Both types of residues were considered as hazardous materials exhibiting substantial leaching of Pb (up to 7130 mg/l) and other inorganic contaminants. However, the APC residue produced by flue gas cooling with alkaline water (sample B) exhibits more favourable leaching and environmental characteristics than that produced by simple deionised water cooling (sample A). At pH 6, phosgenite (PbCl2.PbCO3) became the dominant secondary phase. The results are consistent with the mineralogical and geochemical studies focused on acidic forest soils highly polluted by smelter emissions, where anglesite, as a unique Pb-bearing phase, has been detected. From the technological point of view, the mixing of APC residue with alkaline water, followed by an increase in the suspension pH and equilibration with atmospheric CO2, may be used to ensure the precipitation of less soluble Pb carbonates, which are more easily recycled in the Pb recovery process in the metallurgical plant.

  5. Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations

    Science.gov (United States)

    Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojevic, Ivan; Vandeusen, Jeffrey B.; Hsu, David; Clary, Bryan M.; Clay, Timothy M.; Chen, Wei; Morse, Michael A.; Lyerly, H. Kim

    2011-01-01

    Wnt/β-catenin pathway activation caused by APC mutations occurs in approximately 80% of sporadic colorectal cancers. The anti-helminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined if niclosamide could inhibit the Wnt/ β-catenin pathway in human colorectal cancers and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/ β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling and exerted anti-proliferative effects in human colon cancer cell lines and colorectal cancer cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar anti-proliferative effects in these colorectal cancer model systems. In mice implanted with human colorectal cancer xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity and led to tumor control. Our findings support clinical explorations to reposition niclosamide for treatment of colorectal cancer. PMID:21531761

  6. Maslinic acid-enriched diet decreases intestinal tumorigenesis in Apc(Min/+ mice through transcriptomic and metabolomic reprogramming.

    Directory of Open Access Journals (Sweden)

    Susana Sánchez-Tena

    Full Text Available Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA, a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+ mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01. Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+ mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+ mice model, suggesting its chemopreventive potential against colorectal cancer.

  7. A Case of Recurrent Respiratory Papillomatosis Successfully Removed Via Endoscopic Argon Plasma Coagulation (APC) With No Evidence of Recurrence.

    Science.gov (United States)

    Wong, J L; Tie, S T; Lee, J; Kannan, S K; Rashid Ali, M R; Ibrahim, A; Abdul Rahman, J A

    2014-08-01

    Recurrent respiratory papillomatosis (RRP) is a benign disease caused by the human papilloma virus (HPV), characterized by the formation of recurrent, epithelial neoplastic lesions in the airways. While benign, they can cause significant airway obstruction in some cases. Difficulties in treatment arise from the recurrent nature of the lesions despite repeated procedures. Other known procedures that result in deep tissue damage also cause unacceptable collateral damage to the underlying airway mucosa. We describe a case of recurrent papillomatosis that was successfully treated with argon plasma coagulation ( APC) when laser and electrocautery ablation had failed in the past. After the papillomatasis was treated with APC, there is no recurrence on repeat scope at 4 months and 9 months after the initial procedure. The procedure was done as a day case and there is no complication from the procedure. The property of the APC that allows it to cause only superficial thermal damage to the tissue makes it a suitable adjunct therapy to the treatment of papillomas, which are usually superficial lesions.

  8. Aggregate material formulated with MSWI bottom ash and APC fly ash for use as secondary building material.

    Science.gov (United States)

    del Valle-Zermeño, R; Formosa, J; Chimenos, J M; Martínez, M; Fernández, A I

    2013-03-01

    The main goal of this paper is to obtain a granular material formulated with Municipal Solid Waste Incineration (MSWI) bottom ash (BA) and air pollution control (APC) fly ash to be used as secondary building material. Previously, an optimum concrete mixture using both MSWI residues as aggregates was formulated. A compromise between the environmental behavior whilst maximizing the reuse of APC fly ash was considered and assessed. Unconfined compressive strength and abrasion resistance values were measured in order to evaluate the mechanical properties. From these results, the granular mixture was not suited for certain applications owing to the high BA/APC fly ash content and low cement percentages used to reduce the costs of the final product. Nevertheless, the leaching test performed showed that the concentrations of all heavy metals were below the limits established by the current Catalan legislation for their reutilization. Therefore, the material studied might be mainly used in embankments, where high mechanical properties are not needed and environmental safety is assured. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. [miR-182 promotes cell proliferation of cervical cancer cells by targeting adenomatous polyposis coli (APC) gene].

    Science.gov (United States)

    Li, Pei; Hu, Jing; Zhang, Ying; Li, Jianping; Dang, Yunzhi; Zhang, Rui; Wei, Lichun; Shi, Mei

    2018-02-01

    Objective To investigate the role and mechanism of microRNA-182 (miR-182) in the proliferation of cervical cancer cells. Methods With liposome-mediated transient transfection method, the level of miR-182 in HeLa and SiHa cells was increased or decreased. CCK-8 assay and colony formation assay were used to observe the effect of miR-182 on the proliferation of cervical cancer cells. Using bioinformatics predictions, real-time quantitative PCR, and dual luciferase reporter assay, we clarified the role of miR-182 in posttranscriptional regulation of adenomatous polyposis coli (APC) gene and its effect on the downstream molecules (c-Myc and cyclin D1) of Wnt singling pathway. Results Up-regulation of miR-182 significantly promoted the proliferation of cervical cancer cells, while down-regulation of miR-182 significantly inhibited the proliferation of cervical cancer cells. Over-expression of miR-182 inhibited the expression of APC gene in cervical cancer cells and the regulation of miR-182 affected the expression of canonical Wnt signaling pathway downstream molecules in cervical cancer cells. Conclusion The miR-182 stimulates canonical Wnt signaling pathway by targeting APC gene and enhances the proliferation of cervical cancer cells.

  10. Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras.

    Science.gov (United States)

    Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R; Sauer, Martin G

    2009-04-30

    Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs in vitro with leukemia cell lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETCs resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD rates observed after the transfer of naive donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.

  11. Human xenospecific T suppressor cells inhibit T helper cell proliferation to porcine aortic endothelial cells, and NF-kappaB activity in porcine APC.

    Science.gov (United States)

    Ciubotariu, R; Li, J; Colovai, A I; Platt, J L; Cortesini, R; Suciu Foca Cortesini, N

    2001-05-01

    Human T suppressor cells (Ts), capable of preventing autologous T helper cells (Th) from reacting against xenogeneic pig endothelial cells and pig APC can be generated in vitro. Ts derive from a population of CD3(+)CD8(+)CD28(-) T lymphocytes and specifically recognize the MHC class I antigens of the APC used for in vitro immunization. To study the mechanism that underlies suppression, we investigated whether Ts inhibit the expression of costimulatory molecules in xenogeneic professional and semiprofessional APC. We found that Ts down-regulate Th-induced expression of CD86 in pig APC, and that this effect occurs at the level of transcription, as indicated by nuclear run-on and Northern blot assays. EMSA results revealed that inhibition of CD86 expression is mediated by inactivation of transcription factor NF-kappaB. Furthermore, transfection of pig APC with a vector expressing NF-kappaB p65 partially rescued Th-induced expression of the CD86 molecule. These results strongly support the concept that xenospecific Ts inhibit the APC function of xenogeneic cells by preventing activation of NF-kappaB.

  12. Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis

    DEFF Research Database (Denmark)

    Rohlin, A; Engwall, Y; Fritzell, K

    2011-01-01

    Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Two promoters, 1A and 1B, have been recognized in APC, and 1B is thought to have a minor role in the regulation of the gene. We have identified a novel deletion encompassing half of ...... homozygous inactivation of APC allowing for alternative genetic models as basis for adenoma formation.Oncogene advance online publication, 6 June 2011; doi:10.1038/onc.2011.201....... in a panel of 20 various normal tissues examined. In FAP-related tumors, the APC germline mutation is proposed to dictate the second hit. Mutations leaving two or three out of seven 20-amino-acid repeats in the central domain of APC intact seem to be required for tumorigenesis. We examined adenomas from...... mutation carriers in Family 1 for second hits in the entire gene without any findings, however, loss of the residual expression of the deleterious allele was observed. Three major conclusions of significant importance in relation to the function of APC can be drawn from this study; (i) germline...

  13. Using Data Mining Techniques on APC Data to Develop Effective Bus Scheduling Plans

    Directory of Open Access Journals (Sweden)

    Jayakrishna PATNAIK

    2006-02-01

    Full Text Available Various trip generators (e.g., buildings, shopping malls, recreational centers continually influence travel demand in urban and suburban areas. As a result, the headway regularity that should be kept among transit vehicles is difficult to maintain, specifically during peak hours. The variation of headways lengthens the average wait times and deteriorates service quality. Providing a tool to monitor and maintain most up-to-date information through Advanced Traveler Information Systems (ATIS can assist effective system planning and scheduling, while reducing the door-to-door travel time. This paper develops a methodology for clustering the state variables (number served passengers and halting stations in each vehicle trip and using that for service planning. The data used to develop the models were collected by Automatic Passenger Counters (APC on buses operated by a transit agency in the northeast region of the United States. The results illustrate that the developed tool can provide suggestions for improving systems performance as well as future planning.

  14. APC/C-Cdc20 mediates deprotection of centromeric cohesin at meiosis II in yeast.

    Science.gov (United States)

    Jonak, Katarzyna; Zagoriy, Ievgeniia; Oz, Tugce; Graf, Peter; Rojas, Julie; Mengoli, Valentina; Zachariae, Wolfgang

    2017-06-18

    Cells undergoing meiosis produce haploid gametes through one round of DNA replication followed by 2 rounds of chromosome segregation. This requires that cohesin complexes, which establish sister chromatid cohesion during S phase, are removed in a stepwise manner. At meiosis I, the separase protease triggers the segregation of homologous chromosomes by cleaving cohesin's Rec8 subunit on chromosome arms. Cohesin persists at centromeres because the PP2A phosphatase, recruited by the shugoshin protein, dephosphorylates Rec8 and thereby protects it from cleavage. While chromatids disjoin upon cleavage of centromeric Rec8 at meiosis II, it was unclear how and when centromeric Rec8 is liberated from its protector PP2A. One proposal is that bipolar spindle forces separate PP2A from Rec8 as cells enter metaphase II. We show here that sister centromere biorientation is not sufficient to "deprotect" Rec8 at meiosis II in yeast. Instead, our data suggest that the ubiquitin-ligase APC/C Cdc20 removes PP2A from centromeres by targeting for degradation the shugoshin Sgo1 and the kinase Mps1. This implies that Rec8 remains protected until entry into anaphase II when it is phosphorylated concurrently with the activation of separase. Here, we provide further support for this model and speculate on its relevance to mammalian oocytes.

  15. Detection of irradiated spices with a microbiological method - DEFT/APC method

    International Nuclear Information System (INIS)

    Hammerton, K.M.; Banos, C.

    1996-01-01

    The decontamination of spices that are to be used as ingredients in processed foods is necessary in order to prevent the introduction of spoilage microorganisms and more rarely disease causing organisms. Spices can be contaminated with bacteria and moulds in concentration from 10 3 to 10 8 microorganisms per gram so that, even when used in small amounts, they can contaminate food with large numbers of microorganisms. The most effective means of decontaminating spices is irradiation treatment with an absorbed radiation dose from 5 to 10 kGy. Several countries are commercially using radiation processing of spices. A microbiological screening method based on the use of the direct epifluorescent filter technique (DEFT) and the conventional aerobic plate count (APC) has been established for the detection of irradiated spices. The DEFT count enumerates the total number of contaminating microorganisms, irrespective of viability, in an untreated or treated spice sample. This paper reports recent investigations on the possibility that the inclusion of a mesophilic aerobic spore count will enable irradiated spices to be distinguished from ethylene oxide (EtO) or heat treated spices. (author)

  16. Balance in children born prematurely currently aged 6–7

    Directory of Open Access Journals (Sweden)

    Dziuba Ewa

    2017-12-01

    Full Text Available Study aim: Premature birth is one of the major problems of obstetrics, leading to numerous complications that are associated with prematurity, for instance balance disorders. The aim of the study was to assess the impact of premature birth on the ability to maintain balance in children commencing their school education. Material and methods: The study included children aged 6-7 years. The study group consisted of 59 children (31 girls and 28 boys, mean age 6.38 ± SD 0.73 born prematurely between 24 and 35 weeks of gestation. The control group consisted of 61 children (28 girls and 33 boys, mean age 6.42 ± 0.58 born at term. The research utilized standardized test tools - one-leg open-eyed and closed-eyed standing test, one-leg jumping test - and an original questionnaire survey. Results: The children born at term achieved better results in the majority of tests. The comparison of girls and boys born pre­maturely and at term showed no statistically significant difference between them in terms of dynamic balance, static balance or total balance control. The comparison of the tests performed on the right and left lower limb in prematurely born children showed no statistically significant differences. Conclusion: Premature birth affects the ability to maintain body balance. The results of the study indicate the need to develop coordination skills that shape body balance in prematurely born children.

  17. Environmental impact of APC residues from municipal solid waste incineration: Reuse assessment based on soil and surface water protection criteria

    International Nuclear Information System (INIS)

    Quina, Margarida J.; Bordado, Joao C.M.; Quinta-Ferreira, Rosa M.

    2011-01-01

    Highlights: → The Dutch Building Material Decree (BMD) was used to APC residues from MSWI. → BMD is a straightforward tool to calculate expectable loads to the environment of common pollutants. → Chloride load to the environment lead to classification of building material not allowed. → At least a pre-treatment (e.g. washing) is required in order to remove soluble salts. → The stabilization with phosphates or silicates eliminate the problem of heavy metals. - Abstract: Waste management and environmental protection are mandatory requirements of modern society. In our study, air pollution control (APC) residues from municipal solid waste incinerators (MSWI) were considered as a mixture of fly ash and fine particulate solids collected in scrubbers and fabric filters. These are hazardous wastes and require treatment before landfill. Although there are a number of treatment options, it is highly recommended to find practical applications rather than just dump them in landfill sites. In general, for using a construction material, beyond technical specifications also soil and surface water criteria may be used to ensure environmental protection. The Dutch Building Materials Decree (BMD) is a valuable tool in this respect and it was used to investigate which properties do not meet the threshold criteria so that APC residues can be further used as secondary building material. To this end, some scenarios were evaluated by considering release of inorganic species from unmoulded and moulded applications. The main conclusion is that the high amount of soluble salts makes the APC residues a building material prohibited in any of the conditions tested. In case of moulding materials, the limits of heavy metals are complied, and their use in Category 1 would be allowed. However, also in this case, the soluble salts lead to the classification of 'building material not allowed'. The treatments with phosphates or silicates are able to solve the problem of heavy metals, but

  18. INDEFINITE CONTRACT REVIEW 2000

    CERN Multimedia

    Division des ressources humaines

    2000-01-01

    The Director-General has decided to review staff members in professional categories 2 to 5 satisfying the criteria for consideration for the award of an indefinite contract, in accordance with Article R II 1.20 of the Staff Regulations. Staff members holding a fixed-term contract which it has been decided not to renew will not be considered. The following stages are foreseen:1.\tCandidates qualifying for review in accordance with Article R II 1.20 of the Staff Regulations and the Administrative Circular N° 9 will be contacted by Human Resources Division. 2.\tThe criteria as to when staff members qualify for review are described in Administrative Circular N° 9. These include the following:staff members who are in their fourth year of service on a fixed-term contract;in addition, for staff members having three years or more of previous relevant service in the Organization on a contract of limited duration (or term-contract) and upon proposal by the division leader concerned, consid...

  19. INDEFINITE CONTRACT REVIEW 2001

    CERN Multimedia

    Human Resources Division

    2001-01-01

    The Director-General has decided to review staff members in professional categories 2 to 5 satisfying the criteria for consideration for the award of an indefinite contract, in accordance with Article R II 1.20 of the Staff Regulations. Staff members holding a fixed-term contract which it has been decided not to renew will not be considered. The following stages are foreseen: 1. Candidates qualifying for review in accordance with Article R II 1.20 of the Staff Regulations and the Administrative Circular N° 9 will be contacted by Human Resources Division. 2. The criteria as to when staff members qualify for review are described in Administrative Circular N° 9. These include the following: staff members who are in their fourth year of service on a fixed-term contract; in addition, for staff members having three years or more of previous relevant service in the Organization on a contract of limited duration (or term-contract) and upon proposal by the division leader concerned, consideration fo...

  20. Temporary labour contracts

    CERN Document Server

    2000-01-01

    The five contracts for Temporary Labour assignments on the CERN site (L020/PE, L 021/PE, L 022/PE, L 023/PE and L 024/PE) approved by the Finance Committee in March 1996 (CERN/FC/3857) reached the end of their initial three-year contractual period at the end of December 1999. At CERN?s request, in September 1999 the Finance Committee approved an extension of these contracts for the year 2000 for a total amount not exceeding 6 000 000 Swiss francs (CERN/FC/4196). In December 1999, one of the five contractors, FIRCROFT, withdrew from its contract for 2000. Following the satisfactory execution of the four remaining contracts during 2000, CERN requests approval to extend them from January 2001 for the second of the two optional years provided for in the original adjudication. The Finance Committee is invited to approve the extension of the existing contracts until 31 December 2001 for a total amount not exceeding 6 000 000 Swiss francs at 2000 prices.

  1. Networks and informal contract law

    NARCIS (Netherlands)

    Tjong Tjin Tai, Eric; Brownsword, Roger; van Gestel, Rob A.J.; Micklitz, Hans-W.

    2017-01-01

    It is often argued that formal contract law cannot treat networks correctly. An analysis of networks in an informal contract law system shows that informal contract law is no panacea. Remaining problems require a different approach to legal regulation and contract practice.

  2. HEARING FUNCTION IN PREMATURE CHILDREN WITH INTRAUTERINE GROWTH RESTRICTION

    Directory of Open Access Journals (Sweden)

    I. V. Rakhmanova

    2012-01-01

    Full Text Available Initial audiological test was performed in 136 premature children with various gestational age born from single fetation. The children were divided into 2 groups: prematures with intrauterine growth restriction (IUGR and prematures with normal weight for their gestational age (normotrophy. The study showed that the rate of passing the initial audiological test using the method of DPOAE was lower in both ears in children with IUGR, than in children with normotrophy. The correlation between the results of initial audiological test and birth weight was found: the lower was weight, the higher was risk of absence of acoustic response registration on initial examination.

  3. Thigh circumference and risk of heart disease and premature death

    DEFF Research Database (Denmark)

    Heitmann, Berit L; Frederiksen, Peder

    2009-01-01

    of follow-up for total death. RESULTS: A small thigh circumference was associated with an increased risk of cardiovascular and coronary heart diseases and total mortality in both men and women. A threshold effect for thigh circumference was evident, with greatly increased risk of premature death below...... circumference seems to be associated with an increased risk of developing heart disease or premature death. The adverse effects of small thighs might be related to too little muscle mass in the region. The measure of thigh circumference might be a relevant anthropometric measure to help general practitioners...... in early identification of individuals at an increased risk of premature morbidity and mortality....

  4. [Birth weight distribution among premature infants and related social factors].

    Science.gov (United States)

    Guo, Li-jun; Ye, Rong-wei; Wang, Gui-xia; Wang, Juan; Li, Zhi-wen; Ren, Ai-guo

    2009-12-01

    To understand the distribution of birth weight among premature infants and the associated social factors. The study population consisted of 97 537 women who delivered singleton live birth of 20 to 41 gestational weeks in 4 counties/cities, Jiangsu and Zhejiang provinces, China from 1995 to 2000. Chi-square test was employed to test the difference of proportions between respective groups. One- way ANOVA was used to test the differences regarding the mean of gestational weeks at the first prenatal visit and the mean of prenatal visits between the two groups. Multivariate logistic regression was conducted to examine the factors associated with premature birth. Women aged 35 years had higher (8.8%) premature incidence than those aged less than 24 years (5.6%), 25 - 29 years (4.6%), or 30 - 34 years (4.5%, P premature incidence than those with height taller than 150 cm (5.0%). Women whose BMI were at least 28 and 24 - 28 had higher (5.5%, 5.5%) premature incidences than those whose BMI were 18.5 - 24.0 (5.0%), premature birth was 6.0% among women without previous pregnancy, higher than that among those women with 4 times of pregnancies (5.7%), 2 times of pregnancies (4.3%), and 3 times of pregnancies (4.0%). Parous women with at least two deliveries had higher (9.3%) premature incidence than the primiparous women (5.2%) and whose women with only one delivery (4.5%, P premature incidence than those who did not receive the service (6.1%). The mean times of prenatal visits among women with premature births was 8.53, less than that of those with full term delivery (10.97). Women with less than four times of prenatal visit had higher (18.9%) premature incidence than those with at least five prenatal visits (4.9%). Multivariate logistic regression showed that premature delivery risk was associated with age, height, BMI, gravidity, parity, early prenatal care, the mean of gestational weeks at first prenatal visit and the mean number of prenatal visits etc. Premature delivery

  5. Preventing the premature death of relationship marketing.

    Science.gov (United States)

    Fournier, S; Dobscha, S; Mick, D G

    1998-01-01

    Relationship marketing is in vogue. And why not? The new, increasingly efficient ways that companies have of understanding and responding to customers' needs and preferences seemingly allow them to build more meaningful connections with consumers than ever before. These connections promise to benefit the bottom line by reducing costs and increasing revenue. Unfortunately, a close look suggests that the relationships between companies and customers are troubled ones, at best. Companies may delight in learning more about their customers and in being able to provide features and services to please every possible palate. But customers delight in neither. In fact, customer satisfaction rates in the United States are at an all-time low, while complaints, boycotts, and other expressions of consumer discontent are on the rise. This mounting wave of unhappiness has yet to reach the bottom line. Sooner or later, however, corporate performance will suffer unless relationship marketing becomes what it is supposed to be--the epitome of customer orientation. Ironically, the very things that marketers are doing to build relationships with customers are often the things that are destroying those relationships. Relationship marketing is powerful in theory but troubled in practice. To prevent its premature death, marketers need to take the time to figure out how and why they are undermining their own best efforts, as well as how they can get things back on track.

  6. Control practices contribute to premature transformer failures

    Energy Technology Data Exchange (ETDEWEB)

    Jauch, E.T. [Beckwith Electric Company Inc., Largo, FL (United States)

    2007-07-01

    Studies of premature load tap changer (LTC) transformer failures on utility systems have shown the tap changers to be the primary contributing factor. Some of the LTC factors that lead to transformer failures include oil quality and particulate contamination; LTC contact temperature rise; contact coking; carbon film build-up; short circuit mechanical forces; and contact wear and arcing. These factors create increasing contact resistance thereby increasing voltage drop, localized heating, contact pitting, oil contamination and general deterioration. This paper discussed utility tapchanger control practices and methods of determining control functions to be activated as well as the determination of optimum settings contributing to excessive or untimely tap change operations. The transformer applications that were considered included transmission tie transformers as well as transmission distribution interface transformers. The paper discussed the circulating current paralleling method and the circulating reactive current or var sharing paralleling method. Several common practices were discussed, including basic voltage control ranges and setting effects; timing options available; LDC misapplications; first house protection methods; and various paralleling techniques. It was concluded that although there are several other methods of paralleling power transformers, many are not applicable under certain system configurations. In these applications, improper use of a paralleling method or improper setting and commissioning may cause hunting for appropriate tap positions and dramatically increase the number of tap changes, causing wear and degradation of the tap changer contacts. 3 refs., 5 figs.

  7. An overview of pharmacotherapy in premature ejaculation.

    Science.gov (United States)

    Porst, Hartmut

    2011-10-01

    With increasing interest and clinical research in male sexual disorders, it has become clear that not only psychological but also organic, neurobiological, and genetic factors may play an important role in premature ejaculation (PE). This article provides an overview of the different treatment options both for lifelong (primary, "congenital") and acquired (secondary) PE. Review of the literature. Currently used treatment options for PE. Treatments reviewed include psychological/behavioral/sexual counseling therapy, topical anesthetics, dapoxetine, and other selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and phosphodiesterase-5 (PDE-5) inhibitors. Before starting any therapy for PE, correct diagnosis has to be made considering the patient's reported intravaginal ejaculatory latency time (IELT) and the duration and type of PE. Concomitant erectile dysfunction (ED) should be either ruled out or proven by appropriate means. In uncomplicated cases of PE with stable partnerships, medical treatment represents the first-choice option with a high likelihood of success. Dapoxetine, where available, or other SSRIs provide suitable therapeutic options with a good risk/benefit profile for patients. In complicated ("difficult-to-treat") PE patients, a combination of medication and sexual counseling should be considered the first treatment option. Combination therapies of PDE-5 inhibitors and PE-related medications should be offered to patients suffering from comorbid PE and ED, with ED treatment starting first. In those patients with severe PE-IELTs of IELT, compared with either monotherapy. 2011 International Society for Sexual Medicine.

  8. Retinopathy of prematurity: Past, present and future

    Science.gov (United States)

    Shah, Parag K; Prabhu, Vishma; Karandikar, Smita S; Ranjan, Ratnesh; Narendran, Venkatapathy; Kalpana, Narendran

    2016-01-01

    Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina occurring principally in new born preterm infants. It is an avoidable cause of childhood blindness. With the increase in the survival of preterm babies, ROP has become the leading cause of preventable childhood blindness throughout the world. A simple screening test done within a few weeks after birth by an ophthalmologist can avoid this preventable blindness. Although screening guidelines and protocols are strictly followed in the developed nations, it lacks in developing economies like India and China, which have the highest number of preterm deliveries in the world. The burden of this blindness in these countries is set to increase tremendously in the future, if corrective steps are not taken immediately. ROP first emerged in 1940s and 1950s, when it was called retrolental fibroplasia. Several epidemics of this disease were and are still occurring in different regions of the world and since then a lot of research has been done on this disease. However, till date very few comprehensive review articles covering all the aspects of ROP are published. This review highlights the past, present and future strategies in managing this disease. It would help the pediatricians to update their current knowledge on ROP. PMID:26862500

  9. Apnea of prematurity--perfect storm.

    Science.gov (United States)

    Di Fiore, Juliann M; Martin, Richard J; Gauda, Estelle B

    2013-11-01

    With increased survival of preterm infants as young as 23 weeks gestation, maintaining adequate respiration and corresponding oxygenation represents a clinical challenge in this unique patient cohort. Respiratory instability characterized by apnea and periodic breathing occurs in premature infants because of immature development of the respiratory network. While short respiratory pauses and apnea may be of minimal consequence if oxygenation is maintained, they can be problematic if accompanied by chronic intermittent hypoxemia. Underdevelopment of the lung and the resultant lung injury that occurs in this population concurrent with respiratory instability creates the perfect storm leading to frequent episodes of profound and recurrent hypoxemia. Chronic intermittent hypoxemia contributes to the immediate and long term co-morbidities that occur in this population. In this review we discuss the pathophysiology leading to the perfect storm, diagnostic assessment of breathing instability in this unique population and therapeutic interventions that aim to stabilize breathing without contributing to tissue injury. Copyright © 2013. Published by Elsevier B.V.

  10. Telomeres, telomerase and premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Renata Košir Pogačnik

    2011-11-01

    Full Text Available Telomeres are specialized structures at the ends of chromosomes, consisting of six repeated nucleotides in TTAGGG sequence. Genome stability is partly maintained by the architecture of telomeres and is gradually lost as telomeres progressively shorten with each cell replication. Critically shortened telomeres are recognized by DNA repair mechanisms as DNA damage and the cell replication cycle stops. The cell eventually dies or undergoes cell apoptosis. Telomere represents a cellular marker of biological age and are therefore also called cell mitotic clock. The enzyme that counteracts telomere shortening by adding nucleotides to the 3’ end of DNA strand is called telomerase. It is composed of the RNA subunit (TR, which is special type of messenger RNA (mRNA, the catalytic protein subunit (TERT, which works as a reverse transcriptase and numerous additional proteins. Telomerase is active in some germline, epithelial and haemopoietic cells, but in most somatic cells the activity is undetectable. In literature, the length of telomeres is closely connected with premature ovarian failure (POF. POF is generally defined as the onset of menopause before the age of 40. The causes of disease are genetical, autoimmune, iatrogenic or if we cannot establish the cause – idiopathic. A lot of studies examined correlation between idiopathic POF, length of telomeres and telomerase activity. The studies mostly show that women with POF have shortened telomeres and decreased activity of telomerase as compared to healthy women.

  11. Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer.

    Science.gov (United States)

    Matthaios, Dimitrios; Balgkouranidou, Ioanna; Karayiannakis, Anastasios; Bolanaki, Helen; Xenidis, Nikolaos; Amarantidis, Kyriakos; Chelis, Leonidas; Romanidis, Konstantinos; Chatzaki, Aikaterini; Lianidou, Evi; Trypsianis, Grigorios; Kakolyris, Stylianos

    2016-07-01

    DNA methylation is the most frequent epigenetic alteration. Using methylation-specific polymerase chain reaction (MSP), the methylation status of the adenomatous polyposis coli ( APC ) and Ras association domain family 1 isoform A ( RASSF1A ) genes was examined in cell-free circulating DNA from 155 plasma samples obtained from patients with early and advanced colorectal cancer (CRC). APC and RASSF1A hypermethylation was frequently observed in both early and advanced disease, and was significantly associated with a poorer disease outcome. The methylation status of the APC and RASSF1A promoters was investigated in cell-free DNA of patients with CRC. Using MSP, the promoter methylation status of APC and RASSF1A was examined in 155 blood samples obtained from patients with CRC, 88 of whom had operable CRC (oCRC) and 67 had metastatic CRC (mCRC). The frequency of APC methylation in patients with oCRC was 33%. Methylated APC promoter was significantly associated with older age (P=0.012), higher stage (P=0.014) and methylated RASSF1A status (P=0.050). The frequency of APC methylation in patients with mCRC was 53.7%. In these patients, APC methylation was significantly associated with methylated RASSF1A status (P=0.016). The frequency of RASSF1A methylation in patients with oCRC was 25%. Methylated RASSF1A in oCRC was significantly associated with higher stage (P=0.021). The frequency of RASSF1A methylation in mCRC was 44.8%. Methylated RASSF1A in mCRC was associated with moderate differentiation (P=0.012), high levels of carcinoembryonic antigen (P=0.023) and methylated APC status (P=0.016). Patients with an unmethylated APC gene had better survival in both early (81±5 vs. 27±4 months, PAPC . Patients with an unmethylated RASSF1A gene had better survival in both early (71±6 vs. 46±8 months, PAPC and RASSF1A promoter methylation status and survival may be indicative of a prognostic role for these genes in CRC, which requires additional testing in larger studies.

  12. Capitation, contracts, and control

    International Nuclear Information System (INIS)

    McIsaac, L.H.

    1987-01-01

    The radiology business manager in today's environment must become proficient in contract evaluations and negotiations. Health care is focusing on preventive medicine. Third-party payers are offering plans and programs to provide ''well-patient'' care. For prepaid (HMO-IPA-PTO) plans to succeed, demands for reduced fees and other entrepreneurial contractual arrangements are developed. This presentation will focus on specific items contained in most contracts. The issues of withhold, billing procedures, prompt-payment rewards, medical liability, capitation determinations, and modified capitation plans will be discussed. It is the intent of this presentation to share with the audience methods of evaluating contracts, the importance of negotiating specific terms, and an approach to determination of capitation amounts

  13. PROCUREMENT AND CONTRACT MANAGEMENT

    CERN Multimedia

    Training & Development Group; Linda Orr-Easo; Tel. 72460; Nathalie Dumeaux; Tel. 78144

    2001-01-01

    We are pleased to announce the launch of a new training on: Procurement and Contract Management (This seminar will be run by CERN experts in French or in English) Level 1 The aim is to raise awareness of the key issues involved. Date : 8 June 2001 This level is open to everyone. Participants should register via our Web page as soon as possible. Level 2 To develop the skills needed to effectively manage contracts, from the Technical, Commercial and Legal aspects. Dates : Three days, Autumn 2001 This Level is open to those who are/will be more directly responsible for procurement and contract management. Participants should have followed Level 1. For a description of the seminar, please consult:   Level 1: http://training.web.cern.ch/Training/MANCO/P9798/9-cm_e.htm Level 2: http://training.web.cern.ch/Training/MANCO/P9798/9-cm2_e.htm

  14. Amending Contracts for Choreographies

    Directory of Open Access Journals (Sweden)

    Laura Bocchi

    2011-07-01

    Full Text Available Distributed interactions can be suitably designed in terms of choreographies. Such abstractions can be thought of as global descriptions of the coordination of several distributed parties. Global assertions define contracts for choreographies by annotating multiparty session types with logical formulae to validate the content of the exchanged messages. The introduction of such constraints is a critical design issue as it may be hard to specify contracts that allow each party to be able to progress without violating the contract. In this paper, we propose three methods that automatically correct inconsistent global assertions. The methods are compared by discussing their applicability and the relationships between the amended global assertions and the original (inconsistent ones.

  15. Panel discussion : contract design

    Energy Technology Data Exchange (ETDEWEB)

    Vallas, A. [Sempra Energy Trading, Toronto, ON (Canada); Vegh, G. [MacLeod Dixon, Toronto, ON (Canada); McGee, M. [Energy Profiles Ltd., Etobicoke, ON (Canada); Zaremba, T. [Direct Energy Marketing, Calgary, AB (Canada); Seshan, A. [Larson and Toubro Information Technology, Toronto, ON (Canada); Harricks, P. [Gowlings, Toronto, ON (Canada); Bertoldi, L. [Borden Ladner Gervais, Toronto, ON (Canada); Taylor, R. [Hydro One Networks Inc., Markham, ON (Canada)

    2003-05-01

    This session presented highlights of the comments of 8 panelists who discussed the issue of contract design. The new electricity market in Ontario has introduced the energy trader, who enters into a contract with the consumer, based on the spot price set by the Independent Electricity Market Operator. Every contract has a fixed price payer as well as floating-price payers. If the floating price for a given amount of energy is higher than the fixed price, then the consumer gets the difference. Confusion, however, arises with the purchase of retail physical power in the market, particularly in deciding a fixed rate that the consumer will be paying. Different billing options were also discussed with emphasis on mid to large retail customers that have portfolios in the tens of MW and up to 100 MW or more. figs.

  16. Panel discussion : contract design

    International Nuclear Information System (INIS)

    Vallas, A.; Vegh, G.; McGee, M.; Zaremba, T.; Seshan, A.; Harricks, P.; Bertoldi, L.; Taylor, R.

    2003-01-01

    This session presented highlights of the comments of 8 panelists who discussed the issue of contract design. The new electricity market in Ontario has introduced the energy trader, who enters into a contract with the consumer, based on the spot price set by the Independent Electricity Market Operator. Every contract has a fixed price payer as well as floating-price payers. If the floating price for a given amount of energy is higher than the fixed price, then the consumer gets the difference. Confusion, however, arises with the purchase of retail physical power in the market, particularly in deciding a fixed rate that the consumer will be paying. Different billing options were also discussed with emphasis on mid to large retail customers that have portfolios in the tens of MW and up to 100 MW or more. figs

  17. Adding Concurrency to Smart Contracts

    OpenAIRE

    Dickerson, Thomas; Gazzillo, Paul; Herlihy, Maurice; Koskinen, Eric

    2017-01-01

    Modern cryptocurrency systems, such as Ethereum, permit complex financial transactions through scripts called smart contracts. These smart contracts are executed many, many times, always without real concurrency. First, all smart contracts are serially executed by miners before appending them to the blockchain. Later, those contracts are serially re-executed by validators to verify that the smart contracts were executed correctly by miners. Serial execution limits system throughput and fails ...

  18. Is Contract Law Necessary?

    OpenAIRE

    SCHWARTZ, Alan

    2010-01-01

    This lecture was delivered on 17 March 2010. Alan Schwartz, Sterling Professor of Law; Professor of Management, Yale University This Lecture argues that much of the contract law in the cases (the US, the UK and Canada) and in the codes (Europe and Latin America) is unnecessary. To say that a law is unnecessary is to say that it does not perform a useful social function. The argument below thus sets out the functions that contract laws today are thought to serve, and then shows that many of...

  19. Culture and Contract Laws

    DEFF Research Database (Denmark)

    Lando, Ole

    2007-01-01

    In the article it is argued that the wish to preserve the cultural values of national law should not prevent the EU from preparing a Code or an Optional Instrument. The no-code countries on the British Isles and in Scandinavia are the most ardent opponents to the idea of unifying European Contract...... Law by way of a code on Contracts. In both these regions however the absence of a code causes problems. In England a prominent writer has found that the major weakness of the judge-made law is its immense diffusion and the consequent difficulty of access to it and the Nordic countries face the same...

  20. Do contracts help?

    DEFF Research Database (Denmark)

    Tumennasan, Norovsambuu

    Economists perceive moral hazard as an undesirable problem because it undermines efficiency. Carefully designed contracts can mitigate the moral hazard problem, but this assumes that a team is already formed. This paper demonstrates that these contracts are sometimes the reason why teams do...... transfers, then moral hazard affects stability positively in a large class of games. For example, a stable team structure exists if teams produce public goods or if the quota is two. However, these existence results no longer hold if efforts are verifiable....