HITESH PATEL - Academia.edu (original) (raw)
Papers by HITESH PATEL
International journal of cardiology, Jan 30, 2015
The technology used to perform catheter-based renal artery sympathetic denervation has evolved: c... more The technology used to perform catheter-based renal artery sympathetic denervation has evolved: catheters can now access arteries as small as 3mm in diameter and create ablation zones of up to 10mm in depth. Recent evidence suggests that the procedure may be more effective if a more thorough ablation strategy is employed. Limited data are available regarding inadvertent soft tissue thermal injury during such procedures. We used computed tomography (CT) to identify structures lying within the expected thermal ablation field or the 'at risk zone' (ARZ). 63 consecutive CT aortograms were reviewed, yielding 100 renal arteries anatomically eligible for treatment. Structures lying within a predefined ARZ (within 10mm of the renal artery wall) were recorded. The 63 subjects had a mean age of 74.6years, 48% were males and 88% had hypertension. The inferior vena cava and renal veins were in the ARZ in all cases. Psoas muscles and small bowel were within the ARZ in at least a fifth...
International Letters of Chemistry, Physics and Astronomy, 2014
A library of quinoline analog two novel series of azetidin (SH1-5) and thiazolidin (SHa-e) deriva... more A library of quinoline analog two novel series of azetidin (SH1-5) and thiazolidin (SHa-e) derivatives were designed and synthesized with simple and eco-friendly methodologies. The structures of the compounds were elucidated with the aid of elemental analysis, IR, 1H-NMR and mass spectral data. These novel synthesized compounds were evaluated for antibacterial activity against two gram-positive bacteria (Staphylococcus aureus, Staphylococcus pyogenus) and two gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The title compounds were also studied for their antifungal activity with Candida albicans, Aspergillus niger, Aspergillus clavatus using the broth dilution technique. Most of the compounds were the best bio-active desired antibacterial analog with less MIC value against different tested strains.
2009 International Conference on Telecommunications, 2009
In this paper we examine the behavior of Ad Hoc networks through simulations, using different rou... more In this paper we examine the behavior of Ad Hoc networks through simulations, using different routing protocols and various topologies. We examine the difference in performance, using CBR application, with packets of different size through a variety of topologies, showing the impact node placement has on networks performance. We show that the choice of routing protocol plays an important role on network's performance. We also quantify node mobility effects, by looking into both static and fully mobile configurations. Our paper presents a systematic analysis of a variety of different ad hoc network topologies in terms of node placement, node mobility and routing protocols through several simulated scenarios.
Disease management : DM, 2003
As part of a retrospective evaluation of a diabetes management program, the agreement between sel... more As part of a retrospective evaluation of a diabetes management program, the agreement between self-reported and insurance claim data on hospitalization and emergency room utilization was examined. Data agreement on hospitalization or emergency room visits between the two collection modes was evaluated through the use of simple agreement proportions and the kappa agreement statistic. A total of 1,230 participant responses were studied. The proportions of patients with hospitalization or emergency room visits were indistinguishable between the self-reported and medical claims data, and kappa statistics also indicated good-to-excellent agreement between data sets. The percentages of participants whose self-reported hospitalization and emergency room utilization exactly matched data derived from insurance claims were high (89.1% and 87.2%, respectively). Furthermore, the kappa statistics of agreement for the number of hospitalizations (0.6366) and emergency room visits (0.5390) indicate...
ChemInform, 2014
This review paper describes the synthesis of different endoperoxides, which exhibit anti-malarial... more This review paper describes the synthesis of different endoperoxides, which exhibit anti-malarial, anti-cancer and other biological activity. This review is primarily based on artemisinine. Many researchers have proved that artemisinine is active in malaria and cancer. It is also proved that in artemisinine, the endoperoxide bond plays a key role in the fight against disease. It is expected that this review will provide first-hand information on endoperoxide chemistry to organic chemists, pharmacologists and medicinal chemists who are working on anti-malarial and anti-cancer drug development.
2012 Proceedings of IEEE Southeastcon, 2012
Embry-Riddle Aeronautical University (ERAU) team built a gas/electric hybrid aircraft, called Eco... more Embry-Riddle Aeronautical University (ERAU) team built a gas/electric hybrid aircraft, called EcoEagle, to enter the NASA-funded Green Flight Challenge in 2011. The battery system for EcoEagle consists of multiple battery modules in parallel. Each battery module has a fully functional battery management system (BMS), which is connected to a data bus controlled by a master controller. In this paper, we
Bioanalysis, 2012
The current practice of using calibration curves with narrow concentration ranges during bioanaly... more The current practice of using calibration curves with narrow concentration ranges during bioanalysis of new chemical entities has some limitations and is time consuming. In the present study we describe a split calibration curve approach, where sample dilution and repeat analysis can be avoided without compromising the quality and integrity of the data obtained. A split calibration curve approach is employed to determine the drug concentration in plasma samples with accuracy and precision over a wide dynamic range of approximately 0.6 to 15,000 ng/ml for dapsone and approximately 1 to 25,000 ng/ml for cyclophosphamide and glipizide. A wide dynamic range of concentrations for these three compounds was used in the current study to construct split calibration curves and was successfully validated for sample analysis in a single run. Using this method, repeat analysis of samples can be avoided. This is useful for the bioanalysis of toxicokinetic studies with wide dose ranges and studies...
RSC Adv., 2014
This review article gives information about the recent advances in the synthesis of quinoline der... more This review article gives information about the recent advances in the synthesis of quinoline derivatives by various eco-friendly, green and clean protocols.
Transportation Research Record: Journal of the Transportation Research Board, 1999
One method to enforce speed limits on U.S. highways is through the use of police enforcement. One... more One method to enforce speed limits on U.S. highways is through the use of police enforcement. One major problem with this approach is the high cost associated with the employment of police officers for patrolling purposes. Thus, the effectiveness of police presence in controlling highway speeds should be carefully assessed prior to making a decision on increasing police patrolling operations on the transportation network. A study was undertaken to evaluate the effects of police presence on the speed of vehicles in a recently increased speed-limit zone and to determine the “halo” effects of police presence (lasting effects when police are gone) on vehicular speeds. Data were collected on Interstate 96 in Ionia County, Michigan. Marked police cars circulated in both directions on the study segment, which was approximately 45 km (29 mi) long. Net speed reductions at a distance of 1.6, 3.2, and 4.8 km (1, 2, and 3 mi) upstream and downstream of each counter were used in the data analysi...
Journal of Cell Biology, 2005
Increased intracellular H+ efflux is speculated to be an evolutionarily conserved mechanism neces... more Increased intracellular H+ efflux is speculated to be an evolutionarily conserved mechanism necessary for rapid assembly of cytoskeletal filaments and for morphological polarity during cell motility. In Dictyostelium discoideum, increased intracellular pH through undefined transport mechanisms plays a key role in directed cell movement. We report that a developmentally regulated Na-H exchanger in Dictyostelium discoideum (DdNHE1) localizes to the leading edge of polarized cells and is necessary for intracellular pH homeostasis and for efficient chemotaxis. Starved DdNHE1-null cells (Ddnhe1−) differentiate, and in response to the chemoattractant cAMP they retain directional sensing; however, they cannot attain a polarized morphology, but instead extend mislocalized pseudopodia around the cell and exhibit decreased velocity. Consistent with impaired polarity, in response to chemoattractant, Ddnhe1− cells lack a leading edge localization of F-actin and have significantly attenuated de ...
The EMBO Journal, 2000
Dictyostelium development starts with the chemotactic aggregation of up to 10 6 amoebae in respon... more Dictyostelium development starts with the chemotactic aggregation of up to 10 6 amoebae in response to propagating cAMP waves. cAMP is produced by the aggregation stage adenylyl cyclase (ACA) and cells lacking ACA (aca null) cannot aggregate. Temperature-sensitive mutants of ACA were selected from a population of aca null cells transformed with a library of ACA genes, a major segment of which had been ampli®ed by error-prone PCR. One mutant (tsaca2) that can complement the aggregation null phenotype of aca null cells at 22°C but not at 28°C was characterized in detail. The basal catalytic activity of the enzyme in this mutant was rapidly and reversibly inactivated at 28°C. Using this mutant strain we show that cell movement in aggregates and mounds is organized by propagating waves of cAMP. Synergy experiments between wild-type and tsaca2 cells, shifted to the restrictive temperature at various stages of development, showed that ACA plays an important role in the control of cell sorting and tip formation.
Tetrahedron Letters, 2009
Journal of cheminformatics, Jan 31, 2010
OpenTox provides an interoperable, standards-based Framework for the support of predictive toxico... more OpenTox provides an interoperable, standards-based Framework for the support of predictive toxicology data management, algorithms, modelling, validation and reporting. It is relevant to satisfying the chemical safety assessment requirements of the REACH legislation as it supports access to experimental data, (Quantitative) Structure-Activity Relationship models, and toxicological information through an integrating platform that adheres to regulatory requirements and OECD validation principles. Initial research defined the essential components of the Framework including the approach to data access, schema and management, use of controlled vocabularies and ontologies, architecture, web service and communications protocols, and selection and integration of algorithms for predictive modelling. OpenTox provides end-user oriented tools to non-computational specialists, risk assessors, and toxicological experts in addition to Application Programming Interfaces (APIs) for developers of new ...
Nature Reviews Molecular Cell Biology, 2010
Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein that binds to itself and ce... more Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein that binds to itself and cellular partners through its four-point-one, ezrin, radixin, moesin (FERM) domain. Recent structural work reveals that regulatory protein partners convert auto-inhibited FAK into its active state by binding to its FERM domain. Further, the identity of FAK FERM domain-interacting proteins yields clues as to how FAK coordinates diverse cellular responses, including cell adhesion, polarization, migration, survival and death, and suggests that FERM domains might mediate information transfer between the cell cortex and nucleus. Importantly, the FAK FERM domain might act as a paradigm for the actions of other FERM domain-containing proteins.
Journal of the American College of Cardiology, 1999
OBJECTIVES The purpose of this study was to determine whether the mortality benefit of intravenou... more OBJECTIVES The purpose of this study was to determine whether the mortality benefit of intravenous streptokinase administered within 4 h of the onset of acute myocardial infarction is maintained at 12 years, and whether Thrombolysis in Myocardial Infarction (TIMI) flow grades independently influence late survival. BACKGROUND Treatment with reperfusion therapies and achievement of TIMI 3 flow are associated with increased short-and medium-term survival after infarction. Whether infarct artery flow independently influences survival more than five years after infarction is unknown. METHODS The late survival of patients randomized to receive either streptokinase (1,500,000 IU over 30 to 60 min) or a matching placebo within 4 h of symptom onset in 1984-1986 was determined. Angiography was performed in surviving patients at three to four weeks, and TIMI flow grades were assessed blind to randomization and outcomes. The late vital status was determined in 99% of patients. RESULTS Patients randomized to receive streptokinase (n ϭ 107) had improved survival compared with those randomized to placebo (n ϭ 112) at five years (84% vs. 70%; p ϭ 0.023) and 12 years (66% vs. 51%; p ϭ 0.022). At five years 94% of patients with TIMI grade 3 flow, 81% of those with TIMI grade 2 flow and 72% of those with TIMI grade 0-1 flow survived (p ϭ 0.005). At 12 years 72% of patients with TIMI 3, 67% of those with TIMI 2 and 54% of those with TIMI 0-1 flow survived (p ϭ 0.023). Multivariate analysis identified the ejection fraction (p ϭ 0.014), exercise duration (p ϭ 0.013) and TIMI 3 flow (p ϭ 0.04 compared with TIMI 0-2 flow) as important factors for five-year survival. At 12 years multivariate predictors of late survival were the ejection fraction (p ϭ 0.006), exercise duration (p ϭ 0.003) and myocardial score (p ϭ 0.013). The end-systolic volume index was similar to the ejection fraction as a predictor of survival at five and 12 years. CONCLUSIONS The survival benefits of streptokinase persist for 12 years after infarction. TIMI flow at three to four weeks is an independent predictor of five-year survival.
Journal of the American College of Cardiology, 2012
Background: Current understanding of aortic stenosis (AS) progression is that it is linear, with ... more Background: Current understanding of aortic stenosis (AS) progression is that it is linear, with certain groups showing more rapid progression than others. We aimed to create a mathematical model that describes progression of AS to aid patient assessment and follow up. Methods: We performed a retrospective cohort analysis of all severe AS patients who have either had a valve replacement (AVR) or are on a waiting list and who were not having AVR because of coexisting requirement for coronary artery bypass. All included patients had at least two echocardiograms and the changes in echo parameters with time were examined. Results: We studied 72 patients (age 73.7±10.4 (mean±SD), 37 male). 60 (83%) underwent valve replacement and 11 (15%) were pending. At time of AVR the peak velocity (AVmax) was 4.34±0.51m/s (mean±SD), mean gradient (AVmean) was 44.3± 13.4mmHg (mean±SD), and the estimated aortic valve area (AVA) was 0.72±0.18cm2 (mean±SD). AVmax (m/s), AVmean (mmHg), and AVA (cm2) all showed a logarithmic relationship with time, best described by the following equations: (AVmax= 5.23-0.52 ln(x), where x= time (months), r2=0.98, p<0.001). (AVmean= 59.98-9.45 ln(x), r2=0.95, p<0.001). (AVA= 0.37 + 0.20 ln(x), r2=0.80, p<0.001). See figure 1. Conclusion: The rate of progression of aortic stenosis is not linear in patients requiring AVR. The rate of change for AVmax, AVmean and AVA can be defined mathematically by a logarithmic equation. This may be important in timing follow up echocardiography.
The Journal of Pathology, 2013
Src family kinase activity is elevated in a number of human cancers including breast cancer. This... more Src family kinase activity is elevated in a number of human cancers including breast cancer. This increased activity has been associated with aggressive disease and poor prognosis. Src inhibitors are currently in clinical development with a number of trials currently assessing their activity in breast cancer. However, the results to date have been disappointing and a further evaluation of the preclinical effects of Src inhibitors is required to help establish whether these agents will be useful in the treatment of breast cancer. In this study we investigate the effects of dasatinib, which is a potent inhibitor of Src family kinases, on the initiation and development of breast cancer in a genetically engineered model of the disease. The mouse model utilized is driven by expression of activated ErbB-2 under the transcriptional control of its endogenous promoter coupled with conditional loss of Pten under the control of Cre recombinase expressed by the BLG promoter. We show that daily oral administration of dasatinib delays tumour onset and increases overall survival but does not inhibit the proliferation of established tumours. The striking difference between the dasatinib-treated group of tumours and the vehicle controls was the prominent squamous metaplasia that was seen in six out of 11 dasatinib-treated tumours. This was accompanied by a dramatic up-regulation of both E-cadherin and β-catenin and down-regulation of ErbB-2 in the dasatinib-treated tumours. Dasatinib also inhibited both the migration and the invasion of tumour-derived cell lines in vitro. Together these data support the argument that benefits of Src inhibitors may predominate in early or even pre-invasive disease.
Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, 1995
Studies by electron paramagnetic resonance (EPR), differential scanning calorimetry, thermogravim... more Studies by electron paramagnetic resonance (EPR), differential scanning calorimetry, thermogravimetric analysis, HPLC and NMR showed that radicals produced by thermolysis and photolysis of benzoyl peroxide, l-butyl peroxide and cumene hydroperoxide included in/3-cyclodextrin ()3-CD), undergo significant reaction with the/~-CD. The formation of fl-CD radicals was observed by EPR. Products formed by addition of radicals to/3-CD were also observed. Such host:guest radical reactions explain the reported stabilization of peroxides, found with/3-CD inclusion, as being primarily due to the interruption of chain reactions by trapping of the chain carriers. A small increase in activation barrier for cleavage of the included peroxide in ,3-CD was also observed.
Journal of Cell Science, 2008
FERM domain proteins, including talins, ERMs, FAK and certain myosins, regulate connections betwe... more FERM domain proteins, including talins, ERMs, FAK and certain myosins, regulate connections between the plasma membrane, cytoskeleton and extracellular matrix. Here we show that FrmA, a Dictyostelium discoideum protein containing two talin-like FERM domains, plays a major role in normal cell shape, cell-substrate adhesion and actin cytoskeleton organisation. Using total internal reflection fluorescence (TIRF) microscopy we show that FrmA-null cells are more adherent to substrate than wild-type cells because of an increased number, persistence and mislocalisation of paxillin-rich cell-substrate adhesions, which is associated with decreased motility. We show for the first time that talinA colocalises with paxillin at the distal ends of filopodia to form cell-substrate adhesions and indeed arrives prior to paxillin. After a period of colocalisation, talin leaves the adhesion site followed by paxillin. Whereas talinA-rich spots turnover prior to the arrival of the main body of the cell,...
Journal of Cardiovascular Magnetic Resonance, 2014
International journal of cardiology, Jan 30, 2015
The technology used to perform catheter-based renal artery sympathetic denervation has evolved: c... more The technology used to perform catheter-based renal artery sympathetic denervation has evolved: catheters can now access arteries as small as 3mm in diameter and create ablation zones of up to 10mm in depth. Recent evidence suggests that the procedure may be more effective if a more thorough ablation strategy is employed. Limited data are available regarding inadvertent soft tissue thermal injury during such procedures. We used computed tomography (CT) to identify structures lying within the expected thermal ablation field or the 'at risk zone' (ARZ). 63 consecutive CT aortograms were reviewed, yielding 100 renal arteries anatomically eligible for treatment. Structures lying within a predefined ARZ (within 10mm of the renal artery wall) were recorded. The 63 subjects had a mean age of 74.6years, 48% were males and 88% had hypertension. The inferior vena cava and renal veins were in the ARZ in all cases. Psoas muscles and small bowel were within the ARZ in at least a fifth...
International Letters of Chemistry, Physics and Astronomy, 2014
A library of quinoline analog two novel series of azetidin (SH1-5) and thiazolidin (SHa-e) deriva... more A library of quinoline analog two novel series of azetidin (SH1-5) and thiazolidin (SHa-e) derivatives were designed and synthesized with simple and eco-friendly methodologies. The structures of the compounds were elucidated with the aid of elemental analysis, IR, 1H-NMR and mass spectral data. These novel synthesized compounds were evaluated for antibacterial activity against two gram-positive bacteria (Staphylococcus aureus, Staphylococcus pyogenus) and two gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The title compounds were also studied for their antifungal activity with Candida albicans, Aspergillus niger, Aspergillus clavatus using the broth dilution technique. Most of the compounds were the best bio-active desired antibacterial analog with less MIC value against different tested strains.
2009 International Conference on Telecommunications, 2009
In this paper we examine the behavior of Ad Hoc networks through simulations, using different rou... more In this paper we examine the behavior of Ad Hoc networks through simulations, using different routing protocols and various topologies. We examine the difference in performance, using CBR application, with packets of different size through a variety of topologies, showing the impact node placement has on networks performance. We show that the choice of routing protocol plays an important role on network's performance. We also quantify node mobility effects, by looking into both static and fully mobile configurations. Our paper presents a systematic analysis of a variety of different ad hoc network topologies in terms of node placement, node mobility and routing protocols through several simulated scenarios.
Disease management : DM, 2003
As part of a retrospective evaluation of a diabetes management program, the agreement between sel... more As part of a retrospective evaluation of a diabetes management program, the agreement between self-reported and insurance claim data on hospitalization and emergency room utilization was examined. Data agreement on hospitalization or emergency room visits between the two collection modes was evaluated through the use of simple agreement proportions and the kappa agreement statistic. A total of 1,230 participant responses were studied. The proportions of patients with hospitalization or emergency room visits were indistinguishable between the self-reported and medical claims data, and kappa statistics also indicated good-to-excellent agreement between data sets. The percentages of participants whose self-reported hospitalization and emergency room utilization exactly matched data derived from insurance claims were high (89.1% and 87.2%, respectively). Furthermore, the kappa statistics of agreement for the number of hospitalizations (0.6366) and emergency room visits (0.5390) indicate...
ChemInform, 2014
This review paper describes the synthesis of different endoperoxides, which exhibit anti-malarial... more This review paper describes the synthesis of different endoperoxides, which exhibit anti-malarial, anti-cancer and other biological activity. This review is primarily based on artemisinine. Many researchers have proved that artemisinine is active in malaria and cancer. It is also proved that in artemisinine, the endoperoxide bond plays a key role in the fight against disease. It is expected that this review will provide first-hand information on endoperoxide chemistry to organic chemists, pharmacologists and medicinal chemists who are working on anti-malarial and anti-cancer drug development.
2012 Proceedings of IEEE Southeastcon, 2012
Embry-Riddle Aeronautical University (ERAU) team built a gas/electric hybrid aircraft, called Eco... more Embry-Riddle Aeronautical University (ERAU) team built a gas/electric hybrid aircraft, called EcoEagle, to enter the NASA-funded Green Flight Challenge in 2011. The battery system for EcoEagle consists of multiple battery modules in parallel. Each battery module has a fully functional battery management system (BMS), which is connected to a data bus controlled by a master controller. In this paper, we
Bioanalysis, 2012
The current practice of using calibration curves with narrow concentration ranges during bioanaly... more The current practice of using calibration curves with narrow concentration ranges during bioanalysis of new chemical entities has some limitations and is time consuming. In the present study we describe a split calibration curve approach, where sample dilution and repeat analysis can be avoided without compromising the quality and integrity of the data obtained. A split calibration curve approach is employed to determine the drug concentration in plasma samples with accuracy and precision over a wide dynamic range of approximately 0.6 to 15,000 ng/ml for dapsone and approximately 1 to 25,000 ng/ml for cyclophosphamide and glipizide. A wide dynamic range of concentrations for these three compounds was used in the current study to construct split calibration curves and was successfully validated for sample analysis in a single run. Using this method, repeat analysis of samples can be avoided. This is useful for the bioanalysis of toxicokinetic studies with wide dose ranges and studies...
RSC Adv., 2014
This review article gives information about the recent advances in the synthesis of quinoline der... more This review article gives information about the recent advances in the synthesis of quinoline derivatives by various eco-friendly, green and clean protocols.
Transportation Research Record: Journal of the Transportation Research Board, 1999
One method to enforce speed limits on U.S. highways is through the use of police enforcement. One... more One method to enforce speed limits on U.S. highways is through the use of police enforcement. One major problem with this approach is the high cost associated with the employment of police officers for patrolling purposes. Thus, the effectiveness of police presence in controlling highway speeds should be carefully assessed prior to making a decision on increasing police patrolling operations on the transportation network. A study was undertaken to evaluate the effects of police presence on the speed of vehicles in a recently increased speed-limit zone and to determine the “halo” effects of police presence (lasting effects when police are gone) on vehicular speeds. Data were collected on Interstate 96 in Ionia County, Michigan. Marked police cars circulated in both directions on the study segment, which was approximately 45 km (29 mi) long. Net speed reductions at a distance of 1.6, 3.2, and 4.8 km (1, 2, and 3 mi) upstream and downstream of each counter were used in the data analysi...
Journal of Cell Biology, 2005
Increased intracellular H+ efflux is speculated to be an evolutionarily conserved mechanism neces... more Increased intracellular H+ efflux is speculated to be an evolutionarily conserved mechanism necessary for rapid assembly of cytoskeletal filaments and for morphological polarity during cell motility. In Dictyostelium discoideum, increased intracellular pH through undefined transport mechanisms plays a key role in directed cell movement. We report that a developmentally regulated Na-H exchanger in Dictyostelium discoideum (DdNHE1) localizes to the leading edge of polarized cells and is necessary for intracellular pH homeostasis and for efficient chemotaxis. Starved DdNHE1-null cells (Ddnhe1−) differentiate, and in response to the chemoattractant cAMP they retain directional sensing; however, they cannot attain a polarized morphology, but instead extend mislocalized pseudopodia around the cell and exhibit decreased velocity. Consistent with impaired polarity, in response to chemoattractant, Ddnhe1− cells lack a leading edge localization of F-actin and have significantly attenuated de ...
The EMBO Journal, 2000
Dictyostelium development starts with the chemotactic aggregation of up to 10 6 amoebae in respon... more Dictyostelium development starts with the chemotactic aggregation of up to 10 6 amoebae in response to propagating cAMP waves. cAMP is produced by the aggregation stage adenylyl cyclase (ACA) and cells lacking ACA (aca null) cannot aggregate. Temperature-sensitive mutants of ACA were selected from a population of aca null cells transformed with a library of ACA genes, a major segment of which had been ampli®ed by error-prone PCR. One mutant (tsaca2) that can complement the aggregation null phenotype of aca null cells at 22°C but not at 28°C was characterized in detail. The basal catalytic activity of the enzyme in this mutant was rapidly and reversibly inactivated at 28°C. Using this mutant strain we show that cell movement in aggregates and mounds is organized by propagating waves of cAMP. Synergy experiments between wild-type and tsaca2 cells, shifted to the restrictive temperature at various stages of development, showed that ACA plays an important role in the control of cell sorting and tip formation.
Tetrahedron Letters, 2009
Journal of cheminformatics, Jan 31, 2010
OpenTox provides an interoperable, standards-based Framework for the support of predictive toxico... more OpenTox provides an interoperable, standards-based Framework for the support of predictive toxicology data management, algorithms, modelling, validation and reporting. It is relevant to satisfying the chemical safety assessment requirements of the REACH legislation as it supports access to experimental data, (Quantitative) Structure-Activity Relationship models, and toxicological information through an integrating platform that adheres to regulatory requirements and OECD validation principles. Initial research defined the essential components of the Framework including the approach to data access, schema and management, use of controlled vocabularies and ontologies, architecture, web service and communications protocols, and selection and integration of algorithms for predictive modelling. OpenTox provides end-user oriented tools to non-computational specialists, risk assessors, and toxicological experts in addition to Application Programming Interfaces (APIs) for developers of new ...
Nature Reviews Molecular Cell Biology, 2010
Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein that binds to itself and ce... more Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein that binds to itself and cellular partners through its four-point-one, ezrin, radixin, moesin (FERM) domain. Recent structural work reveals that regulatory protein partners convert auto-inhibited FAK into its active state by binding to its FERM domain. Further, the identity of FAK FERM domain-interacting proteins yields clues as to how FAK coordinates diverse cellular responses, including cell adhesion, polarization, migration, survival and death, and suggests that FERM domains might mediate information transfer between the cell cortex and nucleus. Importantly, the FAK FERM domain might act as a paradigm for the actions of other FERM domain-containing proteins.
Journal of the American College of Cardiology, 1999
OBJECTIVES The purpose of this study was to determine whether the mortality benefit of intravenou... more OBJECTIVES The purpose of this study was to determine whether the mortality benefit of intravenous streptokinase administered within 4 h of the onset of acute myocardial infarction is maintained at 12 years, and whether Thrombolysis in Myocardial Infarction (TIMI) flow grades independently influence late survival. BACKGROUND Treatment with reperfusion therapies and achievement of TIMI 3 flow are associated with increased short-and medium-term survival after infarction. Whether infarct artery flow independently influences survival more than five years after infarction is unknown. METHODS The late survival of patients randomized to receive either streptokinase (1,500,000 IU over 30 to 60 min) or a matching placebo within 4 h of symptom onset in 1984-1986 was determined. Angiography was performed in surviving patients at three to four weeks, and TIMI flow grades were assessed blind to randomization and outcomes. The late vital status was determined in 99% of patients. RESULTS Patients randomized to receive streptokinase (n ϭ 107) had improved survival compared with those randomized to placebo (n ϭ 112) at five years (84% vs. 70%; p ϭ 0.023) and 12 years (66% vs. 51%; p ϭ 0.022). At five years 94% of patients with TIMI grade 3 flow, 81% of those with TIMI grade 2 flow and 72% of those with TIMI grade 0-1 flow survived (p ϭ 0.005). At 12 years 72% of patients with TIMI 3, 67% of those with TIMI 2 and 54% of those with TIMI 0-1 flow survived (p ϭ 0.023). Multivariate analysis identified the ejection fraction (p ϭ 0.014), exercise duration (p ϭ 0.013) and TIMI 3 flow (p ϭ 0.04 compared with TIMI 0-2 flow) as important factors for five-year survival. At 12 years multivariate predictors of late survival were the ejection fraction (p ϭ 0.006), exercise duration (p ϭ 0.003) and myocardial score (p ϭ 0.013). The end-systolic volume index was similar to the ejection fraction as a predictor of survival at five and 12 years. CONCLUSIONS The survival benefits of streptokinase persist for 12 years after infarction. TIMI flow at three to four weeks is an independent predictor of five-year survival.
Journal of the American College of Cardiology, 2012
Background: Current understanding of aortic stenosis (AS) progression is that it is linear, with ... more Background: Current understanding of aortic stenosis (AS) progression is that it is linear, with certain groups showing more rapid progression than others. We aimed to create a mathematical model that describes progression of AS to aid patient assessment and follow up. Methods: We performed a retrospective cohort analysis of all severe AS patients who have either had a valve replacement (AVR) or are on a waiting list and who were not having AVR because of coexisting requirement for coronary artery bypass. All included patients had at least two echocardiograms and the changes in echo parameters with time were examined. Results: We studied 72 patients (age 73.7±10.4 (mean±SD), 37 male). 60 (83%) underwent valve replacement and 11 (15%) were pending. At time of AVR the peak velocity (AVmax) was 4.34±0.51m/s (mean±SD), mean gradient (AVmean) was 44.3± 13.4mmHg (mean±SD), and the estimated aortic valve area (AVA) was 0.72±0.18cm2 (mean±SD). AVmax (m/s), AVmean (mmHg), and AVA (cm2) all showed a logarithmic relationship with time, best described by the following equations: (AVmax= 5.23-0.52 ln(x), where x= time (months), r2=0.98, p<0.001). (AVmean= 59.98-9.45 ln(x), r2=0.95, p<0.001). (AVA= 0.37 + 0.20 ln(x), r2=0.80, p<0.001). See figure 1. Conclusion: The rate of progression of aortic stenosis is not linear in patients requiring AVR. The rate of change for AVmax, AVmean and AVA can be defined mathematically by a logarithmic equation. This may be important in timing follow up echocardiography.
The Journal of Pathology, 2013
Src family kinase activity is elevated in a number of human cancers including breast cancer. This... more Src family kinase activity is elevated in a number of human cancers including breast cancer. This increased activity has been associated with aggressive disease and poor prognosis. Src inhibitors are currently in clinical development with a number of trials currently assessing their activity in breast cancer. However, the results to date have been disappointing and a further evaluation of the preclinical effects of Src inhibitors is required to help establish whether these agents will be useful in the treatment of breast cancer. In this study we investigate the effects of dasatinib, which is a potent inhibitor of Src family kinases, on the initiation and development of breast cancer in a genetically engineered model of the disease. The mouse model utilized is driven by expression of activated ErbB-2 under the transcriptional control of its endogenous promoter coupled with conditional loss of Pten under the control of Cre recombinase expressed by the BLG promoter. We show that daily oral administration of dasatinib delays tumour onset and increases overall survival but does not inhibit the proliferation of established tumours. The striking difference between the dasatinib-treated group of tumours and the vehicle controls was the prominent squamous metaplasia that was seen in six out of 11 dasatinib-treated tumours. This was accompanied by a dramatic up-regulation of both E-cadherin and β-catenin and down-regulation of ErbB-2 in the dasatinib-treated tumours. Dasatinib also inhibited both the migration and the invasion of tumour-derived cell lines in vitro. Together these data support the argument that benefits of Src inhibitors may predominate in early or even pre-invasive disease.
Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, 1995
Studies by electron paramagnetic resonance (EPR), differential scanning calorimetry, thermogravim... more Studies by electron paramagnetic resonance (EPR), differential scanning calorimetry, thermogravimetric analysis, HPLC and NMR showed that radicals produced by thermolysis and photolysis of benzoyl peroxide, l-butyl peroxide and cumene hydroperoxide included in/3-cyclodextrin ()3-CD), undergo significant reaction with the/~-CD. The formation of fl-CD radicals was observed by EPR. Products formed by addition of radicals to/3-CD were also observed. Such host:guest radical reactions explain the reported stabilization of peroxides, found with/3-CD inclusion, as being primarily due to the interruption of chain reactions by trapping of the chain carriers. A small increase in activation barrier for cleavage of the included peroxide in ,3-CD was also observed.
Journal of Cell Science, 2008
FERM domain proteins, including talins, ERMs, FAK and certain myosins, regulate connections betwe... more FERM domain proteins, including talins, ERMs, FAK and certain myosins, regulate connections between the plasma membrane, cytoskeleton and extracellular matrix. Here we show that FrmA, a Dictyostelium discoideum protein containing two talin-like FERM domains, plays a major role in normal cell shape, cell-substrate adhesion and actin cytoskeleton organisation. Using total internal reflection fluorescence (TIRF) microscopy we show that FrmA-null cells are more adherent to substrate than wild-type cells because of an increased number, persistence and mislocalisation of paxillin-rich cell-substrate adhesions, which is associated with decreased motility. We show for the first time that talinA colocalises with paxillin at the distal ends of filopodia to form cell-substrate adhesions and indeed arrives prior to paxillin. After a period of colocalisation, talin leaves the adhesion site followed by paxillin. Whereas talinA-rich spots turnover prior to the arrival of the main body of the cell,...
Journal of Cardiovascular Magnetic Resonance, 2014