Fiona Chandra - Academia.edu (original) (raw)

Papers by Fiona Chandra

Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior in... more Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior in genetic circuits as “hidden” interactions arise. However, ribosomes are also autocatalytic since they are partially made of proteins and autocatalysis can have detrimental effects on a system’s stability and/or robustness. Additionally, there are known feedback regulations on ribosome synthesis such as inhibition of rRNA synthesis via ppGpp. Here, we develop a minimal model of ribosome and protein synthesis, which includes autocatalysis and feedback, to investigate conditions under which these regulatory actions may have a significant effect in situations of increased ribosome demand.

Despite the complexity of biological networks, we find that certain common architectures govern n... more Despite the complexity of biological networks, we find that certain common architectures govern network structures. These architectures impose fundamental constraints on system performance and create tradeoffs that the system must balance in the face of uncertainty in the environment. This means that while a system may be optimized for a specific function through evolution, the optimal achievable state must follow these constraints. One such constraining architecture is autocatalysis, as seen in many biological networks including glycolysis and ribosomal protein synthesis. Using a minimal model, we show that ATP autocatalysis in glycolysis imposes stability and performance constraints and that the experimentally well-studied glycolytic oscillations are in fact a consequence of a tradeoff between error minimization and stability. We also show that additional complexity in the network results in increased robustness. Ribosome synthesis is also autocatalytic where ribosomes must be use...

The AAPS Journal, 2019

A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluat... more A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI). However, these metrics have some limitations. In particular, for biologics with long half-lives, tumor volume (TV) of treated xenografts displays a delay in volume reduction (and in some cases, complete regression) followed by a growth rebound. These observed data cannot be described by exponential functions, which is the underlying assumption of TGI and GRI, and the fit depends on how long the tumor volumes are monitored. On the other hand, T/C and TGI only utilizes information from one chosen time point. Here, we propose a new metric called Survival Prolongation Index (SPI), calculated as the time for drug-treated TV to reach a certain size (e.g., 600 mm 3) divided by the time for control TV to reach 600mm 3 and therefore not dependent on the chosen final time point t f. Simulations were conducted under different scenarios (i.e., exponential vs. saturable growth, linear vs. nonlinear kill function). For all cases, SPI is the most linear and growth-rate independent metric. Subsequently, a literature analysis was conducted using 11 drugs to evaluate the correlation between pre-clinically obtained SPI and clinical overall response. This retrospective analysis of approved drugs suggests that a predicted SPI of 2 is necessary for clinical response.

Annals of vascular surgery, Jan 20, 2016

The rise in office-based interventional vascular laboratories in recent years was prompted in par... more The rise in office-based interventional vascular laboratories in recent years was prompted in part by expedient ambulatory patient experience and favorable outpatient procedural reimbursement. While studies have shown that clinical safety and treatment efficacy can be achieved in office-based vascular facilities, critics have raised various concerns due to inconsistent patient care standards and lack of organizational oversight to ensure optimal patient outcome. Available literature showed widely varied clinical outcomes which were partly attributable to nonuniform standards in reporting clinical efficacy and adverse events. In this report, various concerns and pitfalls of office-based interventional vascular centers are discussed. Strategies to improve patient care delivery in office-based laboratories including accreditations which serve as external validation of processes to ensure patient care and safety are also mentioned. Finally, the requirements to obtain accreditation in an...

Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior of... more Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior of genetic circuits and has recently gained renewed attention with both experimental and theoretical studies. Current models studying the effects of resource competition assume a constant production of ribosomes and these models describe the experimental results well. However, ribosomes are also autocatalytic since they are partially made of protein and autocatalysis has been shown to have detrimental effects on a system's stability and robustness. Additionally, there are known feedback regulations on ribosome synthesis such as inhibition of rRNA synthesis via ppGpp. Here, we develop two-state models of ribosome and protein synthesis incorporating autocatalysis and feedback to investigate conditions under which these regulatory actions have a significant effect in situations of increased ribosome demand. Our modeling results indicate that for sufficiently low demand, defined by the mRN...

2009 American Control Conference, 2009

Autocatalysis is necessary and ubiquitous in both engineered and biological systems but can aggra... more Autocatalysis is necessary and ubiquitous in both engineered and biological systems but can aggravate control performance and cause instability. We analyze the properties of autocatalysis in the universal and well studied glycolytic pathway. A simple two-state model incorporating ATP autocatalysis and inhibitory feedback control captures the essential dynamics, including limit cycle oscillations, observed experimentally. System performance is limited by the inherent autocatalytic stoichiometry and higher levels of autocatalysis exacerbate stability and performance. We show that glycolytic oscillations are not merely a "frozen accident" but a result of the intrinsic stability tradeoffs emerging from the autocatalytic mechanism. This model has pedagogical value as well as appearing to be the simplest and most complete illustration yet of Bode's integral formula. I. INTRODUCTION IN metabolic systems the destabilizing effects of "positive" autocatalytic feedback is often countered by negative feedback loops. Instability due to high autocatalysis is typically via a real pole (i.e. saddle-node bifurcation) whereas high inhibition can drive a system into a limit cycle (sustained oscillations via a Hopf bifurcation). This effect has also been studied in other biological systems such as mitogen-activated protein kinase cascades [1]. We wish to explore the hard limits of stability and performance that arise from such autocatalytic and regulatory mechanisms using a familiar and well-understood example. The glycolytic system is ideal to motivate such theoretical analysis for biological systems. Glycolysis is perhaps the most common control system on the planet as it is found in every one of the more than 10 30 cells, from bacteria to human. It has been widely studied and is one of biology's best understood systems. However, despite the extensive experimental and theoretical studies, many questions as to why oscillations occur in glycolysis remain. Similar to an engineered power plant whose machinery runs on its own energy product, the glycolysis reaction is autocatalytic. Glycolysis generates Adenosine triphosphate Manuscript received March 12, 2009.

49th IEEE Conference on Decision and Control (CDC), 2010

Autocatalytic networks, where a member can stimulate its own production, can be unstable when not... more Autocatalytic networks, where a member can stimulate its own production, can be unstable when not controlled by feedback. Even when such networks are stabilized by regulating control feedbacks, they tend to exhibit non-minimum phase behavior. In this paper, we study the hard limits of the ideal performance of such networks and the hard limit of their minimum output energy. We consider a simplified model of glycolysis as our motivating example. For the glycolysis model, we characterize hard limits on the minimum output energy by analyzing the limiting behavior of the optimal cheap control problem for two different interconnection topologies. We show that some network interconnection topologies result in zero hard limits. Then, we develop necessary tools and concepts to extend our results to a general class of autocatalytic networks.

European Journal of Control, 2011

This paper will review recent progress on developing a unified theory for complex networks from b... more This paper will review recent progress on developing a unified theory for complex networks from biological systems and physics to engineering and technology. Insights into what the potential universal laws, architecture, and organizational principles are can be drawn from three converging research themes: growing attention to complexity and robustness in systems biology, layering and organization in network technology, and new mathematical frameworks for the study of complex networks. We will illustrate how tools in robust control theory and optimization can be integrated towards such unified theory by focusing on their applications in biology, physics, network design, and electric grid.

Annals of Vascular Surgery, 2006

Our objective was to evaluate the impact of the ipsilateral superficial femoral artery (SFA) on p... more Our objective was to evaluate the impact of the ipsilateral superficial femoral artery (SFA) on percutaneous transluminal angioplasty (PTA) of the iliac arteries. From 1993 to 2005, 183 iliac lesions (179 stenoses, 4 occlusions; 37 common, 35 external, and 111 both iliac arteries) in 127 patients with disabling claudication [94 (52%)], rest pain [43 (23%)], and ulcer/gangrene [46 (25%)] were treated by PTA. TransAtlantic Inter-Society Consensus (TASC) iliac lesion types were A in 48 limbs (26%), B in 92 (50%), C in 38 (21%), and D in 5 (3%). Stents were placed selectively for primary angioplasty failure [residual stenosis (>30%) or pressure gradient (>5 mm Hg)]. Seventy-seven limbs (42%) had patent SFAs (66 intact/<50% stenosis and 11 previously bypassed, pSFA group), 28 (15%) had stenotic SFAs (50-99%, sSFA group), 51 (28%) had occluded SFAs (oSFA group), and 27 (15%) had concomitant SFA angioplasty (aSFA group). The Society for Vascular Surgery and the International Society for Cardiovascular Surgery reporting standards were followed to define outcomes. There were no perioperative deaths. Total complication rate was 1.1% (2/183, groin hematomas). The mean follow-up was 20 months (range 1-115). One hundred twenty-five limbs (68%) had PTA alone for iliac lesions, and 58 (32%) had iliac stenting (a total of 91 stents). TASC iliac lesion types and the status of the ipsilateral profunda femoris artery were not significantly different among the four groups. Seventeen limbs (9%) had subsequent infrainguinal bypass: three in the pSFA, seven in the oSFA, four in the sSFA, and three in the aSFA groups (p = 0.19). The primary patency rate was significantly decreased in the sSFA group (29% at 3 years, Kaplan-Meier log-rank, p < 0.0001) compared with the other three groups; however, there were no significant differences among the pSFA, oSFA, and aSFA groups (67%, 67%, and 86% at 3 years, respectively; p = 0.92). The continued clinical improvement rates were significantly decreased in the sSFA group (36% at 3 years, p = 0.0043) compared with the other three groups; however, there was no significant difference between the pSFA, oSFA, and aSFA groups (81%, 84%, and 75% at 3 years, respectively; p = 0.088). The assisted primary and secondary patency and limb salvage rates were not significantly different among the four groups (p > 0.40). Stratified analysis in patients with TASC type B/type C, critical limb ischemia, or claudicants revealed similar results. The primary patency and continued clinical improvement were significantly decreased in patients with stenotic SFAs, suggesting that concomitant SFA angioplasty might improve iliac patency after iliac PTA for patients with stenotic SFAs. The presence of an occluded SFA did not adversely affect the outcomes of iliac PTA. During iliac PTA, a stenotic SFA should be considered for revascularization via endovascular means but an occluded SFA can be observed.

Science, 2011

Gylcolytic oscillations in yeast are a by-product of a trade-off between robustness and efficiency.

Journal of Vascular Surgery, 2005

Objective: To evaluate the pattern of clinical results in patients with neurogenic thoracic outle... more Objective: To evaluate the pattern of clinical results in patients with neurogenic thoracic outlet syndrome (N-TOS) after operative decompression and longitudinal follow-up. Methods: From May 1994 to December 2002, 254 operative sides in 185 patients with N-TOS were treated by the same operative protocol: (1) transaxillary first rib resection and the lower part of scalenectomy for the primary procedure with or without (2) the subsequent upper part of scalenectomy with supraclavicular approach for patients with persistent or recurrent symptoms. This retrospective cohort study included 38 men and 147 women with an age range of 19 to 80 years (mean, 40 years). Evaluated were primary success, defined as uninterrupted success with no procedure performed, and secondary success, defined as success maintained by the secondary operation after the primary failure. Success was defined as >50% symptomatic improvement judged by the patient using a 10-point scale, returning to preoperational work status, or both. Results: Follow-up was 2 to 76 months (mean, 25 months). Eighty sides underwent a secondary operation for the primary clinical failure. No technical failures and no deaths occurred <30 days after the operations. The complication rate was 4% (13/334) and consisted of 7 pneumothoraxes, 3 subclavian vein injuries, 1 nerve injury, 1 internal mammary artery injury, and 1 suture granuloma. Of 254 operative sides, the primary and secondary success was 46% (118/254) and 64% (163/254). Most the primary failures (90%, 122/136) and the secondary failures (66%, 23/35) occurred <18 months after the respective operation. Conclusions: The long-term results of operations for TOS in this study were much worse than those initially achieved, and most of the primary and secondary failures occurred <12 months of the respective operations. A minimum of 18-month follow-up on patients and standardized definition of the outcomes are necessary to determine the true effectiveness and outcome of operative treatment of N-TOS.

Journal of Vascular Surgery, 2006

This study is a review and evaluation of our 12-year experience of revascularization for critical... more This study is a review and evaluation of our 12-year experience of revascularization for critical limb ischemia (CLI) with angioplasty/stenting and bypass surgery to identify specific trends of procedure volume and outcomes in this particular group. Methods: Endovascular and open bypass procedures done for CLI by a single surgeon between 1993 and 2004 were evaluated retrospectively. Thrombolysis and thrombectomy procedures done as the only revascularization procedure were excluded from analysis. The data were divided into three groups by time periods: the first period, 1993 to 1996; the second period, 1997 to 2000; and the third period, 2001 to 2004. Outcomes were defined according to the reporting standards of the Society for Vascular Surgery/International Society for Cardiovascular Surgery. The study included 416 procedures done in 237 limbs in 192 patients. The mean follow-up was 23 months (range, 1 to 122 months). Results: Primary revascularization procedures for CLI were angioplasty in 153 limbs (65%) and bypass surgery in 84 (35%). Subsequent procedures were angioplasty in 102 limbs (57%) and open surgery (bypass and/or patch angioplasty) in 77 limbs (43%). The rates for technical and clinical success and complications in the entire group were 99%, 95%, and 4%, respectively. One patient died perioperatively (0.5%). Among the three periods, TransAtlantic Inter-Society Consensus lesion types were significantly more severe in patients in the first period (P < .05). Additionally, the complication rate was significantly higher and the mean hospital stay was significantly longer in the first period compared with the second and third periods (P < .05). Furthermore, between the first and third periods, the number of endovascular revascularization procedures done as primary and secondary procedures significantly increased from 15 to 84 (؉460%) and from 13 to 57 (؉340%), whereas the number of open surgical procedures done as primary and secondary procedures decreased from 39 to 20 (؊49%) and from 35 to 18 (؊49%), respectively (P < .0001). The assisted primary patency rates in the third period were significantly higher than those in the first and second periods (P ‫؍‬ .012); otherwise, the long-term outcomes among the three periods were not statistically different. Multivariate analysis revealed that, while controlling for other factors, the third period showed improvement in the primary patency (P ‫؍‬ .032) and assisted primary patency (P ‫؍‬ .051), and the bypass group showed improvement in the primary patency (P ‫؍‬ .008). Conclusions: In our experience, open surgical procedures for the treatment of CLI have been largely replaced by angioplasty procedures without compromising outcomes. Angioplasty is a feasible, safe, and effective procedure and can be the procedure of choice for the primary and secondary treatment of CLI. Open surgical procedures can be reserved for lesions technically unsuitable for endovascular procedures and patients who do not demonstrate clinical improvement after angioplasty.

Journal of Vascular Surgery, 2005

To review our 11-year experience of iliac angioplasty with selective stenting and to evaluate the... more To review our 11-year experience of iliac angioplasty with selective stenting and to evaluate the safety, shortand long-term patency, clinical success rates, and predictive risk factors in patients with iliac artery occlusive disease. Methods: From August 1993 to November 2004, 151 iliac lesions (149 stenoses, 2 occlusions) in 104 patients were treated by percutaneous transluminal angioplasty (PTA). The patients had chronic limb ischemia described as disabling claudication (the Society for Vascular Surgery clinical category 2 or 3) in 76 (50%), rest pain (category 4) in 38 (25%), and ulcer/gangrene (category 5) in 37 (25%). Forty-six limbs (30%) were treated with concomitant infrainguinal endovascular (36, 24%) or open procedures (10, 6%). Thirty-four limbs (23%) had one or more stents placed for primary PTA failure, including residual stenosis (>30%), mean pressure gradient (>5 mm Hg), or dissection (stent group); whereas, 117 limbs (77%) underwent PTA alone (PTA group). The affected arteries treated were 28 (19%) common iliac, 31 (20%) external iliac, and 92 (61%) both arteries. According to TransAtlantic Inter-Society Consensus (TASC) classification, 39 limbs (26%) were in type A, 71 (47%) in type B, 36 (24%) in type C, and 5 (3%) in type D. Reporting standards of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery were followed. Results: There was no perioperative death. Total complication rate was 0.7% (one groin hematoma). The mean follow-up was 21 months (median, 10; range, 1 to 94 months). Only 9 (8%) of 117 of the PTA group had subsequent stent placement for recurrent stenosis. The iliac lesions were more severe and extensive in the stent group than those in the PTA group according to TASC classification (Mann-Whitney U test [M-W], P < .0001) and anatomic location (M-W, P ‫؍‬ .0019). The technical success rate was 99%, and the initial clinical success rate was 99%. Overall, the cumulative primary patency rates at 1, 3, and 5 years were 76%, 59%, and 49% (Kaplan-Meier [K-M]). The cumulative assisted primary and secondary patency rates at 7 years were 98% and 99% (K-M). The mean number of subsequent iliac endovascular procedures was 1.4 per limb in patients with primary failure of iliac angioplasty/stenting. The continued clinical improvement rates at 1, 3, and 5 years were 81%, 67%, and 53% (K-M). The limb salvage rates at 7 year were 93% (K-M). Of 15 predictor variables studied in 151 iliac lesions, the significant independent predictors for adverse outcomes were smoking history (P ‫؍‬ .0074), TASC type C/type D lesions (P ‫؍‬ .0001), and stenotic ipsilateral superficial femoral artery (P ‫؍‬ .0002) for the primary patency rates; chronic renal failure with hemodialysis (P ‫؍‬ .014), ulcer/gangrene as an indication for PTA (P < .0001), and stenotic ipsilateral superficial femoral artery (P ‫؍‬ .034) for the continued clinical improvement (K-M, log-rank test and Cox regression model). Conclusions: Although the primary patency rates were not high, the assisted primary and secondary patency rates were excellent without primary stenting. Overall, >70% of iliac lesions were treated successfully with PTA alone. The results of this study show that selective stenting offers satisfactory assisted primary and secondary long-term patency after iliac angioplasty. Patients with TASC type C/type D iliac lesions, a stenotic ipsilateral superficial femoral artery, ulcer/ gangrene, smoking history, and chronic renal failure with hemodialysis should be followed carefully after endovascular iliac revascularization. These risk factors could be considered indications for primary stenting, although further studies are needed to confirm this.

Journal of Surgical Research, 2004

years) have undergone a total of 103 MVR operations. The etiology for valve disease was congenita... more years) have undergone a total of 103 MVR operations. The etiology for valve disease was congenital in 55% of patients, rheumatic in 35%, endocarditis in 8%, and myxomatous in 2%. Xenograft bioprosthesis (n ϭ 13) and mechanical valves (n ϭ 58) were used in 71 patients at initial MVR. Since 2002, four patients have undergone MVR using a pulmonary autograft (Ross MVR). Results. Hospital mortality was 9%. Mean follow-up was 7.8 years (range; 2 months to 30 years). Twenty-three patients required reoperations (34%) after the initial MVR. Actuarial freedom from reoperation at 30 years was 47%. There were 16 late deaths and four patients underwent heart transplantation. Overall 30-year survival was 69%. Mortality for children under 2 years versus over 2 years was 47% versus 26% (P ϭ 0.02), for atrioventricular septal defect versus other pathology mortality was 54% versus 26% (P ϭ 0.05), and for those operated before versus after 1980 it was 57% versus 20% (P ϭ 0.003). Conclusions. MVR is the only surgical option for nonrepairable mitral valve in children. Until recently we have favored mechanical MVR for children with failed reconstructive surgery. Our recent experience with the Ross MVR and aortic homograft MVR has allowed us to offer select patients the possibility of a more durable tissue valve without the need for long-term anticoagulation. The Ross MVR is particularly attractive in young female patients.

Journal of Surgical Research, 2004

Introduction. Homodynamic factors play crucial roles in vascular remodeling, healing, and disease... more Introduction. Homodynamic factors play crucial roles in vascular remodeling, healing, and disease formation. However, the underlying molecular mechanisms are largely unknown. The aim of this study was to test the hypothesis that cyclic strain could affect vascular cell differentiation or transdifferentiation. Methods. Human umbilical vein endothelial cells (HUVECs) were cultured on biaxial stretch silicon membranes at 8% stretch and 60 cycles/min for 2 days. The mRNA levels of two smooth muscle cell (SMC) markers (␣-actin and SM22-␣) as well as a house keeping gene (GAPDH) were quantitatively determined by real-time RT-PCR. The data present as the difference of reaction cycle thresholds (CT) between GAPDH and each of other genes (2 Ϫ⌬CT). Results. The mRNA levels of specific SMC ␣-actin and actin binding protein SM22-␣ were significantly increased by 5-and 2-fold, respectively, in cyclic strain treated HUVECs (0.255 Ϯ 0.05 and 0.282 Ϯ 0.004, respectively) as compared to those in untreated cells (0.042 Ϯ 0.02 and 0.089 Ϯ 0.023, respectively) (P Ͻ 0.05). Conclusion. These data demonstrate that cyclic strain significantly induces expression of two specific SMC markers in HUVECs. This study suggests that homodynamic factors may induce potential transdifferentiation from endothelial cells to smooth muscle cells. P50. Vascular Bone Morphogenetic Protein (BMP) Expression Decreases After Mouse Carotid Ligation.

Journal of Surgical Research, 2006

Clinical and Translational Science, 2021

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmerc... more This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior in... more Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior in genetic circuits as “hidden” interactions arise. However, ribosomes are also autocatalytic since they are partially made of proteins and autocatalysis can have detrimental effects on a system’s stability and/or robustness. Additionally, there are known feedback regulations on ribosome synthesis such as inhibition of rRNA synthesis via ppGpp. Here, we develop a minimal model of ribosome and protein synthesis, which includes autocatalysis and feedback, to investigate conditions under which these regulatory actions may have a significant effect in situations of increased ribosome demand.

Despite the complexity of biological networks, we find that certain common architectures govern n... more Despite the complexity of biological networks, we find that certain common architectures govern network structures. These architectures impose fundamental constraints on system performance and create tradeoffs that the system must balance in the face of uncertainty in the environment. This means that while a system may be optimized for a specific function through evolution, the optimal achievable state must follow these constraints. One such constraining architecture is autocatalysis, as seen in many biological networks including glycolysis and ribosomal protein synthesis. Using a minimal model, we show that ATP autocatalysis in glycolysis imposes stability and performance constraints and that the experimentally well-studied glycolytic oscillations are in fact a consequence of a tradeoff between error minimization and stability. We also show that additional complexity in the network results in increased robustness. Ribosome synthesis is also autocatalytic where ribosomes must be use...

The AAPS Journal, 2019

A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluat... more A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI). However, these metrics have some limitations. In particular, for biologics with long half-lives, tumor volume (TV) of treated xenografts displays a delay in volume reduction (and in some cases, complete regression) followed by a growth rebound. These observed data cannot be described by exponential functions, which is the underlying assumption of TGI and GRI, and the fit depends on how long the tumor volumes are monitored. On the other hand, T/C and TGI only utilizes information from one chosen time point. Here, we propose a new metric called Survival Prolongation Index (SPI), calculated as the time for drug-treated TV to reach a certain size (e.g., 600 mm 3) divided by the time for control TV to reach 600mm 3 and therefore not dependent on the chosen final time point t f. Simulations were conducted under different scenarios (i.e., exponential vs. saturable growth, linear vs. nonlinear kill function). For all cases, SPI is the most linear and growth-rate independent metric. Subsequently, a literature analysis was conducted using 11 drugs to evaluate the correlation between pre-clinically obtained SPI and clinical overall response. This retrospective analysis of approved drugs suggests that a predicted SPI of 2 is necessary for clinical response.

Annals of vascular surgery, Jan 20, 2016

The rise in office-based interventional vascular laboratories in recent years was prompted in par... more The rise in office-based interventional vascular laboratories in recent years was prompted in part by expedient ambulatory patient experience and favorable outpatient procedural reimbursement. While studies have shown that clinical safety and treatment efficacy can be achieved in office-based vascular facilities, critics have raised various concerns due to inconsistent patient care standards and lack of organizational oversight to ensure optimal patient outcome. Available literature showed widely varied clinical outcomes which were partly attributable to nonuniform standards in reporting clinical efficacy and adverse events. In this report, various concerns and pitfalls of office-based interventional vascular centers are discussed. Strategies to improve patient care delivery in office-based laboratories including accreditations which serve as external validation of processes to ensure patient care and safety are also mentioned. Finally, the requirements to obtain accreditation in an...

Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior of... more Resource competition, and primarily competition for ribosomes, can lead to unexpected behavior of genetic circuits and has recently gained renewed attention with both experimental and theoretical studies. Current models studying the effects of resource competition assume a constant production of ribosomes and these models describe the experimental results well. However, ribosomes are also autocatalytic since they are partially made of protein and autocatalysis has been shown to have detrimental effects on a system's stability and robustness. Additionally, there are known feedback regulations on ribosome synthesis such as inhibition of rRNA synthesis via ppGpp. Here, we develop two-state models of ribosome and protein synthesis incorporating autocatalysis and feedback to investigate conditions under which these regulatory actions have a significant effect in situations of increased ribosome demand. Our modeling results indicate that for sufficiently low demand, defined by the mRN...

2009 American Control Conference, 2009

Autocatalysis is necessary and ubiquitous in both engineered and biological systems but can aggra... more Autocatalysis is necessary and ubiquitous in both engineered and biological systems but can aggravate control performance and cause instability. We analyze the properties of autocatalysis in the universal and well studied glycolytic pathway. A simple two-state model incorporating ATP autocatalysis and inhibitory feedback control captures the essential dynamics, including limit cycle oscillations, observed experimentally. System performance is limited by the inherent autocatalytic stoichiometry and higher levels of autocatalysis exacerbate stability and performance. We show that glycolytic oscillations are not merely a "frozen accident" but a result of the intrinsic stability tradeoffs emerging from the autocatalytic mechanism. This model has pedagogical value as well as appearing to be the simplest and most complete illustration yet of Bode's integral formula. I. INTRODUCTION IN metabolic systems the destabilizing effects of "positive" autocatalytic feedback is often countered by negative feedback loops. Instability due to high autocatalysis is typically via a real pole (i.e. saddle-node bifurcation) whereas high inhibition can drive a system into a limit cycle (sustained oscillations via a Hopf bifurcation). This effect has also been studied in other biological systems such as mitogen-activated protein kinase cascades [1]. We wish to explore the hard limits of stability and performance that arise from such autocatalytic and regulatory mechanisms using a familiar and well-understood example. The glycolytic system is ideal to motivate such theoretical analysis for biological systems. Glycolysis is perhaps the most common control system on the planet as it is found in every one of the more than 10 30 cells, from bacteria to human. It has been widely studied and is one of biology's best understood systems. However, despite the extensive experimental and theoretical studies, many questions as to why oscillations occur in glycolysis remain. Similar to an engineered power plant whose machinery runs on its own energy product, the glycolysis reaction is autocatalytic. Glycolysis generates Adenosine triphosphate Manuscript received March 12, 2009.

49th IEEE Conference on Decision and Control (CDC), 2010

Autocatalytic networks, where a member can stimulate its own production, can be unstable when not... more Autocatalytic networks, where a member can stimulate its own production, can be unstable when not controlled by feedback. Even when such networks are stabilized by regulating control feedbacks, they tend to exhibit non-minimum phase behavior. In this paper, we study the hard limits of the ideal performance of such networks and the hard limit of their minimum output energy. We consider a simplified model of glycolysis as our motivating example. For the glycolysis model, we characterize hard limits on the minimum output energy by analyzing the limiting behavior of the optimal cheap control problem for two different interconnection topologies. We show that some network interconnection topologies result in zero hard limits. Then, we develop necessary tools and concepts to extend our results to a general class of autocatalytic networks.

European Journal of Control, 2011

This paper will review recent progress on developing a unified theory for complex networks from b... more This paper will review recent progress on developing a unified theory for complex networks from biological systems and physics to engineering and technology. Insights into what the potential universal laws, architecture, and organizational principles are can be drawn from three converging research themes: growing attention to complexity and robustness in systems biology, layering and organization in network technology, and new mathematical frameworks for the study of complex networks. We will illustrate how tools in robust control theory and optimization can be integrated towards such unified theory by focusing on their applications in biology, physics, network design, and electric grid.

Annals of Vascular Surgery, 2006

Our objective was to evaluate the impact of the ipsilateral superficial femoral artery (SFA) on p... more Our objective was to evaluate the impact of the ipsilateral superficial femoral artery (SFA) on percutaneous transluminal angioplasty (PTA) of the iliac arteries. From 1993 to 2005, 183 iliac lesions (179 stenoses, 4 occlusions; 37 common, 35 external, and 111 both iliac arteries) in 127 patients with disabling claudication [94 (52%)], rest pain [43 (23%)], and ulcer/gangrene [46 (25%)] were treated by PTA. TransAtlantic Inter-Society Consensus (TASC) iliac lesion types were A in 48 limbs (26%), B in 92 (50%), C in 38 (21%), and D in 5 (3%). Stents were placed selectively for primary angioplasty failure [residual stenosis (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;30%) or pressure gradient (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 mm Hg)]. Seventy-seven limbs (42%) had patent SFAs (66 intact/&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50% stenosis and 11 previously bypassed, pSFA group), 28 (15%) had stenotic SFAs (50-99%, sSFA group), 51 (28%) had occluded SFAs (oSFA group), and 27 (15%) had concomitant SFA angioplasty (aSFA group). The Society for Vascular Surgery and the International Society for Cardiovascular Surgery reporting standards were followed to define outcomes. There were no perioperative deaths. Total complication rate was 1.1% (2/183, groin hematomas). The mean follow-up was 20 months (range 1-115). One hundred twenty-five limbs (68%) had PTA alone for iliac lesions, and 58 (32%) had iliac stenting (a total of 91 stents). TASC iliac lesion types and the status of the ipsilateral profunda femoris artery were not significantly different among the four groups. Seventeen limbs (9%) had subsequent infrainguinal bypass: three in the pSFA, seven in the oSFA, four in the sSFA, and three in the aSFA groups (p = 0.19). The primary patency rate was significantly decreased in the sSFA group (29% at 3 years, Kaplan-Meier log-rank, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) compared with the other three groups; however, there were no significant differences among the pSFA, oSFA, and aSFA groups (67%, 67%, and 86% at 3 years, respectively; p = 0.92). The continued clinical improvement rates were significantly decreased in the sSFA group (36% at 3 years, p = 0.0043) compared with the other three groups; however, there was no significant difference between the pSFA, oSFA, and aSFA groups (81%, 84%, and 75% at 3 years, respectively; p = 0.088). The assisted primary and secondary patency and limb salvage rates were not significantly different among the four groups (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.40). Stratified analysis in patients with TASC type B/type C, critical limb ischemia, or claudicants revealed similar results. The primary patency and continued clinical improvement were significantly decreased in patients with stenotic SFAs, suggesting that concomitant SFA angioplasty might improve iliac patency after iliac PTA for patients with stenotic SFAs. The presence of an occluded SFA did not adversely affect the outcomes of iliac PTA. During iliac PTA, a stenotic SFA should be considered for revascularization via endovascular means but an occluded SFA can be observed.

Science, 2011

Gylcolytic oscillations in yeast are a by-product of a trade-off between robustness and efficiency.

Journal of Vascular Surgery, 2005

Objective: To evaluate the pattern of clinical results in patients with neurogenic thoracic outle... more Objective: To evaluate the pattern of clinical results in patients with neurogenic thoracic outlet syndrome (N-TOS) after operative decompression and longitudinal follow-up. Methods: From May 1994 to December 2002, 254 operative sides in 185 patients with N-TOS were treated by the same operative protocol: (1) transaxillary first rib resection and the lower part of scalenectomy for the primary procedure with or without (2) the subsequent upper part of scalenectomy with supraclavicular approach for patients with persistent or recurrent symptoms. This retrospective cohort study included 38 men and 147 women with an age range of 19 to 80 years (mean, 40 years). Evaluated were primary success, defined as uninterrupted success with no procedure performed, and secondary success, defined as success maintained by the secondary operation after the primary failure. Success was defined as >50% symptomatic improvement judged by the patient using a 10-point scale, returning to preoperational work status, or both. Results: Follow-up was 2 to 76 months (mean, 25 months). Eighty sides underwent a secondary operation for the primary clinical failure. No technical failures and no deaths occurred <30 days after the operations. The complication rate was 4% (13/334) and consisted of 7 pneumothoraxes, 3 subclavian vein injuries, 1 nerve injury, 1 internal mammary artery injury, and 1 suture granuloma. Of 254 operative sides, the primary and secondary success was 46% (118/254) and 64% (163/254). Most the primary failures (90%, 122/136) and the secondary failures (66%, 23/35) occurred <18 months after the respective operation. Conclusions: The long-term results of operations for TOS in this study were much worse than those initially achieved, and most of the primary and secondary failures occurred <12 months of the respective operations. A minimum of 18-month follow-up on patients and standardized definition of the outcomes are necessary to determine the true effectiveness and outcome of operative treatment of N-TOS.

Journal of Vascular Surgery, 2006

This study is a review and evaluation of our 12-year experience of revascularization for critical... more This study is a review and evaluation of our 12-year experience of revascularization for critical limb ischemia (CLI) with angioplasty/stenting and bypass surgery to identify specific trends of procedure volume and outcomes in this particular group. Methods: Endovascular and open bypass procedures done for CLI by a single surgeon between 1993 and 2004 were evaluated retrospectively. Thrombolysis and thrombectomy procedures done as the only revascularization procedure were excluded from analysis. The data were divided into three groups by time periods: the first period, 1993 to 1996; the second period, 1997 to 2000; and the third period, 2001 to 2004. Outcomes were defined according to the reporting standards of the Society for Vascular Surgery/International Society for Cardiovascular Surgery. The study included 416 procedures done in 237 limbs in 192 patients. The mean follow-up was 23 months (range, 1 to 122 months). Results: Primary revascularization procedures for CLI were angioplasty in 153 limbs (65%) and bypass surgery in 84 (35%). Subsequent procedures were angioplasty in 102 limbs (57%) and open surgery (bypass and/or patch angioplasty) in 77 limbs (43%). The rates for technical and clinical success and complications in the entire group were 99%, 95%, and 4%, respectively. One patient died perioperatively (0.5%). Among the three periods, TransAtlantic Inter-Society Consensus lesion types were significantly more severe in patients in the first period (P < .05). Additionally, the complication rate was significantly higher and the mean hospital stay was significantly longer in the first period compared with the second and third periods (P < .05). Furthermore, between the first and third periods, the number of endovascular revascularization procedures done as primary and secondary procedures significantly increased from 15 to 84 (؉460%) and from 13 to 57 (؉340%), whereas the number of open surgical procedures done as primary and secondary procedures decreased from 39 to 20 (؊49%) and from 35 to 18 (؊49%), respectively (P < .0001). The assisted primary patency rates in the third period were significantly higher than those in the first and second periods (P ‫؍‬ .012); otherwise, the long-term outcomes among the three periods were not statistically different. Multivariate analysis revealed that, while controlling for other factors, the third period showed improvement in the primary patency (P ‫؍‬ .032) and assisted primary patency (P ‫؍‬ .051), and the bypass group showed improvement in the primary patency (P ‫؍‬ .008). Conclusions: In our experience, open surgical procedures for the treatment of CLI have been largely replaced by angioplasty procedures without compromising outcomes. Angioplasty is a feasible, safe, and effective procedure and can be the procedure of choice for the primary and secondary treatment of CLI. Open surgical procedures can be reserved for lesions technically unsuitable for endovascular procedures and patients who do not demonstrate clinical improvement after angioplasty.

Journal of Vascular Surgery, 2005

To review our 11-year experience of iliac angioplasty with selective stenting and to evaluate the... more To review our 11-year experience of iliac angioplasty with selective stenting and to evaluate the safety, shortand long-term patency, clinical success rates, and predictive risk factors in patients with iliac artery occlusive disease. Methods: From August 1993 to November 2004, 151 iliac lesions (149 stenoses, 2 occlusions) in 104 patients were treated by percutaneous transluminal angioplasty (PTA). The patients had chronic limb ischemia described as disabling claudication (the Society for Vascular Surgery clinical category 2 or 3) in 76 (50%), rest pain (category 4) in 38 (25%), and ulcer/gangrene (category 5) in 37 (25%). Forty-six limbs (30%) were treated with concomitant infrainguinal endovascular (36, 24%) or open procedures (10, 6%). Thirty-four limbs (23%) had one or more stents placed for primary PTA failure, including residual stenosis (>30%), mean pressure gradient (>5 mm Hg), or dissection (stent group); whereas, 117 limbs (77%) underwent PTA alone (PTA group). The affected arteries treated were 28 (19%) common iliac, 31 (20%) external iliac, and 92 (61%) both arteries. According to TransAtlantic Inter-Society Consensus (TASC) classification, 39 limbs (26%) were in type A, 71 (47%) in type B, 36 (24%) in type C, and 5 (3%) in type D. Reporting standards of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery were followed. Results: There was no perioperative death. Total complication rate was 0.7% (one groin hematoma). The mean follow-up was 21 months (median, 10; range, 1 to 94 months). Only 9 (8%) of 117 of the PTA group had subsequent stent placement for recurrent stenosis. The iliac lesions were more severe and extensive in the stent group than those in the PTA group according to TASC classification (Mann-Whitney U test [M-W], P < .0001) and anatomic location (M-W, P ‫؍‬ .0019). The technical success rate was 99%, and the initial clinical success rate was 99%. Overall, the cumulative primary patency rates at 1, 3, and 5 years were 76%, 59%, and 49% (Kaplan-Meier [K-M]). The cumulative assisted primary and secondary patency rates at 7 years were 98% and 99% (K-M). The mean number of subsequent iliac endovascular procedures was 1.4 per limb in patients with primary failure of iliac angioplasty/stenting. The continued clinical improvement rates at 1, 3, and 5 years were 81%, 67%, and 53% (K-M). The limb salvage rates at 7 year were 93% (K-M). Of 15 predictor variables studied in 151 iliac lesions, the significant independent predictors for adverse outcomes were smoking history (P ‫؍‬ .0074), TASC type C/type D lesions (P ‫؍‬ .0001), and stenotic ipsilateral superficial femoral artery (P ‫؍‬ .0002) for the primary patency rates; chronic renal failure with hemodialysis (P ‫؍‬ .014), ulcer/gangrene as an indication for PTA (P < .0001), and stenotic ipsilateral superficial femoral artery (P ‫؍‬ .034) for the continued clinical improvement (K-M, log-rank test and Cox regression model). Conclusions: Although the primary patency rates were not high, the assisted primary and secondary patency rates were excellent without primary stenting. Overall, >70% of iliac lesions were treated successfully with PTA alone. The results of this study show that selective stenting offers satisfactory assisted primary and secondary long-term patency after iliac angioplasty. Patients with TASC type C/type D iliac lesions, a stenotic ipsilateral superficial femoral artery, ulcer/ gangrene, smoking history, and chronic renal failure with hemodialysis should be followed carefully after endovascular iliac revascularization. These risk factors could be considered indications for primary stenting, although further studies are needed to confirm this.

Journal of Surgical Research, 2004

years) have undergone a total of 103 MVR operations. The etiology for valve disease was congenita... more years) have undergone a total of 103 MVR operations. The etiology for valve disease was congenital in 55% of patients, rheumatic in 35%, endocarditis in 8%, and myxomatous in 2%. Xenograft bioprosthesis (n ϭ 13) and mechanical valves (n ϭ 58) were used in 71 patients at initial MVR. Since 2002, four patients have undergone MVR using a pulmonary autograft (Ross MVR). Results. Hospital mortality was 9%. Mean follow-up was 7.8 years (range; 2 months to 30 years). Twenty-three patients required reoperations (34%) after the initial MVR. Actuarial freedom from reoperation at 30 years was 47%. There were 16 late deaths and four patients underwent heart transplantation. Overall 30-year survival was 69%. Mortality for children under 2 years versus over 2 years was 47% versus 26% (P ϭ 0.02), for atrioventricular septal defect versus other pathology mortality was 54% versus 26% (P ϭ 0.05), and for those operated before versus after 1980 it was 57% versus 20% (P ϭ 0.003). Conclusions. MVR is the only surgical option for nonrepairable mitral valve in children. Until recently we have favored mechanical MVR for children with failed reconstructive surgery. Our recent experience with the Ross MVR and aortic homograft MVR has allowed us to offer select patients the possibility of a more durable tissue valve without the need for long-term anticoagulation. The Ross MVR is particularly attractive in young female patients.

Journal of Surgical Research, 2004

Introduction. Homodynamic factors play crucial roles in vascular remodeling, healing, and disease... more Introduction. Homodynamic factors play crucial roles in vascular remodeling, healing, and disease formation. However, the underlying molecular mechanisms are largely unknown. The aim of this study was to test the hypothesis that cyclic strain could affect vascular cell differentiation or transdifferentiation. Methods. Human umbilical vein endothelial cells (HUVECs) were cultured on biaxial stretch silicon membranes at 8% stretch and 60 cycles/min for 2 days. The mRNA levels of two smooth muscle cell (SMC) markers (␣-actin and SM22-␣) as well as a house keeping gene (GAPDH) were quantitatively determined by real-time RT-PCR. The data present as the difference of reaction cycle thresholds (CT) between GAPDH and each of other genes (2 Ϫ⌬CT). Results. The mRNA levels of specific SMC ␣-actin and actin binding protein SM22-␣ were significantly increased by 5-and 2-fold, respectively, in cyclic strain treated HUVECs (0.255 Ϯ 0.05 and 0.282 Ϯ 0.004, respectively) as compared to those in untreated cells (0.042 Ϯ 0.02 and 0.089 Ϯ 0.023, respectively) (P Ͻ 0.05). Conclusion. These data demonstrate that cyclic strain significantly induces expression of two specific SMC markers in HUVECs. This study suggests that homodynamic factors may induce potential transdifferentiation from endothelial cells to smooth muscle cells. P50. Vascular Bone Morphogenetic Protein (BMP) Expression Decreases After Mouse Carotid Ligation.

Journal of Surgical Research, 2006

Clinical and Translational Science, 2021

This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmerc... more This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.