Alexander Nixon - Academia.edu (original) (raw)

Papers by Alexander Nixon

Research paper thumbnail of A Rare Case of Synchronous Cervical Lymph Node Metastasis from Renal and Thyroid Cancer

Hellenic Journal of Surgery

Research paper thumbnail of Anesthesia Management and Recovery after Laparoscopic Colorectal Surgery

Hellenic Journal of Surgery

Research paper thumbnail of Surgical Considerations in Subclinical Cushing’s Syndrome. When is it Time to Operate?

Hellenic Journal of Surgery

Research paper thumbnail of Surgery for pheochromocytoma: A 20-year experience of a single institution

Hormones (Athens, Greece), 2017

Resection of pheochromocytomas is a challenging procedure due to hemodynamic lability. Our aim wa... more Resection of pheochromocytomas is a challenging procedure due to hemodynamic lability. Our aim was to evaluate surgical outcomes in 67 patients with pheochromocytoma and to validate the role of laparoscopic surgery in the treatment of these tumors. This study is a retrospective review. A total of 68 procedures for pheochromocytoma were performed between June 1997 and February 2017. All patients were investigated and operated on using an established departmental protocol. Relevant data were retrieved from the hospital records of 533 patients who underwent 541 adrenalectomies for benign and malignant adrenal tumors in the same period. Sixty-nine tumors were removed from 67 patients. One patient with/MEN2A underwent bilateral resection of pheochromocytomas in two stages. Tumor size in laparoscopic procedures ranged from 1.2 cm to 11.0 cm (mean 5.87 cm). Thirty-seven patients had benign disease, 31 potentially malignant (based on PASS) and 1 malignant with metastasis. Eight were in the ...

Research paper thumbnail of Circulating thyroid cancer biomarkers: Current limitations and future prospects

Clinical Endocrinology

Differentiated thyroid cancer (DTC) is the most common malignancy of the endocrine system. There ... more Differentiated thyroid cancer (DTC) is the most common malignancy of the endocrine system. There has been a significant increase in its incidence over the past two decades attributable mainly to the use of more sensitive diagnostic modalities. Ultrasound-guided fine needle aspiration cytology is the mainstay of diagnosis of benign disorders and malignancy. However, approximately 20% of lesions cannot be adequately categorized as benign or malignant. In the postoperative setting, monitoring of thyroglobulin (Tg) levels has been employed for the detection of disease recurrence. Unfortunately, Tg antibodies are common and interfere with Tg measurement in this subset of patients. Despite this limitation, Tg remains the sole widely used thyroid cancer biomarker in the clinical setting. In an attempt to bypass antibody interference, research has focused mainly on mRNA targets thought to be exclusively expressed in thyroid cells. Tg and thyroid stimulating hormone receptor (TSHR) mRNA have been extensively studied both for discerning between benign disease and malignancy and in postoperative disease surveillance. However, results among reports have been inconsistent probably reflecting considerable differences in methodology. Recently, microRNA (miRNA) targets are being investigated as potential biomarkers in DTC. MiRNAs are more stable molecules and theoretically are not as vulnerable as mRNA during manipulation. Initial results have been encouraging but large-scale studies are warranted to verify and elucidate their potential application in diagnosis and postoperative surveillance of thyroid cancer. Several other novel targets, primarily mutations and circulating cells, are currently emerging as promising thyroid cancer circulating biomarkers. Although interesting and intriguing, data are limited and derive from small-scale studies in specific patient cohorts. Further research findings demonstrating their value are awaited with anticipation.

Research paper thumbnail of Laparoscopic right adrenalectomy for spontaneous hemorrhage in an adrenal incidentaloma, presenting as a case of acute surgical abdomen

Hellenic Journal of Surgery

Research paper thumbnail of Laparoscopic surgery for pancreatic insulinomas: an update

HORMONES, 2016

Insulinomas are the most common functioning neuroendocrine tumors of the pancreas, occurring in a... more Insulinomas are the most common functioning neuroendocrine tumors of the pancreas, occurring in almost 1-4 per 1 million persons each year. In contrast to other pancreatic neuroendocrine tumors, they are usually benign and solitary at the time of diagnosis. Due to their benign nature, surgical excision is the treatment of choice, with excellent long-term results. The introduction of minimally invasive techniques in the surgical treatment of insulinoma has been gaining popularity due to shorter length of hospital stay and better cosmetic results, with serious complications being comparable to those of open surgery. Preoperative localization is of paramount importance in the determination of the appropriate surgical approach. Many invasive and non-invasive methods exist for localization of an insulinoma. A combination of these modalities is usually adequate to preoperatively localize the vast majority of tumors. Laparoscopic ultrasound is mandatory to localize these tumors intraoperatively. Despite extensive experience in highly specialized centers producing encouraging results, no randomized trials have been realized to conclusively validate these case series, this partly due to the rarity of insulinoma in the population. In this article we present the current state of laparoscopic management of insulinoma delineating still unanswered issues and we underscore some of the technical details of the most common laparoscopic procedures employed.

Research paper thumbnail of Prevalence of thrombosis-related DNA polymorphisms in a healthy Greek population

In vivo (Athens, Greece)

Genetic association studies have revealed a correlation between DNA variations in genes encoding ... more Genetic association studies have revealed a correlation between DNA variations in genes encoding factors of the haemostatic system and thrombosis-related disease. This study investigated the prevalence of 13 such genetic risk factors in a sample (N=400 alleles) of the Hellenic population of Greece. Some of these polymorphisms [coagulation factor V (F5) Leiden, coagulation factor II (F2) G20210A, 5,10-methylene tetrahydrofolate reductase (MTHFR) C677T, coagulation factor XIII A1 subunit (F13A1) Val34Leu, serpine1 (SERPINE1) 4G/5G, angiotensin I-converting enzyme (ACE) I/D, angiotensinogen (AGT) Met325Thr, integrin A2 (ITGA2) C807T] have been previously studied in Hellenic populations of Greece and Cyprus, while others such as coagulation factor XII (F12) C46T, plasma carboxypeptidase B2 (CPB2) C1040T, platelet glycoprotein Ib α polypeptide (GP1BA) VNTR, thrombomodulin (THBD) -A33G and protein Z (PROZ) - A13G have not. Most of the allelic frequencies observed are similar to those repo...

Research paper thumbnail of The interplay between hemostasis and malignancy: the oral cancer paradigm

Anticancer research, 2012

Accumulating evidence has revealed the role of various components of the coagulatory system in di... more Accumulating evidence has revealed the role of various components of the coagulatory system in different stages of carcinogenesis including precancerous and initial stages, tumor growth, angiogenesis, stroma generation, and metastasis of malignant cells. This comprehensive review discusses major points of evidence, in addition to recent findings on specific factors associated with the paradigm of oral squamous cell carcinoma. During carcinogenesis, angiogenesis is favored by local conditions of hypoxia, cell-to-cell interactions, and by expression of paracrine growth factors and inflammatory cytokines. In the oral region specifically, genetic association studies have revealed that constitutively high gene expression of certain inflammatory cytokines plays a major role in carcinogenesis. Tissue factor (TF) has a physiological role in hemostasis, but it also constitutes a notable procoagulant in many types of cancer, since it appears to be constitutively expressed by tumor cells. Furt...

Research paper thumbnail of Primary intrahepatic malignant epithelioid mesothelioma

International Journal of Surgery Case Reports, 2014

INTRODUCTION: Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a... more INTRODUCTION: Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a patient with primary intrahepatic malignant mesothelioma who was treated in our department. PRESENTATION OF CASE: A 66-year old male patient was admitted to our department for the evaluation of anemia. An abdominal computed tomography scan revealed a large space occupying lesion in the right liver lobe. DISCUSSION: The tumor was subsequently resected and a diagnosis of primary intrahepatic malignant mesothelioma was made after pathologic examination. The patient did not receive adjuvant therapy and is currently alive and free of disease, 36 months after the resection. CONCLUSION: To our knowledge this is the eighth adult case of primary intrahepatic malignant mesothelioma reported in the literature. These tumors are rarely diagnosed preoperatively. Absence of previous asbestos exposure does not exclude malignant mesothelioma from the differential diagnosis. Proper surgical treatment may offer prolonged survival to the patient, without adjuvant therapy.

Research paper thumbnail of Cyclic Strain Delays the Expression of Tissue Factor Induced by Thrombin in Human Umbilical Vein Endothelial Cells

International Journal of Angiology, 2011

Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stati... more Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stationary culture conditions. The purpose of this study was to determine the influence of mechanical stimuli such as cyclic strain (CS) on the expression of TF in EC exposed to thrombin (Thr). Human umbilical vein endothelial cells (HUVEC) were exposed to 4 UÁmL À1 Thr in the presence or absence of 10% average CS at 60 cyclesÁmin À1 and then TF expression was measured. TF messenger RNA (mRNA) expression peaked at 2 hours in HUVEC exposed to Thr, but at 4 hours in HUVEC exposed to both Thr þ CS. TF expression was inhibited by p38 and extracellular signal-regulated protein kinase (ERK) inhibitors. For both Thr or Thr þ CS stimuli, p38 and ERK activity peaked at 5 minutes (p < 0.05). Nuclear factor-kappa B levels remained high in the Thr group but not in the Thr þ CS group, while Egr-1 levels were elevated in the Thr þ CS group. We demonstrated CS-delayed, Thr-induced TF mRNA expression in HUVEC, which may be modulated by p38 and ERK inhibitors.

Research paper thumbnail of Olive Oil Polyphenols Differentially Inhibit Smooth Muscle Cell Proliferation through a G1/S Cell Cycle Block Regulated by ERK1/2

International Journal of Angiology, 2012

The Mediterranean diet is associated with a reduced risk of coronary artery disease and it has be... more The Mediterranean diet is associated with a reduced risk of coronary artery disease and it has been postulated that the high olive oil consumption in Mediterranean countries may be responsible for this phenomenon. 1,2 This concept is analogous to the "French paradox," where the unexpected low coronary heart disease mortality in France, despite a diet rich in fat, is thought to be due, in part, to the beneficial effects of red wine polyphenols. 3 The major component of olive oil is the saponifiable or glyceride fraction. Minor components (present in $2% of oil weight) include >230 chemical compound rich in hydrocarbons, nonglyceride esters, tocopherols, flavonoids, sterols, and phenolic constituents. Considerable research has centered on these minor components with the premise that they induce important cardiovascular protective effects. 2 A variety of polyphenols have been shown to have several antiatherogenic activities, such as an increase in nitric oxide (NO), inhibition of low-density lipoprotein (LDL) oxidation, and suppression of platelet aggregation. 2 Since vascular smooth muscle cell (SMC) subintimal proliferation is the sine qua non of atherogenesis, the aim of this study was to characterize the action of olive oil polyphenols on SMC proliferation in vitro. Methods SMC Cultures Bovine SMC procured by the aortic explant method 4 were obtained from Dr. Joseph Madri (Dept. of Pathology, Yale University). SMC were positively identified by positive staining for α-SMC actin and failure to uptake acetylated LDL. Cells Keywords ► olive oil ► oleuropein ► hydroxytyrosol ► tyrosol ► smooth muscle cell proliferation ► ERK1/2

Research paper thumbnail of Efficacy and safety of laparoscopic mini gastric bypass. A systematic review

Surgery for Obesity and Related Diseases, 2014

Research paper thumbnail of Laminar shear, but not orbital shear, has a synergistic effect with thrombin stimulation on tissue factor expression in human umbilical vein endothelial cells

Journal of Vascular Surgery, 2011

High levels of tissue factor (TF) have been associated with atherosclerotic plaques. The specific... more High levels of tissue factor (TF) have been associated with atherosclerotic plaques. The specific pathways linked to TF expression in endothelial cells (ECs) have not been well defined. This study compared TF expression in human umbilical vein ECs (HUVECs) exposed to laminar shear stress (LSS) using a parallel flow chamber and to orbital shear stress (OSS) using an orbital shaker. We also compared the effects of thrombin (TH) stimulation of ECs exposed to different shear forces on the expression of TF and investigated the role that second messengers, p38 and extracellular signal-regulated kinase 1 and 2 (ERK1/2), had in the EC response. Methods: HUVECs were subjected to 2, 4, or 6 hours of LSS or OSS in the presence or absence of 4 U/mL of TH. Western blot analysis of ERK1/2 and p38 activation and polymerase chain reaction analysis of TF in the presence of inhibitors to these second messengers was performed in HUVECs subjected to OSS or LSS in the presence or absence of TH. Results: TF expression was increased and peaked at 2 hours in all HUVECs exposed to LSS or TH. Stimulation of static HUVECs with TH resulted in an increase in TF expression of 5.68 ؎ 1.58-, 3.80 ؎ 1.21-, and 2.54 ؎ 0.38-fold at 2, 4, and 6 hours, respectively (n ‫؍‬ 6 experiments). In the absence of TH, HUVECs exposed to LSS demonstrated a 9.51 ؎ 0.62-, 7.31 ؎ 1.43-, and 4.39 ؎ 1.32-fold increase in TF expression at 2, 4, and 6 hours, respectively (n ‫؍‬ 6 experiments). TF was increased significantly more when exposed to LSS in the presence of TH (18.85 ؎ 1.43-, 15.05 ؎ 0.95-, and 8.91 ؎ 1.06-fold increases at 2, 4, and 6 hours, respectively [n ‫؍‬ 6 experiments], P < .01). Between-group analysis showed a significant difference between groups (P < .001). OSS did not significantly increase TF expression in the presence or absence of TH. ERK1/2 and p38 activation was increased in LSS and LSS ؉ TH but not in OSS or OSS ؉ TH (n ‫؍‬ 3 experiments). Conclusion: LSS and TH independently increased TF expression, but OSS did not. LSS ؉ TH stimulation showed a synergistic effect, which suggests that these mechanical and chemical stimuli work through different pathways or that an intracellular interaction between TH and LSS may be present that does not occur in OSS. (J Vasc Surg 2011;54:480-8.) Clinical Relevance: Tissue factor (TF) has been shown to be overexpressed in advanced atherosclerotic lesions where disturbed flow patterns are prevalent. Mechanical stimuli such as shear stress and chemical stimuli such as TH are thought to influence the levels of TF expression and activity. Uncovering how these factors influence TF expression on an intracellular level can lead to a better understanding of atherogenesis and better direct the search for novel therapeutic targets. This study reveals the different effects that TH and distinct hemodynamic stimuli have on TF messenger RNA levels and attempts to elucidate the underlying intracellular signaling pathways leading to these effects.

Research paper thumbnail of Mechanical Stimulation of HUVEC: Different Flow Patterns have Differential Effects on TF Expression

Journal of Vascular Surgery, 2009

Research paper thumbnail of Mechanical stimulation of endothelial cells (ECs) delays the temporal expression of tissue factor (TF) induced by thrombin

Journal of the American College of Surgeons, 2009

Research paper thumbnail of Olive oil polyphenols inhibit smooth muscle cell (SMC) proliferation through cell cycle block regulated by ERK1/2

Journal of the American College of Surgeons, 2010

Research paper thumbnail of Disturbed flow induces greater magnitude of tissue factor (TF) RNA expression in HUVEC than laminar flow

Journal of the American College of Surgeons, 2010

Research paper thumbnail of Laminar Shear, but Not Oscillatory Shear, Has a Synergistic Effect with Thrombin Stimulation on Tissue Factor Expression in HUVEC

Journal of Surgical Research, 2010

Research paper thumbnail of Shear Stress Pre-Conditioning of HUVEC Alters Response to Chemical Stimulation

Journal of Surgical Research, 2010

Research paper thumbnail of A Rare Case of Synchronous Cervical Lymph Node Metastasis from Renal and Thyroid Cancer

Hellenic Journal of Surgery

Research paper thumbnail of Anesthesia Management and Recovery after Laparoscopic Colorectal Surgery

Hellenic Journal of Surgery

Research paper thumbnail of Surgical Considerations in Subclinical Cushing’s Syndrome. When is it Time to Operate?

Hellenic Journal of Surgery

Research paper thumbnail of Surgery for pheochromocytoma: A 20-year experience of a single institution

Hormones (Athens, Greece), 2017

Resection of pheochromocytomas is a challenging procedure due to hemodynamic lability. Our aim wa... more Resection of pheochromocytomas is a challenging procedure due to hemodynamic lability. Our aim was to evaluate surgical outcomes in 67 patients with pheochromocytoma and to validate the role of laparoscopic surgery in the treatment of these tumors. This study is a retrospective review. A total of 68 procedures for pheochromocytoma were performed between June 1997 and February 2017. All patients were investigated and operated on using an established departmental protocol. Relevant data were retrieved from the hospital records of 533 patients who underwent 541 adrenalectomies for benign and malignant adrenal tumors in the same period. Sixty-nine tumors were removed from 67 patients. One patient with/MEN2A underwent bilateral resection of pheochromocytomas in two stages. Tumor size in laparoscopic procedures ranged from 1.2 cm to 11.0 cm (mean 5.87 cm). Thirty-seven patients had benign disease, 31 potentially malignant (based on PASS) and 1 malignant with metastasis. Eight were in the ...

Research paper thumbnail of Circulating thyroid cancer biomarkers: Current limitations and future prospects

Clinical Endocrinology

Differentiated thyroid cancer (DTC) is the most common malignancy of the endocrine system. There ... more Differentiated thyroid cancer (DTC) is the most common malignancy of the endocrine system. There has been a significant increase in its incidence over the past two decades attributable mainly to the use of more sensitive diagnostic modalities. Ultrasound-guided fine needle aspiration cytology is the mainstay of diagnosis of benign disorders and malignancy. However, approximately 20% of lesions cannot be adequately categorized as benign or malignant. In the postoperative setting, monitoring of thyroglobulin (Tg) levels has been employed for the detection of disease recurrence. Unfortunately, Tg antibodies are common and interfere with Tg measurement in this subset of patients. Despite this limitation, Tg remains the sole widely used thyroid cancer biomarker in the clinical setting. In an attempt to bypass antibody interference, research has focused mainly on mRNA targets thought to be exclusively expressed in thyroid cells. Tg and thyroid stimulating hormone receptor (TSHR) mRNA have been extensively studied both for discerning between benign disease and malignancy and in postoperative disease surveillance. However, results among reports have been inconsistent probably reflecting considerable differences in methodology. Recently, microRNA (miRNA) targets are being investigated as potential biomarkers in DTC. MiRNAs are more stable molecules and theoretically are not as vulnerable as mRNA during manipulation. Initial results have been encouraging but large-scale studies are warranted to verify and elucidate their potential application in diagnosis and postoperative surveillance of thyroid cancer. Several other novel targets, primarily mutations and circulating cells, are currently emerging as promising thyroid cancer circulating biomarkers. Although interesting and intriguing, data are limited and derive from small-scale studies in specific patient cohorts. Further research findings demonstrating their value are awaited with anticipation.

Research paper thumbnail of Laparoscopic right adrenalectomy for spontaneous hemorrhage in an adrenal incidentaloma, presenting as a case of acute surgical abdomen

Hellenic Journal of Surgery

Research paper thumbnail of Laparoscopic surgery for pancreatic insulinomas: an update

HORMONES, 2016

Insulinomas are the most common functioning neuroendocrine tumors of the pancreas, occurring in a... more Insulinomas are the most common functioning neuroendocrine tumors of the pancreas, occurring in almost 1-4 per 1 million persons each year. In contrast to other pancreatic neuroendocrine tumors, they are usually benign and solitary at the time of diagnosis. Due to their benign nature, surgical excision is the treatment of choice, with excellent long-term results. The introduction of minimally invasive techniques in the surgical treatment of insulinoma has been gaining popularity due to shorter length of hospital stay and better cosmetic results, with serious complications being comparable to those of open surgery. Preoperative localization is of paramount importance in the determination of the appropriate surgical approach. Many invasive and non-invasive methods exist for localization of an insulinoma. A combination of these modalities is usually adequate to preoperatively localize the vast majority of tumors. Laparoscopic ultrasound is mandatory to localize these tumors intraoperatively. Despite extensive experience in highly specialized centers producing encouraging results, no randomized trials have been realized to conclusively validate these case series, this partly due to the rarity of insulinoma in the population. In this article we present the current state of laparoscopic management of insulinoma delineating still unanswered issues and we underscore some of the technical details of the most common laparoscopic procedures employed.

Research paper thumbnail of Prevalence of thrombosis-related DNA polymorphisms in a healthy Greek population

In vivo (Athens, Greece)

Genetic association studies have revealed a correlation between DNA variations in genes encoding ... more Genetic association studies have revealed a correlation between DNA variations in genes encoding factors of the haemostatic system and thrombosis-related disease. This study investigated the prevalence of 13 such genetic risk factors in a sample (N=400 alleles) of the Hellenic population of Greece. Some of these polymorphisms [coagulation factor V (F5) Leiden, coagulation factor II (F2) G20210A, 5,10-methylene tetrahydrofolate reductase (MTHFR) C677T, coagulation factor XIII A1 subunit (F13A1) Val34Leu, serpine1 (SERPINE1) 4G/5G, angiotensin I-converting enzyme (ACE) I/D, angiotensinogen (AGT) Met325Thr, integrin A2 (ITGA2) C807T] have been previously studied in Hellenic populations of Greece and Cyprus, while others such as coagulation factor XII (F12) C46T, plasma carboxypeptidase B2 (CPB2) C1040T, platelet glycoprotein Ib α polypeptide (GP1BA) VNTR, thrombomodulin (THBD) -A33G and protein Z (PROZ) - A13G have not. Most of the allelic frequencies observed are similar to those repo...

Research paper thumbnail of The interplay between hemostasis and malignancy: the oral cancer paradigm

Anticancer research, 2012

Accumulating evidence has revealed the role of various components of the coagulatory system in di... more Accumulating evidence has revealed the role of various components of the coagulatory system in different stages of carcinogenesis including precancerous and initial stages, tumor growth, angiogenesis, stroma generation, and metastasis of malignant cells. This comprehensive review discusses major points of evidence, in addition to recent findings on specific factors associated with the paradigm of oral squamous cell carcinoma. During carcinogenesis, angiogenesis is favored by local conditions of hypoxia, cell-to-cell interactions, and by expression of paracrine growth factors and inflammatory cytokines. In the oral region specifically, genetic association studies have revealed that constitutively high gene expression of certain inflammatory cytokines plays a major role in carcinogenesis. Tissue factor (TF) has a physiological role in hemostasis, but it also constitutes a notable procoagulant in many types of cancer, since it appears to be constitutively expressed by tumor cells. Furt...

Research paper thumbnail of Primary intrahepatic malignant epithelioid mesothelioma

International Journal of Surgery Case Reports, 2014

INTRODUCTION: Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a... more INTRODUCTION: Primary malignant hepatic mesotheliomas are extremely rare. We report the case of a patient with primary intrahepatic malignant mesothelioma who was treated in our department. PRESENTATION OF CASE: A 66-year old male patient was admitted to our department for the evaluation of anemia. An abdominal computed tomography scan revealed a large space occupying lesion in the right liver lobe. DISCUSSION: The tumor was subsequently resected and a diagnosis of primary intrahepatic malignant mesothelioma was made after pathologic examination. The patient did not receive adjuvant therapy and is currently alive and free of disease, 36 months after the resection. CONCLUSION: To our knowledge this is the eighth adult case of primary intrahepatic malignant mesothelioma reported in the literature. These tumors are rarely diagnosed preoperatively. Absence of previous asbestos exposure does not exclude malignant mesothelioma from the differential diagnosis. Proper surgical treatment may offer prolonged survival to the patient, without adjuvant therapy.

Research paper thumbnail of Cyclic Strain Delays the Expression of Tissue Factor Induced by Thrombin in Human Umbilical Vein Endothelial Cells

International Journal of Angiology, 2011

Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stati... more Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stationary culture conditions. The purpose of this study was to determine the influence of mechanical stimuli such as cyclic strain (CS) on the expression of TF in EC exposed to thrombin (Thr). Human umbilical vein endothelial cells (HUVEC) were exposed to 4 UÁmL À1 Thr in the presence or absence of 10% average CS at 60 cyclesÁmin À1 and then TF expression was measured. TF messenger RNA (mRNA) expression peaked at 2 hours in HUVEC exposed to Thr, but at 4 hours in HUVEC exposed to both Thr þ CS. TF expression was inhibited by p38 and extracellular signal-regulated protein kinase (ERK) inhibitors. For both Thr or Thr þ CS stimuli, p38 and ERK activity peaked at 5 minutes (p < 0.05). Nuclear factor-kappa B levels remained high in the Thr group but not in the Thr þ CS group, while Egr-1 levels were elevated in the Thr þ CS group. We demonstrated CS-delayed, Thr-induced TF mRNA expression in HUVEC, which may be modulated by p38 and ERK inhibitors.

Research paper thumbnail of Olive Oil Polyphenols Differentially Inhibit Smooth Muscle Cell Proliferation through a G1/S Cell Cycle Block Regulated by ERK1/2

International Journal of Angiology, 2012

The Mediterranean diet is associated with a reduced risk of coronary artery disease and it has be... more The Mediterranean diet is associated with a reduced risk of coronary artery disease and it has been postulated that the high olive oil consumption in Mediterranean countries may be responsible for this phenomenon. 1,2 This concept is analogous to the "French paradox," where the unexpected low coronary heart disease mortality in France, despite a diet rich in fat, is thought to be due, in part, to the beneficial effects of red wine polyphenols. 3 The major component of olive oil is the saponifiable or glyceride fraction. Minor components (present in $2% of oil weight) include >230 chemical compound rich in hydrocarbons, nonglyceride esters, tocopherols, flavonoids, sterols, and phenolic constituents. Considerable research has centered on these minor components with the premise that they induce important cardiovascular protective effects. 2 A variety of polyphenols have been shown to have several antiatherogenic activities, such as an increase in nitric oxide (NO), inhibition of low-density lipoprotein (LDL) oxidation, and suppression of platelet aggregation. 2 Since vascular smooth muscle cell (SMC) subintimal proliferation is the sine qua non of atherogenesis, the aim of this study was to characterize the action of olive oil polyphenols on SMC proliferation in vitro. Methods SMC Cultures Bovine SMC procured by the aortic explant method 4 were obtained from Dr. Joseph Madri (Dept. of Pathology, Yale University). SMC were positively identified by positive staining for α-SMC actin and failure to uptake acetylated LDL. Cells Keywords ► olive oil ► oleuropein ► hydroxytyrosol ► tyrosol ► smooth muscle cell proliferation ► ERK1/2

Research paper thumbnail of Efficacy and safety of laparoscopic mini gastric bypass. A systematic review

Surgery for Obesity and Related Diseases, 2014

Research paper thumbnail of Laminar shear, but not orbital shear, has a synergistic effect with thrombin stimulation on tissue factor expression in human umbilical vein endothelial cells

Journal of Vascular Surgery, 2011

High levels of tissue factor (TF) have been associated with atherosclerotic plaques. The specific... more High levels of tissue factor (TF) have been associated with atherosclerotic plaques. The specific pathways linked to TF expression in endothelial cells (ECs) have not been well defined. This study compared TF expression in human umbilical vein ECs (HUVECs) exposed to laminar shear stress (LSS) using a parallel flow chamber and to orbital shear stress (OSS) using an orbital shaker. We also compared the effects of thrombin (TH) stimulation of ECs exposed to different shear forces on the expression of TF and investigated the role that second messengers, p38 and extracellular signal-regulated kinase 1 and 2 (ERK1/2), had in the EC response. Methods: HUVECs were subjected to 2, 4, or 6 hours of LSS or OSS in the presence or absence of 4 U/mL of TH. Western blot analysis of ERK1/2 and p38 activation and polymerase chain reaction analysis of TF in the presence of inhibitors to these second messengers was performed in HUVECs subjected to OSS or LSS in the presence or absence of TH. Results: TF expression was increased and peaked at 2 hours in all HUVECs exposed to LSS or TH. Stimulation of static HUVECs with TH resulted in an increase in TF expression of 5.68 ؎ 1.58-, 3.80 ؎ 1.21-, and 2.54 ؎ 0.38-fold at 2, 4, and 6 hours, respectively (n ‫؍‬ 6 experiments). In the absence of TH, HUVECs exposed to LSS demonstrated a 9.51 ؎ 0.62-, 7.31 ؎ 1.43-, and 4.39 ؎ 1.32-fold increase in TF expression at 2, 4, and 6 hours, respectively (n ‫؍‬ 6 experiments). TF was increased significantly more when exposed to LSS in the presence of TH (18.85 ؎ 1.43-, 15.05 ؎ 0.95-, and 8.91 ؎ 1.06-fold increases at 2, 4, and 6 hours, respectively [n ‫؍‬ 6 experiments], P < .01). Between-group analysis showed a significant difference between groups (P < .001). OSS did not significantly increase TF expression in the presence or absence of TH. ERK1/2 and p38 activation was increased in LSS and LSS ؉ TH but not in OSS or OSS ؉ TH (n ‫؍‬ 3 experiments). Conclusion: LSS and TH independently increased TF expression, but OSS did not. LSS ؉ TH stimulation showed a synergistic effect, which suggests that these mechanical and chemical stimuli work through different pathways or that an intracellular interaction between TH and LSS may be present that does not occur in OSS. (J Vasc Surg 2011;54:480-8.) Clinical Relevance: Tissue factor (TF) has been shown to be overexpressed in advanced atherosclerotic lesions where disturbed flow patterns are prevalent. Mechanical stimuli such as shear stress and chemical stimuli such as TH are thought to influence the levels of TF expression and activity. Uncovering how these factors influence TF expression on an intracellular level can lead to a better understanding of atherogenesis and better direct the search for novel therapeutic targets. This study reveals the different effects that TH and distinct hemodynamic stimuli have on TF messenger RNA levels and attempts to elucidate the underlying intracellular signaling pathways leading to these effects.

Research paper thumbnail of Mechanical Stimulation of HUVEC: Different Flow Patterns have Differential Effects on TF Expression

Journal of Vascular Surgery, 2009

Research paper thumbnail of Mechanical stimulation of endothelial cells (ECs) delays the temporal expression of tissue factor (TF) induced by thrombin

Journal of the American College of Surgeons, 2009

Research paper thumbnail of Olive oil polyphenols inhibit smooth muscle cell (SMC) proliferation through cell cycle block regulated by ERK1/2

Journal of the American College of Surgeons, 2010

Research paper thumbnail of Disturbed flow induces greater magnitude of tissue factor (TF) RNA expression in HUVEC than laminar flow

Journal of the American College of Surgeons, 2010

Research paper thumbnail of Laminar Shear, but Not Oscillatory Shear, Has a Synergistic Effect with Thrombin Stimulation on Tissue Factor Expression in HUVEC

Journal of Surgical Research, 2010

Research paper thumbnail of Shear Stress Pre-Conditioning of HUVEC Alters Response to Chemical Stimulation

Journal of Surgical Research, 2010