Hassan Lemjabbar-Alaoui - Academia.edu (original) (raw)

Papers by Hassan Lemjabbar-Alaoui

BMJ Open, 2012

Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there ... more Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there is a need for biomarkers to improve diagnosis, prognosis and treatment. Sulfatases 2 (SULF2) is an extracellular endosulphatase that regulates several signalling pathways in carcinogenesis and has been associated with poor prognosis. This study evaluates the relationship between SULF2 expression by immunohistochemistry and overall survival in patients with oesophageal cancer.

PLoS ONE, 2006

Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% o... more Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. Methodology/Principal Findings. Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. Conclusions/ Significance. These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.

PLoS ONE, 2011

Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecula... more Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecular events responsible for this are poorly understood. We recently showed that signaling mechanisms triggered by smoke in lung cells could lead to the activation of a growth factor signaling pathway, thereby promoting hyperproliferation of lung epithelial cells. Hyperproliferation is considered a premalignant change in the lung, in that increased rates of DNA synthesis are associated with an increased number of DNA copying errors, events that are exacerbated in the presence of tobacco smoke carcinogens. Despite the existence of DNA repair mechanisms, a small percentage of these errors go unrepaired and can lead to tumorigenic mutations. The results of our previous study showed that an early event following smoke exposure was the generation of oxygen radicals through the activation of NADPH oxidase. Although it was clear that these radicals transduced signals through the epidermal growth factor receptor (EGFR), and that this was mediated by TACE-dependent cleavage of amphiregulin, it remained uncertain how oxygen radicals were able to activate TACE.

Expert Opinion on Therapeutic Targets, 2010

Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans ... more Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans (HSPGs) on the outside of cells and regulate a number of critical signaling pathways. The Sulfs are dysregulated in many cancers with Sulf-2 in particular implicated as a driver of carcinogenesis in NSCLC, pancreatic cancer and hepatocellular carcinoma. This review describes the novel activity of the Sulfs in altering the sulfation pattern of HSPG chains on the outside of cells. Thereby, the Sulfs can change the binding of growth factors to these chains and can either promote (e.g., Wnt) or inhibit (e.g., fibroblast growth factor-2) signaling. The review focuses on the widespread upregulation of both Sulfs in cancers and summarizes the evidence that Sulf-2 promotes the transformed behavior of several types of cancer cells in vitro as well as their tumorigenicity in vivo. Sulf-2 is a bonafide candidate as a cancer-causing agent in NSCLC and other cancers in which it is upregulated. Sulf-2 is an extracellular enzyme and as such would be an attractive therapeutic target for the treatment of NSCLC and other cancers.

PLOS ONE, 2016

Lung cancer is one of the most deadly cancers; median survival from diagnosis is less than one ye... more Lung cancer is one of the most deadly cancers; median survival from diagnosis is less than one year in those with advanced disease. Novel lung cancer biomarkers are desperately needed. In this study, we evaluated SULF2 expression by immunohistochemistry and its association with overall survival in a cohort of patients with non-small cell lung cancer (NSCLC). We also looked for the presence of SULF2 protein in plasma to evaluate its potential as an early detection biomarker for NSCLC. We identified patients who underwent surgical resection for pulmonary adenocarcinoma or squamous cell carcinoma at our institution. A section from each paraffin-embedded specimen was stained with a SULF2 antibody. A pathologist determined the percentage and intensity of tumor cell staining. Survival analysis was performed using a multivariate Cox proportional hazards model. Using a novel SULF2 ELISA assay, we analyzed plasma levels of SULF2 in a small cohort of healthy donors and patients with early stage NSCLC. SULF2 staining was present in 82% of the lung cancer samples. Squamous cell carcinomas had a higher mean percentage of staining than adenocarcinomas (100% vs. 60%; p<0.0005). After adjusting for age, sex, race, histologic type, stage, and neoadjuvant therapy, there was a non-significant (31%; p = 0.65) increase in the risk of death for patients with adenocarcinoma with SULF2 staining in tumor cells. In contrast, there was a significant decrease in the risk of death (89%; p = 0.02) for patients with squamous cell carcinoma with SULF2 staining in tumor cells. SULF2 protein was present in plasma of patients with early stage NSCLC, and soluble SULF2 levels increased with age. Finally, plasma SULF2 levels were significantly elevated in early stage NSCLC patients, compared to healthy controls. Tumor expression of SULF2 may affect prognosis in NSCLC, while blood SULF2 levels may have a significant role in the diagnosis of this fatal disease.

The Galois (or concept) lattice produced from a binary relation has been proved useful for many a... more The Galois (or concept) lattice produced from a binary relation has been proved useful for many applications. Building the Galois lattice can be considered as a conceptual clustering method since it results in a concept hierarchy. This article presents incremental algorithms for updating the Galois lattice and corresponding graph, resulting in an incremental concept formation method. Different strategies are considered based on a characterization of the modifications implied by such an update. Results of empirical tests are given in order to compare the performance of the incremental algorithms to three other batch algorithms. Surprisingly, when the total time for incremental generation is used, the simplest and less efficient variant of the incremental algorithms outperforms the batch algorithms in most cases. When only the incremental update time is used, the incremental algorithm outperforms all the batch algorithms. Empirical evidence shows that, on the average, the incremental update is done in time proportional to the number of instances previously treated. Although the worst case is exponential, when there is a fixed upper bound on the number of features related to an instance, which is usually the case in practical applications, the worst case analysis of the algorithm also shows linear growth with respect to the number of instances.

Biochimica et biophysica acta, Jan 19, 2015

Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldw... more Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldwide. About 90% of lung cancer cases are caused by smoking and the use of tobacco products. However, other factors such as radon gas, asbestos, air pollution exposures, and chronic infections can contribute to lung carcinogenesis. In addition, multiple inherited and acquired mechanisms of susceptibility to lung cancer have been proposed. Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, and targeted therapy. Therapeutic-modalities recommendations depend on several factors, including the type and stage of cancer. Despite the improvements in diagnosis and therapy made during the past 25years, the prognosis for patients with lung cancer is still unsatisfactory. The responses to current st...

BMJ Open, 2012

Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there ... more Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there is a need for biomarkers to improve diagnosis, prognosis and treatment. Sulfatases 2 (SULF2) is an extracellular endosulphatase that regulates several signalling pathways in carcinogenesis and has been associated with poor prognosis. This study evaluates the relationship between SULF2 expression by immunohistochemistry and overall survival in patients with oesophageal cancer.

Advances in Cancer Research, 2015

Alterations in glycosylation are common in cancer and are thought to contribute to disease. Lung ... more Alterations in glycosylation are common in cancer and are thought to contribute to disease. Lung cancer and primary malignant brain cancer, most commonly glioblastoma, are genetically heterogeneous diseases with extremely poor prognoses. In this review, we summarize the data demonstrating that glycosylation is altered in lung and brain cancer. We then use specific examples to highlight the diverse roles of glycosylation in these two deadly diseases and illustrate shared mechanisms of oncogenesis. In addition to alterations in glycoconjugate biosynthesis, we also discuss mechanisms of postsynthetic glycan modification in cancer. We suggest that alterations in glycosylation in lung and brain cancer provide novel tumor biomarkers and therapeutic targets.

[Proceedings] Third International Conference on Tools for Artificial Intelligence - TAI 91, 1991

... Robert Godin, Rokia Missaoui, Hassan Alaoui ... Mod@ed nodes (Mod): nodes for which X' is... more ... Robert Godin, Rokia Missaoui, Hassan Alaoui ... Mod@ed nodes (Mod): nodes for which X' is in G but the X set is changed in G* (#l, #3, #4). The X set of Mod nodes is always equal to Y U (x*) where (Y,Y') is in G and X' =Y'. The corresponding old node (Y,Y') has the property: Y' G ...

Clinica Chimica Acta, 2015

SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates mult... more SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates multiple signaling pathways. It is normally bound to the cell surface but can be released into the medium of cultured cells. SULF2 is known to be increased in cirrhotic liver compared to healthy liver. We asked whether SULF2 protein was present in the blood of healthy controls and increased in patients with liver cirrhosis. We devised a sandwich ELISA for SULF2 using 2 novel monoclonal antibodies (mAbs) and measured its levels in sera of normal individuals and cirrhosis patients. SULF2 was higher in cirrhosis patients (1460±1160pg/ml, N=34) than in healthy individuals (728±400pg/ml, N=37). SULF2 levels increased with age in both healthy and patient groups. SULF2 may be a useful serologic biomarker for liver cirrhosis.

PLoS ONE, 2006

Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% o... more Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. Methodology/Principal Findings. Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. Conclusions/ Significance. These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.

Methods in Enzymology, 2010

Sulf-1 and Sulf-2 are extracellular endoglucosamine 6-sulfatases, which selectively liberate the ... more Sulf-1 and Sulf-2 are extracellular endoglucosamine 6-sulfatases, which selectively liberate the 6-O-sulfate groups on glucosamines present in N, 6-O, and 2-O trisulfated disaccharides of intact heparan sulfate (HS)/heparin chains. The Sulfs are known to regulate signaling of heparin/HS-binding protein ligands, such as morphogens and growth factors, presumably through their ability to decrease the association between the ligands and HS proteoglycans. These enzymes serve important roles in development and are dysregulated in many cancers. We previously described arylsulfatase and endoglucosamine 6-sulfatase assays for the Sulfs. RB4CD12 is a phage display anti-HS antibody. N-sulfation, 2-O-sulfation, and 6-O-sulfation are involved in its binding. In this chapter, we describe the application of RB4CD12 in ELISA, flow cytometry, and immunohistochemistry assays to measure the enzymatic activity of the Sulfs. These newly established methods should facilitate further investigation of the Sulfs in vitro and in vivo.

PLoS ONE, 2011

Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecula... more Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecular events responsible for this are poorly understood. We recently showed that signaling mechanisms triggered by smoke in lung cells could lead to the activation of a growth factor signaling pathway, thereby promoting hyperproliferation of lung epithelial cells. Hyperproliferation is considered a premalignant change in the lung, in that increased rates of DNA synthesis are associated with an increased number of DNA copying errors, events that are exacerbated in the presence of tobacco smoke carcinogens. Despite the existence of DNA repair mechanisms, a small percentage of these errors go unrepaired and can lead to tumorigenic mutations. The results of our previous study showed that an early event following smoke exposure was the generation of oxygen radicals through the activation of NADPH oxidase. Although it was clear that these radicals transduced signals through the epidermal growth factor receptor (EGFR), and that this was mediated by TACE-dependent cleavage of amphiregulin, it remained uncertain how oxygen radicals were able to activate TACE.

Oncogene, 2010

Advances in the field of tumor biology have identified that tumor cells co-opt developmental sign... more Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/b-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors. Although a variety of functions are attributed to EMMPRIN in tumorigenesis, the specific mechanism(s) through which it can exert its effects have not been elucidated, until now. In this study, we identify EMMPRIN as a novel regulator of the canonical Wnt/ b-catenin signaling pathway in lung cancer. Increasing EMMPRIN expression levels in lung cancer epithelial cells upregulated the b-catenin signaling pathway and silencing EMMPRIN inhibited b-catenin signaling, cell migration, proliferation, anchorage-independent growth and tumor growth in a mouse tumor xenograft model. These results provide a compelling rationale for targeting EMMPRIN for anticancer therapies. Understanding the molecular mechanisms driving EMMPRIN-induced lung tumorigenesis will provide enormous benefits in developing new therapeutic treatments for this and other forms of cancer.

Computational Intelligence, 1995

The Galois (or concept) lattice produced from a binary relation has been proved useful for many a... more The Galois (or concept) lattice produced from a binary relation has been proved useful for many applications. Building the Galois lattice can be considered as a conceptual clustering method since it results in a concept hierarchy. This article presents incremental algorithms for updating the Galois lattice and corresponding graph, resulting in an incremental concept formation method. Different strategies are considered based on a characterization of the modifications implied by such an update. Results of empirical tests are given in order to compare the performance of the incremental algorithms to three other batch algorithms. Surprisingly, when the total time for incremental generation is used, the simplest and less efficient variant of the incremental algorithms outperforms the batch algorithms in most cases. When only the incremental update time is used, the incremental algorithm outperforms all the batch algorithms. Empirical evidence shows that, on the average, the incremental update is done in time proportional to the number of instances previously treated. Although the worst case is exponential, when there is a fixed upper bound on the number of features related to an instance, which is usually the case in practical applications, the worst case analysis of the algorithm also shows linear growth with respect to the number of instances.

Cellular Microbiology, 2013

The first step in attachment of Chlamydia to host cells is thought to involve reversible binding ... more The first step in attachment of Chlamydia to host cells is thought to involve reversible binding to host heparan sulfate proteoglycans (HSPGs), polymers of variably sulfated repeating disaccharide units coupled to diverse protein backbones. However, the key determinants of HSPG structure that are involved in Chlamydia binding are incompletely defined. A previous genome-wide Drosophila RNAi screen suggested that the level of HSPG 6-O sulfation rather than the identity of the proteoglycan backbone maybe a critical determinant for binding. Here, we tested in mammalian cells whether SULF1 or SULF2, human endosulfatases, which remove 6-O sulfates from HSPGs, modulate Chlamydia infection. Ectopic expression of SULF1 or SULF2 in HeLa cells, which decreases cell surface HSPG sulfation, diminished C. muridarum binding and decreased vacuole formation. ShRNA depletion of endogenous SULF2 in a cell line that primarily expresses SULF2 augmented binding and increased vacuole formation. C. muridarum infection of diverse cell lines resulted indownregulation of SULF2 mRNA. In a murine model of acute pneumonia, mice genetically deficient in both endosulfatases or in SULF2 alone demonstrated increased susceptibility to C. muridarum lung infection. Collectively, these studies demonstrate that the level of HSPG 6-O sulfation is a critical determinant of C. muridarum infection in vivo and that 6-O endosulfatases are previously unappreciated modulators of microbial pathogenesis.

Oncogene, 2010

Heparan sulfate proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate the... more Heparan sulfate proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS-chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HSchains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small cell lung cancers (NSCLC). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2 + NSCLC cell lines, including two which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling, and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

BMJ Open, 2012

Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there ... more Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there is a need for biomarkers to improve diagnosis, prognosis and treatment. Sulfatases 2 (SULF2) is an extracellular endosulphatase that regulates several signalling pathways in carcinogenesis and has been associated with poor prognosis. This study evaluates the relationship between SULF2 expression by immunohistochemistry and overall survival in patients with oesophageal cancer.

PLoS ONE, 2006

Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% o... more Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. Methodology/Principal Findings. Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. Conclusions/ Significance. These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.

PLoS ONE, 2011

Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecula... more Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecular events responsible for this are poorly understood. We recently showed that signaling mechanisms triggered by smoke in lung cells could lead to the activation of a growth factor signaling pathway, thereby promoting hyperproliferation of lung epithelial cells. Hyperproliferation is considered a premalignant change in the lung, in that increased rates of DNA synthesis are associated with an increased number of DNA copying errors, events that are exacerbated in the presence of tobacco smoke carcinogens. Despite the existence of DNA repair mechanisms, a small percentage of these errors go unrepaired and can lead to tumorigenic mutations. The results of our previous study showed that an early event following smoke exposure was the generation of oxygen radicals through the activation of NADPH oxidase. Although it was clear that these radicals transduced signals through the epidermal growth factor receptor (EGFR), and that this was mediated by TACE-dependent cleavage of amphiregulin, it remained uncertain how oxygen radicals were able to activate TACE.

Expert Opinion on Therapeutic Targets, 2010

Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans ... more Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans (HSPGs) on the outside of cells and regulate a number of critical signaling pathways. The Sulfs are dysregulated in many cancers with Sulf-2 in particular implicated as a driver of carcinogenesis in NSCLC, pancreatic cancer and hepatocellular carcinoma. This review describes the novel activity of the Sulfs in altering the sulfation pattern of HSPG chains on the outside of cells. Thereby, the Sulfs can change the binding of growth factors to these chains and can either promote (e.g., Wnt) or inhibit (e.g., fibroblast growth factor-2) signaling. The review focuses on the widespread upregulation of both Sulfs in cancers and summarizes the evidence that Sulf-2 promotes the transformed behavior of several types of cancer cells in vitro as well as their tumorigenicity in vivo. Sulf-2 is a bonafide candidate as a cancer-causing agent in NSCLC and other cancers in which it is upregulated. Sulf-2 is an extracellular enzyme and as such would be an attractive therapeutic target for the treatment of NSCLC and other cancers.

PLOS ONE, 2016

Lung cancer is one of the most deadly cancers; median survival from diagnosis is less than one ye... more Lung cancer is one of the most deadly cancers; median survival from diagnosis is less than one year in those with advanced disease. Novel lung cancer biomarkers are desperately needed. In this study, we evaluated SULF2 expression by immunohistochemistry and its association with overall survival in a cohort of patients with non-small cell lung cancer (NSCLC). We also looked for the presence of SULF2 protein in plasma to evaluate its potential as an early detection biomarker for NSCLC. We identified patients who underwent surgical resection for pulmonary adenocarcinoma or squamous cell carcinoma at our institution. A section from each paraffin-embedded specimen was stained with a SULF2 antibody. A pathologist determined the percentage and intensity of tumor cell staining. Survival analysis was performed using a multivariate Cox proportional hazards model. Using a novel SULF2 ELISA assay, we analyzed plasma levels of SULF2 in a small cohort of healthy donors and patients with early stage NSCLC. SULF2 staining was present in 82% of the lung cancer samples. Squamous cell carcinomas had a higher mean percentage of staining than adenocarcinomas (100% vs. 60%; p<0.0005). After adjusting for age, sex, race, histologic type, stage, and neoadjuvant therapy, there was a non-significant (31%; p = 0.65) increase in the risk of death for patients with adenocarcinoma with SULF2 staining in tumor cells. In contrast, there was a significant decrease in the risk of death (89%; p = 0.02) for patients with squamous cell carcinoma with SULF2 staining in tumor cells. SULF2 protein was present in plasma of patients with early stage NSCLC, and soluble SULF2 levels increased with age. Finally, plasma SULF2 levels were significantly elevated in early stage NSCLC patients, compared to healthy controls. Tumor expression of SULF2 may affect prognosis in NSCLC, while blood SULF2 levels may have a significant role in the diagnosis of this fatal disease.

The Galois (or concept) lattice produced from a binary relation has been proved useful for many a... more The Galois (or concept) lattice produced from a binary relation has been proved useful for many applications. Building the Galois lattice can be considered as a conceptual clustering method since it results in a concept hierarchy. This article presents incremental algorithms for updating the Galois lattice and corresponding graph, resulting in an incremental concept formation method. Different strategies are considered based on a characterization of the modifications implied by such an update. Results of empirical tests are given in order to compare the performance of the incremental algorithms to three other batch algorithms. Surprisingly, when the total time for incremental generation is used, the simplest and less efficient variant of the incremental algorithms outperforms the batch algorithms in most cases. When only the incremental update time is used, the incremental algorithm outperforms all the batch algorithms. Empirical evidence shows that, on the average, the incremental update is done in time proportional to the number of instances previously treated. Although the worst case is exponential, when there is a fixed upper bound on the number of features related to an instance, which is usually the case in practical applications, the worst case analysis of the algorithm also shows linear growth with respect to the number of instances.

Biochimica et biophysica acta, Jan 19, 2015

Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldw... more Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldwide. About 90% of lung cancer cases are caused by smoking and the use of tobacco products. However, other factors such as radon gas, asbestos, air pollution exposures, and chronic infections can contribute to lung carcinogenesis. In addition, multiple inherited and acquired mechanisms of susceptibility to lung cancer have been proposed. Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, and targeted therapy. Therapeutic-modalities recommendations depend on several factors, including the type and stage of cancer. Despite the improvements in diagnosis and therapy made during the past 25years, the prognosis for patients with lung cancer is still unsatisfactory. The responses to current st...

BMJ Open, 2012

Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there ... more Objectives: Oesophageal cancer is the eighth most commonly diagnosed cancer worldwide, and there is a need for biomarkers to improve diagnosis, prognosis and treatment. Sulfatases 2 (SULF2) is an extracellular endosulphatase that regulates several signalling pathways in carcinogenesis and has been associated with poor prognosis. This study evaluates the relationship between SULF2 expression by immunohistochemistry and overall survival in patients with oesophageal cancer.

Advances in Cancer Research, 2015

Alterations in glycosylation are common in cancer and are thought to contribute to disease. Lung ... more Alterations in glycosylation are common in cancer and are thought to contribute to disease. Lung cancer and primary malignant brain cancer, most commonly glioblastoma, are genetically heterogeneous diseases with extremely poor prognoses. In this review, we summarize the data demonstrating that glycosylation is altered in lung and brain cancer. We then use specific examples to highlight the diverse roles of glycosylation in these two deadly diseases and illustrate shared mechanisms of oncogenesis. In addition to alterations in glycoconjugate biosynthesis, we also discuss mechanisms of postsynthetic glycan modification in cancer. We suggest that alterations in glycosylation in lung and brain cancer provide novel tumor biomarkers and therapeutic targets.

[Proceedings] Third International Conference on Tools for Artificial Intelligence - TAI 91, 1991

... Robert Godin, Rokia Missaoui, Hassan Alaoui ... Mod@ed nodes (Mod): nodes for which X' is... more ... Robert Godin, Rokia Missaoui, Hassan Alaoui ... Mod@ed nodes (Mod): nodes for which X' is in G but the X set is changed in G* (#l, #3, #4). The X set of Mod nodes is always equal to Y U (x*) where (Y,Y') is in G and X' =Y'. The corresponding old node (Y,Y') has the property: Y' G ...

Clinica Chimica Acta, 2015

SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates mult... more SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates multiple signaling pathways. It is normally bound to the cell surface but can be released into the medium of cultured cells. SULF2 is known to be increased in cirrhotic liver compared to healthy liver. We asked whether SULF2 protein was present in the blood of healthy controls and increased in patients with liver cirrhosis. We devised a sandwich ELISA for SULF2 using 2 novel monoclonal antibodies (mAbs) and measured its levels in sera of normal individuals and cirrhosis patients. SULF2 was higher in cirrhosis patients (1460±1160pg/ml, N=34) than in healthy individuals (728±400pg/ml, N=37). SULF2 levels increased with age in both healthy and patient groups. SULF2 may be a useful serologic biomarker for liver cirrhosis.

PLoS ONE, 2006

Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% o... more Background. Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. Methodology/Principal Findings. Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. Conclusions/ Significance. These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.

Methods in Enzymology, 2010

Sulf-1 and Sulf-2 are extracellular endoglucosamine 6-sulfatases, which selectively liberate the ... more Sulf-1 and Sulf-2 are extracellular endoglucosamine 6-sulfatases, which selectively liberate the 6-O-sulfate groups on glucosamines present in N, 6-O, and 2-O trisulfated disaccharides of intact heparan sulfate (HS)/heparin chains. The Sulfs are known to regulate signaling of heparin/HS-binding protein ligands, such as morphogens and growth factors, presumably through their ability to decrease the association between the ligands and HS proteoglycans. These enzymes serve important roles in development and are dysregulated in many cancers. We previously described arylsulfatase and endoglucosamine 6-sulfatase assays for the Sulfs. RB4CD12 is a phage display anti-HS antibody. N-sulfation, 2-O-sulfation, and 6-O-sulfation are involved in its binding. In this chapter, we describe the application of RB4CD12 in ELISA, flow cytometry, and immunohistochemistry assays to measure the enzymatic activity of the Sulfs. These newly established methods should facilitate further investigation of the Sulfs in vitro and in vivo.

PLoS ONE, 2011

Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecula... more Background: Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecular events responsible for this are poorly understood. We recently showed that signaling mechanisms triggered by smoke in lung cells could lead to the activation of a growth factor signaling pathway, thereby promoting hyperproliferation of lung epithelial cells. Hyperproliferation is considered a premalignant change in the lung, in that increased rates of DNA synthesis are associated with an increased number of DNA copying errors, events that are exacerbated in the presence of tobacco smoke carcinogens. Despite the existence of DNA repair mechanisms, a small percentage of these errors go unrepaired and can lead to tumorigenic mutations. The results of our previous study showed that an early event following smoke exposure was the generation of oxygen radicals through the activation of NADPH oxidase. Although it was clear that these radicals transduced signals through the epidermal growth factor receptor (EGFR), and that this was mediated by TACE-dependent cleavage of amphiregulin, it remained uncertain how oxygen radicals were able to activate TACE.

Oncogene, 2010

Advances in the field of tumor biology have identified that tumor cells co-opt developmental sign... more Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/b-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors. Although a variety of functions are attributed to EMMPRIN in tumorigenesis, the specific mechanism(s) through which it can exert its effects have not been elucidated, until now. In this study, we identify EMMPRIN as a novel regulator of the canonical Wnt/ b-catenin signaling pathway in lung cancer. Increasing EMMPRIN expression levels in lung cancer epithelial cells upregulated the b-catenin signaling pathway and silencing EMMPRIN inhibited b-catenin signaling, cell migration, proliferation, anchorage-independent growth and tumor growth in a mouse tumor xenograft model. These results provide a compelling rationale for targeting EMMPRIN for anticancer therapies. Understanding the molecular mechanisms driving EMMPRIN-induced lung tumorigenesis will provide enormous benefits in developing new therapeutic treatments for this and other forms of cancer.

Computational Intelligence, 1995

The Galois (or concept) lattice produced from a binary relation has been proved useful for many a... more The Galois (or concept) lattice produced from a binary relation has been proved useful for many applications. Building the Galois lattice can be considered as a conceptual clustering method since it results in a concept hierarchy. This article presents incremental algorithms for updating the Galois lattice and corresponding graph, resulting in an incremental concept formation method. Different strategies are considered based on a characterization of the modifications implied by such an update. Results of empirical tests are given in order to compare the performance of the incremental algorithms to three other batch algorithms. Surprisingly, when the total time for incremental generation is used, the simplest and less efficient variant of the incremental algorithms outperforms the batch algorithms in most cases. When only the incremental update time is used, the incremental algorithm outperforms all the batch algorithms. Empirical evidence shows that, on the average, the incremental update is done in time proportional to the number of instances previously treated. Although the worst case is exponential, when there is a fixed upper bound on the number of features related to an instance, which is usually the case in practical applications, the worst case analysis of the algorithm also shows linear growth with respect to the number of instances.

Cellular Microbiology, 2013

The first step in attachment of Chlamydia to host cells is thought to involve reversible binding ... more The first step in attachment of Chlamydia to host cells is thought to involve reversible binding to host heparan sulfate proteoglycans (HSPGs), polymers of variably sulfated repeating disaccharide units coupled to diverse protein backbones. However, the key determinants of HSPG structure that are involved in Chlamydia binding are incompletely defined. A previous genome-wide Drosophila RNAi screen suggested that the level of HSPG 6-O sulfation rather than the identity of the proteoglycan backbone maybe a critical determinant for binding. Here, we tested in mammalian cells whether SULF1 or SULF2, human endosulfatases, which remove 6-O sulfates from HSPGs, modulate Chlamydia infection. Ectopic expression of SULF1 or SULF2 in HeLa cells, which decreases cell surface HSPG sulfation, diminished C. muridarum binding and decreased vacuole formation. ShRNA depletion of endogenous SULF2 in a cell line that primarily expresses SULF2 augmented binding and increased vacuole formation. C. muridarum infection of diverse cell lines resulted indownregulation of SULF2 mRNA. In a murine model of acute pneumonia, mice genetically deficient in both endosulfatases or in SULF2 alone demonstrated increased susceptibility to C. muridarum lung infection. Collectively, these studies demonstrate that the level of HSPG 6-O sulfation is a critical determinant of C. muridarum infection in vivo and that 6-O endosulfatases are previously unappreciated modulators of microbial pathogenesis.

Oncogene, 2010

Heparan sulfate proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate the... more Heparan sulfate proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS-chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HSchains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small cell lung cancers (NSCLC). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2 + NSCLC cell lines, including two which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling, and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.