2733 Poster Board II-709 Introduction: APO866, a reversible inhibitor of nicotinamide phosphoribo... more 2733 Poster Board II-709 Introduction: APO866, a reversible inhibitor of nicotinamide phosphoribosyltransferase (Nampt), acts by severely depleting intracellular NAD+ content and thus eliciting mitochondrial dysfunction, ATP depletion, and autophagic cell death. TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and causes apoptosis through activation of caspase-8 and caspase-10. These, in turn, activate effector caspases either directly or via Bid cleavage and subsequent initiation of the mitochondrial apoptotic pathway. In the present work, we have explored the interaction between APO866 and TRAIL in cellular models of hematological malignancies. Materials and Methods: The lymphoma cell lines Jurkat, PEER, MOLT-4, H9, and Namalwa, primary B-cell chronic lymphocytic leukemia (B-CLL) cells, as well as normal peripheral blood mononuclear cells (PBMCs) were treated with increasing concentrations of APO866, TRAIL, or with 1:1, 1:3, or 1:10 comb...
4404 Cancer cells almost invariably exhibit aberrant histone deacetylase (HDAC) activity leading ... more 4404 Cancer cells almost invariably exhibit aberrant histone deacetylase (HDAC) activity leading to changes in chromatine structure, altered gene expression, poor differentiation, impaired apoptosis and increased proliferation. Accordingly, virtually all the HDAC inhibitors currently available show some degree of antitumor activity in preclinical cancer models and several of these compounds are currently under investigation or already approved for the treatment of human malignancies. Such is the case of the hydroxamic acid derivative suberoylanilide hydroxamic acid (Vorinostat, Zolinza), approved for the treatment of cutaneous T cell lymphomas. Sirtuins are a large family of deacetylases characterized by a unique, NAD+-dependent enzymatic mechanism. In addition to their established role in metabolism and longevity, recent evidence points to an emerging role for sirtuins in carcinogenesis. In the attempt to identify drug combinations that would increase the activity of traditional HD...
The aim of this paper was to assess the accuracy of frozen sections histological examination and ... more The aim of this paper was to assess the accuracy of frozen sections histological examination and preoperative CA-125 to select patients with high risk endometrial cancer. We reviewed women with type I endometrial cancer treated from January 2011 through January 2013 at the same university hospital. Preoperative CA-125 and intraoperative frozen sections were analyzed to select patients at high risk for metastases, according to Mayo Clinic algorithm. All patients underwent hysterectomy with bilateral adnexectomy. High risk patients underwent complete surgical staging. Respectively, we compared the accuracy of CA-125, frozen sections, and an algorithm combining Ca-125 plus frozen sections, with permanent sections histology as positive control. χ2 test, Landis and Koch kappa statistics (k), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were determined for each variable. One hundred seventy-two women were included. CA-125 levels, ...
Wiley interdisciplinary reviews. Systems biology and medicine, Jul 30, 2016
Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, su... more Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial lev...
Journal of B.U.ON. : official journal of the Balkan Union of Oncology, 2007
Proteasomal degradation is the main mechanism accounting for intracellular protein degradation. N... more Proteasomal degradation is the main mechanism accounting for intracellular protein degradation. Not only is the proteasome involved in physiological protein turnover, it is also called into play by processes such as signal transduction, cell cycle, and apoptosis. Despite the ubiquitous distribution of the proteasome and its putative essential function, proteasome inhibitors have been developed that can be safely administered with acceptable side effects. Importantly, these compounds have been found to possess antitumor activity and are presently incorporated into the treatment of multiple myeloma and mantle cell lymphoma. In 2003, bortezomib (velcade) was the first compound in this category to have received FDA approval. The mechanisms for the antitumor activity of bortezomib and related drugs remain elusive. NF- kappaB inhibition by proteasome inhibitors may play a role in some instances. Recently, terminally differentiated plasma cells have been shown to downregulate proteasome ex...
The aim of the present report is to support the feasibility and the safety of a new fertility-spa... more The aim of the present report is to support the feasibility and the safety of a new fertility-sparing treatment in young women affected by bulky cervical cancer. Between February 2007 and October 2010, seven patients presenting large IB-IIA1 tumors (30-45 mm) were scheduled for conservative treatment. All patients underwent neoadjuvant chemotherapy (NACT) followed by laparoscopic pelvic lymphadenectomy and vaginal radical trachelectomy (VRT). One patient presented hematological toxicity during NACT (grade 3). All patients showed complete disappearance of tumor (n=4/7) or partial response (a 50% or more decrease in total tumor size, n=3/7) to neoadjuvant treatment, and they were all treated with pelvic lymphadenectomy and VRT. Additional treatment (interstitial brachytherapy) was offered to only one woman because of a persistent parametrial tumoral lesion. After a mean follow up of 22 months (range 5-49), no relapse was observed. To date, only one woman in our study attempted to conceive and she is currently pregnant. Neoadjuvant chemotherapy for fertility sparing treatment is an innovative approach which is potentially quite interesting for many young women affected by bulky cervical cancer. These women, i.e. those with tumors larger than 2 cm (2-5 cm), are traditionally not offered fertility sparing treatment, thus the preliminary data we report here might have a promising impact. Nevertheless, for these patients it may be suitable to use the more radical, and time-tested, conservative surgical approach to allow for a complete and conservative excision of the residual tumor after neoadjuvant treatment. Studies with a larger number of patients and adequate follow-up are required to validate this conservative approach and to define clearly the good indications for this treatment.
Increased methylation of CpG islands and silencing of affected target genes is frequently found i... more Increased methylation of CpG islands and silencing of affected target genes is frequently found in human cancer; however, in vivo the question of causality has only been addressed by loss-of-function studies. To directly evaluate the role and mechanism of de novo methylation in tumor development, we overexpressed the de novo DNA methyltransferases Dnmt3a1 and Dnmt3b1 in ApcMin/+ mice. We found that Dnmt3b1 enhanced the number of colon tumors in ApcMin/+ mice approximately twofold and increased the average size of colonic microadenomas, whereas Dnmt3a1 had no effect. The overexpression of Dnmt3b1 caused loss of imprinting and increased expression of Igf2 as well as methylation and transcriptional silencing of the tumor suppressor genes Sfrp2, Sfrp4, and Sfrp5. Importantly, we found that Dnmt3b1 but not Dnmt3a1 efficiently methylates the same set of genes in tumors and in nontumor tissues, demonstrating that de novo methyltransferases can initiate methylation and silencing of specific...
2733 Poster Board II-709 Introduction: APO866, a reversible inhibitor of nicotinamide phosphoribo... more 2733 Poster Board II-709 Introduction: APO866, a reversible inhibitor of nicotinamide phosphoribosyltransferase (Nampt), acts by severely depleting intracellular NAD+ content and thus eliciting mitochondrial dysfunction, ATP depletion, and autophagic cell death. TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and causes apoptosis through activation of caspase-8 and caspase-10. These, in turn, activate effector caspases either directly or via Bid cleavage and subsequent initiation of the mitochondrial apoptotic pathway. In the present work, we have explored the interaction between APO866 and TRAIL in cellular models of hematological malignancies. Materials and Methods: The lymphoma cell lines Jurkat, PEER, MOLT-4, H9, and Namalwa, primary B-cell chronic lymphocytic leukemia (B-CLL) cells, as well as normal peripheral blood mononuclear cells (PBMCs) were treated with increasing concentrations of APO866, TRAIL, or with 1:1, 1:3, or 1:10 comb...
4404 Cancer cells almost invariably exhibit aberrant histone deacetylase (HDAC) activity leading ... more 4404 Cancer cells almost invariably exhibit aberrant histone deacetylase (HDAC) activity leading to changes in chromatine structure, altered gene expression, poor differentiation, impaired apoptosis and increased proliferation. Accordingly, virtually all the HDAC inhibitors currently available show some degree of antitumor activity in preclinical cancer models and several of these compounds are currently under investigation or already approved for the treatment of human malignancies. Such is the case of the hydroxamic acid derivative suberoylanilide hydroxamic acid (Vorinostat, Zolinza), approved for the treatment of cutaneous T cell lymphomas. Sirtuins are a large family of deacetylases characterized by a unique, NAD+-dependent enzymatic mechanism. In addition to their established role in metabolism and longevity, recent evidence points to an emerging role for sirtuins in carcinogenesis. In the attempt to identify drug combinations that would increase the activity of traditional HD...
The aim of this paper was to assess the accuracy of frozen sections histological examination and ... more The aim of this paper was to assess the accuracy of frozen sections histological examination and preoperative CA-125 to select patients with high risk endometrial cancer. We reviewed women with type I endometrial cancer treated from January 2011 through January 2013 at the same university hospital. Preoperative CA-125 and intraoperative frozen sections were analyzed to select patients at high risk for metastases, according to Mayo Clinic algorithm. All patients underwent hysterectomy with bilateral adnexectomy. High risk patients underwent complete surgical staging. Respectively, we compared the accuracy of CA-125, frozen sections, and an algorithm combining Ca-125 plus frozen sections, with permanent sections histology as positive control. χ2 test, Landis and Koch kappa statistics (k), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were determined for each variable. One hundred seventy-two women were included. CA-125 levels, ...
Wiley interdisciplinary reviews. Systems biology and medicine, Jul 30, 2016
Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, su... more Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial lev...
Journal of B.U.ON. : official journal of the Balkan Union of Oncology, 2007
Proteasomal degradation is the main mechanism accounting for intracellular protein degradation. N... more Proteasomal degradation is the main mechanism accounting for intracellular protein degradation. Not only is the proteasome involved in physiological protein turnover, it is also called into play by processes such as signal transduction, cell cycle, and apoptosis. Despite the ubiquitous distribution of the proteasome and its putative essential function, proteasome inhibitors have been developed that can be safely administered with acceptable side effects. Importantly, these compounds have been found to possess antitumor activity and are presently incorporated into the treatment of multiple myeloma and mantle cell lymphoma. In 2003, bortezomib (velcade) was the first compound in this category to have received FDA approval. The mechanisms for the antitumor activity of bortezomib and related drugs remain elusive. NF- kappaB inhibition by proteasome inhibitors may play a role in some instances. Recently, terminally differentiated plasma cells have been shown to downregulate proteasome ex...
The aim of the present report is to support the feasibility and the safety of a new fertility-spa... more The aim of the present report is to support the feasibility and the safety of a new fertility-sparing treatment in young women affected by bulky cervical cancer. Between February 2007 and October 2010, seven patients presenting large IB-IIA1 tumors (30-45 mm) were scheduled for conservative treatment. All patients underwent neoadjuvant chemotherapy (NACT) followed by laparoscopic pelvic lymphadenectomy and vaginal radical trachelectomy (VRT). One patient presented hematological toxicity during NACT (grade 3). All patients showed complete disappearance of tumor (n=4/7) or partial response (a 50% or more decrease in total tumor size, n=3/7) to neoadjuvant treatment, and they were all treated with pelvic lymphadenectomy and VRT. Additional treatment (interstitial brachytherapy) was offered to only one woman because of a persistent parametrial tumoral lesion. After a mean follow up of 22 months (range 5-49), no relapse was observed. To date, only one woman in our study attempted to conceive and she is currently pregnant. Neoadjuvant chemotherapy for fertility sparing treatment is an innovative approach which is potentially quite interesting for many young women affected by bulky cervical cancer. These women, i.e. those with tumors larger than 2 cm (2-5 cm), are traditionally not offered fertility sparing treatment, thus the preliminary data we report here might have a promising impact. Nevertheless, for these patients it may be suitable to use the more radical, and time-tested, conservative surgical approach to allow for a complete and conservative excision of the residual tumor after neoadjuvant treatment. Studies with a larger number of patients and adequate follow-up are required to validate this conservative approach and to define clearly the good indications for this treatment.
Increased methylation of CpG islands and silencing of affected target genes is frequently found i... more Increased methylation of CpG islands and silencing of affected target genes is frequently found in human cancer; however, in vivo the question of causality has only been addressed by loss-of-function studies. To directly evaluate the role and mechanism of de novo methylation in tumor development, we overexpressed the de novo DNA methyltransferases Dnmt3a1 and Dnmt3b1 in ApcMin/+ mice. We found that Dnmt3b1 enhanced the number of colon tumors in ApcMin/+ mice approximately twofold and increased the average size of colonic microadenomas, whereas Dnmt3a1 had no effect. The overexpression of Dnmt3b1 caused loss of imprinting and increased expression of Igf2 as well as methylation and transcriptional silencing of the tumor suppressor genes Sfrp2, Sfrp4, and Sfrp5. Importantly, we found that Dnmt3b1 but not Dnmt3a1 efficiently methylates the same set of genes in tumors and in nontumor tissues, demonstrating that de novo methyltransferases can initiate methylation and silencing of specific...
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Papers by Eva Moran