Monica Beltran - Academia.edu (original) (raw)

Papers by Monica Beltran

American Journal of Obstetrics and Gynecology, 2011

OBJECTIVE: Preeclampsia is called hypertension(Ͼ140/90 mm Hg) with proteinuria in 24 hours upper ... more OBJECTIVE: Preeclampsia is called hypertension(Ͼ140/90 mm Hg) with proteinuria in 24 hours upper 300 mg after 20 weeks and before 6 weeks after delivery. The aim of this study is report results taking in 2010 to determine whether 8 and 12 hours proteinuria could be used instead of 24 hour proteinuria. STUDY DESIGN: Sixty two women with clinical hypertensive disorder of pregnancy were enrolled in 2008-2009 and were analyzed and reported the results in the last congress of MFM in Chicago. 31 patients more was collected from 2010 and enrolled to the original study. Total protein level was measured in aliquots of urine in the 8 and 12 and 24 hour samples. A new ROC curve was made with the total of the patients (92 women) to determine new results about cut-off point to diagnose preeclampsia in 8 and 12 hour proteinuria. RESULTS: The mean age of our patients was 29.7 (SD 6.7) years; the mean gestational age was 32.7 (SD 4.0). Proteinuria median value was 198.9 mg (IQR 100-400), 12-hours proteinuria median value was 68.5 (IQR 27.2-208.2) mg, and 8-hours proteinuria median one was 32. 9 (IQR 12. 8-110.8) mg. Better cut-off point in 12-hours sample was 114.4 mg, with sensitivity of 87.9%, specifity of 88.3%, and positive likelihood ratio 7.5; and for 8-hours sample cut-off was 60 mg with sensitivity of 84.9%, specifity of 86.7%, and LR of 6.36. 8-Hours proteinuria greater than or equal to 150 mg/dL, (100% specifity and sensitivity to diagnosis preeclampsia) if less than or equal to 11 mg/ dL(100% of specifity and sensitivity to rules out it diagnosis). 12-hour proteinuria greater than or equal to 230 mg/dL(100% specifity and sensitivity to diagnosis preeclampsia) if less than or equal to 22 mg/ dL(100% of specifity and sensitivity to rules out it diagnosis). CONCLUSIONS: Based on the results of our study, we suggested that 12 hour proteinuria can be used as a tool to perform early diagnosis of preeclampsia with a cut-off point of 114.4 mg and this value could replace the cut-off point of 300 mg for 24 proteinuria with a sensitivity of 87.9%, specifity of 88.3%, and positive likelihood ratio 7.5.

Cancer Letters, 2010

We have previously demonstrated that melatonin protects against ischemia/reperfusion (I/R)-induce... more We have previously demonstrated that melatonin protects against ischemia/reperfusion (I/R)-induced oxidative damage to mitochondria in the fetal rat brain. At the same time, Takagi et al (Virchows Archiv 2004) said that FGR associated with preeclampsia may be due to decompensation of placental function against oxidative stress. The purpose of the present study was to evaluate the effects of maternally-administered melatonin on I/R-induced oxidative placental damage and FGR in rats. The utero-ovarian arteries were occluded bilaterally for 30 min in rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (20μg/ml) or the vehicle alone was administered orally during pregnancy. A sham operation was performed in control rats which were treated with vehicle alone. Laparotomy was performed on day 20 of pregnancy and the number and weight of fetal rats and placentas were measured. Placental mitochondrial respiratory control index (RCI), a marker of mitochondrial respiratory activity, was also calculated for each group. Using immunohistochemistry, we investigated the degree of immunostaining of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and redox factor-1 (ref-1), which repairs DNA damage and acts as a redox-modifying factor in rat placenta. Predictably, the I/R operation significantly decreased the weight of fetal rats and placentas and the RCI. Melatonin prevented I/R-induced changes in RCI (1.55±0.05 to 1.83±0.09, P < 0.05) and fetal growth (3.04±0.17 to 3.90±0.1, P < 0.0001). Immunohistochemistry revealed significant positive staining for 8-OHdG and ref-1 following I/R; these effects were also reduced by melatonin treatment. Results indicated that I/R-induced oxidative placental DNA and mitochondrial damage and FGR can be prevented by maternally-administered melatonin.

Cancer Letters, 2010

infection with C. pneumoniae and CMV and immune response in normal and preeclampsia complicated p... more infection with C. pneumoniae and CMV and immune response in normal and preeclampsia complicated pregnancies. The first noteworthy finding of this work has shown that preeclampsia was associated with increased C. pneumonia genomic DNA loads compared with normal pregnancy controls and had higher anti-CMV IgG seropositivity than in women with normotensive interuterine growth restriction and normal pregnancy controls. Additionally, data synthesis revealed that IgG seropositivity of C. pneumonia and CMV was more prevalent among women with preeclampsia than normal pregnancy controls. The second finding of this work observed that early onset preeclampsia had increased Toll like receptor (TLR)-2 and -4 mRNA and protein expressions, elevated mRNA expressions of cryopyrin, NF-κB subunits and IL-1β, as well as increased TNF-α: IL-10 and IL-6: IL-10 ratios compared with normal pregnancy controls. Third, through a comprehensive review of published literatures and in combination of our study results, data suggested that TLR2 (Arg753Gln) and TLR4 co-segregating (Asp299Gly and Thr399Ile) gene polymorphisms seems in susceptibility to development of early onset preeclampsia. Our research findings indicated that TLR-microbial with C. pneumonia and CMV interactions play an important role in maternal inflammatory syndroms in preeclampsia. This work may contribute for identification of novel anti-inflammatory targets for preeclampsia treatment, eventually leading to improved health care for both mom and fetus.

Journal of Medicinal Chemistry, 2008

The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylamino... more The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such ureabased ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using shortterm cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.

Angewandte Chemie-international Edition, 2007

Journal of Medicinal Chemistry, 2009

The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations ... more The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumour regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus kinase resistance may be circumvented. A naphthalene dimiide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilises both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (ca 1μM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modelling studies with a telomeric quadruplex have been used to rationalise aspects of the experimental quadruplex melting data.

Analytical Biochemistry, 2008

The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is... more The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is to maintain the length of telomeric DNA by synthesizing telomeric DNA repeats, and its enzymatic activity is assayed by means of the telomere repeat amplification protocol (TRAP) assay. We show here that this assay is unable to reliably determine the ability of small molecules to inhibit the enzyme because they interfere with the PCR step of the assay, resulting in a major overestimation of their activity. We report a modified TRAP assay that incorporates the addition of an intermediate step, enabling ligand to be removed from the final PCR process using a commercially available oligonucleotide purification kit, so that more reliable estimates of telomerase inhibition can be made.

Journal of Medicinal Chemistry, 2008

The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylamino... more The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such ureabased ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using shortterm cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.

Angewandte Chemie-international Edition, 2007

Journal of Medicinal Chemistry, 2009

The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations ... more The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumour regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus kinase resistance may be circumvented. A naphthalene dimiide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilises both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (ca 1μM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modelling studies with a telomeric quadruplex have been used to rationalise aspects of the experimental quadruplex melting data.

Analytical Biochemistry, 2008

The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is... more The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is to maintain the length of telomeric DNA by synthesizing telomeric DNA repeats, and its enzymatic activity is assayed by means of the telomere repeat amplification protocol (TRAP) assay. We show here that this assay is unable to reliably determine the ability of small molecules to inhibit the enzyme because they interfere with the PCR step of the assay, resulting in a major overestimation of their activity. We report a modified TRAP assay that incorporates the addition of an intermediate step, enabling ligand to be removed from the final PCR process using a commercially available oligonucleotide purification kit, so that more reliable estimates of telomerase inhibition can be made.

American Journal of Obstetrics and Gynecology, 2011

OBJECTIVE: Preeclampsia is called hypertension(Ͼ140/90 mm Hg) with proteinuria in 24 hours upper ... more OBJECTIVE: Preeclampsia is called hypertension(Ͼ140/90 mm Hg) with proteinuria in 24 hours upper 300 mg after 20 weeks and before 6 weeks after delivery. The aim of this study is report results taking in 2010 to determine whether 8 and 12 hours proteinuria could be used instead of 24 hour proteinuria. STUDY DESIGN: Sixty two women with clinical hypertensive disorder of pregnancy were enrolled in 2008-2009 and were analyzed and reported the results in the last congress of MFM in Chicago. 31 patients more was collected from 2010 and enrolled to the original study. Total protein level was measured in aliquots of urine in the 8 and 12 and 24 hour samples. A new ROC curve was made with the total of the patients (92 women) to determine new results about cut-off point to diagnose preeclampsia in 8 and 12 hour proteinuria. RESULTS: The mean age of our patients was 29.7 (SD 6.7) years; the mean gestational age was 32.7 (SD 4.0). Proteinuria median value was 198.9 mg (IQR 100-400), 12-hours proteinuria median value was 68.5 (IQR 27.2-208.2) mg, and 8-hours proteinuria median one was 32. 9 (IQR 12. 8-110.8) mg. Better cut-off point in 12-hours sample was 114.4 mg, with sensitivity of 87.9%, specifity of 88.3%, and positive likelihood ratio 7.5; and for 8-hours sample cut-off was 60 mg with sensitivity of 84.9%, specifity of 86.7%, and LR of 6.36. 8-Hours proteinuria greater than or equal to 150 mg/dL, (100% specifity and sensitivity to diagnosis preeclampsia) if less than or equal to 11 mg/ dL(100% of specifity and sensitivity to rules out it diagnosis). 12-hour proteinuria greater than or equal to 230 mg/dL(100% specifity and sensitivity to diagnosis preeclampsia) if less than or equal to 22 mg/ dL(100% of specifity and sensitivity to rules out it diagnosis). CONCLUSIONS: Based on the results of our study, we suggested that 12 hour proteinuria can be used as a tool to perform early diagnosis of preeclampsia with a cut-off point of 114.4 mg and this value could replace the cut-off point of 300 mg for 24 proteinuria with a sensitivity of 87.9%, specifity of 88.3%, and positive likelihood ratio 7.5.

Cancer Letters, 2010

We have previously demonstrated that melatonin protects against ischemia/reperfusion (I/R)-induce... more We have previously demonstrated that melatonin protects against ischemia/reperfusion (I/R)-induced oxidative damage to mitochondria in the fetal rat brain. At the same time, Takagi et al (Virchows Archiv 2004) said that FGR associated with preeclampsia may be due to decompensation of placental function against oxidative stress. The purpose of the present study was to evaluate the effects of maternally-administered melatonin on I/R-induced oxidative placental damage and FGR in rats. The utero-ovarian arteries were occluded bilaterally for 30 min in rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (20μg/ml) or the vehicle alone was administered orally during pregnancy. A sham operation was performed in control rats which were treated with vehicle alone. Laparotomy was performed on day 20 of pregnancy and the number and weight of fetal rats and placentas were measured. Placental mitochondrial respiratory control index (RCI), a marker of mitochondrial respiratory activity, was also calculated for each group. Using immunohistochemistry, we investigated the degree of immunostaining of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and redox factor-1 (ref-1), which repairs DNA damage and acts as a redox-modifying factor in rat placenta. Predictably, the I/R operation significantly decreased the weight of fetal rats and placentas and the RCI. Melatonin prevented I/R-induced changes in RCI (1.55±0.05 to 1.83±0.09, P < 0.05) and fetal growth (3.04±0.17 to 3.90±0.1, P < 0.0001). Immunohistochemistry revealed significant positive staining for 8-OHdG and ref-1 following I/R; these effects were also reduced by melatonin treatment. Results indicated that I/R-induced oxidative placental DNA and mitochondrial damage and FGR can be prevented by maternally-administered melatonin.

Cancer Letters, 2010

infection with C. pneumoniae and CMV and immune response in normal and preeclampsia complicated p... more infection with C. pneumoniae and CMV and immune response in normal and preeclampsia complicated pregnancies. The first noteworthy finding of this work has shown that preeclampsia was associated with increased C. pneumonia genomic DNA loads compared with normal pregnancy controls and had higher anti-CMV IgG seropositivity than in women with normotensive interuterine growth restriction and normal pregnancy controls. Additionally, data synthesis revealed that IgG seropositivity of C. pneumonia and CMV was more prevalent among women with preeclampsia than normal pregnancy controls. The second finding of this work observed that early onset preeclampsia had increased Toll like receptor (TLR)-2 and -4 mRNA and protein expressions, elevated mRNA expressions of cryopyrin, NF-κB subunits and IL-1β, as well as increased TNF-α: IL-10 and IL-6: IL-10 ratios compared with normal pregnancy controls. Third, through a comprehensive review of published literatures and in combination of our study results, data suggested that TLR2 (Arg753Gln) and TLR4 co-segregating (Asp299Gly and Thr399Ile) gene polymorphisms seems in susceptibility to development of early onset preeclampsia. Our research findings indicated that TLR-microbial with C. pneumonia and CMV interactions play an important role in maternal inflammatory syndroms in preeclampsia. This work may contribute for identification of novel anti-inflammatory targets for preeclampsia treatment, eventually leading to improved health care for both mom and fetus.

Journal of Medicinal Chemistry, 2008

The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylamino... more The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such ureabased ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using shortterm cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.

Angewandte Chemie-international Edition, 2007

Journal of Medicinal Chemistry, 2009

The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations ... more The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumour regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus kinase resistance may be circumvented. A naphthalene dimiide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilises both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (ca 1μM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modelling studies with a telomeric quadruplex have been used to rationalise aspects of the experimental quadruplex melting data.

Analytical Biochemistry, 2008

The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is... more The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is to maintain the length of telomeric DNA by synthesizing telomeric DNA repeats, and its enzymatic activity is assayed by means of the telomere repeat amplification protocol (TRAP) assay. We show here that this assay is unable to reliably determine the ability of small molecules to inhibit the enzyme because they interfere with the PCR step of the assay, resulting in a major overestimation of their activity. We report a modified TRAP assay that incorporates the addition of an intermediate step, enabling ligand to be removed from the final PCR process using a commercially available oligonucleotide purification kit, so that more reliable estimates of telomerase inhibition can be made.

Journal of Medicinal Chemistry, 2008

The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylamino... more The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such ureabased ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using shortterm cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.

Angewandte Chemie-international Edition, 2007

Journal of Medicinal Chemistry, 2009

The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations ... more The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumour regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus kinase resistance may be circumvented. A naphthalene dimiide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilises both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (ca 1μM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modelling studies with a telomeric quadruplex have been used to rationalise aspects of the experimental quadruplex melting data.

Analytical Biochemistry, 2008

The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is... more The telomerase enzyme is implicated in a large proportion of human cancers. Its major function is to maintain the length of telomeric DNA by synthesizing telomeric DNA repeats, and its enzymatic activity is assayed by means of the telomere repeat amplification protocol (TRAP) assay. We show here that this assay is unable to reliably determine the ability of small molecules to inhibit the enzyme because they interfere with the PCR step of the assay, resulting in a major overestimation of their activity. We report a modified TRAP assay that incorporates the addition of an intermediate step, enabling ligand to be removed from the final PCR process using a commercially available oligonucleotide purification kit, so that more reliable estimates of telomerase inhibition can be made.