Publications by authors named "Gregory Reid"

28 Publications

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A dynamic microscale mid-throughput fibrosis model to investigate the effects of different ratios of cardiomyocytes and fibroblasts.

Lab Chip 2021 Sep 21. Epub 2021 Sep 21.

Departments of Biomedicine and Surgery, University Basel and University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.

Cardiac fibrosis is a maladaptive remodeling of the myocardium hallmarked by contraction impairment and excessive extracellular matrix deposition (ECM). The disease progression, nevertheless, remains poorly understood and present treatments are not capable of controlling the scarring process. This is partly due to the absence of physiologically relevant, easily operable, and low-cost models, which are of the utmost importance to uncover pathological mechanisms and highlight possible targets for anti-fibrotic therapies. In classic models, fibrotic features are usually obtained using substrates with scar mimicking stiffness and/or supplementation of morphogens such as transforming growth factor β1 (TGF-β1). Qualities such as the interplay between activated fibroblasts (FBs) and cardiomyocytes (CMs), or the mechanically active, three-dimensional (3D) environment, are, however, neglected or obtained at the expense of the number of experimental replicates achievable. To overcome these shortcomings, we engineered a micro-physiological system (MPS) where multiple 3D cardiac micro-tissues can be subjected to cyclical stretching simultaneously. Up to six different biologically independent samples are incorporated in a single device, increasing the experimental throughput and paving the way for higher yielding drug screening campaigns. The newly developed MPS was used to co-culture different ratios of neonatal rat CMs and FBs, investigating the role of CMs in the modulation of fibrosis traits, without the addition of morphogens, and in soft substrates. The expression of contractile stress fibers and of degradative enzymes, as well as the deposition of fibronectin and type I collagen were superior in microtissues with a low amount of CMs. Moreover, high CM-based microconstructs simulating a ratio similar to that of healthy tissues, even if subjected to both cyclic stretch and TGF-β1, did not show any of the investigated fibrotic signs, indicating a CM fibrosis modulating effect. Overall, this fibrosis model could help to uncover new pathological aspects studying, with mid-throughput and in a mechanically active, physiologically relevant environment, the crosstalk between the most abundant cell types involved in fibrosis.
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http://dx.doi.org/10.1039/d1lc00092fDOI Listing
September 2021

Long-Term Severe In Vitro Hypoxia Exposure Enhances the Vascularization Potential of Human Adipose Tissue-Derived Stromal Vascular Fraction Cell Engineered Tissues.

Int J Mol Sci 2021 Jul 24;22(15). Epub 2021 Jul 24.

Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland.

The therapeutic potential of mesenchymal stromal/stem cells (MSC) for treating cardiac ischemia strongly depends on their paracrine-mediated effects and their engraftment capacity in a hostile environment such as the infarcted myocardium. Adipose tissue-derived stromal vascular fraction (SVF) cells are a mixed population composed mainly of MSC and vascular cells, well known for their high angiogenic potential. A previous study showed that the angiogenic potential of SVF cells was further increased following their in vitro organization in an engineered tissue (patch) after perfusion-based bioreactor culture. This study aimed to investigate the possible changes in the cellular SVF composition, in vivo angiogenic potential, as well as engraftment capability upon in vitro culture in harsh hypoxia conditions. This mimics the possible delayed vascularization of the patch upon implantation in a low perfused myocardium. To this purpose, human SVF cells were seeded on a collagen sponge, cultured for 5 days in a perfusion-based bioreactor under normoxia or hypoxia (21% and <1% of oxygen tension, respectively) and subcutaneously implanted in nude rats for 3 and 28 days. Compared to ambient condition culture, hypoxic tension did not alter the SVF composition in vitro, showing similar numbers of MSC as well as endothelial and mural cells. Nevertheless, in vitro hypoxic culture significantly increased the release of vascular endothelial growth factor ( < 0.001) and the number of proliferating cells ( < 0.00001). Moreover, compared to ambient oxygen culture, exposure to hypoxia significantly enhanced the vessel length density in the engineered tissues following 28 days of implantation. The number of human cells and human proliferating cells in hypoxia-cultured constructs was also significantly increased after 3 and 28 days in vivo, compared to normoxia. These findings show that a possible in vivo delay in oxygen supply might not impair the vascularization potential of SVF- patches, which qualifies them for evaluation in a myocardial ischemia model.
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http://dx.doi.org/10.3390/ijms22157920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348696PMC
July 2021

Outcome of right ventricular assist device implantation following left ventricular assist device implantation: Systematic review and meta-analysis.

Perfusion 2021 Jun 11:2676591211024817. Epub 2021 Jun 11.

Department of Cardiac Surgery, University Hospital Basel, Basel, Switzerland.

Objectives: The main aim was a systematic evaluation of the current evidence on outcomes for patients undergoing right ventricular assist device (RVAD) implantation following left ventricular assist device (LVAD) implantation.

Methods: This systematic review was registered on PROSPERO (CRD42019130131). Reports evaluating in-hospital as well as follow-up outcome in LVAD and LVAD/RVAD implantation were identified through Ovid Medline, Web of Science and EMBASE. The primary endpoint was mortality at the hospital stay and at follow-up. Pooled incidence of defined endpoints was calculated by using random effects models.

Results: A total of 35 retrospective studies that included 3260 patients were analyzed. 30 days mortality was in favour of isolated LVAD implantation 6.74% (1.98-11.5%) versus 31.9% (19.78-44.02%) p = 0.001 in LVAD with temporary need for RVAD. During the hospital stay the incidence of major bleeding was 18.7% (18.2-19.4%) versus 40.0% (36.3-48.8%) and stroke rate was 5.6% (5.4-5.8%) versus 20.9% (16.8-28.3%) and was in favour of isolated LVAD implantation. Mortality reported at short-term as well at long-term was 19.66% (CI 15.73-23.59%) and 33.90% (CI 8.84-59.96%) in LVAD respectively versus 45.35% (CI 35.31-55.4%) p ⩽ 0.001 and 48.23% (CI 16.01-80.45%) p = 0.686 in LVAD/RVAD group respectively.

Conclusion: Implantation of a temporary RVAD is allied with a worse outcome during the primary hospitalization and at follow-up. Compared to isolated LVAD support, biventricular mechanical circulatory support leads to an elevated mortality and higher incidence of adverse events such as bleeding and stroke.
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http://dx.doi.org/10.1177/02676591211024817DOI Listing
June 2021

Simple endovascular thoracic aortic stenting rescues a wrongly deployed frozen elephant trunk during a modified procedure.

J Int Med Res 2021 Feb;49(2):300060520986710

Department of Cardiac Surgery, University Hospital Basel, Basel, Switzerland.

We report a bail out approach of endovascular thoracic aorta repair following incorrect deployment of a modified frozen elephant trunk stent graft into the false lumen. A 76-year-old patient was admitted to our Emergency Department. A computed tomography angiography scan showed type I DeBakey aortic dissection. An emergency modified frozen elephant trunk procedure was performed. Immediate postoperative computed tomography angiography showed that the distal segment of the stent was deployed in the false lumen, probably through a re-entry tear at the descending thoracic aorta. Emergency endovascular repair of the thoracic aorta, as well as angioplasty of the superior mesenteric artery and left iliac artery, were performed.
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http://dx.doi.org/10.1177/0300060520986710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869178PMC
February 2021

Next Stage Approach to Tissue Engineering Skeletal Muscle.

Bioengineering (Basel) 2020 Sep 30;7(4). Epub 2020 Sep 30.

Department of Women's and Children's Health, University of Padova, 35128 Padova, Italy.

Large-scale muscle injury in humans initiates a complex regeneration process, as not only the muscular, but also the vascular and neuro-muscular compartments have to be repaired. Conventional therapeutic strategies often fall short of reaching the desired functional outcome, due to the inherent complexity of natural skeletal muscle. Tissue engineering offers a promising alternative treatment strategy, aiming to achieve an engineered tissue close to natural tissue composition and function, able to induce long-term, functional regeneration after in vivo implantation. This review aims to summarize the latest approaches of tissue engineering skeletal muscle, with specific attention toward fabrication, neuro-angiogenesis, multicellularity and the biochemical cues that adjuvate the regeneration process.
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http://dx.doi.org/10.3390/bioengineering7040118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711907PMC
September 2020

Modified frozen elephant trunk procedure as standard approach in acute type A aortic dissection: A propensity-weighted analysis.

J Thorac Cardiovasc Surg 2020 Jul 17. Epub 2020 Jul 17.

Department of Cardiac Surgery, University Hospital, Basel, Switzerland.

Objectives: To evaluate whether the modified frozen elephant trunk (mFET) procedure provides comparable outcome compared with the standard approach for DeBakey type I aortic dissection.

Methods: From November 2008 to December 2018, 262 (mean age 62.7 ± 12.4 years) patients with acute DeBakey type I aortic dissection were included. mFET was performed in 100 (38.2%) patients and isolated ascending aorta and hemiarch replacement (iAoA) were performed in 162 (61.8%). Outcome analyses included in-hospital mortality, stroke rate, incidence of composite cardiovascular events, survival, freedom from aorta-related intervention, as well as freedom from neurologic event. Inverse probability of treatment weighting was applied.

Results: After inverse probability of treatment weighting, in-hospital mortality was greater in the iAoA group. The incidence of cardiac cause of death, new postoperative renal failure, as well as stroke rate were similar in both groups. The survival at 1 year, 3 years, and 4 years was 84%, 81%, and 77%, respectively, in the iAoA group and 91%, 86%, and 86%, P = .025, respectively, in the mFET group. Cause-specific HR for aortic reoperation 1.03 (confidence interval [CI], 0.43-2.48, P = .95) and neurovascular event 2.72 (CI, 0.62-11.93, P = .19) was similar in 2 groups. Subhazard ratio (sHR) for mortality as competing outcome for aorta-related reintervention sHR of 0.52 (CI, 0.32-0.86, P = .011) and neurologic event sHR of 0.45 (95% CI, 0.26-0.76, P = .003) was significantly lower in mFET.

Conclusions: The mFET procedure as surgical treatment modality for DeBakey type I acute aortic dissection may be considered as viable alternative with beneficial mid-term outcome.
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http://dx.doi.org/10.1016/j.jtcvs.2020.05.120DOI Listing
July 2020

"Noninfective Endocarditis": A Case Report of Hereditary Coagulation Disorders in a 28-Year-Old Male.

Diagnostics (Basel) 2020 Jun 8;10(6). Epub 2020 Jun 8.

Department of Cardiac Surgery, University Hospital Basel, 4031 Basel, Switzerland.

We report a case of a young male who presented with acute limb ischemia after sport. With no prior history of disease, a non-infective endocarditis of the native aortic valve was diagnosed. After surgical valve replacement, the patient suffered from acute myocardial ischemia under phenprocoumon therapy. Anti-coagulant monitoring was subsequently changed to Factor II analysis after a rare Factor VII deficiency and prothrombin mutation (G20210A) was diagnosed.
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http://dx.doi.org/10.3390/diagnostics10060384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345217PMC
June 2020

Severe Rh alloimmunization and hemolytic disease of the fetus managed with plasmapheresis, intravenous immunoglobulin and intrauterine transfusion: A case report.

Transfus Apher Sci 2015 Dec 7;53(3):399-402. Epub 2015 Aug 7.

George & Fay Yee Centre for Healthcare Innovation, University of Manitoba/Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada; Department of Internal Medicine, Sections of Critical Care and of Haematology/Medical Oncology, University of Manitoba, Winnipeg, Manitoba, Canada.

Rh alloimmunization remains a potentially devastating complication of pregnancy, with fetal anemia causing hydrops and intrauterine death. Intrauterine transfusion is the standard treatment, but is particularly dangerous before 20 weeks gestation. When the need for intrauterine transfusion is anticipated early in pregnancy, immune-modulating therapies such as plasmapheresis and IVIG have been used to delay transfusion to a later gestational age. We report a 35-year-old G5P1 Rh(D)-negative woman with severe Rh alloimmunization managed successfully with sequential plasmapheresis, intravenous immune globulin and intrauterine transfusion. The optimal plasmapheresis treatment protocol and incremental benefit of IVIG remains unknown.
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http://dx.doi.org/10.1016/j.transci.2015.07.010DOI Listing
December 2015

Effects of vaginal delivery, cesarean section and exposure to labor on endothelial function of pregnant women.

Thromb Res 2014 Nov 8;134(5):1004-7. Epub 2014 Sep 8.

Department of Obstetrics, University of Manitoba, Health Sciences Centre, Winnipeg, MB, Canada; Department of Gynecology & Reproductive Sciences, University of Manitoba, Health Sciences Centre, Winnipeg, MB, Canada.

Introduction: This study was undertaken to assess the influence of labor and cesarean section on endothelial function.

Materials And Methods: Flow-mediated vasodilatation (FMD) was measured before and after delivery for an assessment of endothelial function in three groups: (1) the Vaginal delivery group (with spontaneous labor or induction of labor, n = 48), (2) the Elective C/S group (with a cesarean planned, n = 20), and (3) the C/S after FP group (scheduled for vaginal delivery but required to have an emergency cesarean section because of failure in progress, n = 11).

Results: There were statistically significant changes between the antepartum and postpartum FMD values in the Vaginal delivery group and the Elective C/S group but not in the C/S after FP group (P < 0.001, P = 0.023 and P = 0.22 respectively).

Conclusions: These observations suggest that labor may enhance endothelial function and that cesarean section may impair endothelial function.
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http://dx.doi.org/10.1016/j.thromres.2014.08.029DOI Listing
November 2014

Evaluating the safety of labour in women with a placental edge 11 to 20 mm from the internal cervical Os.

J Obstet Gynaecol Can 2014 Aug;36(8):674-677

Women's Hospital, Department of Obstetrics, Gynaecology and Reproductive Sciences, University of Manitoba, Winnipeg MB.

Objective: The purpose of this study was to evaluate pregnancy outcomes in a cohort of women with a placental edge between 11 and 20 mm from the internal cervical os, and to determine the likelihood of a successful vaginal delivery when trial of labour is attempted in these women.

Methods: We carried out a prospective observational study of women with singleton pregnancies and a placental edge between 11 and 20 mm from the internal cervical os (identified by transvaginal sonography) who underwent a trial of labour.

Results: Fourteen women with the above characteristics underwent a trial of labour during the study period. The mean interval (± SD) from ultrasound to delivery was 17.2 ± 9.6 days. Thirteen women (92.9%) delivered vaginally with no complications, and only one woman (7.1%) required an emergency Caesarean section for intrapartum bleeding. The risks of antepartum and postpartum hemorrhage were 21.4% and 14.3%, respectively.

Conclusion: Having a placental edge more than 10 mm from the internal os, measured by transvaginal sonography near term, justifies allowing a trial of labour and carries a low risk of subsequent obstetrical hemorrhage.
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http://dx.doi.org/10.1016/S1701-2163(15)30508-9DOI Listing
August 2014

MG98, a second-generation DNMT1 inhibitor, in the treatment of advanced renal cell carcinoma.

Cancer Invest 2012 Jun;30(5):415-21

Department of Internal Medicine, The University of Texas Medical School/ Memorial Hermann Cancer Center, Houston, Texas 77030, USA.

Background: In carcinogenesis, methylation of DNA promoter regions results in inactivation of tumor-suppressing genes. MG98 was designed to inhibit DNA methyltransferases enzyme 1 production.

Methods: This multicenter study explored two schedules of MG98 with Interferon-α-2β to identify schedule and dose for patients with metastatic RCC.

Results: Doses of IFN 9 MIU/MG98 125 mg/m(2) for a continuous schedule and IFN 9 MIU/MG98 200 mg/m(2) for an intermittent schedule were considered the MTDs. Treatment resulted in one PR and eight SD.

Conclusion: MG98 combined with IFN was safe and resulted in clinical activity.
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http://dx.doi.org/10.3109/07357907.2012.675381DOI Listing
June 2012

Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors.

Clin Cancer Res 2009 May 21;15(9):3177-83. Epub 2009 Apr 21.

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro.

Experimental Design: In this phase I, open-label study, patients with advanced solid malignancies were treated with escalating doses of MG98 administered as a continuous i.v. infusion over 7 days repeated every 14 days. Cohorts of three patients, which could be expanded to six patients, were studied. The maximum tolerated dose was defined as the highest dose at which no more than 33% of subjects experienced dose-limiting toxicity. Pharmacokinetic and pharmacodynamic parameters of MG98 were also characterized.

Results: Thirty-three patients were treated at doses of 100 to 250 mg/m(2)/d MG98. MG98 was well tolerated with mild fatigue and myalgia, dose-limiting toxicity was asymptomatic transaminitis, and the maximum tolerated dose was 200 mg/m(2)/d. One patient achieved a partial response and another prolonged disease stabilization. Plasma half-life of MG98 was short (2 hours), drug concentrations reaching a dose-dependent steady state during infusion with a volume of distribution equivalent to plasma volume. Suppression of DNMT1 expression was observed in 26 of 32 patients studied.

Conclusions: MG98 was well tolerated with early evidence of clinical activity. Proof of mechanism was observed and measurement of DNMT1 expression in peripheral blood mononuclear cells may be useful in future phase II development.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-2859DOI Listing
May 2009

Increased nuchal translucency thickness: a potential indicator for Ritscher-Schinzel syndrome.

Fetal Diagn Ther 2008 28;24(4):395-9. Epub 2008 Oct 28.

Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Man., Canada.

Objective: The Ritscher-Schinzel syndrome (RSS), also known as the 3C syndrome, is an autosomal recessive disorder classically comprising craniofacial, cerebellar and cardiac defects. The underlying molecular etiology remains unknown; therefore, prenatal diagnosis of recurrences depends on identification of the associated structural anomalies on second trimester ultrasound examination. Identification of recurrences using first-trimester ultrasound has not been reported previously.

Methods: Two women who presented at our center with fetal nuchal abnormalities on first trimester ultrasound went on to have children with RSS. One of the women had also undergone a previous pregnancy termination for fetal anomalies consistent with RSS. The ultrasound findings and details of these 3 cases were reviewed.

Results: Both cases of RSS and the third suspected case were found to have nuchal abnormalities on first-trimester scan. All went on to develop malformations consistent with RSS detectable on second-trimester ultrasound. The later 2 cases continued to term and the children had facial characteristics consistent with RSS.

Conclusion: First-trimester ultrasound assessment of nuchal translucency could be considered as a method for identifying sib recurrences of RSS. In addition, RSS should be on the differential diagnosis when increased nuchal translucency is seen on first-trimester scan.
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http://dx.doi.org/10.1159/000165697DOI Listing
April 2009

Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay.

Clin Cancer Res 2008 Jun;14(11):3441-9

MethylGene, Inc., Montreal, Quebec, Canada.

Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay.

Experimental Design: Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients.

Results: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheral WBC correlated with induction of histone acetylation in blood and in implanted tumors in mice. In cancer patients, sustained pharmacodynamic effect of MGCD0103 was visualized only by dose-dependent enzyme inhibition in peripheral WBC but not by histone acetylation analysis.

Conclusions: This study shows that MGCD0103 has sustained pharmacodynamic effects that can be monitored both in vitro and in vivo with a cell-based HDAC enzyme assay.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444140PMC
June 2008

Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia.

Blood 2008 Aug 21;112(4):981-9. Epub 2008 May 21.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m(2), with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts
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http://dx.doi.org/10.1182/blood-2007-10-115873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081529PMC
August 2008

Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors.

J Clin Oncol 2008 Apr;26(12):1940-7

Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Ste 5-718, Toronto, Ontario, M5G 2M9, Canada.

Purpose: MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies.

Patients And Methods: A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs.

Results: Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103.

Conclusion: At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.
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http://dx.doi.org/10.1200/JCO.2007.14.5730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501257PMC
April 2008

A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia.

Clin Cancer Res 2008 Apr;14(8):2444-9

Division of Hematology and Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Purpose: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML.

Experimental Design: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which > or =50% of patients experienced >50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days).

Results: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients.

Conclusions: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-1320DOI Listing
April 2008

Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study.

Invest New Drugs 2006 Mar;24(2):159-67

London Health Sciences Centre, 790 Commissioners Road East, London, Ontario, Canada, N6A 4L6.

DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.
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http://dx.doi.org/10.1007/s10637-006-5938-1DOI Listing
March 2006

The use of folic acid for the prevention of neural tube defects and other congenital anomalies.

J Obstet Gynaecol Can 2003 Nov;25(11):959-73

Objective: To provide information regarding the use of folic acid for the prevention of neural tube defects (NTDs) and other congenital anomalies, in order that physicians, midwives, nurses, and other health-care workers can assist in the education of women in the preconception phase of their health care. OPTION: Folic acid supplementation is problematic, since 50% of pregnancies are unplanned and the health status of women may not be optimal.

Outcomes: Folic acid supplementation has been proven to decrease or minimize specific birth defects.

Evidence: A systematic review of the literature, including review and peer-reviewed articles, government publications, the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of March 1993, and statements from the American College of Obstetrics and Gynecology, was used to develop a new clinical practice guideline for the SOGC.

Values: Peer-review process within the committee structure.

Benefits, Harms, And Costs: The benefit is reduced lethal and severe morbidity birth defects and the harm is minimal. The personal cost is of vitamin supplementation on a daily basis and eating a healthy diet.

Recommendations: 1. Women in the reproductive age group should be advised about the benefits of folic acid supplementation during wellness visits (birth control renewal, Pap testing, yearly examination), especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy nutritional diet, as recommended in Canada's Food Guide to Healthy Eating (good or excellent sources of folic acid: broccoli, spinach, peas, Brussels sprouts, corn, beans, lentils, oranges). (III-A) 3. Women who could become pregnant should be advised to take a multivitamin containing 0.4 mg to 1.0 mg of folic acid daily. (II-1A) 4. Women taking a multivitamin with folic acid supplement should be advised not to take more than 1 daily dose of vitamin supplement, as indicated on the product label. (II-2A) 5. Women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin-dependent diabetes, epilepsy treatment with valproic acid or carbamazepine) should be advised that high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A. (I-A) 6. The choice of a 5 mg folic acid daily dose for women considering a pregnancy should be made under medical supervision after minimizing the risk of undiagnosed vitamin B12 deficiency (hypersegmentation of polymorphonuclear cells, macrocystic indices, large ovalocytes, leukopenia, thrombocytopenia, markedly elevated lactate dehydrogenase level, confirmed red blood cell folate level). (II-2A) 7. Signs or symptoms of vitamin B12 deficiency should be considered before initiating folic acid supplementation of doses greater than 1.0 mg. (III-A) 8. A three-generation pedigree on the families of both the pregnant woman and the biological father should be obtained to identify increased risk for congenital birth defects (i.e., NTD, cardiac, chromosomal, genetic). (III-A) 9. Women who become pregnant should be advised of the availability of noninvasive screening tests and invasive diagnostic tests for congenital birth defects (including NTDs): maternal serum "triple marker screen" at 15 to 20 weeks, ultrasound at 16 to 20 weeks, and amniocentesis after 15 weeks of pregnancy if a positive screening test is present. (I-A) VALIDATION: This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used.
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http://dx.doi.org/10.1016/s1701-2163(16)30248-1DOI Listing
November 2003

Prevention of Rh alloimmunization.

J Obstet Gynaecol Can 2003 Sep;25(9):765-73

Objective: To provide guidelines on use of anti-D prophylaxis to optimize prevention of rhesus (Rh) alloimmunization in Canadian women.

Outcomes: Decreased incidence of Rh alloimmunization and minimized practice variation with regards to immunoprophylaxis strategies.

Evidence: The Cochrane Library and MEDLINE were searched for English-language articles from 1968 to 2001, relating to the prevention of Rh alloimmunization. Search terms included: Rho(D) immune globulin, Rh iso- or allo-immunization, anti-D, anti-Rh, WinRho, Rhogam, and pregnancy. Additional publications were identified from the bibliographies of these articles. All study types were reviewed. Randomized controlled trials were considered evidence of highest quality, followed by cohort studies. Key individual studies on which the principal recommendations are based are referenced. Supporting data for each recommendation is briefly summarized with evaluative comments and referenced.

Values: The evidence collected was reviewed by the Maternal-Fetal Medicine and Genetics Committees of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on the Periodic Health Exam.

Recommendations: 1. Anti-D Ig 300 microg IM or IV should be given within 72 hours of delivery to a postpartum nonsensitized Rh-negative woman delivering an Rh-positive infant. Additional anti-D Ig may be required for fetomaternal hemorrhage (FMH) greater than 15 mL of fetal red blood cells (about 30 mL of fetal blood). Alternatively, anti-D Ig 120 microg IM or IV may be given within 72 hours of delivery, with testing and additional anti-D Ig given for FMH over 6 mL of fetal red blood cells (12 mL fetal blood). (I-A) 2. If anti-D is not given within 72 hours of delivery or other potentially sensitizing event, anti-D should be given as soon as the need is recognized, for up to 28 days after delivery or other potentially sensitizing event. (III-B) 3. There is poor evidence regarding inclusion or exclusion of routine testing for postpartum FMH, as the cost-benefit of such testing in Rh mothers at risk has not been determined. (III-C) 4. Anti-D Ig 300 microg should be given routinely to all Rh-negative nonsensitized women at 28 weeks' gestation when fetal blood type is unknown or known to be Rh-positive. Alternatively, 2 doses of 100-120 microg may be given (120 microg being the lowest currently available dose in Canada): one at 28 weeks and one at 34 weeks. (I-A) 5. All pregnant women (D-negative or D-positive) should be typed and screened for alloantibodies with an indirect antiglobulin test at the first prenatal visit and again at 28 weeks. (III-C) 6. When paternity is certain, Rh testing of the baby's father may be offered to all Rh-negative pregnant women to eliminate unnecessary blood product administration. (III-C) 7. A woman with "weak D" (also known as Du-positive) should not receive anti-D. (III-D) 8. A repeat antepartum dose of Rh immune globulin is generally not required at 40 weeks, provided that the antepartum injection was given no earlier than 28 weeks' gestation. (III-C) 9. After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, nonsensitized D-negative women should be given a minimum anti-D of 120 microg. After 12 weeks' gestation, they should be given 300 microg. (II-3B) 10. At abortion, blood type and antibody screen should be done unless results of blood type and antibody screen during the pregnancy are available, in which case antibody screening need not be repeated. (III-B) 11. Anti-D should be given to nonsensitized D-negative women following ectopic pregnancy. A minimum of 120 microg should be given before 12 weeks' gestation and 300 microg after 12 weeks' gestation. (III-B) 12. Anti-D should be given to nonsensitized D-negative women following molar pregnancy because of the possibility of partial mole. Anti-D may be withheld if the diagnosis of complete mole is certain. (III-B) 13. At amniocentesis, anti-D 300 microg should be given to nonsensitized D-negativeesis, anti-D 300 microg should be given to nonsensitized D-negative women. (II-3B) 14. Anti-D should be given to nonsensitized D-negative women following chorionic villous sampling, at a minimum dose of 120 microg during the first 12 weeks' gestation, and at a dose of 300 microg after 12 weeks' gestation. (II-B) 15. Following cordocentesis, anti-D Ig 300 microg should be given to nonsensitized D-negative women. (II-3B) 16. Quantitative testing for FMH may be considered following events potentially associated with placental trauma and disruption of the fetomaternal interface (e.g., placental abruption, blunt trauma to the abdomen, cordocentesis, placenta previa with bleeding). There is a substantial risk of FMH over 30 mL with such events, especially with blunt trauma to the abdomen. (III-B) 17. Anti-D 120 microg or 300 microg is recommended in association with testing to quantitate FMH following conditions potentially associated with placental trauma and disruption of the fetomaternal interface (e.g., placental abruption, external cephalic version, blunt trauma to the abdomen, placenta previa with bleeding). If FMH is in excess of the amount covered by the dose given (6 mL or 15 mL fetal RBC), 10 microg additional anti-D should be given for every additional 0.5 mL fetal red blood cells. There is a risk of excess FMH, especially when there has been blunt trauma to the abdomen. (III-B) 18. Verbal or written informed consent must be obtained prior to administration of the blood product Rh immune globulin. (III-C) VALIDATION: These guidelines have been reviewed by the Maternal-Fetal Medicine Committee and the Genetics Committee, with input from the Rh Program of Nova Scotia. Final approval has been given by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.
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http://dx.doi.org/10.1016/s1701-2163(16)31006-4DOI Listing
September 2003

Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks.

Invest New Drugs 2003 Feb;21(1):85-97

National Cancer Institute, Canada.

Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks.

Patients And Methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45.

Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed.

Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.
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http://dx.doi.org/10.1023/a:1022976528441DOI Listing
February 2003

Amniocentesis and women with hepatitis B, hepatitis C, or human immunodeficiency virus.

J Obstet Gynaecol Can 2003 Feb;25(2):145-48, 149-52

Objective: To review the risk of in utero infection through amniocentesis in women with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).

Outcomes: Fetal and neonatal morbidity and mortality.

Evidence: Review articles, meta-analyses, and MEDLINE searches from 1966 to 2002 for English-language articles related to amniocentesis, fetal and neonatal infection, and hepatitis B, hepatitis C, or HIV.

Values: The evidence collected was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on the Periodic Health Exam.

Recommendations: 1. The risk of fetal hepatitis B infection through amniocentesis is low. However, knowledge of the maternal hepatitis B e antigen status is valuable in the counselling of risks associated with amniocentesis. (II-1C) 2. Amniocentesis in women infected with hepatitis C does not appear to significantly increase the risk of vertical transmission, but women should be counselled that very few studies have properly addressed this possibility. (II-2C) 3. In HIV-positive women all noninvasive screening tools should be used prior to considering amniocentesis. (II-2D) 4. For women infected with hepatitis B, hepatitis C, or HIV, the addition of noninvasive methods of prenatal risk screening, such as nuchal translucency, triple screening, and anatomic ultrasound, may help in reducing the age-related risk to a level below the threshold for genetic amniocentesis. (II-2C) 5. For those women infected with hepatitis B, hepatitis C, or HIV who insist on amniocentesis, every effort should be made to avoid inserting the needle through the placenta. (II-1B) VALIDATION: These guidelines have been approved by the SOGC Genetics Committee, SOGC Executive, and SOGC Council.

Sponsors: The Society of Obstetricians and Gynaecologists of Canada.
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http://dx.doi.org/10.1016/s1701-2163(16)30211-0DOI Listing
February 2003

PREVENTION AND TREATMENT OF VENOUS THROMBOEMBOLISM (VTE) IN OBSTETRICS.

J SOGC 2000 Sep;22(9):736-749

OBJECTIVE: to identify risk factors for venous thromboembolism (VTE) in the peripartum period and to provide guidelines for risk assessment and thromboprophylactic measures for VTE in pregnant women. Guidelines for diagnostic testing and for acute and long term treatment of VTE are also provided.OPTIONS: specific subgroups of pregnant women are defined and appropriate prophylactic measures are outlined. OUTCOMES: venous thromboembolism remains a major cause of morbidity and mortality in pregnancy and the postpartum period. Identification of risk and adequate prophylaxis can decrease the incidence of VTE.EVIDENCE: evidence was gathered using Medline (National Library of Medicine) to identify relevant studies and from bibliographies of articles thus identified.RECOMMENDATIONS: although evidence is lacking to date from Grade I studies (properly controlled randomized studies) in pregnant patients, there is good evidence to support the role of prophylaxis in reducing the incidence of VTE in patients identified to be at risk in the non-pregnant population (II B). Based on risk assessment more patients should be considered for thromboprophylaxis, including women with a past history of a VTE and a known thrombophilia on long-term anticoagulation, women with a past history of a VTE, women with a known thrombophilia who have never experienced a VTE and potentially considered in women at the time of Caesarean section (II B; III C). The occurrence of VTE is effectively reduced by the use of low dose unfractionated heparin. Experience with low molecular weight heparin and pregnancy is building, but is limited at present. Unfractionated heparin remains the standard for the treatment of VTE in pregnancy at the present time. Following initial heparinization for the treatment of VTE, patients should be continued on anticoagulation throughout pregnancy and for six to 12 weeks postpartum or a total of three months of anticoagulation (II A).
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September 2000

Screening for gestational diabetes mellitus.

J Obstet Gynaecol Can 2002 Nov;24(11):894-912

Toronto, Ontario, Canda.

Objective: The purpose of this document is to briefly review the existing data regarding the effect of a diagnosis of gestational diabetes mellitus (GDM), the different screening and diagnostic practices for GDM, and, finally, outline the recommended options for GDM screening in Canada.

Options: Consideration has been given to the existing screening practices for GDM including universal screening, risk factor-based screening, and the option of not screening for GDM.

Outcomes: The short- and long-term maternal-fetal outcomes in GDM were reviewed with emphasis given to examination of the data regarding the effect of diagnosis and treatment of GDM on these outcomes.

Evidence: A comprehensive search of the literature from 1990 through April 2002 using MEDLINE and the Cochrane Database and a review of randomized controlled trials (RCTs) was undertaken. Additional studies and clinical guidelines published outside this time frame but with specific clinical relevance were also reviewed. The level of evidence of the recommendations in this document has been determined using the criteria described by the Canadian Task Force on the Periodic Health Examination.

Recommendations: I. A single approach of testing for GDM cannot be recommended at the present as there is not enough evidence-based data proving the beneficial effect of a large screening program. Until a large prospective RCT shows a clear clinical benefit for screening and consequently treating GDM, recommendations will by necessity be based on consensus or expert opinion. Each of the following approaches is acceptable. a. Routine screening of women at 24-28 weeks of gestation may be recommended with the 50 g glucose challenge test (GCT), using a threshold of 7.8 mmol/L (140 mg/dL), except in those women who fulfill the criteria for low risk, which includes the following: * maternal age < 25 * Caucasian or member of other ethnic group with low prevalence of diabetes * pregnant body mass index (BMI)
Sponsor: The Society of Obstetricians and Gynaecologists of Canada.
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http://dx.doi.org/10.1016/s1701-2163(16)31047-7DOI Listing
November 2002

Cystic fibrosis carrier testing in pregnancy in Canada.

J Obstet Gynaecol Can 2002 Aug;24(8):644-51

Objective: To assess the role of cystic fibrosis (CF) testing within the Canadian health care environment.

Methods: The Genetics and Maternal Fetal Medicine Committees of the Society of Obstetricians and Gynaecologists of Canada (SOGC) reviewed Preconception and Prenatal Carrier Screening for Cystic Fibrosis Clinical and Laboratory Guidelines produced by the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG) and other educational material from ACOG and ACMG.

Results: Background information related to cystic fibrosis, genetic mutation analysis, and one large clinical cystic fibrosis screening trial are reviewed.

Evidence: The quality of evidence reported in this document has been described using the Evaluation of Evidence criteria outlined in the report of the Canadian Task Force on the Periodic Health Exam.

Recommendations: 1. CF testing in pregnancy is indicated for individuals who may be at increased risk for CF due to considerations of family history or clinical manifestations. (II-2A). 2. Before CF screening could be undertaken, each province/territory would have to review the ethnic diversity of its reproductive population to ensure that CF screening would be appropriate. (III-C). 3. Screening of all women during pregnancy for CF carrier status cannot be recommended at this time. (III-C).
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http://dx.doi.org/10.1016/s1701-2163(16)30196-7DOI Listing
August 2002

Placental expression of insulin-like growth factor receptor-1 and insulin receptor in the growth-restricted fetal rat.

J Soc Gynecol Investig 2002 Jul-Aug;9(4):210-4

Department of Obstetrics and Gynecology, Northwestern University Medical School, Children's Memorial Hospital, Chicago, Illinois, USA.

Objective: The type 1 insulin-like growth factor receptor (IGF-R1), which resembles the insulin receptor (INS-R), is expressed abundantly in the placenta. The regulation of fetal growth by IGFs and insulin might reflect their actions on the placenta. This study compared the placental expression of IGF-R1 and INS-R in growth-restricted and normal pregnancies.

Methods: Fetal growth restriction was produced in Sprague-Dawley rats by bilateral ligation of the uterine artery on day 19 (term = 21.5 days). Fetuses were delivered by hysterotomy on day 20, and placental samples were frozen. Fetuses that had been subjected to a sham operation of maternal laparotomy without uterine artery manipulation were studied as matched controls. IGF-R1 and INS-R message was assessed by reverse transcription and polymerase chain reaction amplification of extracted placental RNA. The receptors also were assessed by Western blotting of extracted placental protein. Measurements for the growth-restricted group were expressed as a multiple of that of the matched sham litter.

Results: Placental IGF-R1 messenger RNA (mRNA) level was significantly lower in the growth-restricted fetuses (0.66 x sham [0.47-0.93], P <.05), but INS-R mRNA was not different (0.89 x sham [0.63-1.3], P >.5). IGF-R1 protein transcript was similarly reduced in the growth-restricted fetuses (0.78 x sham [0.69-0.88], P <.005), but the INS-R protein transcript was not (0.98 x sham [0.69-1.4], P >.8). Birth weights were significantly less in the growth-restricted group (3.06 +/- 0.07 versus 3.29 +/- 0.06 g, P =.016); placental weights were not (0.54 +/- 0.02 versus 0.54 +/- 0.02 g, P =.90).

Conclusions: The placenta responds to decreased nutrient delivery with decreased expression of IGF-R1. This would reduce the growth-promoting effects of insulin-like growth factors, which include augmentation of placental lactogen production and glucose and amino acid transport. INS-R was unaffected, which suggests that placental response to insulin is less important than its response to insulin-like growth factors in growth restriction.
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December 2002

Selective inhibition of DNA methyltransferase enzymes as a novel strategy for cancer treatment.

Curr Opin Mol Ther 2002 Apr;4(2):130-7

MethylGene Inc, Montreal, Québec, Canada.

A common event in the development of human neoplasia is the loss of growth regulatory tumor suppressor functions. Methylation of 5'-CpG islands of tumor suppressor genes and elevated levels of the DNA-(cytosine-5)-methyltransferase enzymes (DNMT1, 3A and 3B) are also prevalent features of human neoplasia. However, direct evidence that elevated DNMT enzyme levels alter gene expression and influence oncogenesis has been difficult to obtain due to the lack of specific DNMT inhibitors. We have developed potent and selective antisense inhibitors of the known DNA methyltransferases. MG-98, a second-generation DNMT1-specific antisense inhibitor currently in phase II clinical trials, reactivates silenced tumor suppressor genes and inhibits the growth of cancer cells in vitro and in preclinical in vivo models. Here, we will review the discovery and development of MG-98 as a cancer therapeutic.
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April 2002
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