Cardiac troponin I release after open heart surgery: a marker of myocardial protection?

Background. Unlike creatine kinase MB isoenzyme, cardiac troponin I (cTnI) is a highly specific marker of myocardial injury. Its release has recently been studied after coronary artery bypass grafting operation. However, its significance after open heart surgery (OHS) remains to be determined. This protein release could be a marker of myocardial protection. We sought to study cTnI release after OHS in patients with normal coronary arteries and to compare it with cTnI release in patients after coronary artery bypass graft (CABG) surgery.

Methods. Eighty-five patients undergoing OHS and 86 patients undergoing CABG were enrolled in the study. CTnI concentrations were measured in serial venous blood samples drawn before surgery and immediately, 12 hours, 24 hours, 48 hours, and 5 days after aortic unclamping.

Results. In the OHS group and in the CABG group without acute myocardial infarction (AMI), cTnI peaked at 12 hours postoperatively (6.35 ± 6.5 and 5.38 ± 8.55 ng/mL, respectively) and normalized on day 5 postoperatively (0.57 ± 2 and 0.72 ± 1.62 ng/mL, respectively). CTnI concentration did not differ significantly between the OHS group and the CABG group in the absence of AMI for any samples considered. In the CABG group, 2 patients had AMI. In the OHS group, cTnI levels at 12 hours postoperatively were found to correlate closely with CPB and aortic cross-clamping (ACC) times, contrary to the CABG group, which correlated only with occurrence of AMI. CTnI release was independent of age and ejection fraction in either group.

Conclusions. cTnI release in patients after OHS with normal coronary arteries has the same profile as cTnI release in patients after CABG in the absence of AMI. However, its peak at 12 hours postoperatively is only correlated to ACC and CPB times, which is contrary to cTnI release after CABG surgery. This observation suggests that cTnI could be a marker of myocardial ischemia after OHS.     

The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis

Uterine cancer is the most common cancer of the female genital tract and is the fourth most frequent cause of cancer death in women in the U.S. Despite the high prevalence of uterine cancers, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. Moreover, there are limited mouse models to study these malignancies. We generated transgenic mice with high-mobility group A1 gene (HMGA1a) expression targeted to uterine tissue and all female mice developed tumors by 9 months of age. Histopathologically, the tumors resemble human uterine adenosarcoma and are transplantable. To determine whether these findings are relevant to human disease, we evaluated primary human uterine neoplasms and found that HMGA1a mRNA and protein levels are increased in most high-grade neoplasms but not in normal uterine tissue, benign tumors, or most low-grade neoplasms. We also found that HMGA1a up-regulates cyclooxygenase 2 (COX-2) expression in transgenic tumors. Moreover, both HMGA1a and COX-2 expression are up-regulated in high-grade human leiomyosarcomas. Using chromatin immunoprecipitation, HMGA1a binds directly to the COX-2 promoter in human uterine cancer cells in vivo and activates its expression in transfection experiments. We also show that blocking either HMGA1a or COX-2 in high-grade human uterine cancer cells blocks anchorage-independent cell growth in methylcellulose. These findings show that HMGA1a functions as an oncogene when overexpressed in the uterus and contributes to the pathogenesis of human uterine cancer by activating COX-2 expression. Although a larger study is needed to confirm these results, HMGA1a may be a useful marker for aggressive human uterine cancers.     

MLL-AF1q fusion resulting from t(1;11) in acute leukemia.

The MLL gene, located on chromosome band 11q23 is fused to different partner genes as a result of various chromosomal translocations in hematopoietic malignancies. A t(1;11) (q21;q23) resulting in a MLL-AF1q fusion gene has previously been reported. Cytogenetic studies on six cases are reported, including one three-way translocation. FISH analysis using a YAC encompassing the MLL gene and a YAC encompassing the AF1q locus showed splitting in three cases and two patients, respectively. PCR analysis of two cases confirmed that AF1q is specifically associated with t(1;11)(q21;q23). The MLL-AF1q fusion mRNA was similar to that previously described in one case and involved MLL exon 7 in the other. This study confirms the specific involvement of AF1q in t(1;11) (q21;q23)-positive acute leukemia with monocytic involvement.     

hTERT promotes imatinib resistance in chronic myeloid leukemia cells: therapeutic implications

Imatinib mesylate has shown remarkable efficacy in the treatment of patients in the chronic phase of chronic myeloid leukemia. However, despite an overall significant hematological and cytogenetic response, imatinib therapy may favor the emergence of drug-resistant clones, ultimately leading to relapse. Some imatinib resistance mechanisms had not been fully elucidated yet. In this study we used sensitive and resistant sublines from a Bcr-Abl positive cell line to investigate the putative involvement of telomerase in the promotion of imatinib resistance. We showed that sensitivity to imatinib can be partly restored in imatinib-resistant cells by targeting telomerase expression, either by the introduction of a dominant-negative form of the catalytic protein subunit of the telomerase (hTERT) or by the treatment with all-trans-retinoic acid, a clinically used drug. Furthermore, we showed that hTERT overexpression favors the development of imatinib resistance through both its antiapoptotic and telomere maintenance functions. Therefore, combining antitelomerase strategies to imatinib treatment at the beginning of the treatment should be promoted to reduce the risk of imatinib resistance development and increase the probability of eradicating the disease.     

Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts

Uterine cancer is a common cause for cancer death in women and there is no effective therapy for metastatic disease. Thus, research is urgently needed to identify new therapeutic agents. We showed previously that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo. We also demonstrated that HMGA1a up-regulates cyclooxygenase-2 (COX-2) during tumorigenesis in this model. Similarly, we found that HMGA1a and COX-2 are overexpressed in human leiomyosarcomas, a highly malignant uterine cancer. Although epidemiologic studies indicate that individuals who take COX inhibitors have a lower incidence of some tumors, these inhibitors have not been evaluated in uterine cancer. Here, we show that HMGA1a mice on sulindac (a COX-1/COX-2 inhibitor) have significantly smaller uterine tumors than controls. To determine if COX inhibitors are active in human uterine cancers that overexpress HMGA1a, we treated cultured cells with sulindac sulfide or celecoxib (a specific COX-2 inhibitor). Both drugs block anchorage-independent growth in high-grade human uterine cancer cells that overexpress HMGA1a (MES-SA cells). In contrast, neither inhibitor blocked transformation in cells that do not overexpress HMGA1a. Moreover, xenograft tumors from MES-SA cells were significantly inhibited in mice on sulindac. More strikingly, no tumors formed in mice on celecoxib. These preclinical studies suggest that COX inhibitors could play a role in preventing tumor onset or progression in uterine cancers with dysregulation of the HMGA1a-COX-2 pathway. Importantly, these drugs have lower toxicity than chemotherapeutic agents used to treat advanced-stage uterine cancers.     

Diagnostics, prognostic and therapeutic exploitation of telomeres and telomerase in leukemias

Telomeres are specialized structures at the end of human chromosomes. Telomere length decreases with each cell division, thus, reflecting the mitotic history of somatic cells. Telomerase, the ribonucleoprotein enzyme which maintains telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasia but not in normal somatic tissues. In contrast to other somatic cells, normal primitive human hematopoietic cells and some peripheral blood cells expressed low levels of telomerase activity. This activity is thought to play an important role in self-renewal of hematopoietic stem cells. In malignant disorders, telomere lengths are generally shortened and telomerase expression and activity enhanced with high differences in the levels. Although it is necessary to be cautious in interpreting these data, there are indications that telomere length and telomerase expression and activity can serve as a molecular marker of the clinical progression and prognosis of most leukemias. Approaches that directly target telomerase, telomeres or telomerase regulatory mechanisms have been developed. Some of these anti-telomerase strategies in combination with conventional drugs proved to be promising in some types of leukemias.     

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death.

Acute promyelocytic leukemia (APL) is efficiently treated with a cell differentiation inducer, all-trans retinoic acid (ATRA). However, a significant percentage of patients still develop resistance to this treatment. Recently, arsenic trioxide (As2O3), alone or in combination with ATRA, has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. Previous investigations restricted the mechanism of this synergism to the modulation and/or degradation of PML-RARalpha oncoprotein through distinct pathways. In this study, using several ATRA maturation-resistant APL cell lines, we demonstrate in vitro that the success of ATRA/As2O3 treatment in APL pathology can be explained, at least in part, by a synergistic effect of these two drugs in triggering downregulation of telomerase efficient enough to cause telomere shortening and subsequent cell death. Such long-term low-dose combinatorial therapy strategies, developed also to avoid acute side effects, reinforce the notion that the antitelomerase strategy, based on a combination of active agents, should now be considered and evaluated not only in APL but also in other malignancies.     

Long-term results of surgery for type A acute aortic dissection

The cases of 160 patients (126 men, mean age 57.5 +/- 13.3 years) operated consecutively as an emergency for a Stanford type A dissection of the aorta between 1980 and 2000 were reviewed. The cumulative follow-up was 716.7 patient-years with an average follow-up of 4.51 +/- 5.6 patient-years. The risk factors for early postoperative mortality (up to 3 months), late mortality (> 3 months) and reoperation (cardiac and/or vascular) were determined by multivariate analysis. The hospital mortality was 27.5%. Older ages, obesity, previous cardiac surgery, preoperative shock, medullary, renal or mesenteric ischaemia were significant risk factors for early mortality. The probability of actuarial survival was 66.1 +/- 3.8%, 57.7 +/- 4.2%, 52.2 +/- 4.6% and 45.3 +/- 5.5% respectively at 1, 5, 10 and 15 years. Chronic obstructive airways disease and a more recent operation date were significant risk factors for late mortality. Thirty patients underwent 37 reoperations after an average of 5.7 +/- 4.5 years. The actuarial probability for no reoperation was 96.9 +/- 1.8%, 74.7 +/- 5.3%, 60.8 +/- 6.8% and 39.3 +/- 9.1% at 1, 5, 10 and 15 years respectively. The presence of severe preoperative aortic regurgitation was the only significant risk factor for reoperation. Type A acute dissection of the aorta continues to have a high early mortality and a significant incidence of late complications. Patients with severe aortic regurgitation before surgery are at high risk for reoperation and should probably have more radical aortic repair at the initial operation.