Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer

Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.     

Investigation of breast cancer using two‐dimensional MRS

Proton (¹H) MRS enables non‐invasive biochemical assay with the potential to characterize malignant, benign and healthy breast tissues. In vitro studies using perchloric acid extracts and ex vivo magic angle spinning spectroscopy of intact biopsy tissues have been used to identify detectable metabolic alterations in breast cancer. The challenges of ¹H MRS in vivo include low sensitivity and significant overlap of resonances due to limited chemical shift dispersion and significant inhomogeneous broadening at most clinical magnetic field strengths. Improvement in spectral resolution can be achieved in vivo and in vitro by recording the MR spectra spread over more than one dimension, thus facilitating unambiguous assignment of metabolite and lipid resonances in breast cancer. This article reviews the recent progress with two‐dimensional MRS of breast cancer in vitro, ex vivo and in vivo. The discussion includes unambiguous detection of saturated and unsaturated fatty acids, as well as choline‐containing groups such as free choline, phosphocholine, glycerophosphocholine and ethanolamines using two‐dimensional MRS. In addition, characterization of invasive ductal carcinomas and healthy fatty/glandular breast tissues non‐invasively using the classification and regression tree (CART) analysis of two‐dimensional MRS data is reviewed. Copyright © 2008 John Wiley & Sons, Ltd.     

Impact of pretransplant antinuclear antibody and antismooth muscle antibody titers on disease recurrence and graft survival following liver transplantation in autoimmune hepatitis patients

Background and Aims: Disease recurrence following transplantation occurs in 20–45% of patients with autoimmune hepatitis (AIH). Factors associated with an increased risk of recurrence include human leukocyte antigen (HLA) DR3 and HLA DR4 positivity, inadequate immunosuppression, and severity of inflammation in the native liver. Titers of several autoantibodies can be elevated in patients with AIH, including antinuclear antibody (ANA) and antismooth muscle antibody (SMA); however, it is unclear whether or not the degree of elevation influences the risk of disease recurrence following transplantation. Methods: We conducted a retrospective study to evaluate the potential impact of pretransplant titers on post‐transplant outcomes for patients with AIH. Sixty‐three patients with AIH who underwent 72 liver transplants between 1 January 1989 and 1 January 2009 were included, with a median follow up of 10 months. Patients were divided into group A (ANA or SMA ≥ 1 : 160) and group B (titers ≤ 1 : 160). Results: There was no significant difference in the recurrence rates or death between patients in groups A and B, respectively. Only race appeared to impact outcomes, with African American patients having a higher incidence of death and recurrent disease post‐transplant compared to other ethnicities. Conclusions: Based on our findings, pretransplant ANA and SMA levels do not appear to impact recurrence rates or outcomes following liver transplantation for AIH.     

Role of macrophage inflammatory protein-2 in aspiration-induced lung injury

OBJECTIVE: To determine the role of the chemokine, macrophage inflammatory protein (MIP)-2, in the pathogenesis of aspiration-induced lung injury in the rat. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratories. SUBJECTS: Adult, male Long-Evans rats. INTERVENTIONS: Anesthetized rats underwent induction of lung injury by well-described models of aspiration triggered by intra-tracheal delivery of acid alone, gastric particles alone, or the combination. After injury, induction of MIP-2 messenger RNA in whole lungs and immunoreactive MIP-2 in bronchoalveolar lavage (BAL) fluids was determined. The contribution of MIP-2 to BAL fluid chemotactic activity was defined by using an in vitro chemotaxis assay. The in vivo effect of blocking MIP-2 on pulmonary vascular leak, BAL fluid neutrophils, PaO2/FIO2 ratio, and alveolar-arterial oxygen tension gradient in acid-induced lung injury was determined. MEASUREMENTS AND MAIN RESULTS: Induction of MIP-2 messenger RNA and protein over time was observed in response to all three stimuli. A significant portion (25% to 41%) of the chemotactic activity in BAL fluids from injured rats was inhibited by anti-MIP-2 antibody. After acid injury, blocking of MIP-2 was associated with a 53% decrease in BAL fluid neutrophils and a 33% decrease in pulmonary vascular leak. Although acid injury both impaired oxygenation and increased venous admixture, in vivo blocking of MIP-2 was associated with improved oxygenation as well as decreased venous admixture. CONCLUSIONS: MIP-2 was up-regulated during the development of aspiration-induced lung injury in rats. MIP-2 contributed to lung accumulation of neutrophils via a chemotactic mechanism. Although oxygenation and venous admixture are worsened by acid-induced lung injury in vivo, blocking of MIP-2 at the onset of injury improved these physiologic alterations. Because the aspiration event often is witnessed, chemokines may be valid therapeutic targets for inhibiting the subsequent inflammatory response.     

Blood pressure reactivity to exercise: stability, determinants, family aggregation, and prediction

Previous studies have shown blood pressure reactivity to exercise predicts future resting blood pressure. Subjects in this study were 206 healthy Mexican-American and Anglo-American families with fifth or sixth grade children. A total of 539 children (mean age = 12 years) and parents (mean age = 37 years) had complete data at baseline, and 79% were remeasured 48 months later. Blood pressure was measured during a submaximal cycle ergometer fitness test. Reactivity measures included systolic blood pressure at 70% of maximal heart rate (SBP70) and slope of the blood pressure-heart rate association during exercise (SLOPE). Stability of reactivity measures over 24 months varied from .22 to .63 (all p less than 0.001). Correlates of blood pressure reactivity in parents included resting heart rate, gender, age, and sodium intake. Correlates of reactivity in children included resting heart rate, body mass index, and age. Modest but significant levels of family aggregation of blood pressure reactivity were observed. In stepwise multiple regression analyses, SBP70 at baseline predicted resting blood pressure 48 months later in parents but not in children. The present results confirm previous studies indicating systolic blood pressure reactivity to exercise is a significant predictor of later resting blood pressure.     

The role of the pediatrician in abolishing corporal punishment in schools. Committee on School Health, American Academy of Pediatrics

Corporal punishment in school is allowed in 30 states in the United States. The American Academy of Pediatrics, together with numerous other child-advocacy groups, has reaffirmed its position that corporal punishment in schools should be prohibited by state statute in all states. This article provides background information and recommendations regarding the potential role for pediatricians in attaining this goal.     

Polycystic ovary syndrome and the androgen-insulin connection

The association of hyperandrogenism, insulin resistance, and polycystic ovarian disease is well established. The accompanying hyperinsulinemia results in acanthosis nigricans, an epiphenomenon of this syndrome. The knowledge that states of insulin resistance of diverse causes are associated with ovarian hyperandrogenism makes the argument for insulin-driven ovarian androgen secretion compelling. However, equally compelling evidence suggests that hyperandrogenism may contribute to insulin resistance and hyperinsulinemia. The irreconcilable differences between these two hypotheses have resulted in an array of contradictory studies. In this article a unified concept of polycystic ovary syndrome and its androgen-insulin connection is proposed. The hypothesis incorporates the role of hyperinsulinemia in the androgen excess observed (and vice versa); the key to this connection is the androgen-dependent change in regional body fat distribution and its metabolic consequence. The pathophysiologic features of polycystic ovary syndrome, which has important clinical sequelae, deserve further consideration.