High expression of focal adhesion kinase (p125<Superscript>FAK</Superscript>) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome

Introduction

Focal adhesion kinase (FAK) regulates multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis. In breast carcinoma, FAK overexpression has been linked to cancer progression but the prognostic relevance remains unknown. In particular, with regard to lymph node-negative breast cancer it is important to identify high-risk patients who would benefit from further adjuvant therapy.

Methods

We analyzed 162 node-negative breast cancer cases to determine the prognostic relevance of FAK expression, and we investigated the relationship of FAK with major associated signaling pathways (HER2, Src, Akt and extracellular regulated kinases) by immunohistochemistry and western blot analysis.

Results

Elevated FAK expression did not predict patient outcome, in contrast to tumor grading (P = 0.005), Akt activation (P = 0.0383) and estrogen receptor status (P = 0.0033). Significant positive correlations were observed between elevated FAK expression and HER2 overexpression (P = 0.001), as well as phospho-Src Tyr-215 (P = 0.021) and phospho-Akt (P < 0.001), but not with phospho-ERK1/2 (P = 0.108). Western blot analysis showed a significant correlation of FAK Tyr-861 activation and HER2 overexpression (P = 0.01).

Conclusions

Immunohistochemical detection of FAK expression is of no prognostic significance in node-negative breast cancer but provides evidence that HER2 is involved in tumor malignancy and metastatic ability of breast cancer through a novel signaling pathway participating FAK and Src.

     

Prolonged mechanical ventilation induces pulmonary inflammation in preterm infants

Lung inflammation plays an important role in the pathogenesis of chronic lung disease in preterm infants. To test the hypothesis that prolonged mechanical ventilation induces pulmonary inflammation, we analyzed pro- and anti-inflammatory mediators in bronchoalveolar lavage fluid obtained from ventilated preterm infants having respiratory distress syndrome. Our results show a strong correlation between the duration of mechanical ventilation and the amount of proinflammatory mediators. However, the anti-inflammatory cytokine interleukin 10 remained stable during the whole period of mechanical ventilation. These data support the hypothesis that prolonged mechanical ventilation contributes to the development of chronic lung disease by the induction of lung inflammation without adequate stimulation of the counterregulatory cytokine interleukin 10 in preterm infants with respiratory distress syndrome.     

The effect of low-dose simvastatin in children with familial hypercholesterolaemia: a 1-year observation

Familial hypercholesterolaemia (FH) is a severe disorder of lipid metabolism associated with an enhanced risk to develop cardiovascular disease later in life, with atherosclerotic lesions beginning already in childhood. These are facts which make an early diagnosis and therapy necessary to prevent or delay such complications. The aim of this study was to investigate the efficacy and safety of low-dose simvastatin, a potent HMG-CoA reductase inhibitor, in children and adolescents with FH. Therefore, 20 children and adolescents (12 females, 8 males) aged between 10 and 17 years with FH were recruited for this 1-year simvastatin study. According to baseline levels of low density lipoprotein (LDL)-C, girls and boys were divided into two groups, one group (with LDL-C <220 mg/dl) starting with a simvastatin dosage of 5 mg/day, the other (with LDL-C >220 mg/dl) 10 mg/day with the possibility to increase dosages up to a daily maximum of 20 mg, if not reaching LDL-C concentrations of <170 mg/dl within the first period. Every 4-8 weeks, weight, height, lipids, Lp(a) and routine safety parameters of all participants were determined by a paediatrician, documenting exactly all side-effects. The percentage decrease was 25% for LDL-C in the 5 mg simvastatin period (19% for total cholesterol (tChol)), 30% for LDL-C in the 10 mg period (26% for tChol) and 36% decrease for LDL-C in the 20 mg period (29% for tChol). The changes for high density lipoprotein (HDL)-C were -5.9% (5 mg), +2.9% (10 mg) and -10.9% (20 mg) the percentage decrease in triglycerides was 12.6% (5 mg), 14.3% (10 mg) and 21% (20 mg). The side-effects of simvastatin were of no clinical relevance and all disappeared after a couple of days.CONCLUSION: our results showed that simvastatin seems to be an effective and safe medical therapy even in children and adolescents with familial hypercholesterolaemia.     

Revascularization of myocardial scar tissue following prostaglandin E1-therapy in patients with ischemic heart disease

Prostaglandin E1 (PGE-1) treatment has proved to stimulate angiogenesis in vital non-infarcted myocardium of patients with ischemic cardiomyopathy (ICMP). We investigated infarcted myocardial tissue for a possible angiogenic response to PGE-1. Neovascularization was investigated in infarcted areas of 12 hearts explanted from patients with ICMP who had been treated with PGE-1 before heart transplantation (HTX). In transmural sections containing myocardial scar tissue, CD34 and VEGF were immunohistochemically quantified to estimate capillary density and the extent of angiogenesis. To investigate a possible effect of PGE-1 on collagen turnover, the collagen content was determined in myocardial scar tissue by assessing the intensity of the area positively stained with sirius red. PGE-1-treated patients had significantly more CD34- and VEGF-positive cells in infarcted areas, and showed a significant reduction in collagen content as compared with the non-PGE-1 group (CD34: 120.3 +/- 6.1 vs. 47.7 +/- 6.1 capillary profiles/mm2; VEGF: 52.8 +/- 5.6 vs. 24.0 +/- 4.8 capillary profiles/mm2, and collagen content: 2.18 +/- 0.4 eU vs. 3.59 +/- 0.38 eU). Our data demonstrate that PGE-1 stimulates angiogenesis by upregulating VEGF expression, and reduces fibrosis in cardiac scar tissue of ischemic origin. The induction of therapeutic angiogenesis in vital and at sites of putative dead myocardial scar tissue, along with the hemodynamic improvement in patients with severe ICMP, might explain the favorable clinical outcome in PGE-1-treated patients before HTX.     

Lung cancer during pregnancy involving the products of conception and a review of the literature

Approximately 1 per 1,000-1,500 pregnancies is complicated by maternal malignancies. Metastatic involvement of the products of conception is a rare event. There have been 62 cases of placental and/or fetal metastatic involvement originating from maternal cancer reported since 1866. Only 14 cases of lung cancer associated with pregnancy have been documented. We report on an additional case involving the products of conception, and the management of lung cancer in pregnancy is discussed based on an extensive review of the literature. The case of a 29-year-old woman presenting during the 31(st) week of gestation with metastatic non small-cell lung cancer to the placenta, liver and bone is described. The mother was delivered by caesarean section of a healthy baby girl during her 32(nd) week of gestation. The mother's postpartum course was complicated by disseminated pulmonary and bony metastases and malignant pericardial and pleural effusions causing the patient's death within 1 month after lung cancer was diagnosed. Malignancies spreading to the products of conception are melanoma (32%), leukemia and lymphomas (15%), breast cancer (13%), lung cancer (11%), sarcoma (8%), gastric cancer (3%) and gynecologic cancers (3%), reflecting malignancies with a high incidence in women of reproductive age. All lung cancers were diagnosed with widely disseminated, inoperable neoplastic disease, including distant metastases in 46%. The mean age was 35.1 years (range, 30-45 years) and 60% of patients had a history of tobacco use. The mean survival was 7.5 months (range: 1-42 months). Placenta involvement was present in 7 out of 15 cases. Fetal involvement was reported in only one case. Because there is no evidence of a direct adverse effect of pregnancy on the course of lung cancer, we recommend delivery at a time when enough fetal maturity can be assumed and the subsequent treatment of the mother.     

Motor-unit coherence during isometric contractions is greater in a hand muscle of older adults

The purpose of this study was to quantify the strength of motor-unit coherence from the first dorsal interosseus muscle in young and old adults using data obtained in a previous study, where no differences in motor-unit synchronization between the two groups were observed. The strength of motor-unit coherence was quantified from 47 motor-unit pairs in 11 young adults (age 24.1 +/- 4.1 yrs) and from 48 motor-unit pairs in 14 old adults (age 70.4 +/- 5.9 yrs). The strength of motor-unit coherence was greater in old adults, particularly at low frequencies of 5-9 Hz (85% greater in old adults at 5 Hz). In addition, the older adults expressed an extra oscillation at approximately 12-13 Hz that was not present in the young subjects. These data demonstrate that common oscillatory inputs to motor neurons (motor-unit coherence) are enhanced in older adults despite no age-related difference in the strength of shared inputs (synchronization). Furthermore, the data emphasize that measures of motor-unit synchronization and coherence highlight different features of the same common input, and a coherence analysis may be a more sensitive tool to characterize shared input to motor neurons.     

Antiprothrombin antibodies are associated with pregnancy loss in patients with the antiphospholipid syndrome

OBJECTIVE: To document the clinical association between the history of pregnancy loss in patients with the diagnosis of primary or secondary antiphospholipid syndrome (APS) and the presence of different antiprothrombin antibody subtypes [immunoglobulin G (IgG), IgM and IgA] in a cohort of patients with APS. METHODS: Records of 170 female patients with primary APS, or APS secondary to systemic lupus erythematosus (SLE) or secondary to other autoimmune diseases were studied. RESULTS: In female APS patients with IgG antiprothrombin antibodies (n = 105) significant associations to pregnancy loss (p < 0.0001), early pregnancy loss (p < 0.0001) and a negative association to thrombocytopenia (p < 0.01) could be identified. In the group of patients with IgG antiprothrombin antibodies and at least one pregnancy (n = 84) a significant association with pregnancy loss (p < 0.005) and especially with early pregnancy loss (p < 0.0001) was demonstrated. No association with other immunoglobulin subtypes of antiprothrombin antibodies could be documented. In the subgroup of patients with primary APS and at least one pregnancy in the history, pregnancy loss (p < 0.005) and early pregnancy loss (p < 0.0001) were found to be highly associated with the presence of IgG antiprothrombin antibodies. IgG antiprothrombin antibodies represent the highest independent risk factor for pregnancy loss with an odds ratio of 4.5. There was no statistically significant association with venous or arterial thrombosis in all IgG antiprothrombin antibody positive patients. CONCLUSION: The results of this study document the association of IgG antiprothrombin antibodies with pregnancy loss and in particular early pregnancy loss in a large and well-characterized cohort of patients. We would recommend routine testing for antiprothrombin antibodies in young female patients with APS.     

Development of a photolytic artificial lung: preliminary concept validation

There is an established need for pulmonary technology capable of facilitated gas exchange in the blood, thereby bypassing the alveolar-capillary interface. To address this need, we emulated one of the best-known photolytic reactions in nature, photosynthesis, in which green plants use sunlight to drive the exchange of oxygen for carbon dioxide. Our goal in the current study was to demonstrate the feasibility of direct photolytic conversion of water to liquid phase oxygen (dissolved oxygen [DO]) in synthetic serum. To this end, we constructed a test flow cell consisting of a conductive coating of vacuum-deposited titanium (Ti) metal, adherent TiO2 (anatase), and MnO2, applied as a laminate to a glass substrate, and then immersed the device in Locke's-Ringer solution (synthetic blood serum). Long wavelength (low energy) ultraviolet A laser light, directed to the transparent glass slide, reproducibly resulted in the generation of an active form of oxygen (AO), which was subsequently converted directly by the catalytic action of MnO2 to DO. The absence of light activation provided an entirely null response. We conclude that the photolytic production of DO from water in a blood serum surrogate, with commensurate CO2 clearance, is feasible. A prototype photolytic module is proposed, which uses multiple parallel photolytic surfaces to improve system production capacity and CO2 clearance through selective gas-liquid separation from the oxygen-enriched fluid.