Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma.

PURPOSE: Nitroglycerin may improve the response to chemotherapy in advanced non-small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported. EXPERIMENTAL DESIGN: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb. RESULTS: The rates of immunoreactive cells for HIF-1alpha, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1alpha in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma. CONCLUSIONS: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1alpha.     

Three-dimensional sonographic features of Hydrops fetalis.

OBJECTIVE: To describe three-dimensional (3-D) sonographic features of hydrops fetalis. METHODS: A total of 6 cases with hydrops fetalis from 15 to 32 weeks of gestation were studied with transabdominal 3-D sonography (3.5 MHz). RESULTS: Before around 20 weeks of gestation, the skin becomes a transparent-like structure, so internal organs can be clearly identified. After 25 weeks, skin edema, pleural effusion, and ascites were well depicted. In the case with pleural effusion, hypoplastic lungs were clearly recognized. CONCLUSION: These results suggest that 3-D sonography provides a novel means of visualizing hydrops fetalis in utero.     

Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information

Precision or personalized medicine is currently gaining a lot of attention. Clinical evidence for its effectiveness has been established based on randomized clinical trials accounting for classical risk factors, such as hypertension, diabetes, and serum lipids. However, besides such classical risk factors, the genetic background should be considered, at least for heritable traits, including atherosclerotic cardiovascular disease (ASCVD). Such classical risk factors are almost always incidents that have already occurred in which it may be too late to start treatment, instead of indicators of presymptomatic state. Human genome information is associated with most traits, including ASCVD. Two methods of implementing precision medicine for ASCVD using human genome information are currently being investigated: the use of rare genetic variations that have large effect sizes and polygenic risk scores that are composed of multiple common genetic variations. This review article emphasizes the importance of clinical as well as genetic diagnoses when implementing precision medicine. Precision medicine should be considered based on comprehensive genetic analyses, encompassing rare to common genetic variations.     

Three-dimensional sonographic volume measurement of the fetal stomach

The objective of this study was to measure the fetal gastric volume using three-dimensional (3-D) ultrasound during pregnancy. Three-dimensional sonographic examinations were performed involving 35 pregnant women from 12 to 38 weeks of gestation. The fetal gastric volume was monitored every 5 min for a minimum of 40 min (40-60 min) in each woman. The rotational technique with Virtual Organ Computer-aided AnaLysis (VOCAL) was used to calculate the fetal gastric volume. Maximum and minimum gastric volumes were curvilinearly associated with the gestational age, respectively (R(2) = 0.611, p < 0.0001, and R(2) = 0.407, p < 0.0001, respectively). A curvilinear relationship was noted between the functional capacity (maximum volume - minimum volume) of the fetal stomach and gestational age (R(2) = 0.531, p < 0.0001). The maximum volume change [(maximum volume - minimum volume/maximum volume) × 100] did not change during pregnancy (mean and standard deviation, 64.1% ± 16.1%). However, gastric emptying cycles could not be determined in this study because of the short observation period and small number of subjects. Our findings suggest that the fetal gastric volume calculated by conventional two-dimensional ultrasound in previous investigations is approximately one-third of the maximum volume using 3-D ultrasound in the present study and that 3-D ultrasound is a superior means of evaluating the fetal gastric volume in utero. However, the data and their interpretation in the present study should be viewed with some degree of caution because of the small number of subjects. Further studies involving a larger sample size are needed to confirm these findings.     

The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis.

The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1(GFP/+)) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (<1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFbetaR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit(+)lin(-)Sca-1(+) (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1(GFP/+) mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.     

Effect of systemic zinc administration on delayed neuronal death in the gerbil hippocampus

The divalent cation zinc has been reported to possess several physiological properties such as blocking apoptotic cell death through an inhibitory effect on Ca²⁺-Mg²⁺ endonuclease activity, or modulating the neurotoxicity via glutamate receptor subtypes. In the present study, we investigated the effect of peripherally injected zinc on delayed neuronal death seen in the hippocampus after transient global ischemia, in order to elucidate a possible beneficial role on zinc in ischemic neuronal cell death. Forty-five adult Mongolian gerbils of both sexes underwent transient bilateral clipping of the common carotid arteries for 3 min. In the pretreated animals, ZnCl₂ (20 mg/kg) was injected subcutaneously once, 1 h before ischemia (superacute group; n=6) or twice at 24 and 48 h before ischemia (subacute group; n=14). Histological survey was carried out 3 days later by in situ DNA fragmentation method and 4 days later by hematoxylin-eosin staining by semiquantatively counting dead neurons in the CA1 sector. Subacute zinc pre-administration significantly reduced the nuclear damage and subsequent neuronal death; however, superacutely pre-administered zinc did not protect hippocampal neurons against ischemia but it did not aggravate the effect of ischemia, either. The present study suggested that transfer of exogenous zinc into the intracellular space is required for neuroprotection, presumably via the anti-endonuclease activity.     

Acquired activated protein C resistance is associated with IgG antibodies to protein S in patients with systemic lupus erythematosus

The objective of this study was to clarify the roles of anti-phospholipid antibodies (aPLs) in the pathogenesis of acquired activated protein C resistance (APC-R) in patients with systemic lupus erythematosus (SLE). We examined several aPLs levels (lupus anticoagulant, anti-cardiolipin antibodies, anti-β2-glycoprotein I antibodies, anti-protein C antibodies, and anti-protein S antibodies), the APC-R test, and the factor V Leiden test in 85 SLE patients. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 26 (30.6%) of 85 patients, and confirmed that acquired APC-R was a significant risk factor for thromboembolic complications [odd ratio (OR), 3.36; 95% confidence interval (CI), 1.24-9.11]. Multivariate logistic analysis revealed that both LA and anti-PS strongly associated with the presence of APC-R, and that the correlation between anti-PS and APC-R was much stronger (OR, 46.7; 95%CI, 6.99-311) than that between LA and APC-R (OR, 11.3; 95%CI, 2.26-57.0). Furthermore, the mean value of APC sensitivity ratios was significantly lower in SLE patients with anti-PS (mean ± SD, 1.68 ± 0.37, p < 0.0001) than in those without anti-PS (2.23 ± 0.40). These results suggest that acquired APC-R is most strongly attributable to functional interference of the APC pathway by anti-PS, which contribute to risk of thromboembolic complications.