Extracellular calcium stimulates Na+-dependent putrescine uptake in B16 melanoma cells

The regulation of putrescine transport in difluoromethylornithine-treated B16 melanoma cells by extracellular Ca2+ has been investigated. It was found that physiological concentrations of Ca2+ were essential for optimum uptake of putrescine and spermidine. Mg2+, albeit at higher concentrations, also could potentiate polyamine transport. The maximum rate of putrescine uptake increased from 1698 +/-: 67 pmol/min/mg DNA in the absence of Ca2+ to 3100 +/- 98 pmol/min/mg DNA in the presence of 0.5 mM Ca2+. There was no change in K-m. While Ca2+ enhanced transport of both putrescine and spermidine it did not affect the uptake of deoxyglucose, thymidine or leucine. Putrescine did not alter Ca2+ fluxes suggesting that the two cations do not share a common transport system. The effects of Ca2+ on putrescine uptake appeared to be mediated extracellularly firstly because Ca2+ did not potentiate putrescine uptake in the presence of A23187 and secondly, because the effects of Ca2+ were completely inhibited by the lanthanide Tb3+, which binds to calcium-dependent proteins and does not readily cross biological membranes. Ca2+ did not affect putrescine transport in the absence of extracellular Na+. Moreover, the rate of putrescine uptake in the absence of Ca2+ was similar to that in the absence of extracellular Na+. The results from this study indicate that polyamine transport is stimulated by extracellular Ca2+ and suggest that Ca2+ is required for activity of the Na+-dependent transporter only. This transporter appears to possess a regulatory binding site for divalent cations. (C) 1997 Elsevier Science Ltd.

Tris(ethylenediamine-N,N')zinc(II) dinitrate

The Zn-II atom in [Zn(C2H8N2)(3)](NO3)(2) has a distorted octahedral geometry of D-3 symmetry With three ethylenediamine bidentate Ligands completing the coordination.

PHASE I/II STUDY OF ERLOTINIB COMBINED WITH CISPLATIN AND RADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m(2) of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase 11 was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase 11 dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months` follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC. (C) 2010 Elsevier Inc.

Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma

Purpose We evaluated the involvement of angiotensin II (AngII)-dependent pathways in melanoma growth, through the pharmacological blockage of AT1 receptor by the antihypertensive drug losartan (LOS). Results We showed immunolabeling for both AngII and the AT1 receptor within the human melanoma microenvironment. Like human melanomas, we showed that murine melanomas also express the AT1 receptor. Growth of murine melanoma, both locally and at distant sites, was limited in mice treated with LOS. The reduction in tumor growth was accompanied by a twofold decrease in tumorassociated microvessel density and by a decrease in CD31 mRNA levels. While no differences were found in the VEGF expression levels in tumors from treated animals, reduction in the expression of the VEGFR1 (Flt-1) at the mRNA and protein levels was observed. We also showed downregulation of mRNA levels of both Flt-4 and its ligand, VEGF-C. Conclusions Together, these results show that blockage of AT1 receptor signaling may be a promising anti-tumor strategy, interfering with angiogenesis by decreasing the expression of angiogenic factor receptors.

Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance

Purpose We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance. Patients and Methods We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD). Results Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001). Conclusion Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

Spin-orbit mixing and nephelauxetic effects in the electronic spectra of nickel(II)-encapsulating complexes involving nitrogen and sulfur donors

A study of spin-orbit mixing and nephelauxetic effects in the electronic spectra of nickel(II)-encapsulating complexes involving mixed nitrogen and sulfur donors is reported. As the number of sulfur donors is systematically varied through the series [Ni(N6-xSx)](2+) (x = 0-6), the spin-forbidden (3)A(2)g --> E-1(g) and (3)A(2g) --> (1)A(1g) transitions undergo a considerable reduction in energy whereas the spin-allowed transitions are relatively unchanged. The [Ni(diAMN(6)sar)](2+) and [Ni(AMN(5)Ssar)](2+) complexes exhibit an unusual band shape for the (3)A(2g) --> T-3(2g) transition which is shown to arise from spin-orbit mixing of the E spin-orbit levels associated with the E-1(g) and T-3(2g) states. A significant differential nephelauxetic effect also arises from the covalency differences between the t(2g) and e(g) orbitals with the result that no single set of Racah B and C interelectron repulsion parameters adequately fit the observed spectra. Using a differential covalency ligand-field model, the spectral transitions are successfully reproduced with three independent variables corresponding to 10Dq and the covalency parameters f(t) and f(e), associated with the t(2g) and e(g) orbitals, respectively. The small decrease in f(t) from unity is largely attributed to central-field covalency effects whereas the dramatic reduction in f(e) with increasing number of sulfur donors is a direct consequence of the increased metal-ligand covalency associated with the sulfur donors. Covalency differences between the t(2g) and e(g) orbitals also result in larger 10Dq values than those obtained simply from the energy of the (3)A(2g) --> T-3(2g) spin-allowed transition.

Genetic basis of the formation and identity of type I and type II neurons in Drosophila embryos

The embryonic peripheral nervous system of Drosophila contains two main types of sensory neurons: type I neurons, which innervate external sense organs and chordotonal organs, and type II multidendritic neurons, Here, we analyse the origin of the difference between type I and type II in the case of the neurons that depend on the proneural genes of the achaete-scute complex (ASC), We show that, in Notch(-) embryos, the type I neurons are missing while type nr neurons are produced in excess, indicating that the type I/type II choice relies on Notch-mediated cell communication, In contrast, both type I and type II neurons are absent in numb(-) embryos and after ubiquitous expression of tramtrack, indicating that the activity of numb and the absence of tramtrack are required to produce both external sense organ and multidendritic neural fates, The analysis of string(-) embryos reveals that when the precursors are unable to divide they differentiate mostly into type II neurons, indicating that the type II is the default neuronal fate, We also report a new mutant phenotype where the ASC-dependent neurons are converted into-type II neurons, providing evidence for the existence of one or more genes required for maintaining the alternative (type I) fate, Our results suggest that the same mechanism of type I/type II specification may operate at a late step of the ASC-dependent lineages, when multidendritic neurons arise as siblings of the external sense organ neurons and, at an early step, when other multidendritic neurons precursors arise as siblings of external sense organ precursors.

Bone mineral and calcium accretion during puberty

We measured bone mineral content (BMC) and estimated calcium accretion in children to provide insight into dietary calcium requirements during growth. Anthropometric measurements were done semiannually and whole-body BMC was measured annually by dual-energy X-ray absorptiometry for 4 y in 228 children (471 scans in 113 boys and 507 scans in 115,girls). Mean values for BMC, skeletal area, and height were calculated for 1-y age groups from 9.5 to 19.5 y of age. Cross-sectional analysis of the pooled data gave peak height velocity and peak BMC velocity (PBMCV) and the ages at which these occurred (13.3 y in boys and 11.4 y in girls). PBMCV did not peak until 1.2 y after peak height velocity in boys and 1.6 y after peak height velocity in girls. Within 3 y on either side of PBMCV, boys had consistently higher BMC and BMC velocity compared with girls and the discrepancy increased steadily through puberty. Three years before PBMCV, BMC Values in girls were 69% of those in boys; 3 y after peak height velocity this proportion fell to 51%. PBMCV was 320 g/y in boys and 240 g/y in girls. Under the assumption that bone mineral is 32.2% calcium, these values corresponded to a daily calcium retention of 282 mg in boys and 212 mg in girls. Individual Values could be much greater. In one boy in a group of six subjects for whom there were enough data for individual analysis through puberty, PBMCV was 555 g Ca/y or 490 mg Ca/d. Such high skeletal demands for calcium require large dietary calcium intakes and such requirements may not be met immediately in some children.

Aerobic conditioning and allergic pulmonary inflammation in mice. II. Effects on lung vascular and parenchymal inflammation and remodeling

Vieira RP, de Andrade VF, Duarte AC, dos Santos AB, Mauad T, Martins MA, Dolhnikoff M, Carvalho CR. Aerobic conditioning and allergic pulmonary inflammation in mice. II. Effects on lung vascular and parenchymal inflammation and remodeling. Am J Physiol Lung Cell Mol Physiol 295: L670-L679, 2008. First published August 29, 2008; doi: 10.1152/ajplung.00465.2007.-Recent evidence suggests that asthma leads to inflammation and remodeling not only in the airways but also in pulmonary vessels and parenchyma. In addition, some studies demonstrated that aerobic training decreases chronic allergic inflammation in the airways; however, its effects on the pulmonary vessels and parenchyma have not been previously evaluated. Our objective was to test the hypothesis that aerobic conditioning reduces inflammation and remodeling in pulmonary vessels and parenchyma in a model of chronic allergic lung inflammation. Balb/c mice were sensitized at days 0, 14, 28, and 42 and challenged with ovalbumin ( OVA) from day 21 to day 50. Aerobic training started on day 21 and continued until day 50. Pulmonary vessel and parenchyma inflammation and remodeling were evaluated by quantitative analysis of eosinophils and mononuclear cells and by collagen and elastin contents and smooth muscle thickness. Immunohistochemistry was performed to quantify the density of positive cells to interleukin (IL)-2, IL-4, IL-5, interferon-gamma, IL-10, monocyte chemotatic protein (MCP)-1, nuclear factor (NF)-kappa B p65, and insulin-like growth factor (IGF)-I. OVA exposure induced pulmonary blood vessels and parenchyma inflammation as well as increased expression of IL-4, IL-5, MCP-1, NF-kappa B p65, and IGF-I by inflammatory cells were reduced by aerobic conditioning. OVA exposure also induced an increase in smooth muscle thickness and elastic and collagen contents in pulmonary vessels, which were reduced by aerobic conditioning. Aerobic conditioning increased the expression of IL-10 in sensitized mice. We conclude that aerobic conditioning decreases pulmonary vascular and parenchymal inflammation and remodeling in this experimental model of chronic allergic lung inflammation in mice.

Macrocycle formation through carbon acid-formaldehyde condensation reactions of bis(propane-1,2-diamine)- and bis (2-methylpropane-1,2-diamine)-copper(II) ions

The reaction of the bis(1,2-diamine) copper(II) complexes of racemic propane-1,2-diamine (pn) and 2-methylpropane-1,2-diamine (dmen) with formaldehyde and nitroethane in methanol under basic conditions yields minor macrocyclic condensation products in addition to the major acyclic products. Where C-pendant methyl groups on the pair of coordinated diamines are in cis dispositions, the first -NH-CH2-C(CH3)(NO2)-CH2-NH- ring formation occurs at amine pairs distant from these C-methyl substituents, and further reaction to yield a macrocycle is not observed. However, where the C-methyl substituents are in trans dispositions, the chemistry proceeds to yield the macrocycle. Commencing with pn, trans-(6,13-diammonio-2,6,9,13-tetramethyl-1,4,7,10-tetraazacyclotetradecane)copper(II) perchlorate formed and crystallized in the space group P2(1)/n, with a 9.782(2), b 9.2794(6), c 17.017(4) Angstrom, beta 103.24(1)degrees. The copper ion is found in a square-planar environment, with the two methyl groups of the pn residues and the pairs of introduced pendant groups all in trans arrangements.

Calcium intake and metabolic bone disease after eight years of Roux-en-Y gastric bypass

Background Roux-en-Y gastric bypass (RYGBP) has been found to be the most efficient way to lose weight and maintain the weight loss in morbid obesity. However, with the formation of a new stomach and the modification of intestinal anatomy, there are significant changes on physiological properties of these organs that lead to nutrient deficiency, including calcium. The objectives of this study were to evaluate calcium intake, bone metabolism, and prevalence of metabolic bone disease in women subjected to RYGBP after 8 years. Methods Food frequency questionnaire and 3-day dietary recall, laboratory tests of bone metabolism and bone mineral density were accessed. Results Calcium intake was below the recommendation in all women. Serum PTH and alkaline phosphatase were elevated, whereas vitamin D and urinary calcium were significantly lower. Also, a higher prevalence of metabolic bone disease than the one expected for the normal population at the same age was noted. Conclusion These data suggest that metabolic bone disease could be a complication of this type of surgery.

Major histocompatibility complex (MHC) class II-positive dendritic cells in the rat iris - In situ development from MHC class II-negative precursors

Purpose. To examine the postnatal development of major histocompatibility complex (MHC) class II-positive dendritic cells (DC) in the iris of the normal rat eye. Methods. Single-and double-color immunomorphologic studies were performed on whole mounts prepared from rat iris taken at selected postnatal ages (2 to 3 days to 78 weeks). Immunopositive cells were enumerated, using a quantitative light microscope, and MHC class II expression on individual cells was assessed by microdensitometric analysis. Results. Major histocompatibility class II-positive DCs in the iris developed in an age-dependent manner and reached adult-equivalent density and structure at approximately 10 weeks of age, considerably later than previously described in other DC populations in the rat. In contrast, the anti-rat DC monoclonal antibody OX62 revealed a population of cells present at adult-equivalent levels as early as 3 weeks after birth. Dual-color immunostaining and microdensitometric analysis demonstrated that during postnatal growth, development of the network of MHC class II-positive DCs was a consequence of the progressive increase in expression of MHC class II antigen by OX62-positive cells. Conclusions. During postnatal growth, the DC population of the iris develops initially as an OX62-positive-MHC class II-negative population, which then develops increasing MHC class II expression in situ and finally resembles classic DC populations in other tissue sites. Maturation of the iris DC population is temporally delayed compared with time to maturation in other tissue sites in the rat.

Calcium potassium tris(oxalato-O-1, O-2)-chromate(III) pentahydrate

The Cr-III atom in CaK[Cr(C2O4)(3)].5H(2)O, has a regular octahedral geometry with three oxalato groups completing the coordination, Both the calcium and potassium cations are coordinated to the O atom of the oxalate group.