IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling

Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8.     

Anabolic growth hormone action improves submaximal measures of physical performance in patients with HIV-associated wasting

Growth hormone (GH) treatment reverses the muscle loss allegedly responsible for diminished aerobic capacity and increased fatigue in patients with HIV-associated wasting. This study examined whether submaximal measures of physical performance can be used as objective measures of the functional impact of GH treatment-induced anabolism. We randomized 27 HIV-positive men [mean (SD) age, 43.9 (7.2) yr; body mass, 71.9 (10.4) kg; BMI, 23.1 (2.8) kg/m2] with unintentional weight loss despite antiretroviral therapy to receive GH (6 mg) or placebo in a double-blinded, placebo-controlled, cross-over trial with a 3-mo washout. Lean body mass (LBM), maximum oxygen uptake (Vo2 peak), ventilatory threshold (VeT), 6-min walk test (6MWT) distance and work, profile of mood states (POMS) fatigue and vigor scores, and Nottingham health profile (NHP) energy and physical mobility scores were measured. LBM significantly increased after 3 mo of GH treatment vs. placebo (means +/- SE, 3.7 +/- 0.6 vs. 0.3 +/- 0.4 kg; P < 0.001). VeT significantly improved (17.6 +/- 3.7 vs. -5.9 +/- 2.5%; P < 0.001), but Vo2 peak did not change significantly. 6MWT distance improved (24.9 +/- 9.7 vs. 19.9 +/- 11.6 m; P > 0.05) and 6MWT work increased significantly more after 3 mo of GH treatment (33.3 +/- 8.8 vs. 16.5 +/- 7.5 kJ; P < 0.05). POMS scores of fatigue and vigor and the NHP score of energy improved, yet the changes were not statistically significant. GH treatment improved VeT linearly to the increase in LBM (r =0.43, P = 0.037) and 6MWT work (r = 0.51, P = 0.008), and the increase in 6MWT work correlated with increase in LBM (r = 0.45, P = 0.024). Improvement in 6MWT work above the median (27.3 kJ) showed a decrease in fatigue (r = -0.62, P = 0.024). We concluded that GH treatment-induced LBM gains in HIV-associated wasting were functionally relevant, as determined by effort-independent submaximal measures of cardiopulmonary exercise testing.     

Statin decreases endothelial microparticle release from human coronary artery endothelial cells: implication for the Rho-kinase pathway

OBJECTIVE: Elevated plasma levels of endothelial microparticles (EMPs) are associated with the presence of clinical atherosclerosis. Considering the anti-inflammatory properties of HMG-CoA reductase inhibitors on the endothelium, we studied the effect of fluvastatin on the release of EMPs in cultured human coronary artery endothelial cells (HCAEC). METHODS AND RESULTS: EMPs were generated in TNF-alpha-activated HCAECs. The absolute number of EMPs was enumerated using a novel two-color flow cytometric immunostaining technique with TruCount beads as an internal reference. EMPs are defined as EC membrane vesicles (1-2 microm in size) with a characteristic immunophenotype. The addition of fluvastatin to TNF-alpha-activated HCAECs significantly suppressed EMP release. Fluvastatin suppressed TNF-alpha-induced Rho activation.The Rho-kinase inhibitor, Y-27632, reproduced the effect of statin. CONCLUSION: EMP release from TNF-alpha-activated HCAECs is suppressed by fluvastatin. In addition, the Rho/Rho-kinase may play an important role in modulating EMP release.     

Reassignment of the methine resonances of D-fructose based on the carbon-13 n.m.r. spectrum of 3-O-methyl-D-fructose

Several disagreements in the ¹³C n.m.r. assignments of the methine carbons of D-fructose exist in the literature. In order to settle these inconsistencies, we examined the ¹³C n.m.r. spectrum of 3-O-methyl-D-fructose. By following the methyl induced shift in this spectrum, as compared to the parent sugar, we identified the alkylated C-3 resonance of all four tautomeric forms of D-fructose. This information, together with our previous identification of the C-5 resonances of the α- and β-forms of D-fructofuranose 6-phosphate, allow the unambiguous identification of all methine carbons of D-fructose in its ¹³C n.m.r. spectrum. The tautomeric composition of 3-O-methyl-D-fructose at 16.5°, in aqueous solution, was found to be as follows: α-pyranose 18%, β-pyranose 37%, α-furanose 11% and β-furanose 34%.     

Tautomeric composition of D-fructose phosphates in solution by fourier transform carbon-13 nuclear magnetic resonance

The Fourier transform ¹³C magnetic resonance spectra of D-fructose 6-phosphate (F6P) and D-fructose 1,6-diphosphate (FDP) were obtained. The signal assignments made on the basis of ¹³C chemical shifts and ¹³C-³¹P spin-spin couplings indicate that the earlier assignments of the C-4 and C-5 resonances of α- and β-fructofuranose in oligosaccharides and D-fructose [Allerhand, A. and Doddrell, D., J. Amer. Chem. Soc., $\text{93}$, 2777, 2779 (1971)] should be reversed. Integration of signal intensities yields the following equilibrium composition at 35°C: F6P, α-anomer 19±2% and β-anomer 81±2%, FDP, α-anomer 23±4% and β-anomer 77±4%. Less than 1.5% keto or hydrated keto form is present in solutions of either fructose phosphate. The bearing of these findings on the tautomeric specificity of phosphofructokinase is discussed.     

Eco-physiological studies on desert plants

Summary The Egyptian Zygophyllum species, though limited in number, contribute in considerable measure to the desert vegetation. They represent a group of succulent plants which are drought resistant or salt tolerant living under severe dry climatic conditions. Their abundance is attributed to these characteristics in addition to their unpalatibility.The distribution of the studied species is deduced from the data collected by the present authors and others working in the Egyptian desert. The growth and distribution of some Zygophyllum species are dependant on the chemical nature of the substratum. Z. occineum is a widespread species in the limestone territories of the Eastern desert. Z. decumbens is confined to a limited area within the borders of the area inhabited by Z. coccineum. Z. album is a salt tolerant plant with wide geographical range growing in dry littoral or inland salt marshes. Z. simplex, the only ephemeral species, has wide geographical and ecological ranges. The soil carbonate content does not exercise any significant effect on its distribution though it is more ecologically related to Z. occineum than the other species. Z. decumbens is ecologically related to Z. coccineum, while Z. album has its own ecological amplitude.     

The Childhood Leukemia International Consortium

Background: Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions. Objectives: The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods: By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions: CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.