Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells

Stromal-derived factor (SDF)-1 and its G protein-coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein-coupled receptor signaling and function of mammalian precursors.     

Prognostic importance of COX-2 expression in patients with colorectal cancer

A relationship between cyclooxygenase-2 (COX-2) expression and the pathogenesis of colorectal cancer has been reported in recent studies. Moreover, it has been indicated that COX-2 expression may have a prognostic role in colorectal cancer patients. In this study, we investigated the prognostic significance of COX-2 expression in 83 patients with colorectal cancer. COX-2 expression was assessed using immunohistochemical methods and was evaluated by grading both staining intensity and staining extension. The relationships between COX-2 expression and clinicopathological features of the patients and patient survival were evaluated. There was no relationships between COX-2 expression and tumor size (tm < 3 cm or tm > or = 3 cm), tumor histopathological differentiation (poorly differentiated or moderately + well differentiated), number of metastatic lymph nodes (< 4 or 3 > or = 4), histopathology of the tumor, localization of the tumor (colon or rectum), distant metastasis, and vascular invasion of the tumor. In the multivariate analysis, COX-2 expression was not found as an independent prognostic factor. We demonstrated that COX-2 expression was not correlated with clinicopathological characteristics of colon carcinoma and disease outcome.     

The relationship between ghrelin and adiponectin levels in breast milk and infant serum and growth of infants during early postnatal life

Ghrelin and adiponectin have been found in breast milk and are considered to take part in the regulation of growth and energy metabolism of infants. Our aims were to determine ghrelin and adiponectin levels in breast milk and serum samples of mothers and their infants, and to investigate the relationship between their levels and anthropometry of newborn infants during early postnatal life. Total and active ghrelin and adiponectin levels were studied in breast milk, and the serum samples of 25 healthy lactating women and their healthy fullterm infants were taken at the 1st and 4th months of life. Anthropometric measurements of infants were also performed during the study period. Breast milk and infant serum active ghrelin levels were found to be significantly increased at the 4th month of life compared with 1st month levels (p < 0.05). Maternal serum total ghrelin and infant serum adiponectin levels were found to be significantly reduced at the 4th month of life (p < 0.05). Breast milk active ghrelin levels were higher than the infant and maternal serum active ghrelin at the 1st and 4th months (p < 0.05). There was a negative significant correlation between the level of infant serum active ghrelin levels and BMI of infants at the 1st month. A positive significant correlation was found between the level of 1st month infant serum adiponectin levels and weight gain of infants during the study period. Fourth month infant serum adiponectin were also positively correlated with weight and BMI of infants at the 4th month and the weight gain during study period. There was a positive significant correlation between the level of 4th month breast milk active ghrelin and weight gain of infants during the study period. Ghrelin and adiponectin are involved in postnatal growth of infants. Ghrelin in breast milk also seems to be related to the growth of infants during early postnatal life. The sources of these peptides in breast milk are probably both maternal serum and breast tissue itself.     

Neuraminidase produces a decrease of adherence of slime-forming <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> to gelatin-impregnated polyester fiber graft fabric: an experimental study

Because slime-forming microorganisms are the major causative agents of graft infections, we aimed to investigate bacterial adherence in slime-forming and nonslime-forming Staphylococcus aureus and to determine the role of neuraminidase (NANase) on adherence to gelatin-impregnated polyester fiber graft fabric. An in vitro model was developed to quantitatively measure bacterial adherence to the surface of the graft. The grafts were divided into two groups – those colonized with slime-forming S. aureus and those colonized with nonslime-forming S. aureus. The grafts were put into sterile tubes and human plasma was instilled and incubated at 37°C to perform fibrin deposition on the grafts. After 48 h of incubation, grafts were drained and inoculated with slime-forming or nonslime-forming S. aureus in triptic soy broth in the presence or absence of NANase. Following 36 h of incubation at 36°C, grafts were vortexed and cultured to perform a colony count. Bacterial counts were expressed as total colony-forming units per square centimeter of graft. Slime-forming S. aureus had greater affinity with the graft compared with nonslime-forming S. aureus (P < 0.05). The adherence of slime-forming S. aureus was impaired by NANase treatment (P < 0.001) but NANase treatment of nonslime-forming S. aureus did not change the adherence to the graft (P > 0.05). These results show that slime plays an important role in the pathogenesis of vascular graft infection. Adherence of slime-forming S. aureus can be decreased by NANase treatment. This may have implications for the development of neuraminidase-embedded vascular grafts to diminish biomaterial-related infections.     

Postnatal Cerebral Cortical Multipotent Progenitors: Regulatory Mechanisms and Potential Role in the Development of Novel Neural Regenerative Strategies

In the developing postnatal cerebral cortex, protracted generation of glia and neurons occurs and precise matching of local cell types is needed for the functional organization of regional microdomains characteristic of complex CNS tissues. Recent studies have suggested that multipotent progenitors play an important role in neural lineage elaboration during neurogenesis and gliogenesis after migration from paramedian generative zones. The presence of a separate reservoir of cerebral cortical multipotent cells under strict local environmental regulation would provide an appropriate mechanism for terminal developmental sculpting and for reconstitution of regional cellular pools after injury. We have isolated distinct pools of EGF- and bFGF-responsive multipotent progenitors from the postnatal mammalian cerebral cortex independent of the subventricular zone. These progenitor populations are under tight environmental regulation by specific hierarchies of cytokine subclasses that program the progressive elaboration of intermediate lineage-restricted progenitors and differentiated type I and II astrocytes, myelinating oligodendrocytes and neuronal subtypes that express specific neuromodulatory proteins. Neural lineage development from these cortical multipotent progenitors is a graded developmental process involving sequential induction of specific cytokine receptors, acquisition of factor responsiveness and complex lineage interdependence. The cortical multipotent progenitor pathways program the elaboration of neural lineage species with distinct cellular response properties when compared with analogous species derived from subventricular zone progenitors, indicating that the cortical multipotent cells contribute to the establishment of lineage diversity within the developing cortical cortex. In addition, the cortical multipotent cells generate dynamic intermediate progenitor pools that utilize temporally-coded environmental cues to alter neural fate decisions. These cumulative observations suggest that postnatal cerebral cortical multipotent cells represent a novel set of progenitor pathways necessary for normal mammalian cortical maturation, and may have important implications for our understanding of a wide variety of neuropathological conditions and for the development of more effective regenerative strategies to combat these pervasive neurological disorders.     

Cell segmentation in histopathological images with deep learning algorithms by utilizing spatial relationships

In many computerized methods for cell detection, segmentation, and classification in digital histopathology that have recently emerged, the task of cell segmentation remains a chief problem for image processing in designing computer-aided diagnosis (CAD) systems. In research and diagnostic studies on cancer, pathologists can use CAD systems as second readers to analyze high-resolution histopathological images. Since cell detection and segmentation are critical for cancer grade assessments, cellular and extracellular structures should primarily be extracted from histopathological images. In response, we sought to identify a useful cell segmentation approach with histopathological images that uses not only prominent deep learning algorithms (i.e., convolutional neural networks, stacked autoencoders, and deep belief networks), but also spatial relationships, information of which is critical for achieving better cell segmentation results. To that end, we collected cellular and extracellular samples from histopathological images by windowing in small patches with various sizes. In experiments, the segmentation accuracies of the methods used improved as the window sizes increased due to the addition of local spatial and contextual information. Once we compared the effects of training sample size and influence of window size, results revealed that the deep learning algorithms, especially convolutional neural networks and partly stacked autoencoders, performed better than conventional methods in cell segmentation.     

Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity

Current evidence strongly suggests that aberrant activation of the nuclear factor kappa B (NF-kB) signaling cascade is connected to carcinogenesis. The matrix metalloproteinases (MMP) which are also the key agents for tumor metastasis may be potent candidates for tumor diagnosis in clinics. In this in vitro study, we hypothesized that metformin with an effective dose can inhibit tumor cell proliferation and metastasis by modulating the expressions of MMP-2 and -9 and interfering with NF-kB signaling in primary breast cancer cells (PBCCs). 300 000 cells per ml were obtained from biopsies of breast tumors from five human donors. The cell viability and proliferation were tested. Immunocytochemistry was performed for MMP-2, MMP-9, and NF-kB, and enzyme-linked immunosorbent assay for NF-kB activity, quantitative real-time PCR for RELA/p65, IkBα, MMP-2, and MMP-9. Three different doses of metformin (5, 10, and 25 mM) (Met) reduced the viability and proliferation of PBCCs in a dose-dependent manner, maximum inhibition was observed at 25 mM Met. The expression of RELA/p65 was not affected by 25 mM Met. Nuclear immunoreactivity and activity of NF-kB reduced while cytoplasmic NF-kB (p65) elevated by 25 mM Met compared to non-treatment (P < 0.05). The expression and immunoreactivity of MMP-9 but not MMP-2 were decreased by 25 mM Met treatment, compared with the non-treatment (P < 0.05). Metformin may have an essential antitumor role in the invasion and metastasis pathways of PBCCs by downregulating the MMP-9 expression blocking both the activity and nuclear translocation of NF-kB.     

Effect of vitamin D deficiency on the 75 g oral glucose tolerance test screening and insulin resistance

Abstract

Gestational diabetes mellitus (GDM), is the most common medical complications of pregnancy. This study aimed to clarify the effect of second-trimester vitamin D deficiency on the 75?g oral glucose tolerance test (OGTT) screening and insulin resistance. A total of 120 pregnant women with a singleton pregnancy at a gestational age of 26–28?weeks were analyzed. Participants were divided into two groups according to 25-hydroxyvitamin D levels; vitamin D deficiency, and control groups. For GDM scan, 75?g OGTT was preferred. GDM prevalence was 17.5% in vitamin D deficiency group and 13.75% in control group, there is no significant difference in GDM prevalence (p?=?0.149). Fasting plasma glucose and 1-h plasma glucose levels were significantly higher in the vitamin D deficiency group than in the control group (p?<?.001 and p?<?.001, respectively). No significant differences were observed between 2-hour plasma glucose levels (p?=?.266). The HOMA-IR level was significantly higher in the vitamin D deficiency group than in the control group (p?<?.001). The findings of the present study suggested that vitamin D deficiency in the second trimester was inversely correlated with fasting and 1-h plasma glucose after 75?g glucose challenge test; also, low 25 OHD₃ levels were associated with insulin resistance.     

Right ventricular involvement in anterior myocardial infarction: a tissue Doppler-derived strain and strain rate study

OBJECTIVE:

Strain and strain rate imaging is currently the most popular echocardiographic technique that reveals subclinical myocardial damage. There are currently no available data on this imaging method with regard to assessing right ventricular involvement in anterior myocardial infarction. Therefore, we aimed to evaluate right ventricular regional functions using a derived strain and strain rate imaging tissue Doppler method in patients who were successfully treated for their first anterior myocardial infarction.

METHODS:

The patient group was composed of 44 patients who had experienced their first anterior myocardial infarction and had undergone successful percutaneous coronary intervention. Twenty patients were selected for the control group. The right ventricular myocardial samplings were performed in three regions: the basal, mid, and apical segments of the lateral wall. The individual myocardial velocity, strain, and strain rate values of each basal, mid, and apical segment were obtained.

RESULTS:

The right ventricular myocardial velocities of the patient group were significantly decreased with respect to all three velocities in the control group. The strain and strain rate values of the right mid and apical ventricular segments in the patient group were significantly lower than those of the control group (excluding the right ventricular basal strain and strain rate). In addition, changes in the right ventricular mean strain and strain rate values were significant.

CONCLUSION:

Right ventricular involvement following anterior myocardial infarction can be assessed using tissue Doppler based strain and strain rate     

Glycopolymer Code: Programming Synthetic Macromolecules for Biological Targeting

Targeting in a cellular level is still one of the major challenges in biomedical treatments. However, new synthetic and analytical techniques now allow the development of precisely prepared macromolecules. Thus, glycopolymer chains are reported to be prepared with controlled length, monomer sequences, as well as chain‐folded structures. A high level of complexity in synthetic macromolecules also allows increased selectivity in targeting, which is a key factor in biomedical applications.