Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance.

Neuroblastoma (NB) is a pediatric tumor of neural crest origin with heterogeneous phenotypes. Although low-stage tumors carry a favorable prognosis, >50% of high-risk NB relapses after treatment with a fatal outcome. Thus developing therapies targeting refractory NB remains an unsolved clinical problem. Brain-derived neurotrophic factor (BDNF) and its TrkB receptor are known to protect NB cells from chemotherapy-induced cell death, while neuropeptide Y (NPY), acting via its Y2 receptor (Y2R), is an autocrine proliferative and angiogenic factor crucial for maintaining NB tumor growth. Here we show that in NB cells, BDNF stimulates the synthesis of NPY and induces expression of another one of its receptors, Y5R. In human NB tissues, the expression of NPY and Y5R positively correlated with the expression of BDNF and TrkB. Functionally, BDNF triggered Y5R internalization in NB cells, whereas Y5R antagonist inhibited BDNF-induced p44/42 mitogen-activated protein kinase activation and its pro-survival activity. These observations suggested TrkB-Y5R transactivation that resulted in cross-talk between their signaling pathways. Additionally, NPY and Y5R were upregulated in a BDNF-independent manner in NB cells under pro-apoptotic conditions, such as serum deprivation and chemotherapy, as well as in cell lines and tissues derived from posttreatment NB tumors. Blocking Y5R in chemoresistant NB cells rich in this receptor sensitized them to chemotherapy-induced apoptosis and inhibited their growth in vivo by augmenting cell death. In summary, the NPY/Y5R axis is an inducible survival pathway activated in NB by BDNF or cellular stress. Upon such activation, Y5R augments the pro-survival effect of BDNF via its interactions with TrkB receptor and exerts an additional BDNF-independent anti-apoptotic effect, both of which contribute to NB chemoresistance. Therefore, the NPY/Y5R pathway may become a novel therapeutic target for patients with refractory NB, thus far an incurable form of this disease.

Interleukin 1-ß, interleukin-1 receptor antagonist, and interleukin 18 in children with acute spontaneous urticaria.

UNLABELLED: Very little is known about the role of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in urticaria. MATERIAL AND METHODS: Serum levels of IL-1ß, IL-1 receptor antagonist (IL-1RA), and IL-18 were measured in 56 children with urticaria and in 41 healthy subjects. RESULTS: Serum IL-1ß did not differ between children with acute urticaria and controls. Children with single episode of urticaria had higher levels of IL-1RA and IL-18 than healthy subjects. In children with single episode of urticaria, level of IL-1RA correlated with C-reactive protein (CRP), D-dimer, and IL-1ß levels. In subjects with recurrence of urticaria IL-1RA was positively correlated with WBC and D-dimer levels. No correlation of cytokine levels and urticaria severity scores (UAS) in all children with urticaria was observed. In children with single episode of urticaria UAS correlated with CRP level. In the group with single episode of urticaria and in children with symptoms of upper respiratory infection, IL-1RA and IL-18 levels were higher than in controls. The former was higher than in noninfected children with urticaria. In conclusion, this preliminary study documents that serum IL-1RA and IL-18 levels are increased in some children with acute urticaria. However further studies are necessary to define a pathogenic role of IL-1ß, IL-1RA, and IL-18 in urticaria.

Myelodysplastic syndromes according to FAB and WHO classification. Single center experience.

The results of clinical and laboratory observations of 119 MDS patients divided acc. to FAB, and - after excluding RAEB-t and CMML groups -- of 95 patients divided accordingly to WHO classification are presented. The diagnosis of MDS was based on medical interview, physical examination, blood biochemistry, peripheral blood (PB) and bone marrow (BM) cytomorphology and cytochemistry, trephine biopsy and cytogenetic examination. All hematologic examinations were done according to routine methods. Cytogenetic analyses were carried out on BM cells from 24-48 h cultures in standard conditions. At least 15-20 GTG-banded metaphases were analyzed in every patient. The survival time (ST) of patients differed significantly between the FAB or WHO groups, with p=0.0004 for FAB and p=0.02 for WHO. The progression to AML was more common in less favorable groups, with p=0.0001 for FAB and p=0.00016 for WHO. The distribution of IPSS prognostic index among the groups showed statistically significant difference (p=0.0004 for FAB, and p=0.0001 for WHO), whereas the distribution of karyotypic abnormalities did not. However, in univariate analysis statistically significant influence on ST showed, beside the both classification systems: cytogenetics, the presence of blasts in PB, age and IPSS index. In multivariate analysis the sole independent prognostic factors were: PB blasts and cytogenetics. The authors conclude that the WHO classification offers a good prognostic tool for MDS patients. However, the karyotype and the presence of blasts in PB should always be taken into account.

[Rheumatoid arthritis as a risk factor for development of multiple myeloma]. / Reumatoidalne zapalenie stawów jako czynnik ryzyka w rozwoju szpiczaka plazmocytowego.

7 out of 154 patients with multiple myeloma (MM) with concomitant rheumatoid arthritis (RA) (5 persons) and Bechterev disease (BD) (2 persons) have been presented. There were 5 women and 2 men at age from 52 to 67 years. Four of them had joint's disease for 4, 5, 24 and 25 years prior to MM, and in the next there MM was diagnosed simultaneously with RA. Two patients are still living (50 and 55 months from the diagnosis of MM), the mean survival time of the five already dead was 34.5 months, and did not differ from the survival of patients with MM alone. The contribution of interleukin-6 (Il-6) and adhesion molecules ICAM-1, VCAM-1, CD44 in pathogenesis of both diseases are discussed.

[Usefulness of the phototherapy lamp in treating hyperbilirubinemia in newborn infants]. / Przydatnosc lampy do fototerapii w modyfikacji wlasnej w leczeniu hiperbilirubinemi u noworodków.

An efficiency of the treatment of jaundice with the lamp for phototherapy in own modification has been discussed. The lamp was used for the treatment of 82 neonates divided into three groups depending on the type of therapy: group I included 43 neonates treated with phototherapy alone; group II--32 neonates treated with phototherapy combined with blood transfusions, and group III--7 neonates treated with exchange blood transfusions alone. A mean time of irradiation in neonates of group I did not differ significantly from that used in group II (combined therapy) and did not depend on the cause of the jaundice. The number of blood transfusions decreased markedly with the use of phototherapy carried out with the lamp in own modification. This lamp proved highly effective in the treatment of the jaundice of various etiology and is the method of choice in case of life-threaten neonates.

Psychological aspects of the symptomatology and clinical course of myocardial infarction.

Randomly selected males who suffered from myocardial infarction (MI) were examined. The investigated group was subdivided into two: the patients with no ischemic heart disease (IHD) preceding MI and patients with IHD symptoms occurring prior to MI. The compared groups differed significantly in some psychological parameters and clinical features of MI.

Influence of sodium palmitate on the cellular action of potentials of the left ventricle of isolated, perfused guinea-pig heart.

Influence of sodium palmitate on the cellular action potentials of the left ventricle of isolated, perfused guinea-pig heart. Acta Physiol. Pol. 1975, 26 (1): 1-11. Transmembrane action potentials (APs) were recorded from the left ventricle and glucose uptake was estimated in the isolated guinea-pig hearts perfused with Langendorff method. After the control period the perfusion fluid was changed for the solution of altered composition containing: 1) 0.5 mM of palmitate complexed with 4% albumin and no glucose; 2) 0.1 mM or 0.5 mM of palmitate added to solution containing 11 mM of glucose; 3) substrate-free solution; 4) solution equilibrated with 5% CO-2 + 95% N-2. In all experimental groups marked shortening of AP duration was observed accompanied by the shortening of the functional refractory period and by the desynchronization of repolarization. The effect of perfusion with the substrate-free solution was similar to that evoked by substituting palmitate for glucose. In all the groups except for anoxia, fibrillation either occurred spontaneously or it was evoked by early extra stimuli. Fibrillation was reversible in all groups except for substitution 0.5 mM palmitate for glucose. Under anoxic conditions loss of excitability was observed, and shortening of AP was smaller than under palmitate. Glucose uptake was inhibited by 30% in the presence of 0.5 mM of palmitate, but not by 0.1 mM of palmitate. Thus changes in the shape of AP are not related to the glucose uptake. The possible effect of palmitate on inhibition of cellular respiration and glycolysis is discussed.