Receptor regulation of the volume-sensitive efflux of taurine and iodide from human SH-SY5Y neuroblastoma cells: differential requirements for Ca(2+) and protein kinase C

The basal (swelling-induced) and receptor-stimulated effluxes of (125)I(-) and taurine have been monitored to determine whether these two osmolytes are released from human SH-SY5Y cells under hypotonic conditions via common or distinct mechanisms. Under basal conditions, both (125)I(-) (used as a tracer for Cl(-)) and taurine were released from the cells in a volume-dependent manner. The addition of thrombin, mediated via the proteinase-activated receptor-1 (PAR-1) subtype, significantly enhanced the release of both (125)I(-) and taurine (3-6-fold) and also increased the threshold osmolarity for efflux of these osmolytes ("set-point") from 200 to 290 mOsM. Inclusion of a variety of broad-spectrum anion channel blockers and of 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid attenuated the release of both (125)I(-) and taurine under basal and receptor-stimulated conditions. Basal release of (125)I(-) and taurine was independent of Ca(2+) or the activity of protein kinase C (PKC). However, although PAR-1-stimulated taurine efflux was attenuated by either a depletion of intracellular Ca(2+) or inhibition of PKC by chelerythrine, the enhanced release of (125)I(-) was independent of both parameters. Stimulated efflux of (125)I(-) after activation of muscarinic cholinergic receptors was also markedly less dependent on Ca(2+) availability and PKC activity than that observed for taurine release. These results indicate that, although the osmosensitive release of these two osmolytes from SH-SY5Y cells may occur via pharmacologically similar membrane channels, the receptor-mediated release of (125)I(-) and taurine is differentially regulated by PKC activity and Ca(2+) availability.     

No One-Size-Fits-All: Sexual Health Education Preferences in Patients with Breast Cancer

Annals of Surgical Oncology - Using explanatory mixed methods, we characterize the education that patients with breast cancer received about potential sexual health effects of treatment and explore...     

Adverse Tumor Biology Associated with Mesenterico-Portal Vein Resection Influences Survival in Patients with Pancreatic Ductal Adenocarcinoma

Background

Although pancreatoduodenectomy (PD) with mesenterico-portal vein resection (VR) can be performed safely in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the impact of this approach on long-term survival is controversial.

Patients and Methods

Analyses of a prospectively collected database revealed 122 consecutive patients with PDAC who underwent PD with (PD+VR) or without (PD?VR) VR between January 2004 and May 2012. Clinical data, operative results, and survival outcomes were analysed.

Results

Sixty-four (53 %) patients underwent PD+VR. The majority (84 %) of the venous reconstructions were performed with a primary end-to-end anastomosis. Demographic and postoperative outcomes were similar between the two groups. American Society of Anesthesiologists (ASA) score, duration of operation, intraoperative blood loss, and blood transfusion requirement were significantly greater in the PD+VR group compared with the PD?VR group. Furthermore, the tumor size was larger, and the rates of periuncinate neural invasion and positive resection margin were higher in the PD+VR group compared with the PD?VR group. Histological venous involvement occurred in 47 of 62 (76 %) patients in the PD+VR group. At a median follow-up of 29 months, the median overall survival (OS) was 18 months for the PD+VR group, and 31 months for the PD?VR group (p = 0.016). ASA score, lymph node metastasis, neurovascular invasion, and tumor differentiation were predictive of survival. The need for VR in itself was not prognostic of survival.

Conclusions

PD with VR has similar morbidity but worse OS compared with a PD?VR. Although VR is not predictive of survival, tumors requiring a PD+VR have more adverse biological features.     

Three-dimensional echocardiography of mitral Barlow's disease with infective endocarditis: Perforations or cleft-like indentations?

Barlow's disease is a complicated form of degenerative mitral valve (MV) disease. Infective endocarditis (IE) often occurs on the basis of primary heart diseases and may be combined with valve perforations. Cleft-like indentations (CLIs) were suggested by Ring et al. in 2013. They are located at the inter-scallop position and involve at least one-half of the valve. Herein, we report a case of Barlow's disease combined with IE and CLIs, which was confirmed intra-operatively and by histopathological examination. The CLIs were misdiagnosed by two-dimensional transthoracic echocardiography as perforations, but rightly interpreted by preoperative three-dimensional echocardiography. The possibility of CLIs should be considered in the evaluation of mitral regurgitation caused by myxomatous MV diseases.     

Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q)

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL- 3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).     

A randomized study of high-dose cytarabine in induction in acute myeloid leukemia [see comments]

High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3-7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7-3-7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC- 3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3- 7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC- 3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.     

Plasma cells induce apoptosis of pre-B cells by interacting with bone marrow stromal cells

By using two-color phenotypic analysis with fluorescein isothiocyanate- anti-CD38 and phycoerythrin-anti-CD19 antibodies, we found that pre-B cells (CD38+CD19+) signifcantly decreased depending on the number of plasma cells (CD38++CD19+) in the bone marrow (BM) in the cases with BM plasmacytosis, such as myelomas and even polyclonal gammopathy. To clarify how plasma cells suppress survival of pre-B cells, we examined the effect of plasma cells on the survival of pre-B cells with or without BM-derived stromal cells in vitro. Pre-B cells alone rapidly entered apoptosis, but interleukin-7 (IL-7), a BM stromal cell line (KM- 102), or culture supernatants of KM-102 cells could support pre-B cell survival. On the other hand, inhibitory factors such as transforming growth factor-beta1 (TGF-beta1) and macrophage inflammatory protein- 1beta (MIP-1beta) could suppress survival of pre-B cells even in the presence of IL-7. Plasma cells alone could not suppress survival of pre- B cells in the presence of IL-7, but coculture of plasma cells with KM- 102 cells or primary BM stromal cells induced apoptosis of pre-B cells. Supernatants of coculture with KM-102 and myeloma cell lines (KMS-5) also could suppress survival of pre-B cells. Furthermore, we examined the expression of IL-7, TGF-beta1, and MIP-1beta mRNA in KM-102 cells and primary stromal cells cocultured with myeloma cell lines (KMS-5). In these cells, IL-7 mRNA was downregulated, but the expression of TGF- beta1 and MIP-1beta mRNA was augmented. Therefore, these results suggest that BM-derived stromal cells attached to plasma (myeloma) cells were modulated to secrete lesser levels of supporting factor (IL- 7) and higher levels of inhibitory factors (TGF-beta1 and MIP-1beta) for pre-B cell survival, which could explain why the increased number of plasma (myeloma) cells induced suppression of pre-B cells in the BM. This phenomenon may represent a feedback loop between pre-B cells and plasma cells via BM stromal cells in the BM.