Stem cell mobilization chemotherapy with gemcitabine is effective and safe in myeloma patients with bortezomib-induced neurotoxicity.

Vinorelbine chemotherapy with granulocyte-colony stimulating factor (G-CSF) stimulation is a widely applied non-myelosuppressive mobilization regimen in Switzerland for myeloma patients, but its neurotoxic potential limits its use in patients with bortezomib-induced polyneuropathy. In this single-center study, we alternatively evaluated safety and effectiveness of gemcitabine chemotherapy with G-CSF for mobilization of autologous stem cells. Between March 2012 and February 2013, all bortezomib-pretreated myeloma patients planned to undergo first-line high-dose melphalan chemotherapy received a single dose of 1250 mg/m(2) gemcitabine, with G-CSF started on day 4. The 24 patients in this study had received a median of four cycles of bortezomib-dexamethason-based induction. Bortezomib-related polyneuropathy was identified in 21 patients (88%) by clinical evaluation and a standardized questionnaire. Administration of gemcitabine mobilization did not induce new or aggravate pre-existing neuropathy. Stem cell mobilization was successful in all 24 patients, with a single day of apheresis being sufficient in 19 patients (78%). The median yield was 9.51 × 10(6) CD34+ cells/kg. Stem collection could be accomplished at day 8 in 67%. Our data suggest that single-dose gemcitabine together with G-CSF is an effective mobilization regimen in myeloma patients and a safe alternative non-myelosuppressive mobilization chemotherapy for myeloma patients with bortezomib-induced polyneuropathy.

Neurotoxicity of stem cell mobilization chemotherapy with vinorelbine in myeloma patients after bortezomib treatment.

Vinorelbine chemotherapy with G-CSF stimulation is the standard mobilization regimen in Switzerland for multiple myeloma patients. However, with the increasing use of bortezomib during induction treatment, adding the neurotoxic compound vinorelbine for mobilization may aggravate bortezomib-induced polyneuropathy. In this retrospective single-center study, we aimed to explore vinorelbine mediated neuropathy in 106 consecutive bortezomib pretreated myeloma patients. We confirmed that vinorelbine with G-CSF represents a reliable and effective regimen for mobilization of autologous stem cells. However, the single administration of 35 mg/m(2) vinorelbine added significant neurotoxicity. We found that 24 patients (24%) reported vinorelbine mediated neurotoxicity: Aggravation of bortezomib-induced neuropathy was observed in 17 patients (17%), and vinorelbine mobilization induced first occurrence of polyneuropathy in additional 7 patients (7%). We observed that development of polyneuropathy was not associated with differing survival rates. Finally, affected patients reported polyneuropathy associated disease burden as "very high" in 13% and "high" in 50%. Our data indicate that a single administration of vinorelbine to mobilize autologous stem cells is associated with significant additional polyneuropathy in bortezomib pretreated myeloma patients. The efficacy of vinorelbine mobilization should be balanced against its neurotoxic potential.

Decreased phosphatidylcholine plasmalogens - A putative novel lipid signature in patients with stable coronary artery disease and acute myocardial infarction.

OBJECTIVE Glycerophospholipids and sphingolipids are structurally heterogeneous due to differences in the O- and N-linked fatty acids and head groups. Sphingolipids also show a heterogeneity in their sphingoid base composition which up to now has been little appreciated. The aim of this study was to investigate the association of certain glycerophospholipid and sphingolipid species with stable coronary artery disease (CAD) and acute myocardial infarction (AMI). METHODS The lipid profile in plasma from patients with stable CAD (n = 18) or AMI (n = 17) was compared to healthy subjects (n = 14). Sixty five glycerophospholipid and sphingolipid species were quantified by LC-MS. The relative distribution of these lipids into lipoprotein fractions was analyzed. RESULTS In the CAD cohort, 45 glycerophospholipid and sphingolipid species were significantly lower compared to healthy controls. In the AMI group, 42 glycerophospholipid and sphingolipid species were reduced. Four PC plasmalogens (PC33:1, PC33:2, PC33:3 and PC35:3) showed the most significant difference. Out of eleven analyzed sphingoid bases, four were lower in the CAD and six in the AMI group. Sphingosine-1-phosphate (S1P) levels were reduced in the AMI group whereas an atypical C16:1 S1P was lower in both groups. Phosphatidylcholine and sphingomyelin species were exclusively present in lipoprotein particles, whereas lysophosphatidylcholines were mainly found in the lipoprotein-free fraction. The observed differences were not explained by the use of statins as confirmed in a second, independent cohort. CONCLUSIONS Reduced levels of four PC plasmalogens (PC33:1, PC33:2, PC33:3 and PC35:3) were identified as a putatively novel lipid signature for CAD and AMI.

Racing against Time: Varying Patterns of Social Mobilization in Serbia and Georgia

After the collapse of the Soviet Union and Yugoslavia, a number of actors started to engage in the power struggle for the opportunities to shape the new order in successive nation-states. In Serbia and Georgia historically hegemonic Orthodox Christian churches were among the firsts in the frontlines for political and economic power. More than a decade has passed since the so-called Coloured Revolutions in Georgia and Serbia, and the Orthodox churches still remain participants of an ongoing socio-political transition of these states. The revival of public role of religion appeared temporary in Serbia followed by a gradual decline of an influence of the Orthodox Church over political life and legal process. However, in Georgia the public and political role of religion increased rather than declined albeit changed shape. Examining the degree to which the two Orthodox churches can influence the political agenda in Serbia and Georgia, the paper attempts to understand how church-State relations work in practice. By bringing rich empirical data from the field (70 interviews with (arch)bishops, priests and religious clerics in Georgia and Serbia added to field observations), the paper reflects on the themes under which the two Orthodox churches mobilize public protest in Serbia and Georgia. The paper further looks at varying State responses and their broader implication for church-state problematique.

Lipid topogenesis - 35years on

Glycerophospholipids are the principal fabric of cellular membranes. The pathways by which these lipids are synthesized were elucidated mainly through the work of Kennedy and colleagues in the late 1950s and early 1960s. Subsequently, attention turned to cell biological aspects of lipids: Where in the cell are lipids synthesized? How are lipids integrated into membranes to form a bilayer? How are they sorted and transported from their site of synthesis to other cellular destinations? These topics, collectively termed 'lipid topogenesis', were the subject of a review article in 1981 by Bell, Ballas and Coleman. We now assess what has been learned about early events of lipid topogenesis, i.e. "lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes", in the 35years since the publication of this important review. We highlight the recent elucidation of the X-ray structures of key membrane enzymes of glycerophospholipid synthesis, progress on identifying lipid scramblase proteins needed to equilibrate lipids across membranes, and new complexities in the subcellular location and membrane topology of phosphatidylinositol synthesis revealed through a comparison of two unicellular model eukaryotes.

Sediment mobilization deposits from episodic subsurface fluid flow—A new tool to reveal long-term earthquake records?

Subsurface fluid flow can be affected by earthquakes; increased spring activity, mud vol- cano eruptions, groundwater fluctuations, changes in geyser frequency, and other forms of altered subsurface fluid flow have been documented during, after, or even prior to seismic shaking. Recently discovered giant pockmarks on the bottom of Lake Neuchâtel, Switzerland, are the lake-floor expression of subsurface fluid flow. They discharge groundwater from the Jura Mountains karstic aquifers and experience episodically increased subsurface fluid flow documented by subsurface sediment mobilization deposits at the levees of the pockmarks. In this study, we present the spatio-temporal distribution of event deposits from these phases of sediment expulsion and of multiple time-correlative mass-transport deposits. We report five striking instances of concurrent multiple subsurface sediment deposits and multiple mass- transport deposits since late glacial times, for which we propose past earthquakes as a trigger. Comparison of this new event catalogue with historic earthquakes and other independent paleoseismic records suggests that initiation of sediment expulsion requires a minimum mac- roseismic intensity of VII. Thus, our study presents for the first time sedimentary deposits resulting from increased subsurface fluid flow as a paleoseismic proxy.

Membrane Lipid Integrity Relies on a Threshold of ATP Production Rate in Potato Cell Cultures Submitted to Anoxia

In this paper we report on our study of the changes in biomass, lipid composition, and fermentation end products, as well as in the ATP level and synthesis rate in cultivated potato (Solanum tuberosum) cells submitted to anoxia stress. During the first phase of about 12 h, cells coped with the reduced energy supply brought about by fermentation and their membrane lipids remained intact. The second phase (12–24 h), during which the energy supply dropped down to 1% to 2% of its maximal theoretical normoxic value, was characterized by an extensive hydrolysis of membrane lipids to free fatty acids. This autolytic process was ascribed to the activation of a lipolytic acyl hydrolase. Cells were also treated under normoxia with inhibitors known to interfere with energy metabolism. Carbonyl-cyanide-4-trifluoromethoxyphenylhydrazone did not induce lipid hydrolysis, which was also the case when sodium azide or salicylhydroxamic acid were fed separately. However, the simultaneous use of sodium azide plus salicylhydroxamic acid or 2-deoxy-D-glucose plus iodoacetate with normoxic cells promoted a lipid hydrolysis pattern similar to that seen in anoxic cells. Therefore, a threshold exists in the rate of ATP synthesis (approximately 10 μmol g−1 fresh weight h−1), below which the integrity of the membranes in anoxic potato cells cannot be preserved.