Sulfatide activator protein : alternative splicing that generates three mRNAs and a newly found mutation responsible for a clinical disease

The sulfatide activator protein, also known as SAP-1, is derived from a gene that generates an mRNA coding for four homologous proteins. Its physiological function is to stimulate hydrolysis of sulfatide by arylsulfatase A in vivo. A genetic defect in the sulfatide activator results in a metabolic disorder similar to classical metachromatic leukodystrophy, which is itself caused by a genetic defect in arylsulfatase A. In a patient with sulfatide activator deficiency, a nucleotide transversion G722----C (counted from A of the initiation codon ATG) was found in the mRNA of the sulfatide activator precursor, resulting in the substitution of serine for Cys241 in the mature sulfatide activator. The remainder of the coding sequence was completely normal except for a polymorphism C to T in position 1389, which does not change the amino acid sequence. The patient produces at least three different forms of mRNA for the precursor. Two of them include a stretch of an additional 9 and 6 bases, respectively, within the sulfatide activator coding region. In normal individuals this stretch of additional bases has also been observed. This could be explained by the presence of a small 9-base pair exon which can be introduced, or not, by alternative splicing as a stretch of 9 or 6 bases into the mature mRNA. The shortest form of the mRNA yields an active sulfatide activator (Fürst, W., Schubert, J., Machleidt, W., Meier, H. E., and Sandhoff, K. (1990) Eur. J. Biochem. 192, 709-714)

Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice

Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific deficiency was created in mice by a knock-in mutation of an essential cysteine in exon 7 of the prosaposin locus. No saposin B protein was detected in the homozygotes (B−/−) mice, whereas prosaposin, and saposins A, C and D were at normal levels. B−/− mice exhibited slowly progressive neuromotor deterioration and minor head tremor by 15 months. Excess hydroxy and non-hydroxy fatty acid sulfatide levels were present in brain and kidney. Alcian blue positive (sulfatide) storage cells were found in the brain, spinal cord and kidney. Ultrastructural analyses showed lamellar inclusion material in the kidney, sciatic nerve, brain and spinal cord tissues. Lactosylceramide (LacCer) and globotriaosylceramide (TriCer) were increased in various tissues of B−/− mice supporting the in vivo role of saposin B in the degradation of these lipids. CD68 positive microglial cells and activated GFAP positive astrocytes showed a proinflammatory response in the brains of B−/− mice. These findings delineate the roles of saposin B for the in vivo degradation of several GSLs and its primary function in maintenance of CNS function. B−/− provide a useful model for understanding the contributions of this saposin to GSL metabolism and homeostasis

Final analysis of the ALTTO trial:adjuvant trastuzumab in sequence or in combination with lapatinib in patients with HER2-positive early breast cancer [BIG 2-06/NCCTG N063D (Alliance)]

BACKGROUND: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial.PATIENTS AND METHODS: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety.RESULTS: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups.CONCLUSIONS: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy.</p

Procedures for the detection of circulating tumor cells in peripheral blood of patients with glioblastoma multiforme

Eine klinisch manifeste Metastasierung bei primären Hirntumoren ist ein seltenes Ereignis. Es wird geschätzt, dass es beim Glioblastoma Multiforme nur in 0,2% bis 2% der Erkrankungsfälle zu diesem generalisierten Erkrankungsstadium kommt. Veröffentlichungen aus der Transplantationschirurgie zeigen, dass eine solche okkulte Disseminierung in die parenchymatösen Organe häufiger sein könnte als bislang vermutet. In dieser Arbeit sollte untersucht werden, ob sich zirkulierende Tumorzellen (CTC) im peripheren Blut von Glioblastom-Patienten als Zeichen eines frühen Stadiums der Disseminierung nachweisen lassen. Zum Einsatz kamen Verfahren zur Anreicherung der CTC mit Dichtegradienten, ferromagnetischen Antikörpern und Mikromanipulation. Die Detektion zirkulierender Glioblastom-Tumorzellen erfolgte mit immunologischen Färbeverfahren. Als Markerprotein diente das saure Gliafaserprotein GFAP, das den Hauptbestandteil des Zytoskelettes glialer Zellen stellt. Eine weitere Charakterisierung GFAP-positiver CTC erfolgte mit Fluoreszenz-in-situ-Hybridisierung FISH und komparativer genomischer Hybridisierung CGH. Bei einem vom 12 Glioblastompatienten liessen sich an GFAP-positiven Zellen des peripheren Blutes weitere Malignitätskriterien mit CGH nachweisen. Dies wird als starker Hinweis für das Vorhandensein CTC im Blut von Glioblastompatienten gewertet.Metastasation is a rare event in primary brain tumors. In approximately 0,2% to 2% of the patients clinically overt metastases are detected. Case reports from transplant surgery suggest that a tumor cell dissemination in patients with glioblastoma may occur more often than expected. This study evaluates different procedures for the enrichment and detection of circulating tumor cells CTC from the peripheral blood of patients with glioblastoma using density gradients, immunomagnetic separation and micromanipulation. Via immunologic stains GFAP was detected in these CTC. Further characterisation was performed by FISH and CGH. In one out of 12 patients genomic aberrations as seen in the primary tumor were detected in GFAP-positive CTC by CGH

Coaching: gut beraten

ZusammenfassungManchmal wird man betriebsblind. Ein professioneller Blick von außen hilft, gewohnte Prozesse neu zu bewerten. Lesen Sie mehr über Coaching für Führungskräfte im Pflegemanagement. </jats:p