Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.

Parcours scolaires, accès aux études supérieures et mobilité sociale: comparaison entre la France, la Suisse et le Canada

Le présent article examine dans quelle mesure l’organisation des trajectoires scolaires et les parcours conduisant à l’enseignement supérieur favorisent la mobilité sociale ou au contraire la reproduction des inégalités. Nous avons comparé trois pays : la France, la Suisse et le Canada. Les résultats obtenus à partir des données tirées des panels d’enquêtes menées dans ces trois pays permettent d’observer deux situations opposées. Plus l’enseignement supérieur est valorisé au détriment de la formation professionnelle, plus les inégalités d’accès à l’enseignement supérieur ont tendance à s’exacerber. La compétition y est telle que ce sont les jeunes de milieu favorisé qui tirent davantage profit de son expansion. Par contre, lorsque la formation professionnelle est valorisée, les inégalités auraient plutôt tendance à être modérées.

Whole-exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow-up of a large family.

Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-α (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We utilized whole-exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPα. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mutant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow-up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia.

Inactivation of the p53-KLF4-CEBPA Axis in Acute Myeloid Leukemia.

PURPOSE In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved. EXPERIMENTAL DESIGN One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines. RESULTS We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53-KLF4-CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring non-genotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells. CONCLUSIONS The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments. Clin Cancer Res; 22(3); 746-56. ©2015 AACR.

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.

Functional interplay of SP family members and nuclear factor Y is essential for transcriptional activation of the human Calreticulin gene

Calreticulin (CALR) is a highly conserved, multifunctional protein involved in a variety of cellular processes including the maintenance of intracellular calcium homeostasis, proper protein folding, differentiation and immunogenic cell death. More recently, a crucial role for CALR in the pathogenesis of certain hematologic malignancies was discovered: in clinical subgroups of acute myeloid leukemia, CALR overexpression mediates a block in differentiation, while somatic mutations have been found in the majority of patients with myeloproliferative neoplasms with nonmutated Janus kinase 2 gene (JAK2) or thrombopoietin receptor gene (MPL). However, the mechanisms underlying CALR promoter activation have insufficiently been investigated so far. By dissecting the core promoter region, we could identify a functional TATA-box relevant for transcriptional activation. In addition, we characterized two evolutionary highly conserved cis-regulatory modules (CRMs) within the proximal promoter each composed of one binding site for the transcription factors SP1 and SP3 as well as for the nuclear transcription factor Y (NFY) and we verified binding of these factors to their cognate sites in vitro and in vivo.

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.

CD34+ selected versus unselected autologous stem cell transplantation in patients with advanced-stage mantle cell and diffuse large B-cell lymphoma

Novel strategies aiming to increase survival rates in patients with advanced-stage mantle cell lymphoma (MCL) and relapsing diffuse large B-cell lymphoma (DLBCL) are a clinical need. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has improved progression-free (PFS) and overall survival (OS) in MCL and relapsed DLBCL. However, the role of CD34+ cell selection before ASCT in MCL and DLBCL is unclear. We retrospectively analyzed the outcome of 62 consecutive patients with advanced-stage MCL or relapsed DLBCL undergoing ASCT with (n=31) or without (n=31) prior CD34+ selection. All patients had stage III or IV disease, with 47% having DLBCL and 53% MCL. The median duration for neutrophil and platelet recovery was 12 and 16 days in CD34+ selected patients, and 11 (P<.001) and 14 days (P=.012) in the group without selection, respectively. No differences in toxicities were observed. The 5-year PFS for CD34+ selected versus not selected patients was 67% and 39% (P=.016), and the 5-year OS was 86% and 54% (P=.007). Our data suggest that using CD34+ selected autografts for ASCT in advanced stage MCL and DLBCL is associated with longer PFS and OS without increased toxicity.

DTI and VBM reveal white matter changes without associated gray matter changes in patients with idiopathic restless legs syndrome

BACKGROUND AND PURPOSE We evaluated cerebral white and gray matter changes in patients with iRLS in order to shed light on the pathophysiology of this disease. METHODS Twelve patients with iRLS were compared to 12 age- and sex-matched controls using whole-head diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) techniques. Evaluation of the DTI scans included the voxelwise analysis of the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). RESULTS Diffusion tensor imaging revealed areas of altered FA in subcortical white matter bilaterally, mainly in temporal regions as well as in the right internal capsule, the pons, and the right cerebellum. These changes overlapped with changes in RD. Voxel-based morphometry did not reveal any gray matter alterations. CONCLUSIONS We showed altered diffusion properties in several white matter regions in patients with iRLS. White matter changes could mainly be attributed to changes in RD, a parameter thought to reflect altered myelination. Areas with altered white matter microstructure included areas in the internal capsule which include the corticospinal tract to the lower limbs, thereby supporting studies that suggest changes in sensorimotor pathways associated with RLS.

Panels of cytokines and other secretory proteins as potential biomarkers of ovarian endometriosis.

Endometriosis is a gynecologic disease that is characterized by nonspecific symptoms and invasive diagnostics. To date, there is no adequate noninvasive method for the diagnosis of endometriosis. Although more than 100 potential biomarkers have been investigated in blood and/or peritoneal fluid, none of these has proven useful in clinical practice. The aim to find a suitable panel of biomarkers that would allow noninvasive diagnosis thus remains of interest. We evaluated the concentrations of 16 cytokines and other secretory proteins in serum and peritoneal fluid of 58 women with ovarian endometriosis (cases) and 40 healthy women undergoing sterilization or patients with benign ovarian cysts (controls) using multiplexed double fluorescence-based immunometric assay platform and enzyme-linked immunosorbent assay. Significantly higher concentrations of glycodelin-A were shown in serum, and significantly higher levels of glycodelin-A, IL-6, and IL-8, and lower levels of leptin were measured in the peritoneal fluid of cases versus controls. In serum, the best performance was shown by models that included the ratio of leptin/glycodelin-A and the ratio of ficolin 2/glycodelin-A, whereas in the peritoneal fluid the best models included the ratio of biglycan/leptin, regulated on activation normal T-cell expressed and secreted/IL-6 and ficolin-2/glycodelin-A, and IL-8 per milligram of total protein, all in combination with age. The models using serum and peritoneal fluid distinguished between ovarian endometriosis patients and controls regardless of the menstrual cycle phase with relatively high sensitivity (72.5% to 84.2%), specificity (78.4% to 91.2%), and area under the curve (0.85 to 0.90).

Entwicklung und Implementierung eines Wort-Bild Trainings zur Förderung der Lesefertigkeiten bei Lernschwierigkeiten und / oder onkologischen Erkrankungen des Zentralnervensystems

Neurokognitive Spätfolgen nach pädiatrischem Hirntumor spielen bei der immer grösser werdenden Anzahl von Überlebenden eine wichtige Rolle. Im Bereich der schulischen Fertigkeiten zeigen sich vor allem Defizite in der Lesekompetenz. Die Hauptziele der vorliegenden Studien bestanden darin, Hirnfunktionsstörungen bei einer ausgewählten Gruppe von Kindern und Jugendlichen (Hirntumorpatienten) zum Zeitpunkt der Diagnose zu erfassen, sowie Wissen über alters- und intelligenzunabhängige Einflussmöglichkeiten auf die kognitive Leistung am Beispiel des Lesens bereitzustellen. Insgesamt flossen Daten von rund 180 Kindern und Jugendlichen in die jeweiligen Analysen ein, wobei sowohl ein klinisches Sample (Kinder und Jugendliche mit Krebserkrankungen) als auch Kinder aus unterschiedlichen Altersgruppen und in zwei verschiedenen Schulmodellen (Primarschule und Heilpädagogische Schule) berücksichtigt wurden. Zusammenfassend kann gesagt werden, dass Krebserkrankungen, welche das zentrale Nervensystem betreffen, schon zum Zeitpunkt der Diagnose Auswirkungen auf basale neurokognitive Fähigkeiten haben. Diese Defizite können zu einer Verzögerung der neurokognitiven Entwicklung beitragen. Daher müssen möglichst früh pädagogische und/oder therapeutische Massnahmen eingeleitet werden, welche in den Patienten- und Schulalltag implementiert werden können. Das hier vorgestellte neu entwickelte Wort-Bild-Training, das in einem ersten Schritt bei normalbegabten und geistig behinderten Kindern verschiedener Altersstufen positive Effekte auf die Verbesserung der Lesefertigkeit und des Leseverständnisses gezeigt hat, könnte ebenfalls eine wertvolle Fördermöglichkeit für Kinder mit Hirnfunktionsstörungen aufgrund onkologischer Erkrankungen darstellen. Obwohl die erreichte Verbesserung der Lesekompetenz eher klein ausfiel, wiesen die Effekte zumindest über kurze Zeit eine gewisse Stabilität auf. Dieser Befund spricht für die Möglichkeit der Einflussnahme auf die Leseprozesse durch das (auf implizitem statistischen Lernen basierende) Training, widerspiegelt gleichzeitig aber auch deren Grenzen. Das gewonnene Wissen wird in Bezug auf die Relevanz für die klinische und pädagogische Praxis diskutiert. Ausgehend von den eigenen Studienergebnissen wird schliesslich angeregt, impliziten Lernstrategien in den Lehrplänen einen höheren Stellenwert einzuräumen und mit der Förderung von einfachen Lesestrategien bei pädiatrischen Hirntumorpatienten möglichst frühzeitig zu beginnen.

Transitionen im Jugend- und jungen Erwachsenenalter: Ergebnisse der Schweizer Längsschnittstudie TREE

Nach dem ersten, 2011 erschienenen Band versammelt der vorliegende zweite wiederum eine Auswahl von Beiträgen, die auf Analysen der Daten der Schweizer Längsschnittstudie TREE (Transitionen von der Erstausbildung ins Erwerbsleben) basieren. Die kritischen Übergänge im Jugend- und jungen Erwachsenenalter werden aus soziologischen, ökonomischen, psychologischen und erziehungswissenschaftlichen Blickwinkeln beleuchtet. Die Beiträge widerspiegeln damit eindrücklich das analytische und interdisziplinäre Potenzial der TREE-Daten. Thematisch steht der langfristige Einfluss der sozialen Herkunft auf Bildungs- und Erwerbsverläufe, insbesondere auf den Zugang zu höherer Bildung, im Zentrum.

Leistung oder soziale Herkunft? Bestimmungsfaktoren für erwarteten und tatsächlichen beruflichen Erfolg im jungen Erwachsenenalter

Welchen berulichen Status haben junge Erwachsene in der Schweiz zehn Jahre nach Beendigung der obligatorischen Schule im Alter von durchschnittlich 26 Jahren erreicht – und welche Faktoren beeinlussen ihn? Wie nehmen junge Erwachsene ihren Status im Vergleich zum elterlichen wahr und wie, denken sie, wird er sich in Zukunt noch verändern? Diese Forschungsfragen werden auf der Basis der TREE-Daten (Transitionen von der Erstausbildung ins Erwerbsleben) analysiert. Die Ergebnisse dieses Beitrags zeigen, dass viele 26-Jährige den elterlichen Status bereits erreicht haben, in Zukunt aber noch mit einem weiteren Statusanstieg rechnen. Askriptive Merkmale wie Geschlecht, soziale Herkunt und Migrationshintergrund sowie der auf Sekundarstufe I besuchte Schultyp haben unter sonst vergleichbaren Bedingungen über den ganzen Bildungsverlauf hinweg einen bedeutsamen Einluss auf den berulichen Status. Dies deutet einerseits auf eine vergleichsweise hohe Status-“Vererblichkeit“ zwischen den Generationen hin, andererseits auf erhebliche Verletzungen des meritokratischen Prinzips, wonach für den Bildungserfolg und die erreichte Position in der Gesellschat vor allem die individuelle Leistung massgeblich sein sollte.