University of Kiel

About: University of Kiel is a education organization based out in Kiel, Germany. It is known for research contribution in the topics: Population & Transplantation. The organization has 27816 authors who have published 57114 publications receiving 2061802 citations. The organization is also known as: Christian Albrechts University & Christian-Albrechts-Universität zu Kiel.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma

Abstract: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Treatment of Older Patients with Mantle-Cell Lymphoma

Abstract: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of ritux imab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to main tenance therapy with rituximab or interferon alfa, each given until progression. RESULTS Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P = 0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P = 0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects oc curred more frequently in the R-FC group than in the R-CHOP group, but the fre quency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% con fidence interval, 0.36 to 0.87; P = 0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall sur vival (4-year survival rate, 87%, vs. 63% with interferon alfa; P = 0.005). CONCLUSIONS R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.)

Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death.

Abstract: Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic carcinoma patients. The current study examined the relevance of nuclear factor kappaB (NF-kappaB) and PI3K/Akt in the resistance of five pancreatic carcinoma cell lines towards gemcitabine. Treatment for 24 h with gemcitabine (0.04-20 micro M) led to a strong induction of apoptosis in PT45-P1 and T3M4 cells but not in BxPc-3, Capan-1 and PancTu-1 cells. These resistant cell lines exhibited a high basal NF-kappaB activity in contrast to the sensitive cell lines. Furthermore, gemcitabine showed a dose-dependent induction of NF-kappaB. At a dose of 0.04 micro M, gemcitabine still induced apoptosis in the sensitive cell lines, but did not induce NF-kappaB. In addition, NF-kappaB inhibition by MG132, sulfasalazine or the IkappaBalpha super-repressor strongly diminished the resistance against gemcitabine (0.04-20 micro M). In contrast to this obvious correlation between basal NF-kappaB activity and gemcitabine resistance, PI3K/Akt seems not to be involved in gemcitabine resistance of these cell lines. Neither did the basal Akt activity correlate with the sensitivity towards gemcitabine treatment, nor did the inhibition of PI3K/Akt by LY294002 alter gemcitabine-induced apoptosis. These results indicate that constitutive NF-kappaB activity confers resistance against gemcitabine and that modulation of this activity by pharmacological or genetic approaches may have therapeutical potential when combined with gemcitabine in the treatment of pancreatic carcinoma.

Translation of symptoms and signs into mechanisms in neuropathic pain

Abstract: 1. IntroductionFor centuries, clinicians have been taught to examine andclassify patients on the basis of topographical lesion and theunderlying pathology. In most clinical specialities, such anapproach has been a key element in understanding thepathophysiology of diseases and has led to progress interms of finding disease modifying or even disease curingtherapies. Examples are multiple including bacterial menin-gitis, painful neuroborrelosis, osteoarthrosis, cancer, rheu-matoid arthritis, ischaemic heart disease etc. In most ofthese disorders, pain can be a major complaint, whichthen rapidly disappears after the relevant therapy has beengiven.But what happens when the symptom itself becomes adisease? When pain persists and becomes a chronic problemand when the underlying diseases such as diabetes, cancer,vasculitis are known, or cannot be cured? Are we thenhelped by the classical ‘Sherlock Holmes’ approach, first,to look for the ‘crime site’ (topography of lesion) andsecond, for the ‘criminal’ (the disease) that caused thispain? The short answer is: no. Clinical experience anddecades of rather discouraging systematic research mainlyrelated to therapy in chronic pain have shown that a strategydirected at examining, classifying and treating pain on basisof anatomy or underlying disease is of limited help to thesepatients and their pain. These observations have then raisedthe question whether an entirely different strategy in whichpain is analysed on the basis of underlying mechanismscould be an alternative approach to examine and classifypatients to obtain a better outcome. Our increasing under-standing of mechanisms underlying chronic pain togetherwith the discovery of new molecular targets for modifyingpain has strengthened the demand for other ways to treatpain. Woolf and other authors (Woolf et al., 1998; Woolfand Decosterd, 1999; Sindrup and Jensen, 1999) haveemphasised the rational for a treatment approach directedat mechanism(s) rather than at diseases because new treat-ments are being developed on basis of the biologicalmechanisms that underlie the pain. One area that needssuch a new approach is neuropathic pain.2. Neuropathic pain classification problemsAccording to the current International Association forthe Study of Pain (IASP) definition of neuropathic pain,these disorders are characterised by lesions or dysfunctionof the system(s) that under normal conditions transmitnoxious information to the central nervous system. Thusin theory, neuropathic pain should be easy to distinguishfrom other conditions, but in practise, they are both diffi-cult to identify and to treat and there are several reasonwhy this is the case:† There is rarely one diagnostic test that can confirm orrefute the hypothesis of nerve lesion/dysfunction.† The perception of neuropathic (and other types of) painis a pure subjective phenomenon, which despite use ofthe most sophisticated equipment can’t be measured;only correlates to the perceived content can be obtained.† The borderland between definite, probable, possible andunlikely diagnoses is not clear. Prevalent disorders suchas cancer, low back pain, traumatic injuries may containa considerable (although as yet undetermined) neuro-pathic component.† In contrast to other sensory systems, the pain system isnot static, but changes in a dynamic and somewhatunpredictable fashion whenever the system has beenactivated.