PI3K inhibition enhances doxorubicin-induced apoptosis in sarcoma cells
- We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia - a randomised SAL pilot study
Christian Hubertus Brandts
Wolfgang E. Berdel
- INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML.
TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint.
RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days.
CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm.
Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients
Gilberto Sousa Alves
Carlos Eduardo Alves
- Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia.
Identification and characterization of FAM124B as a novel component of a CHD7 and CHD8 containing complex
Tamara I. Rabe
Silke Jeannette Pauli
- BACKGROUND: Mutations in the chromodomain helicase DNA binding protein 7 gene (CHD7) lead to CHARGE syndrome, an autosomal dominant multiple malformation disorder. Proteins involved in chromatin remodeling typically act in multiprotein complexes. We previously demonstrated that a part of human CHD7 interacts with a part of human CHD8, another chromodomain helicase DNA binding protein presumably being involved in the pathogenesis of neurodevelopmental (NDD) and autism spectrum disorders (ASD). Because identification of novel CHD7 and CHD8 interacting partners will provide further insights into the pathogenesis of CHARGE syndrome and ASD/NDD, we searched for additional associated polypeptides using the method of stable isotope labeling by amino acids in cell culture (SILAC) in combination with mass spectrometry.
PRINCIPLE FINDINGS: The hitherto uncharacterized FAM124B (Family with sequence similarity 124B) was identified as a potential interaction partner of both CHD7 and CHD8. We confirmed the result by co-immunoprecipitation studies and showed a direct binding to the CHD8 part by direct yeast two hybrid experiments. Furthermore, we characterized FAM124B as a mainly nuclear localized protein with a widespread expression in embryonic and adult mouse tissues.
CONCLUSION: Our results demonstrate that FAM124B is a potential interacting partner of a CHD7 and CHD8 containing complex. From the overlapping expression pattern between Chd7 and Fam124B at murine embryonic day E12.5 and the high expression of Fam124B in the developing mouse brain, we conclude that Fam124B is a novel protein possibly involved in the pathogenesis of CHARGE syndrome and neurodevelopmental disorders.
Borrelia valaisiana resist complement-mediated killing independently of the recruitment of immune regulators and inactivation of complement components
Peter F. Zipfel
- Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato complex differ in their resistance to complement-mediated killing, particularly in regard to human serum. In the present study, we elucidate the serum and complement susceptibility of B. valaisiana, a genospecies with the potential to cause Lyme disease in Europe as well as in Asia. Among the investigated isolates, growth of ZWU3 Ny3 was not affected while growth of VS116 and Bv9 was strongly inhibited in the presence of 50% human serum. Analyzing complement activation, complement components C3, C4 and C6 were deposited on the surface of isolates VS116 and Bv9, and similarly the membrane attack complex was formed on their surface. In contrast, no surface-deposited components and no aberrations in cell morphology were detected for serum-resistant ZWU3 Ny3. While further investigating the protective role of bound complement regulators in mediating complement resistance, we discovered that none of the B. valaisiana isolates analyzed bound complement regulators Factor H, Factor H-like protein 1, C4b binding protein or C1 esterase inhibitor. In addition, B. valaisiana also lacked intrinsic proteolytic activity to degrade complement components C3, C3b, C4, C4b, and C5. Taken together, these findings suggest that certain B. valaisiana isolates differ in their capability to resist complement-mediating killing by human serum. The molecular mechanism utilized by B. valaisiana to inhibit bacteriolysis appears not to involve binding of the key host complement regulators of the alternative, classical, and lectin pathways as already known for serum-resistant Lyme disease or relapsing fever borreliae.
The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network
Caroline J. Voskens
Simone M. Goldinger
Carmen A. Loquai
Katharina C. Kähler
Tanja Regina Bergmann
Clemens Luitpold Bockmeyer
Thomas Kurt Eigentler
Roger von Moos
Lucie M. Heinzerling
- Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
C-clamp and pelvic packing for control of hemorrhage in patients with pelvic ring disruption
Philipp M. Lenzlinger
Marius Johann Baptist Keel
- BACKGROUND: Exsanguinating hemorrhage is the major cause of death in patients with pelvic ring disruption.
AIMS: The aim of this study was to document outcomes after the stabilization of pelvic ring injuries by a C-clamp and control of hemorrhage by pelvic packing. Physiological parameters were tested as prognostic factors.
SETTING AND DESIGN: This was a retrospective study at a level I trauma center. The study period was from January 1996 to December 2007.
MATERIALS AND METHODS: Fifty patients with pelvic ring disruption and hemorrhagic shock were analyzed. The pelvic rings were fixed by a C-clamp, and patients with ongoing hemorrhage underwent laparotomy and extra- and/or intra-peritoneal pelvic packing. Clinical parameters (heart rate, mean arterial pressure) and physiological parameters (lactate levels, hemoglobin, hematocrit) were documented at admission and at different time points during the initial treatment (1, 2, 3, 4, 6, 8, and 12h after admission).
RESULTS: Within 12 h of admission, 16 patients died (nonsurvivors) due to hemorrhagic shock (n=13) or head injuries (n=3). In this group, 12 patients underwent laparotomy with pelvic packing. Thirty-four patients survived the first 12 h (early survivors) after fixation by a C-clamp and additional packing in 23 patients. Four of these patients died 12.3±7.1 days later due to multiple organ failure (n=3) or severe head injury (n=1). The blood lactate level at admission was significantly higher in the group of nonsurvivors (7.2±0.8 mmol/L) compared to the early survivors (4.3±0.5 mmol/L, P<0.05). While hemoglobin values improved within the first 2 h in nonsurvivors, lactate levels continued to increase.
CONCLUSION: Pelvic packing in addition to the C-clamp fixation effectively controls severe hemorrhage in patients with pelvic ring disruption. Early sequential measurements of blood lactate levels can be used to estimate the severity of shock and the response to the shock treatment.
"Wenn ich alle Pillen genommen habe, bin ich satt" : Multimorbidität und Multimedikation: Herausforderungen in einer alternden Gesellschaft
Marjan van den Akker
- Mit den Krankheiten häuft sich im Alter auch die Zahl der einzunehmenden Medikamente. Das bringt viele Probleme mit sich. Das Institut für Allgemeinmedizin der Goethe-Universität untersucht in enger Kooperation mit der Universität Maastricht die Folgen der Multimedikation und entwickelt gemeinsam mit Hausärzten Strategien, um unerwünschte Wirkungen zu vermeiden.
Patienten mit Gerinnungsstörungen optimal versorgen : PICANT-Studie setzt auf ein geschultes Praxisteam und die Motivation zu Selbstmanagement
- Patienten mit einem erhöhten Risiko für Thrombosen oder Embolien müssen oft ein Leben lang medikamentös behandelt werden. Doch nicht jeder, der Gerinnungshemmer benötigen würde, erhält sie auch, und umgekehrt erhält mancher die Medikamente, obwohl sie nicht indiziert wären. Schließlich kann es sein, dass aufgrund von einer Wechselwirkung mit anderen Medikamenten oder einer fehlerhaften medikamentösen Einstellung das Blutungsrisiko oder das Risiko für Embolien erhöht ist. Um die Versorgung auf diesem Gebiet zu verbessern und Komplikationen durch Blutungen oder Embolien zu reduzieren, hat das Institut für Allgemeinmedizin im März 2012 eine Studie mit hessischen Hausarztpraxen begonnen.
"Ein System der organisierten Verantwortungslosigkeit" : Prof. Ferdinand Gerlach kritisiert falsche Anreizsysteme und die Kluft zwischen ambulanter und stationärer Versorgung
Ferdinand M. Gerlach
- Prof. Ferdinand Gerlach im Gespräch mit FF-Redakteurin Dr. Anne Hardy.