Showing papers by "Christian Junghanss published in 2014"
TL;DR: It is pointed out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.
Abstract: B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.
104 citations
TL;DR: Using longitudinal data sets from the large‐scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, a protocol is described to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence, which reflect anti‐inflammatory, anti‐immunosenescent or anti‐anaemic mechanisms.
Abstract: Traditionally, biomarkers of aging are classified as either pro-longevity or antilongevity. Using longitudinal data sets from the large-scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, we describe a protocol to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence. Our protocol also identifies biomarkers for which, at first sight, there is conflicting evidence. Conflict resolution is possible by postulating a role switch. In these cases, high biomarker values are, for example, antilongevity in early life and pro-longevity in later life. Role-switching biomarkers correspond to features that must, for example, be minimized early, but maximized later, for optimal longevity. The clear-cut pro-longevity biomarkers we found reflect anti-inflammatory, anti-immunosenescent or anti-anaemic mechanisms, whereas clear-cut antilongevity biomarkers reflect inflammatory mechanisms. Many highly significant blood biomarkers relate to immune system features, indicating a shift from adaptive to innate processes, whereas most role-switching biomarkers relate to blood serum features and whole-body phenotypes. Our biomarker classification approach is applicable to any combination of longitudinal studies with life expectancy data, and it provides insights beyond a simplified scheme of biomarkers for long or short lifespan.
16 citations
TL;DR: PDA-66 displays significant antileukemic activity in ALL cells and classifies as candidate for further evaluation as a potential drug in targeted therapy of ALL.
Abstract: Prognosis of adult patients suffering from acute lymphoblastic leukemia (ALL) is still unsatisfactory. Targeted therapy via inhibition of deregulated signaling pathways appears to be a promising therapeutic option for the treatment of ALL. Herein, we evaluated the influence of a novel arylindolylmaleimide (PDA-66), a potential GSK3β inhibitor, on several ALL cell lines. ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were exposed to different concentrations of PDA-66. Subsequently, proliferation, metabolic activity, apoptosis and necrosis, cell cycle distribution and protein expression of Wnt and PI3K/Akt signaling pathways were analyzed at different time points. PDA-66 inhibited the proliferation of ALL cells significantly by reduction of metabolic activity. The 72 h IC50 values ranged between 0.41 to 1.28 μM PDA-66. Additionally, caspase activated induction of apoptosis could be detected in the analyzed cell lines. PDA-66 influenced the cell cycle distribution of ALL cell lines differently. While RS4;11 and MOLT4 cells were found to be arrested in G2 phase, SEM cells showed an increased cell cycle in G0/1 phase. PDA-66 displays significant antileukemic activity in ALL cells and classifies as candidate for further evaluation as a potential drug in targeted therapy of ALL.
15 citations
TL;DR: Combined immunosuppression of RAD001 and MMF after nonmyeloablative HSCT is associated with significant toxicities, including a prolonged platelet recovery time as well as increased infections compared to the CsA/MMF regimen.
11 citations
TL;DR: The effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML was evaluated and there were no differences between CT and HCT regarding gender, AML type and FLT3 mutation status.
7 citations
TL;DR: Data show RAD induction to be very effective in newly diagnosed multiple myeloma and to be well tolerated, and Correlative studies suggests response to be independent of known unfavourable conditions.
5 citations
TL;DR: This trial evaluated whether TPFC would be feasible and superior to PFC in patients with RM-HNSCC without limiting comorbidities in an open-label randomized multicenter trial.
Abstract: 6018 Background: This trial was based on the findings that D in addition to PF in induction treatment and C in addition to PF in RM disease both improved outcome in HNSCC. The question was, whether...
5 citations
TL;DR: Allogeneic stem cell transplantation following conditioning with treosufan and fludarabine constitutes a viable therapeutic option for patients with refractory or relapsed NHL and should be considered early during the course of salvage treatment.
Abstract: The treatment of refractory or relapsed non-Hodgkin lymphoma (NHL) remains challenging. In this retrospective study, 88 patients with refractory or relapsed NHL received treosulfan and fludarabine as a reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Of the 88 intensely pre-treated patients, 73 experienced a relapse, with 18 of the 88 patients experiencing an early relapse (ER; <6 months from the last chemotherapy). At the time of allo-HSCT, 26 patients were in complete remission (CR) and 43 in partial remission (PR), 12 patients had progressive disease (PD) and 7 had stable disease (SD). A total of 47 patients received an autologous graft followed by allo-HSCT. Following allo-HSCT, 69 of the 88 patients were in CR and 7 were in PR, resulting in an overall response rate of 86.4% (76/88). A total of 33 patients achieved a CR from PR, as did 6 patients from PD and 5 from SD. Of the 88 patients, 43 (49%) were alive at the end of the follow-up period. The patients who directly underwent allo-HSCT without prior auto-HSCT exhibited a better disease-free survival (DFS; P=0.038) with a tendency (P=0.077) for a better overall survival (OS). The patients with ER exhibited a probability of OS of 0.35±0.12 after 3 and 7 years. Chronic graft-versus-host disease (cGvHD) exerted a positive effect on OS and DFS (for limited cGvHD vs. no cGvHD, P=0.002 and 0.004, respectively). In conclusion, allogeneic stem cell transplantation following conditioning with treosufan and fludarabine constitutes a viable therapeutic option for patients with refractory or relapsed NHL and should be considered early during the course of salvage treatment.
4 citations
TL;DR: The final report of the G-PCNSL-SG-1 trial evaluating WBRT in primary therapy of PCNSL after a median follow-up (MFU) of 81.2 months is published.
Abstract: 8527 Background: The role of whole brain radiotherapy (WBRT) in first-line therapy of primary CNS lymphoma (PCNSL) has been increasingly questioned. This is the final report of the G-PCNSL-SG-1 tri...
3 citations
TL;DR: Examining the feasibility and efficiency of IBM allogeneic HSCT in comparison to IV HS CT in dog leukocyte antigen (DLA) identical canine littermates using a RIC regimen and results demonstrated faster engraftment with an IBM HSCT approach compared to intravenous (IV) HSCT following myeloablative conditioning found it feasible.
1 citations