Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study

BACKGROUND: Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete. METHODS: mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines. RESULTS: The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents. CONCLUSIONS: Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response

Adaptive Pulse Width Control for Precise Positioning Under the Influence of Stiction and Coulomb Friction

For the robustness experiment, the friction is increased by increasing the sealing pressure. The PID control exhibits a large overshoot during the transient state, while the other controllers exhibit no overshoot, as shown in Figs. 4 and 5. In the SMC, errors are reduced very slowly and the steady-state error is relatively large as shown in Fig. 5. Settling times of the PID control, the TDC, and the TDSMC are 3.32 s, 2.96 s, and 1.94 s, respectively, as shown in Figs. 4{b) and 5(^). The PID control and the TDC perform very poorly and their settling times are increased by 90.8 and 105.6 percent, respectively, from their nominal values. On the other hand, the TDSMC performs very well and its settling time is increased only by 9 percent from the nominal value. Therefore, the TDSMC has the best performance robustness. Conclusions The TDSMC which is a combination of the TDC and the SMC is proposed for the system with unknown dynamics and disturbances. This method uses the idea of switching of the sliding mode control while reducing the chattering associated with it. Experiments on the position control of a DC motor system with stick-slip friction, were conducted to evaluate performances of the control algorithms. Experiments show that the TDSMC exhibits the best performance robustness and that the TDC and the TDSMC perform better than the PID control with an anti-windup filter and the integral sliding mode control. 227. Youcef-Touini, K., and Bobbet, J., 1991, "Stability of Uncertain Linear Systems With Time Delay," ASME JOURNAL OF DYNAMIC SYSTEMS, MEASUREMENT, AND CONTROL, Vol. 113, pp. 558-567. Youcef-Toumi, K., and Ito, O., 1990, "A Time Delay Controller for Systems With Unknown Dynamics," ASME JOURNAL OF DYNAMIC SYSTEMS, MEASURE- MENT, AND CONTROL, Vol. 112, Youcef-Toumi, K., and Reddy, S., 1992, "Analysis of Linear Time Invariant Systems With Time Delay," ASME JOURNAL OF DYNAMIC SYSTEMS, MEASURE- MENT, AND CONTROL, Vol. 114, Youcef-Toumi, K., and Wu, S.-T., 1992, "Input/Output Linearization Using Time Delay Control," ASME JOURNAL OF DYNAMIC SYSTEMS, MEASUREMENT, AND CONTROL, Vol. 114, pp. 10-19

Avelumab as neoadjuvant therapy in patients with urothelial non-metastatic muscle invasive bladder cancer: a multicenter, randomized, non-comparative, phase II study (Oncodistinct 004 - AURA trial)

Introduction Cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies. Methods and analysis Oncodistinct 004 - AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety. Ethics and dissemination The study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals

Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response,and biomarkers

Background: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. Patients and methods: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. Results: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin,and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. Conclusions: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance