Радиолокационное сечение рассеяния летательных аппаратов

Тез. докл. Междунар. науч.-техн. конф. (науч. чтения, посвящ. П. О. Сухому), Гомель, 4-6 июля. 2002 г

Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial

<p>Abstract</p> <p>Background</p> <p>Adjuvant trastuzumab (Herceptin) treatment of breast cancer patients significantly improves their clinical outcome. Vaccination is an attractive alternative approach to provide HER-2/neu (Her2)-specific antibodies and may in addition concomitantly stimulate Her2-reactive T-cells. Here we report the first administration of a Her2-plasmid DNA (pDNA) vaccine in humans.</p> <p>Patients and Methods</p> <p>The vaccine, encoding a full-length signaling-deficient version of the oncogene Her2, was administered together with low doses of GM-CSF and IL-2 to patients with metastatic Her2-expressing breast carcinoma who were also treated with trastuzumab. Six of eight enrolled patients completed all three vaccine cycles. In the remaining two patients treatment was discontinued after one vaccine cycle due to rapid tumor progression or disease-related complications. The primary objective was the evaluation of safety and tolerability of the vaccine regimen. As a secondary objective, treatment-induced Her2-specific immunity was monitored by measuring antibody production as well as T-cell proliferation and cytokine production in response to Her2-derived antigens.</p> <p>Results</p> <p>No clinical manifestations of acute toxicity, autoimmunity or cardiotoxicity were observed after administration of Her2-pDNA in combination with GM-CSF, IL-2 and trastuzumab. No specific T-cell proliferation following <it>in vitro </it>stimulation of freshly isolated PBMC with recombinant human Her2 protein was induced by the vaccination. Immediately after all three cycles of vaccination no or even decreased CD4⁺T-cell responses towards Her2-derived peptide epitopes were observed, but a significant increase of MHC class II restricted T-cell responses to Her2 was detected at long term follow-up. Since concurrent trastuzumab therapy was permitted, λ-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab. Her2-pDNA vaccination induced and boosted Her2-specific antibodies that could be detected for several years after the last vaccine administration in a subgroup of patients.</p> <p>Conclusion</p> <p>This pilot clinical trial demonstrates that Her2-pDNA vaccination in conjunction with GM-CSF and IL-2 administration is safe, well tolerated and can induce long-lasting cellular and humoral immune responses against Her2 in patients with advanced breast cancer.</p> <p>Trial registration</p> <p>The trial registration number at the Swedish Medical Products Agency for this trial is Dnr151:785/2001.</p

Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppresses the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirm the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses

Immunological recognition and tumor escape mechanisms of ovarian carcinoma

Ovarian carcinoma is a leading cause of cancer mortality and there is an urgent need for new and better therapeutic modalities that result in improved long-term outcome for this severe malignancy. One promising treatment modality for patients suffering from ovarian carcinoma is immunotherapy. Several different immunotherapeutic approaches targeting ovarian carcinoma, including infusion of monoclonal antibodies, adoptive transfer of T cells and administration of tumor vaccines, are currently being tested in the clinic. To date, the clinical efficacy of these treatments has been limited, partially because of the development of tumor cell escape and induction of immune suppression. In order to improve the success rate of future immunotherapy protocols it will be important to gain a further understanding of the molecular mechanisms underlying the escape of ovarian carcinoma from the immune system. This thesis deals with several mechanisms that all lead to lack of immune recognition, and describes one possibility of exploiting this new knowledge in the design of alternative treatment strategies. The first part of my thesis demonstrates that metastatic ovarian carcinoma often exhibit heterogeneous human leukocyte antigen -A2 (HLA-A2) expression. The down-regulation may reflect a specific and progressive loss of this HLA allele. One underlying molecular mechanism was found to be haplotype loss, associated with the presence of HLA-A2-restricted HER-2/neu specific Tcell immunity. Based on these findings, this study suggested that antitumoral cytotoxic T lymphocytes (CTL) favor tumor escape variants lacking HLA-A2 expression, which is required for most TceU-based antitumoral immunotherapeutic strategies. Moreover, our studies also showed that short-term tumor cell lines from patients with advanced ovarian carcinoma (OVACs) were protected from lysis by peptide- and allospecific CD8+ T cells upon interferon-γ IFN-γ) treatment. This paradoxical phenomenon was dependent on enhanced inhibitory signaling via CD94/NKG2A receptors expressed on the CTL. IFN-γ treatment of OVACs induced HLA-G expression, and data suggested that the underlying mechanism of protection was increased surface expression of HLA-E molecules, binding a peptide derived from the leader sequence of HLA-G. This study reveals that IFN-y modulation may shift the balance of triggering and inhibitory signals leading to tumor escape from CTL-mediated immunity. Natural killer (NK) cell function in cancer patients is often impaired and we describe how down-modulation of the expression of multiple activating receptors on NK cells may be one underlying mechanism. We found that in particular DNAM-1, which is one of the activating receptors, was severely down-modulated in tumor associated NK cells as compared to NK cells in autologous peripheral blood and blood from healthy donors. NK cells in the tumor environment also had lower expression of CD16 and the costimulatory receptor 2B4 while exhibiting moderately increased levels of both NKG2D and the natural cytotoxicity receptor NKp46. There was also a significant overrepresentation of regulatory C1356bright NK cells in ascites. These complex perturbations resulted in an impaired functional capacity of tumor associated NK cells as demonstrated by their poor ability to recognize K562 cells. These results provide mechanistic insights into the failure of innate immunity to control progression of ovarian carcinoma. Loss or reduction of HLA class 1 expression should render tumor cells susceptible to NK cell lysis in agreement with the missingself hypothesis. Indeed, freshly isolated ovarian carcinoma cells triggered degranulation of resting allogeneic NK cells. This lead to detectable levels of granzyme B and caspase-6 activation in the tumor cells and induction of significant tumor cell lysis. Ovarian carcinoma cells exhibited ubiquitous expression of the poliovirus receptor (PVR, a ligand for DNAM-1) and sparse/ heterogeneous expression of NKG2D ligands. Blocking experiments suggested that DNAM-1 engagement was critical for the direct NK cell recognition of ovarian carcinoma, while NKG2D and natural cytotoxicity receptor signaling resulted in a complementary contribution to tumor cell recognition. These results demonstrate that resting NK cells readily recognize and kill freshly isolated human tumor cells, and identify ovarian carcinoma as a potential target for adoptive NK cell-based therapy. In conclusion, this work provides new insights into the mechanisms of tumor escape of ovarian carcinoma and describes successful targeting of this tumor type by resting allogeneic NK cells

Automatic Generation of Spatial and Temporal Memory Architectures for Embedded Video Processing Systems

This paper presents a tool for automatic generation of the memory management implementation for spatial and temporal real-time video processing systems targeting field programmable gate arrays (FPGAs). The generator creates all the necessary memory and control functionality for a functional spatio-temporal video processing system. The required memory architecture is automatically optimized and mapped to the FPGAs' memory resources thus producing an efficient implementation in terms of used internal resources. The results in this paper show that the tool is able to efficiently and automatically generate all required memory management modules for both spatial and temporal real-time video processing systems.STC - Sensible Things that Communicat

Fe(III) distribution varies substantially within and between atherosclerotic plaques

PURPOSE: Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture. METHODS: Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy. RESULTS: Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P &lt; 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P &lt; 0.01). CONCLUSION: Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity

Nonlinear distortion mitigation by machine learning of SVM classification for PAM-4 and PAM-8 modulated optical interconnection

We demonstrated a support vector machine (SVM) based machine learning method to mitigate modulation nonlinearity distortion for PAM-4 and PAM-8 vertical cavity surface emitter laser multi-mode fiber (VCSEL-MMF) optical link. Simulations at 100 Gb/s data rate and experimental work at 60 Gb/s data rate were carried out. We achieved a significant improvement in bit error rate (BER) when complete binary tree SVMs (CBT-SVMs) are applied for both PAM-4 and PAM-8 signals. Quantitative analysis of the sensitivity gain versus modulation nonlinearity distortion is presented with experimentally verification. The results indicate that CBT-SVMs have better performance for PAM-8 compared to PAM-4. The sensitivity gain increases almost linearly with the increase of eye-linearity (increase of modulation nonlinearity distortion). Up to 2.5-dB sensitivity improvement is achieved by the proposed CBT-SVMs at eye-linearity of 1.72 for PAM-4.</p