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A Mackiewicz

Publications and source records attributed to A Mackiewicz.

At least 19 recordsLinked to original sources
PubMed2006

BRCA1-positive breast cancers in young women from Poland.

We identified 4316 unselected incident cases of early-onset breast cancers (<51 ears of age at diagnosis) in 18 Polish hospitals between 1996 and 2003. We were able to obtain a blood sample for DNA analysis from 3472 of these (80.4%). All cases were tested for the presence of three founder mutations in BRCA1. The proportion of cases with a BRCA1 mutation was 5.7%. The hereditary proportions were higher than this for women with breast cancer diagnosed before age 40 (9%), for women with cancer of medullary or atypical medullary histology (28%), for those with bilateral cancer (29%) or with a family history of breast or ovarian cancer (13%). It is reasonable to offer genetic testing to women with early-onset breast cancer in Poland.

Adult↗
PubMed2005

A common variant of CDKN2A (p16) predisposes to breast cancer.

BACKGROUND: A common missense variant of the CDKN2A gene (A148T) predisposes to malignant melanoma in Poland. An association between malignant melanoma and breast cancer has been reported in several families with CDKN2A mutations, OBJECTIVE: To determine whether this variant also predisposes to breast cancer. METHODS: Genotyping was undertaken in 4209 cases of breast cancer, unselected for family history, from 18 hospitals throughout Poland and in 3000 controls. RESULTS: The odds ratio (OR) associated with the CDKN2A allele for women diagnosed with breast cancer before the age of 50 was 1.5 (p = 0.002) and after age 50 it was 1.3 (p = 0.2). The effect was particularly strong for patients diagnosed at or before the age of 30 (OR = 3.8; p = 0.0002). CONCLUSIONS: CDKN2A appears to be a low penetrance breast cancer susceptibility gene in Poland. The association should be confirmed in other populations.

Adult↗
PubMed2004

Loss of tumorigenicity of murine colon carcinoma MC38/0 cell line after transduction with a retroviral vector carrying murine IL-12 genes.

Cells of transplantable MC38 colon carcinoma of C57BL/6 mice were adapted to growth in vitro as the MC38/0 cell line. Along the establishing process, MC38/0 cells preserved their tumorigenicity. After transduction with a retroviral vector carrying murine interleukin 12 (mIL-12) genes and further selection, stable MC38/IL-12 transductant cells were obtained. These cells produced IL-12 (approx. 2500 ng/ml/5x10(5) cells/48 h) as evaluated in the optimized bioassay. After subcutaneous inoculation into syngeneic mice, the IL-12-modified cells demonstrated reduced tumorigenicity as compared to parental MC38/0 cells. Mice that rejected the MC38/IL-12 tumour became protected against subsequent challenge with MC38/0 cells. The obtained data indicate that the IL-12-transduced murine colon carcinoma cells could be used both as a model tumour for the study of mechanisms of anticancer immunity and/or as an adjuvant to cancer vaccines.

Animals↗
PubMed2004

Human cancer gene therapy with cytokine gene-modified cells.

Cytokines can impede tumour growth and activate innate and adaptive immune responses, leading to elimination of cancer cells. For many years, it was believed that systemic administration of recombinant cytokines might become a standard treatment of different cancer types. However, due to a high toxicity of therapeutic doses and a low efficacy, even in combination with chemotherapy, this strategy is generally not accepted. On the other hand, cancer gene therapy approaches utilising cells modified with cytokine genes seem to represent a novel promising approach. For the last decade, numerous Phase I and II clinical trials evaluating different therapies based on cytokine gene-modified cells have been carried out. In the early studies, several strategies have been shown to improve clinical outcomes and induce strong antitumour immune responses. Recently, a few prospective, randomised, Phase III clinical trials have been initiated in order to finally determine the efficacy of particular cancer immunogene therapy strategies. This article reviews the present status and perspectives of clinical trials of cancer immunotherapies utilising cytokine gene-modified cells.

Adenoviridae↗
PubMed2004

The 34th Annual Meeting of the German Society of Immunology with participation of the Polish Society of Experimental and Clinical Immunology.

The 34th Annual Meeting of the German Society of Immunology was held in Berlin on 24 - 27 September 2003. This meeting, organised for the first time in cooperation with the Polish Society for Experimental and Clinical Immunology, gathered 1200 participants, mostly from central Europe. The programme comprised > 30 symposium lectures and > 750 oral and poster presentations. The main concept of this meeting was based on the rule of ABC--Applied, Basic and Clinical immunology. The state-of-the-art lectures devoted to immuno-based therapies provided by experts in the particular fields discussed some well-known therapeutic approaches. However, several workshop presentations demonstrated novel approaches employing biological therapies. These lectures are the focus of these meeting highlights.

Allergy and Immunology↗
PubMed2002

Genetically modified dendritic cells--a new, promising cancer treatment strategy?

Dendritic cells (DCs), the most potent antigen-presenting cells (APCs), were discovered almost 30 years ago. Due to the priming of antigen-specific immune responses mediated by CD4+ and CD8+ lymphocytes, DCs are crucial for the induction of adaptive immunity against cancer. Therefore, vaccination of cancer patients with DCs presenting tumour-associated antigens (TAAs) have been believed to be a promising anticancer strategy. Multiple clinical trials have been carried out in order to evaluate the safety and efficacy of cancer vaccines based on antigen-pulsed DCs. However, pulsing of DCs with particular peptides has several disadvantages: i) short-time duration of antigen-major histocompatability complex (MHC) complexes, ii) a requirement for matching defined peptides with MHC complexes and iii) exclusive presentation of single antigen epitopes. Application of gene transfer technologies in the field of DC-based vaccines made possible the development of novel, anticancer immunisation strategies. In several animal models, DCs modified with genes encoding TAA or immunostimulatory proteins have been shown to be effective in the induction of antitumour immune responses. Based on these encouraging results, a first clinical trial of prostate cancer patients vaccinated with gene modified DCs has recently been initiated. In this article, methods used for genetic modification of DCs and anticancer vaccination strategies based on genetically modified DCs are reviewed.

Animals↗
PubMed2001

IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness.

Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11c(high) DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-alpha, IFN-alphabeta, or nitric oxide, or the NF-kappaB family members p50, p52, or RelB.

Animals↗
PubMed2001

The designer cytokine hyper-IL-6 mediates growth inhibition and GM-CSF-dependent rejection of B16 melanoma cells.

The low immunogenic B16 melanoma cell line was transfected with a mammalian expression vector containing the complementary DNA for a sIL-6R/IL-6 fusion protein, termed Hyper-IL-6 (H-IL-6), which was shown to have biological activities at 100-1000-fold lower concentrations than IL-6 in combination with sIL-6R. The secreted p84 glycoprotein was detected in the supernatant of transfected cells and was fully active on BAF3/gp130 cells, which respond to IL-6/sIL-6R but not to IL-6 alone. Administration of recombinant H-IL-6 to C57BL/6 mice resulted in a prolonged acute phase protein gene expression indicating long systemic persistence of the fusion protein. Transfected B16 cells (B16/H-IL6 cells) showed morphological alterations in combination with a dramatic growth inhibition in vitro. Subcutaneous injection in C57BL/6 mice resulted in an almost complete rejection of B16/H-IL6 cells. This effect was partially abolished in FVB/BL/6 mice transgenic for a GM-CSF receptor antagonist, indicating a GM-CSF-dependent rejection of H-IL-6 transfected B16 cells. These results demonstrate that the anti-tumor effect of cytokines like IL-6 which are secreted by transfected melanoma cells at least in part depends on GM-CSF activity.

Animals↗
PubMed2001

BRCA2 germline mutations in male breast cancer patients in the Polish population.

Breast cancer is a rare disease in men. Germ-line mutations in BRCA2 and androgen receptor (AR) genes are thought to be responsible for a proportion of male breast cancer cases. The present study was performed on a series of 37 consenting patients not selected for family history of breast/ovarian cancer. The entire coding region of the BRCA2 gene and two exons of the AR gene were analyzed for germ-line mutations to evaluate the association between BRCA2 and AR genes and male breast cancer in Poland. We identified four frameshift mutations (11%) in exons 10, 11, 17 and 18, two of them were novel: 6495del3insC and 8457insA. Three missense unclassified variants (8%) of the BRCA2 gene were also identified. The frequencies of missense alterations were examined in a set of 200 chromosomes. No alteration of the AR gene was found. We did not observe much difference in clinicopathological features between carriers and non-carriers of BRCA2 mutations. Five of 37 patients (14%) had a family history of breast cancer, in one first- or second-degree relative, among the latter was one mutation carrier. The results of this study suggest that germ-line BRCA2 mutations account for rather small proportion of male breast cancer in Poland.

Adult↗
PubMed2001

Potentiatied antitumor effectiveness of combined chemo-immunotherapy with interleukin-12 and 5-fluorouracil of L1210 leukemia in vivo.

In this study we investigated the efficacy of a combination of IL-12 and 5-FU, a chemotherapeutic exerting several immunomodulatory effects, in murine L1210 leukemia. Mice inoculated with 1 x 10(5) leukemia cells were treated with a single dose of 5-FU (50 mg/kg) and seven daily doses of IL-12 (100 ng/dose), and were observed for survival. Treatment with IL-12 or 5-FU given alone produced moderate anti-leukemic effects. However, combination of both drugs resulted in a significant prolongation of mouse survival time. Importantly, there were 70% of long-term (>60 days) survivors among mice treated with both agents simultaneously. Moreover, we observed 100% of long-term survivors when mice were treated with a minimally increased dose of IL-12 (170 ng) in combination with 5-FU (50 mg/kg). The antileukemic effects were completely abrogated in scid/scid mice and in mice depleted of peritoneal macrophages and significantly decreased after administration of anti-CD3+, anti-CD4+ or anti-CD8+ monoclonal antibodies. Administration of anti-NK1.1 antibodies did not decrease the antileukemic effects indicating that NK cells are not important effectors of this treatment regimen. Collectively, these results indicate that the combination of IL-12 and 5-FU is inducing strong antileukemic responses that are dependent on the presence and activity of macrophages and T lymphocytes and warrant further studies of combined chemo-immunotherapy with IL-12.

Animals↗
PubMed2001

The 14th European Immunology Meeting--EFIS 2000. 23-27 September 2000, Poznañ, Poland.

The 14th European Immunology Meeting--EFIS 2000, held in Poznan, Poland on 23-27 September 2000, was the last major meeting of European immunologists in the second millennium. This conference was intended to summarise past achievements and to present future prospects in immunology. The philosophy of the scientific program was to fuse fundamental and clinical immunology and give a chance for basic scientists and clinicians to discuss mutual topics in a general view. There were eight state-of-art lectures, 12 'meet an expert' sessions, 20 plenary sessions and 46 workshops. More than 900 works were presented. Significant interest was focused on several aspects of cancer immunology and immunotherapy. EFIS 2000 was accompanied by six pre-congress satellite symposia held in various Polish cities. The topics were, 'Heat shock proteins: immune, stress response and apoptosis' (Gdansk), 'Infectious immunity and vaccines' (Kazimierz Dolny), 'Mononuclear phagocytes in basic and clinical immunology' (Cracow), 'Immunology of reproduction' (Poznan), 'Primary immunodeficiencies' (Warsaw) and 'Glycoimmunology' (Wroclaw).

Allergy and Immunology↗