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Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP+ signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138+/CD38+ plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target., Graphical Abstract, Receptors of oncolytic herpes simplex virus (oHSV-1), NECTIN-1, and HVEM are expressed on multiple myeloma (MM) cells. Whereas NECTIN-1 expression is variable among MM cells, HVEM is ubiquitously and highly expressed on all samples tested. However, no viral replication occurred. Instead, oHSV-1 induced MM cell apoptosis via caspase-3 cleavage.

Purpose of review This article focuses on the immunosuppressive impact of myeloid-derived suppressor cells (MDSCs) and the potential clinical implications in hematological malignancies. Recent findings MDSCs play a critical role in the regulation of the immune response in cancer. They inhibit activation of adaptive immune response and as a result foster the growth of the malignancy. Recent studies have shown that MDSCs serve as prognostic biomarkers and as targets for cancer immunotherapy. Preclinical and clinical studies have identified new approaches to deplete MDSC populations and inhibit MDSC function with combination immunomodulatory therapies including chemotherapeutic agents with immune checkpoint-directed treatment. Summary A broad spectrum of publications indicate that direct targeting of MDSCs may abrogate their protumorigenic impact within the tumor microenvironment through activation of the adaptive immune response.

Key Points Teriflunomide, the active metabolite of leflunomide, downregulates c-Myc expression through inhibition of PIM kinases. Leflunomide together with lenalidomide significantly extended survival in an in vivo MM model.

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) within the BM. The BM microenvironment supports survival of the malignant cells and is composed of cellular fractions that foster myeloma development and progression by suppression of the immune response. Despite major progress in understanding the biology and pathophysiology of MM, this disease is still incurable and requires aggressive treatment with significant side effects. CD84 is a self-binding immunoreceptor belonging to the signaling lymphocyte activation molecule (SLAM) family. Previously, we showed that CD84 bridges between chronic lymphocytic leukemia cells and their microenvironment, and it regulates T cell function. In the current study, we investigated the role of CD84 in MM. Our results show that MM cells express low levels of CD84. However, these cells secrete the cytokine macrophage migration inhibitory factor (MIF), which induces CD84 expression on cells in their microenvironment. Its activation leads to an elevation of expression of genes regulating differentiation to monocytic/granulocytic-myeloid-derived suppressor cells (M-MDSCs and G-MDSCs, respectively) and upregulation of PD-L1 expression on MDSCs, which together suppress T cell function. Downregulation of CD84 or its blocking reduce MDSC accumulation, resulting in elevated T cell activity and reduced tumor load. Our data suggest that CD84 might serve as a novel therapeutic target in MM.

Background: Tumor-associated macrophages (TAMs) play a key role in cutaneous T cell lymphoma (CTCL) growth and neoplastic T cells escape immune surveillance via PD1-PD-L1 axis (Querfeld, C., et al., Blood 2019; Khodadoust, M.S., et al., J Clin Oncol, 2020). There remains a lack of knowledge about how cytokines regulate the mechanisms controlling tumor-growth and polarize the tumor microenvironment (TME). Methods and Results: To investigate PD-L1 and PD1 expression on TAMs and T cells in mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SS) patients, we performed multiplex immunofluorescence (IF) staining of lesional skin samples of MF patients that demonstrated co-localization of PD-L1 on CD163+ M2 macrophages and PD1 expression on CD4+ and CD8+ T cells. In addition, significant enrichment of CD14+ and CD16+/CD14dim CD163+ M2-like monocytes/macrophages with upregulated PD-L1 expression in SS patients compared to healthy donors (HDs) was found via FACS analysis. We also performed 30-plex Luminex cytokine assay on plasma samples, which showed significantly increased IL-6, IL-10, IFNγ and TNFα levels in plasma of MF/SS compared to HDs. To investigate whether polarization towards an M2-like macrophage phenotype with increased PD-L1 expression correlated with the cytokine expression from CTCL-TME, we cultured total PBMCs from HDs with conditioned media (CM) from well established CTCL cell lines MyLa and HuT78 and analyzed PD-L1 mRNA, total PD-L1 protein and PD-L1 surface expression on M2-like macrophages. Significantly increased expression of PD-L1 protein in total PBMCs, especially on CD14+ and CD16+/CD14dim M2-like macrophages was seen. To understand whether distinct cytokines are associated with PD-L1 upregulation on CD163+ M2-like populations, total PBMCs from HDs were stimulated with human recombinant IL-6, IL-10, IFNγ or TNFα. Antibody blocking studies were conducted by adding anti human IL-6, IL-10, IFNγ or TNFα to the cultures with CM. TNFα stimulation significantly increased the CD14+ M2-like subset, but did not affect CD16+/CD14dim M2-like subset. We observed increased PD-L1 expression on both M2-like populations with TNFα compared to other cytokines. In contrast, blockade of TNFα significantly decreased the CD14+ M2-like subset with reduced PD-L1 expression and increased CD16+/CD14dim M2-like cells with upregulated PD-L1 expression. To explore whether the STAT pathway regulates PD-L1 expression through cytokines from CTCL TME, we incubated total PBMCs from HDs in CM of MyLa and HuT78 cells with/without a pan-STAT inhibitor, and in media alone. Inhibition of STAT signaling decreased CD14+ M2-like macrophage population, but did not alter the CD16+/CD14dim M2-like population. In addition, pan-STAT inhibition significantly reduced surface expression of PD-L1 on both CD14+ and CD16+/CD14dim M2-like macrophages. The effects of cytokines on STAT signaling components in regulating PD-L1 expression were also investigated by FACS and immunoblots. TNFα blockade significantly downregulated PD-L1, but also pSTAT1, pSTAT3 and pNF-κB levels, illustrating the role of TNFα on STAT1, STAT3 and NF-κB pathways in conjunction with PD-L1 expression. Stimulation with TNFα increased pSTAT3 level in CD14+ M2-like macrophages, while it did not significantly change pSTAT3 in CD16+/CD14dim M2-like macrophages. Anti-TNFα reduced pSTAT3 levels in CD14+ M2-like macrophages, but profoundly increased PD-L1 in CD16+/CD14dim M2-like macrophages, which aligns with our data of increased PD-L1 expression on CD16+/CD14dim M2-like macrophages following TNFα blockade. Conclusion: We profiled immune alterations of monocyte/macrophages populations and PD-L1 expression in CTCL regulated by selected cytokines. Our results support the dominant role of TNFα in the CTCL microenvironment. Here we show that TNFα potentiates the immunosuppressive TME through macrophage polarization and STAT-mediated PD-L1 regulation. Our results identify potential targets for combination immunotherapy. Disclosures Zain: Seattle Genetics: Research Funding; Mundai Pharma: Research Funding; Kyowa Kirlin: Research Funding. Abdulla:Johnson Johnson: Research Funding; Mallinckrodt: Consultancy, Speakers Bureau. Rosen:Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Querfeld:Trillium: Consultancy; Stemline: Consultancy; Bioniz: Consultancy; Helsinn: Consultancy; Celgene: Research Funding; Kyowa Kirin: Consultancy; MiRagen: Consultancy.

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR-15a-16-1-KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.

Aim: The aim of this study was to assess the association between human fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism and pre-eclampsia (PE) by carrying out a case–control study in Turkish women. Materials and Methods: In the present study 159 PE patients and 161 controls were included. DNA was extracted from peripheral blood leukocyte and FGFR4 Gly388Arg polymorphism was investigated using polymerase chain reaction–restriction fragment length polymorphism methods. Results: For Gly388Arg polymorphism of FGFR4 we found no significant association between controls and PE patients. The frequencies of GlyGly, GlyArg and ArgArg genotypes were 56.6%, 36.4% and 7% for the study group and 50.3%, 44.7% and 5% for the control group, respectively. The risk of women with the GlyArg (odds ratio = 0.7, 95% confidence interval: 0.45–1.14) and ArgArg (odds ratio = 1.2, 95% confidence interval: 0.47–3.22) genotypes for PE did not differ significantly from that of GlyGly genotype carriers. Conclusion: As we could not find any association between genetic variability in Gly388Arg of FGFR4 and PE, this specific polymorphism of FGFR4 can be eliminated as a risk factor for PE at least for Turkish women.

Introduction: Daratumumab (Dara) is a human monoclonal antibody targeting the highly expressed multiple myeloma (MM) surface receptor CD38, with significant activity in relapsed MM. However, resistance to Dara develops in virtually all patients (pts). Thus, in order to maximize its clinical activity and prevent resistance, it is imperative to understand why pts stop responding. Our group recently reported that, in addition to the malignant cells, several immune-effector cells also express CD38. Thus, we hypothesized that the expression of CD38 or lack of it on non-cancer immune cell-subsets may also play a role in both clinical response and resistance to Dara. Results: To address our hypothesis, we analyzed CD38 surface expression in CD138+ MM cells isolated from 5 Dara-naïve (D-naïve) pts and from 8 Dara progressing pts (D-prg) who had discontinued Dara therapy for at least 4 weeks prior to analysis. We observed that the CD138+ MM-cells of D-prg displayed a lower median fluorescence intensity (MFI) of CD38 compared to the MFI of MM cells isolated from the D-naïve (p=0.04); no significant difference was however observed in the percentage of CD38+ MM cells between the two groups. In fact, all of the MM cells expressed CD38 in both D-naïve and D-prg, supporting the hypothesis that resistance to Dara was not mediated by loss of CD38 expression on MM cells. Next, we looked at whether CD38 on the surface of MM cells from D-prg was still recognizable by Dara. Thus, we treated MM cells ex-vivo with Dara at the clinically achievable concentration of 100 μg/ml. We showed that Dara was still able to bind CD38 on the surface of the D-prg CD138+ MM cells, since, after Dara treatment, no CD38+ signal was detected upon staining with a CD38 monoclonal antibody sharing the same targeting CD38 epitope (clone IB6) (Fig.1a). Conversely, we detected a CD38+ signal when a different anti-human CD38 multi-epitope antibody was used in a similar experiment (Cytognos) (Fig.1b). CD38 mRNA expression was observed in all MM cells isolated from D-prg, and we were not able to identify any missense mutations in CD38 mRNA from MM cells of D-prg for whom material was available for analysis. Thus, having demonstrated that resistance to Dara was not related to the expression of CD38 on the MM-cells, we turned our attention to the MM bone marrow (BM) microenvironment (ME). We performed RNA-sequencing of the BM-ME depleted of the CD138+ MM cells obtained from the D-prg (n=5) and D-naïve (n=5). A gene expression signature differentiated the two groups. In D-prg, we observed a significant downregulation (fold-change Conclusions: Our data are supportive of the hypothesis that loss of Dara binding to MM-cell surface CD38 or the complete loss of CD38 on MM cells may not necessarily be the cause of Dara treatment resistance. We instead propose that Dara binding on CD38+ immune effector cells may be critical and that the loss of CD38 expression on these cells can lead to mechanisms of Dara-acquired resistance. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Celgene: Consultancy, Equity Ownership, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Sutro: Speakers Bureau; Takeda: Speakers Bureau; Onyx: Speakers Bureau.

Introduction: Multiple Myeloma (MM) cell survival strictly depends on the interaction with multiple cell types in the bone marrow (BM), collectively referred to as the MM microenvironment (MM-ME). CD84 (SLAMF5) belongs to the signaling lymphocyte activation molecule family of immunoreceptors; previous data from our group have shown that CD84 mediates malignant B cells and their ME (Marom et al. 2017); however, its role within the MM-ME has not yet been investigated. Results: Using the MMRF CoMMpass IA9 dataset, we found that CD84 mRNA expression is low or absent in CD138+MM cells isolated from 660 newly diagnosed patients. In agreement with these data, flow analysis showed an absence of CD84 expression in all MM cell lines tested (n=9) and minimal surface expression (5.5-13%) in primary cells (n=3). However, a significantly higher expression of CD84 was detected on the surface of BM and peripheral blood (PB) monocytic fractions (CD14+) (76-97%) compared to that of matched CD14 negative fractions (2-9%) obtained from 16 different MM patients (p Next, to understand whether the expansion of Mo-MDSC and associated CD84 up-regulation is directly dependent on the MM cells, we investigated Mo-MDSC expansion and CD84 expression in two different MM mouse models. Specifically, 5TGM1 murine MM cells were IV injected into syngeneic immune-competent KaLwRijHsd mice (n=7), and human MM.1S cells were IV injected into immune-deficient NSG mice (n=10). Our data show that MM progression leads to significant Mo-MDSC expansion (p Since T cell checkpoint inhibitors PD-1/PD-L1 are tumor immune escape receptors that play a pivotal role in supporting an immunosuppressive MM-ME, we also investigated the expression of PD-L1 on the CD14+ fraction in MM patients. BM-CD14+ cells (n=3) were compared with matched CD14 negative cells. We found that the CD14+ fraction had a higher PD-L1 expression in the BM of MM patients compared to the CD14 negative fraction (60-96% versus 3-8%). Hence, we investigated whether CD84-mediated cell-cell contact may increase the level of PD-L1 expression on Mo-MDSCs and whether MM cells can regulate CD84 and PD-L1 expression on CD14+ cells. Co-culture assays were performed using several human MM cell lines (MM1S, U266 and KMS11) with PB CD14+ cells derived from healthy donors (n=3). Our data show a 1.9-fold increase from the basal level of CD84 (27±16% to 50±9.4%) and a 2.9-fold increase from the basal level of PD-L1 (18±8.5% to 52.3±5.7%). Our recently generated mouse anti-human CD84 blocking antibody (Marom et al. 2017) was used to determine whether CD84 direct targeting can affect MM-induced CD84 and PD-L1 expression on the surface of CD14+cells. Co-culture experiments show that targeting CD84 lowered CD84 (1.6-fold decrease) and PD-L1 expression (1.8-fold decrease) on a CD14+ population co-cultured with MM cells. Moreover, when T cells were included in the co-culture experiments, we observed reduced expression of exhaustion markers PD-1 (1.1-fold decrease) and CTLA4 (1.4-fold decrease) in the presence of the CD84 blocking antibody. Conclusion: We show here that CD84 is expressed on Mo-MDSCs in MM and that the expansion of this myeloid population is strictly associated with MM progression. Disruption of CD84 contacts with a blocking antibody decreases the expression of PD-L1 on CD14+ cells and exhaustion markers on T cells. Thus, our results reveal a novel role for CD84 in regulating PD-L1 in the MM-ME and provides the scientific rationale to investigate whether targeting CD84 expression on Mo-MDSCs can restore T cell functions. To further confirm the role of CD84 regulating T cell activity and Mo-MDSC, in vivo mouse studies are ongoing and results will be presented at the meeting. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Sutro: Speakers Bureau; Onyx: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau; Takeda: Speakers Bureau.

WOS: 000297256400065, PubMed ID: 21069480, Polymorphism of AXIN2, a component of Wnt signaling, has been shown to play a role in tumorigenesis and dysregulated in cancer cells. In order to find out if AXIN2 polymorphism is a risk factor for prostate cancer, we analyzed eight polymorphic regions of this gene in 84 patients with prostate cancer and compared the results with 100 healthy controls in a Turkish population using PCR-RFLP methods. The genotype frequencies and risk factors of prostate cancer and control groups were analyzed by Chi-square test. We found a statistically significant result between prostate cancer risk and AXIN2 Intron2-956 + 16A/G (rs35285779) SNP. The frequency of the homozygous G/G (0%) and heterozygous A/G (18%) genotypes was significantly less in patients with prostate cancer than in healthy controls (7 and 32%, respectively) (P < 0.05) for this SNP. When compared with the wild-type A/A genotype of the controls, prostate cancer patients with the A/G and G/G genotype showed reduced risk of cancer; the adjusted odds ratio (OR) for patients with the homozygous G/G genotype was 0.87 (95% CI: 0.81-0.95) and for heterozygous A/G genotype was 0.42 (95% CI: 0.20-0.85). We found no statistically significant association between controls and prostate cancer for other seven SNPs of AXIN2 including Exon1-148 C/T (rs2240308), Exon1-432 T/C (rs2240308), Exon5-1365 G/A (rs9915936), Exon5-1386 C/T (rs1133683), Intron5-1712 + 19 T/G, Exon7-2062 C/T, and Intron7-2141 + 73 G/A (rs4072245) (P > 0.05). These results suggest that the AXIN2 Intron2 rs35285779 SNP is associated with development of prostate cancer as a protective SNP, while an association between other seven SNPs of the AXIN2 and risk of prostate cancer was not observed., Cumhuriyet University CUBAP, Sivas, Turkey [T-299], This study was supported by Grant no. T-299 from Cumhuriyet University CUBAP, Sivas, Turkey. The technical assistance of Ms. Meral Yilmaz is gratefully acknowledged.

Daratumumab (Dara), a human immunoglobulin G1 kappa (IgG1κ) monoclonal anti-CD38 antibody, has been approved by the U.S. Food and Drug Administration for the treatment of relapsed multiple myeloma (MM) as a single agent as well as in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). Although the scientific rationale behind the use of Dara in combination with IMiDs has been extensively explored, the molecular mechanisms underlying Dara-PI regimens have not yet been investigated. Here, we demonstrate that CD38 on the surface of MM cells is rapidly internalized after Dara treatment; we also show that Dara treatment impairs MM cell adhesion, an effect that can be rescued by using the endocytosis inhibitor Dynasore. Finally, we show that Dara potentiates bortezomib (BTZ) killing of MM cells in vitro and in vivo, independent of its function as an immune activator. In conclusion, our data show that Dara impairs MM cell adhesion, which results in an increased sensitivity of MM to proteasome inhibition.

The aim of this study was to assess the association between human fibroblast growth factor receptor 4 (FGFR4) Gly(388) Arg polymorphism and pre-eclampsia (PE) by carrying out a case-control study in Turkish women.In the present study 159 PE patients and 161 controls were included. DNA was extracted from peripheral blood leukocyte and FGFR4 Gly(388) Arg polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism methods.For Gly388Arg polymorphism of FGFR4 we found no significant association between controls and PE patients. The frequencies of GlyGly, GlyArg and ArgArg genotypes were 56.6%, 36.4% and 7% for the study group and 50.3%, 44.7% and 5% for the control group, respectively. The risk of women with the GlyArg (odds ratio = 0.7, 95% confidence interval: 0.45-1.14) and ArgArg (odds ratio = 1.2, 95% confidence interval: 0.47-3.22) genotypes for PE did not differ significantly from that of GlyGly genotype carriers.As we could not find any association between genetic variability in Gly(388) Arg of FGFR4 and PE, this specific polymorphism of FGFR4 can be eliminated as a risk factor for PE at least for Turkish women.

WOS: 000270569200025, PubMed ID: 21475939, Accumulated evidence suggests that alterations due to mutations or genetic polymorphisms in the AXIN2 tumor suppressor gene, a component of the Wnt signaling pathway, contributes to carcinogenesis. The effect of the AXIN2 exon 1 148 C -> T polymorphism was recently investigated in a Japanese population, but has not been investigated in other populations. Additionally, other common polymorphisms of this gene have not been studied. In the present study, 8 polymorphisms of the AXIN2 gene, including exon 1 148 C -> T, were investigated in a Turkish population of 100 lung cancer patients using PCR-RFLP methods. For the exon 1 432 C -> T, exon 5 1365 G -> A, exon 5 1386 C -> T, intron 5 1712+19 G -> T, exon 7 2062 C -> T and intron 7 2141+73 G -> A single nucleotide polymorphisms of AXIN2, no significant association was found between the controls and the lung cancer patients. For exon 1 148 C -> T, a statistically significant association between the controls and lung cancer patients was found. For this region, lung cancer patients with the TT genotype showed a decreased risk [odds ratio (ORTT) 0.33, 95% confidence interval (CI) 0.12-0.89; p=0.032 (adjusted for, gender and smoking status)] as compared with the controls age. with the CC genotype. Concerning histological tumor type, it has been found that exon 1 148 C -> T SNP is associated with a significant decreased risk in squamous cell carcinoma patients (ORTT 0.16; 95% CI 0.03-0.79; p=0.014). Male (ORTT 0.19; 95% CI 0.4-0.77; p=0.015) and smoker (ORTT 0.11; 95% CI 0.01-0.71; p=0.019) lung cancer patients with the TT genotype showed a decreased risk for the same region. Our results suggest that the risk of lung cancer in a Turkish population is related to poly morph isms of the AXIN2 gene., Cumhuriyet University CUBAP, Sivas, Turkey [T-299], This study was supported by Grant no. T-299 from Cumhuriyet University CUBAP, Sivas, Turkey. The technical assistance of Ms. Metal Yilimaz is gratefully acknowledged.

WOS: 000279207000027, PubMed ID: 21472303, The product of AXIN2, a component of Writ signalling, plays a role in tumorigenesis and is dysregulated in cancer cells. In order to determine whether the AXIN2 polymorphism is a risk factor for astrocytoma, we analysed eight polymorphic regions of this gene in 100 astrocytoma patients compared to 100 healthy controls in a Turkish population using PCR-RFLP methods. For the Exon1-148 TIC, Exon 1-432 C/T, Exon5-1365 G/A, Intron5-1712+19G/T, Exon7-2062 C/T and Intron7-2141+73 G/A SNPs of AXIN2, no significant association between controls and astrocytoma patients was found. For the Exon5-1386 C/T SNP, a statistically significant association between controls and patients was found (p, Cumhuriyet University CUBAP (Sivas, Turkey) [T-299], This study was supported by Grant no. T-299 from Cumhuriyet University CUBAP (Sivas, Turkey). The technical assistance of Ms. Meral Yilmaz is gratefully acknowledged. We also thank Dr Mustafa Gurelik.

WOS: 000298061200010, PubMed ID: 21827571, Aim: The aim of this study was to assess the association between human fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism and pre-eclampsia (PE) by carrying out a casecontrol study in Turkish women. Materials and Methods: In the present study 159 PE patients and 161 controls were included. DNA was extracted from peripheral blood leukocyte and FGFR4 Gly388Arg polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism methods. Results: For Gly388Arg polymorphism of FGFR4 we found no significant association between controls and PE patients. The frequencies of GlyGly, GlyArg and ArgArg genotypes were 56.6%, 36.4% and 7% for the study group and 50.3%, 44.7% and 5% for the control group, respectively. The risk of women with the GlyArg (odds ratio = 0.7, 95% confidence interval: 0.45-1.14) and ArgArg (odds ratio = 1.2, 95% confidence interval: 0.47-3.22) genotypes for PE did not differ significantly from that of GlyGly genotype carriers. Conclusion: As we could not find any association between genetic variability in Gly388Arg of FGFR4 and PE, this specific polymorphism of FGFR4 can be eliminated as a risk factor for PE at least for Turkish women.