bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of Notch3 signaling pathway in pancreatic cancer
Authors: Dang T. , Vo k. , Washington K. , Berlin J. 
Published: March 2020

21049 Background: Given the extremely poor prognosis of patients diagnosed with pancreatic cancer, identifying new targets for therapeutic intervention is crucial in improving clinical outcome. Existing data support a role for Notch3 pathway in human cancer, pancreas cancer in specific and in normal pancreas development. Method: We developed a pancreatic tissue array. An antibody targeting the extracellular domain of Notch3 was used to evaluate expression levels, grading from 0 to 4+ to determine the prevalence of Notch3 in pancreatic cancer. Notch3 expression was used to correlate with clinical data (IRB approved). Using small interfering RNA (siRNA) we tested the downstream effects of Notch3 in pancreatic cancer cell line BxP3 in vitro. Furthermore, to study pharmacologic inhibition of Notch3 processing and activation we exposed Panc-1, HPAF II and BxP3 pancreas cancer cell lines to γ-secretase inhibitors (previously demonstrated to block upstream of Notch3 thereby inhibiting Notch3). Results: Strong staining (+2 or greater) for Notch3 was seen in 50 of 72 (69%) resected specimens. No correlation with survival or tumor grade was seen. Using siRNA, we demonstrated that inhibiting Notch3 downregulated the antiapoptotic protein Bcl-xL but not Bcl-2. When γ-secretase inhibitors (GSI and L-685,458) were used, the previously mentioned pancreatic cell lines demonstrated reduction in proliferation rates. Conclusion: Notch3 overexpression is common in pancreas cancer. While Notch 3 expression does not clearly correlate with survival, our in vitro data suggest that Notch3 affects apoptotic pathways and may represent a potential target for intervention in patients with pancreatic cancer. No significant financial relationships to disclose.
Relationship between polymorphisms in cordon 118 and C8092A in ERCC1 and clinical outcome in optimally-resected, stage III epithelial ovarian cancer treated with intraperitoneal or intravenous cisplatin and paclitaxel: A gynecologic oncology
Authors: Krivak T. C. , Darcy K. M. , Tian C. , Baysal B. E. , Armstrong D. K. , Gallion H. H. , Deloia J. A. 
Published: March 2020

21050 Background: The association between polymorphisms in the excision nuclease ERCC1 and progression-free survival (PFS) or overall survival (OS) was examined in women with epithelial ovarian cancer (EOC) treated with cisplatin and paclitaxel. Methods: Women who were evaluable for the phase III trial, GOG-172, with sufficient leukocyte DNA for testing were eligible for this study. Participants were randomized to intraperitoneal (IP) or intravenous (IV) cisplatin and paclitaxel. Single nucleotide polymorphism (SNP) analysis was carried out by direct pyrosequencing. Results: Among the 233 eligible cases, the genotype distribution at codon 118 was 17% with C/C, 43% with C/T and 40% with T/T and at C8092A was 56% with C/C, 37% with C/A and 7% with A/A. Adjusted Cox regression analysis revealed that the codon 118 polymorphism was not significantly associated with disease progression or death, but women with the C/A or A/A genotype compared with the C/C genotype at C8092A had an increased risk of disease progression (hazard ratio [HR]=1.48, 95% confidence interval [CI]=1.09–2.00, p=0.011) and death (HR=1.46, 95% CI=1.04–2.04, p=0.029). Subset analysis stratified by treatment suggested that the C8092A polymorphism was significantly associated with increased risk of PFS and OS in the IP but not the IV arm. Conclusions: Although the ERCC1 codon 118 polymorphism does not appear to be associated with clinical outcome, the C8092A polymorphism in ERCC1 was an independent predictor of PFS and OS in optimally-resected EOC treated with cisplatin- paclitaxel chemotherapy. The preferential clinical utility of the C8092A polymorphism in the IP but not the IV arm requires validation. No significant financial relationships to disclose.
Confirmation of the distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene expression analysis
Authors: Van Laere S. J. , Van der Auwera I. , Van den Eynden G. G. , Trinh X. , Van Hummelen P. , van Dam P. , Van Marck E. A. , Vermeulen P. B. , Dirix L. Y. 
Published: March 2020

21055 Background: We have shown with cDNA microarrays that inflammatory breast cancer (IBC) and non-IBC are distinct biological entities. The purpose of this study was to confirm our previous results using Affymetrix chips. Methods: RNA was extracted from 19 IBC samples and 42 non-stage matched non-IBC samples. RNA was hybridized onto Affymetrix HG U133 Plus 2.0 chips. Gene expression data were normalized using GCRMA and genes with a gene expression of at least 250 in 50% of the cases were filtered in. Hierarchical clustering and principle component analysis was executed. Identification of the different cell-of-origin subtypes in our expression data set was done using the intrinsic gene list. A NFkB signature, a MAPK signature and our own IBC signature were tested by clustering analysis. Results: Clustering using 11341 genes resulted in the identification of two clusters: one containing 14/19 IBC samples and a second containing 32/42 non-IBC (Pearson χ2; p<0.0001). Principle component analysis separated IBC from non-IBC samples along the first principle component. Interestingly, IBC samples more closely resemble T1 - T2 tumours than T3 - T4 tumours. Application of the intrinsic gene set to our IBC/non-IBC data set resulted in the classification of 14/19 IBC samples as basal-like or ErbB2-overexpressing tumours compared to only 4/42 non-IBC tumours (Pearson χ2; p<0.0001). Our own IBC signature was confronted with the new data set and performed well in separating IBC specimens form non-IBC specimens. Clustering identified three clusters from which one cluster contained 18 samples, including 12 IBC specimens (p<0.0001). Using the NFkB and MAPK signatures, similar results were obtained. Conclusions: These results confirm our findings that IBC is a distinct biologic phenotype, characterized by activation of NFkB, possibly through activation of MAPK's. IBC tumours more often demonstrate characteristics from basal-like and ErbB2-overexpressing breast tumours. The fact that IBC tumours are rapidly developing tumours instead of longstanding tumourigenic processes might explain the close resemblance of the IBC gene expression profile to the gene expression profile of T1 and T2 tumours. No significant financial relationships to disclose.
Expression of the WAVE (WASP Verprolin-homologous) molecules in human breast cancer
Authors: Fernando H. , Chhabra A. , Davies S. , Watkins G. , Kynaston H. , Mansel R. E. , Jiang W. G. ,   Metastasis and Angiogensis Research Group
Published: March 2020

21061 Background: WAVEs (WASP Verprolin-homologous) belongs to the CCN family which comprises of nine members, the cysteine-rich 61 (Cyr61/CCN1), connective tissue growth factor (CTGF/CCN2) and nephroblastoma over-expressed (Nov/CCN3), Wnt-induced secreted proteins(WISPs)1, 2 and 3 (CCN4–6) as well as the WAVE-1,2 and 3 (also known as CCN7–9 respectively). Some members of the CCN family, such as Cyr61 and CTGF are known to stimulate mitosis, adhesion, apoptosis, extracellular matrix production, cell migration and growth arrest in cancer cells including breast cancer cells. However, there is no knowledge of the expression pattern and the function of WAVEs in human breast cancer. Here, we report the expression of WAVE-1,-2 and -3 transcripts and proteins in relation to clinical and pathological characteristics in human breast cancer. Methods: The expression of the three WAVE molecules at the mRNA and protein levels in a cohort of 122 human breast cancers and 32 normal breast tissues were analysed and correlated with the patients’ clinical outcome. The respective transcripts were quantitative determined using real time RT-PCR and distribution of the proteins were investigated by immunohistochemical methods. Results: All three WAVE proteins were detected in mammary epithelial cells and are of cytoplasmic nature. Breast cancer cells from the tissues also displayed positive staining of the WAVE proteins, with WAVE-2 staining appears weaker compared with normal epithelial cells. WAVE-1 transcripts were expressed in significantly high levels (p=0.03) in high grade breast cancers. Low levels of WAVE-2 were associated with higher TNM staging (p=0.038 in TNM3 and p=0.017 in TNM4) and were also found in patients with poor prognosis. Interesting, a marginal reduction of WAVE-3 transcripts was seen in patients who developed systemic metastasis. No other significant associations were found between the WAVE1 and WAVE3 transcripts and the breast cancer cells. Conclusions: WAVEs are widely expressed in human mammary tissues and have a differential expression in human breast cancer with WAVE2 appearing to be associated with the aggressiveness of breast tumors. No significant financial relationships to disclose.
An association between thyroid disease and breast cancer
Authors: Karlin N. J. , Chopra I. , Mirocha J. , Feldman N. 
Published: March 2020

21063 Background: Anecdotal studies and isolated case reports have observed an association of thyroid disease and breast cancer. This purported association remains controversial. We describe a retrospective case-control study on the prevalence of breast cancer in patients with abnormal thyroid function studies. Age-matched subjects served as controls. Methods: We reviewed 6211 cases of abnormal TSH values between 1/04 and 12/05 and determined the number of cases with breast cancer. We compared those data to 3,151 control subjects with normal TSH seen during the same period. We excluded patients with thyroid cancer from the total number of malignancies in both groups because abnormal TSH would be expected to result from its treatment. We also reviewed the ER, PR, her 2 neu status and free thyroxine of patients with breast cancers. Results: Breast cancer rate of 36% of all cancers (37/102) in the abnormal TSH group was significantly higher than that of 18% (14/77) in the normal TSH group. (p = 0.012). Breast cancers in the study group with abnormal thyroid function were more frequently hormone receptor positive (74% vs. 67%) and her 2 neu negative (67% vs. 50%). Conclusions: The data suggest that there is an increased rate of breast cancer in patients with abnormal thyroid function. The trend of hormone receptor positive disease in the abnormal TSH group suggests that the IGF receptor may play an important role in the relationship between thyroid disease and breast cancer. The IGF receptor may be a potential target for therapeutic drug development for breast cancer prevention and management. Further studies are warranted. No significant financial relationships to disclose.
CCR5 gene polymorphism in patients with cutaneous melanoma: Impact on survival following immunotherapy
Authors: Becker J. C. , Ugurel S. , Zapatka M. , Kaufmann H. L. , Schrama D. 
Published: March 2020

21071 Background: Chemokines are supposed to influence both tumor progression and anti-tumoral immune responses. In this regard, a 32-bp-deletion polymorphism in the chemokine receptor 5 gene (CCR5Δ32) resulting in a non-functional receptor protein allows to study the potential impact of the CCR5 system on the clinical course and treatment outcome of malignant diseases. Methods: CCR5 genotyping was performed by PCR on DNA extracted from serum samples of 782 cutaneous melanoma patients with known disease history and long-term clinical follow-up. Genotypes were correlated with patient survival in consideration of different therapeutic modalities. Results: Out of 782 patients, 90 (11.5%) were heterozygous and 12 (1.5%) were homozygous for CCR5Δ32. Disease-specific survival starting from primary diagnosis was not influenced by CCR5 status. Equally, no impact of the CCR5 status could be detected on treatment outcomes of stage III patients. In 139 stage IV patients treated with immunotherapeutics, however, CCR5Δ32 was associated with a diminished survival compared to patients not carrying the Δ32 allele (p=0.029). Multivariate analysis revealed the CCR5 genotype as an independent factor impacting disease-specific survival in this patient group (p=0.0084), followed by gender (p=0.017), and type of primary (p=0.029). Vice versa, stage IV patients without immunotherapy revealed a trend towards a favorable survival when harboring CCR5?32 (p=0.12). Conclusions: The disadvantage of CCR5Δ32-bearing stage IV melanoma patients with respect to outcome of immunotherapy indicates a strong impact of the CCR5 mediator system on anti-tumoral immune responses, and should be taken into account when choosing therapeutic modalities for these patients. No significant financial relationships to disclose.
Use of nuclear androgen receptor status to predict early biochemical recurrence of prostate cancer patients
Authors: Diallo J. , Aldejmah A. , Alam Fahmy M. , Koumakpayi I. , Mes-Masson A. , Saad F. 
Published: March 2020

21073 Background: Prostate cancer (PCa) is a leading cause of cancer death in North American men. The androgen receptor (AR) has an established role in the progression of this disease; however, it is unclear at what stage it intervenes. It is also uncertain whether the AR can be a useful prognostic marker for PCa. In this study, we assessed AR expression and sub-cellular localization in normal prostate as well as in androgen sensitive and insensitive PCa (AIPCa) tissues, and evaluated the ability of the AR to predict biochemical recurrence (BCR). Methods: We used tissue micro-arrays containing prostate tissue cores obtained from cancer-free patients (n=43), AIPCa patients (n=36), and patients with hormone-sensitive cancers (n=64) from which were collected both cancerous and normal adjacent tissue. Using immmunohistochemistry, we stained the tissue micro-arrays with a monoclonal antibody recognizing the AR. Two observers assessed the frequency and intensity of both cytoplasmic and nuclear AR staining. AR cytoplasmic (Ci) and nuclear (Ni) indices were calculated by multiplying nuclear staining frequency and nuclear staining intensity. Kaplan Meier, and Cox multivariate analyses were done using SPSS. Results: We found that AR Ci increased significantly in AIPCa although a modest but significant increase in PCa Ci was observed compared to normal tissues. In contrast, AR Ni was significantly lower in cancer-free patients as opposed to that seen in normal tissue adjacent to cancer. Similarly, cancerous tissue exhibited higher AR Ni than its adjacent normal tissue (p<0.05, Kruskal-Wallis). Kaplan Meier analyses revealed that low AR Ni was predictive of an early onset of BCR (before 3-years) in the sub-cohort of hormone-sensitive patients (LR=6.51, p=0.011). Futhermore, low AR Ni remained an independent predictor of early BCR in a Cox multivariate model controlling for age, pre-operative PSA, lymph node invasion, Gleason score and surgical margin status (HR=2.28, 95% CI=1.04 - 5, p<0.05). Conclusions: We conclude that increased nuclear AR activity could be a pre-malignant step in PCa progression whereas its role within cancer cells may be more complex, as low AR nuclear activity was associated with early onset of BCR. No significant financial relationships to disclose.
Insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 is active in breast cancer cells and enhances growth inhibition by herceptin through an increase in cell cycle arrest
Authors: Esparís-Ogando A. , Rodríguez-Barrueco R. , Borges J. , Ferreira L. , Pandiella A. , Ocana A. 
Published: March 2020

21077 Background: Targeting ErbB2 with the monoclonal antibody trastuzumab (Herceptin) has shown to be active in breast cancer. However, a proportion of patients do not benefit from this treatment due to primary resistance. Mechanisms proposed for this resistance include activation of other receptors involved in proliferation as is the case of the insulin-like growth factor receptor (IGF-1R).Different strategies have been proposed for the inhibition of IGF-1R such as antibodies or small tyrosine-kinase inhibitors. In this study we analyzed the mechanism of action and the antiproliferative activity of an specific IGF-1R tyrosine-kinase inhibitor termed NVP-AEW541 alone and in combination with Herceptin. Methods: MCF7, SKBR3, BT474, and MDA-MB-231 breast cancer cells were used for this study. Proliferation and apoptosis were analyzed by MTT uptake assays or Annexin-V-FITC, respectively. The levels of different signalling proteins were analyzed by Western blotting. Microarray studies were performed using the HU-133A oligonucleotide arrays (Affymetrix, Santa Clara, CA). Real time quantitative PCR was used to confirm the differentially regulated genes. Results: The IGF-1R was expressed in all the cell lines studied. Exogenous addition of IGF-1 increased the tyrosine phosphorylation of IGF-1R, and this was prevented by preincubation with NVP- AEW541. The latter also decreased MTT uptake, and provoked a slight increase in apoptosis of BT474 cells. Combination of NVP-AEW541 and Herceptin had a synergistic effect on the inhibition of BT474 proliferation. Cell cycle analyses indicated that the combined addition of NVP- AEW541 and Herceptin increased the number of cells in the G0/G1 phases. These data were complemented with an increase in p27 levels upon treatment with both compounds. Microarray analyses identified several genes whose expression was modified by each agent alone and by the combination. Conclusions: Our results indicate that the combined targeting of two receptor tyrosine kinases known to play important roles in tumor cell proliferation may be more efficient than individual targeting of these receptors. No significant financial relationships to disclose.
Zoledronic acid induces anti-cancer effects on prostate cancer cells through the modulation of the angiogenesis associated CYR61 and the androgen-differentiation associated NDRG-1 genes
Authors: Tonini G. , Vincenzi B. , Marra M. , Baldi A. , Addeo S. , Loeffler M. , Rosolowski M. , Budillon A. , Caraglia M. , Santini D. 
Published: March 2020

21079 Background: Aminobisphosphonates (ABPs) has a definite direct anti-tumour activity but a limited activity in vivo. Their molecular targets are still not completely defined. Therefore, we have studied the effects of zoledronic acid (ZOL) addition to prostate cancer PC3 cells on gene expression profile. Methods: We have treated PC3 cells with 100 μM ZOL for 24 hours, extracted mRNAs and probed on Affimetrix HG-U133. Thereafter, we have identified down modulated and upregulated genes and checked for modulation of mRNA with RT PCR and of the relative encoded proteins with western blotting. Results: We have found 6 down modulated and 32 upregulated genes. We have focused our attention on NDRG1 associated to the androgen-differentiation and on Cysteine rich 61 (CYR61) involved in the regulation of proliferation and angiogenesis. NDRG1 mRNA was up-regulated and CYR61 mRNA was downregulated by ZOL in a dose-dependent manner. Similar effects were observed at protein product levels with an about 2-fold change recorded already in cells treated with 50 μM ZOL. Interestingly, also Gefitinib, Sorafenib and Tipifarnib used at their IC:50s could induce changes in both NDRG1 and CYR61 expression, but 50 μM ZOL was about 2-fold more potent. On the other hand, cytotoxic agents such as docetaxel did not have any effect. The addition of farnesol (FOH) or geranylgeraniol (GGOH) to ZOL-treated cells was able to counteract the effect of ZOL on CYR61 expression partially or completely, respectively. On the other hand, both FOH and GGOH had poor effect on the regulation of NDRG1 expression induced by ZOL. Conclusions: ZOL induces a strong regulation of the expression of NDRG1 and CYR61 at both mRNA and protein levels that appears to be dose-dependent and specific. CYR61 modulation seems to be more dependent from the inhibition of geranylgeranylation processes while NDRG1 changes could be at least in part independent from the inhibition of isoprenylation induced by ZOL. The study of the biological relevance of these effects on the anti-cancer effects of ZOL is ongoing with small interference RNA approaches. No significant financial relationships to disclose.
Persistence of circulating tumour cells after treatment predicts clinical outcome in breast cancer patients
Authors: Serrano M. , Sánchez-Rovira P. , Campos M. , Warleta F. , Ruiz-Mora J. , Algarra I. , Delgado-Rodríguez M. , Fernández M. , de la Torre C. , Peiró A. , Gaforio J. J. 
Published: March 2020

21080 Background: The hematogenous distant metastasis is the leading cause of cancer death. This process involves the passage through the blood and lymphatic circulation of circulating tumor cells (CTC) with metastatic properties. Thus, the early detection of such cells has important implication for cancer prognosis, monitoring of treatment and to predict clinical outcome. We present the results that showed that CTC are prognostic factor after chemotherapy independently of treatment. Methods: A total of 59 patients with breast cancer were enrolled in this study between April 2000 and December 2002. The median follow-up was 50 months. All patients received chemotherapy as first line treatment. Results of this work included CTC detection one month after of the end of chemotherapy. After informed consent, 10ml of heparinized peripheral blood was collected from patients. For enrichment of CTC we use the Carcinoma Cell Enrichment and Detection kit using MACS technology (Miltenyi Biotec). After enrichment of epithelial tumor cells immunomagnetic labeled with a multi- cytokeratin-specific antibody, the positive cells were detected by immunocytochemical staining with alkaline phosphatase substrate. Results: Analysis of CTC after chemotherapy: Circulating tumor cells were detected in 32 patients (54.23%). A mean number of cells were detected 3.7 (SD 13.9; range 1–105).The number of CTC was correlationed with progression free of disease (PFS) and overall survival (OS). In the univariate Cox proportional hazard regression analysis number cells were significantly associated with OS (p = 0.020) and PFS (p = 0.008). In the multivariate Cox proportional hazard regression analysis, number cells admit borderline statically significance with PFS (p = 0.052) and OS (p = 0.071). Conclusions: Our results suggest that the persistence of CTC after the treatment predicts clinical outcome and therefore the detection of CTC in breast cancer patients might allow monitoring of chemotherapy response. No significant financial relationships to disclose.