bluuebunny/crossref_metadata_2025_split huggingface dataset:
FoxM1 as a potential therapeutic target for triple-negative breast cancer.
Authors: Yom Cha Kyong , Lee Kyung-Min , Han Wonshik , Kim Sung-Won , Moon Hyeong-Gon , Noh Dong-Young 
Published: March 2020

e22063 Background: Elevated expression or activity of the transcription factor forkhead box M1 (FoxM1) is associated with development and progression of breast cancer. In this study, we show that whether inhibition of FoxM1 in triple negative breast cancer (TNBC) cell lines causes the changes of cancer progress and response to the treatment. Methods: We inhibited FoxM1 using thiostrepton (FoxM1 inhibitor) and identified the activity of VEGF, cyclin B, cyclin D1, p27, CD44 and cleaved capase-3 in MDA-MB-231 cells. Invasion assay was evaluated in BT-20 cells and combination with cisplatin and inhibition of FoxM1 were treated in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, MDA-MB-157, and BT-20. Results: When FoxM1 was inhibited using thiostrepton in MDA-MB-231 cells, expressions of VEFG, cyclin B, cyclin D1, p27, and CD44 were decreased. On the other hand, cleaved caspase-3 expression was increased. Intersetingly, response to inhibition of FoxM1 depended on the expression of p53 in each cell lines. Invasiveness of BT-20 cells is markedly reduced by inhibitioh of FoxM1. Co-treatment with thiotrepton and cisplatin synergistically induced apoptosis of breast cancer cells in MDA-MB-231, MDA-MB-157, and BT-20. Conclusions: Inhibition of FoxM1 increases apoptosis and decreases invasiveness and VEGF exprsssion of TNBC cells. And when inhibition of FoxM1 combines with cisplatin treament, synergistic effect was shown. Therefore, FoxM1 is valuable as a potential target for not only anticancer activity but also overcoming cisplatin resistance in TNBC.
Predicting erlotinib resistance in EGFR wild type NSCLC patients.
Authors: Jensen Peter Buhl , Knudsen Steen , Hansen Anker , Jensen Thomas , Askaa Jon 
Published: March 2020

e22065 Background: Cancer patients with wild type EGFR respond to treatment with erlotinib at a lower rate than patients with EGFR mutations. It would be relevant to predict which EGFR wild type patients benefit from erlotinib. We have developed a response predictor based on NCI60 cancer cell lines measurements of erlotinib effect and gene expression measurements. Clinical relevance was improved by filtering the model through expression profiles from more than 3,000 clinical samples.The erlotinib response predictor consists of 94 sensitivity genes and 10 resistance genes and is completely defined before independent validation on patients treated with erlotinib. Methods: Gene expression data from pre-treatment core biopsies from 25 patients with refractory NSCLC (clinicaltrials.gov: NCT00409968) later treated with erlotinib (The BATTLE trial; Kim, ES et al. Cancer Discov. 2011; 1:44-53) were downloaded from Gene Expression Omnibus with accession number GSE33072. PFS after erlotinib treatment was recorded. The erlotinib response predictor was applied retrospectively to the gene expression measurements.Patients with a predicted sensitivity above the 0.15 quantile were categorized as sensitive, patients with a predicted sensitivity below were categorized as resistant.The median was also tested as a cutoff, and correction for multiple testing was taken into consideration. Results: In a Kaplan-Meier analysis of PFS comparing predicted sensitive and predicted resistant patients, the predicted sensitive patients survived longer (PFS 2.3 months (1.9-2.7)) than predicted resistant patients (PFS 1.2 months (0.5-1.8)). A log-rank test for PFS found the difference significant (p=0.005). Hazard ratio 4.6 (1.4-15.2). Conclusions: The small clinical data set validated the cell line derived erlotinib response predictor. It identified a subset of 16% of patients with no apparent benefit from erlotinib. We have performed similar validations for 24 other response predictors in 24 clinical trials. In 20 out of the 24 clinical trials, the agreement between prediction and clinical outcome was statistically significant. Thus, our cell line based method represents a general method for predicting clinical response to cytotoxic or cytostatic agents.
Detection of solid tumors by infrared biochemical analysis of peripheral blood mononuclear cells.
Authors: Kapelushnik Joseph , Zelig A. , Geffen David Barry , Gusakova Irena , Mordichai S. 
Published: March 2020

e22069 Background: Detection of malignancies such as breast, colorectal and lung at early stages can improve survival rates from 20% up to 80%. Over the past few years, great efforts have been taken to develop novel, non invasive and effective methods for early diagnosis of cancer; however, a low sensitivity and/or specificity, has prevented their introduction as methods for early detection of cancer in populations at risk Methods: The clinical study was conducted at Todos Medical Ltd., Ben-Gurion University of the Negev and Soroka University Medical Center. 2 ml of peripheral blood was collected from each of 67 cancer patients (breast 26; gastrointestinal 27; lung 13; other 11) and 46 healthy controls. Peripheral blood mononuclear cells (PBMC) were extracted from whole blood and measured under Fourier transformed infrared microscope spectroscopy(FTIR-MSP). The differences between spectra of cancer and controls subjects' PBMCs were analyzed. Results: Significant differences were observed between healthy subjects and cancer patients at multiple bands along the infrared spectra of the PBMCs. Furthermore, we observed a distinct spectral pattern for each type of cancer which may indicate a difference in composition and activity of PBMC population. Several absorption bands may indicate for the stage of the disease.with sensitivity of 84% and specificity 94%. Conclusions: This study suggests the potential of FTIR spectroscopy analysis as a simple, low cost and minimally invasive method for cancer detection. The present research is preliminary and additional clinical trials are required for further validation and verification.
Identification of germ-line 185delAG BRCA1 mutation among breast cancer families in Iran: An experience from northeastern Iran.
Authors: Kooshyar Mohammad Mahdi , Nassiri Mohammad Reza , Mahdavi Morteza , Doosti Mohammad , Parizadeh Amir Reza 
Published: March 2020

e22079 Background: The present study evaluated the prevalence of 185DelAG BRCA1 mutation in the group of Iranian women breast cancer patients, or their relative with family history of breast cancer. Breast cancer is the most common malignancy in women and the leading cause of cancer death in females worldwide. BRCA1 is among the best known cancer susceptibility genes with high penetrance and have multiple cellular functions including critical roles in homologous DNA repair. Identifying gremlin BRCA mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. The combination of breast cancer susceptibility alleles together with other risk factors may be important clinically. Methods: Subjects included in this study were thirty nine patients diagnosed with breast cancer and 29 women, from first degree relative of patients. The clinical and demographic details from these individuals were collected from medical records, pathological reports, and when needed and using a detailed questionnaire. Genomic DNA from peripheral blood mononuclear cells was extracted and analyzed by polymerase chain reaction and SSCP methods in order to finding 185DelAG founder mutation. Results: The results indicated that four patients and three healthy relatives had this founder mutation. The identification of these founder mutations facilitates mutation population screening and subsequent management options available to an individual woman including screening or prevention are then dependent on this level of assessed risk. Conclusions: Finally identifying the effective risks regarding breast cancer among Iranian women requires many works. However, a complete BRCA1 gene sequence analysis might be useful, regarding targeted cancer prevention and therapeutics.
Outcomes of patients with advanced cancer and KRAS mutation in phase I clinical trials.
Authors: Tsimberidou Apostolia Maria , Said Rabih , Falchook Gerald Steven , Janku Filip , Naing Aung , Zinner Ralph , Blumenschein George R. , Fu Siqing , Hong David S. , Piha-Paul Sarina Anne , Wheler Jennifer J. , Ye Yang , Hess Kenneth R. , Palmer Gary A. , Wolff Robert A. , Kurzrock Razelle 
Published: March 2020

e22086 Background: The prognostic significance of KRAS mutations varies by mutation type. We compared the outcomes of patients with different KRASmutations treated in phase I clinical trials. Methods: Patients with advanced cancer and KRAS mutation who were treated in the phase I program from 9/08 to 12/12 were analyzed. The presence and type of KRAS mutation in the patients’ tumor samples were assessed in a CLIA-certified laboratory using PCR, sequenom analysis or next-generation sequencing. We compared clinical outcomes according to type of mutation, tumor, and therapy. Results: KRAS mutations were identified in 365 patients (codon 12, n=278; codon 13, n = 49; other codon, n = 38). The median age was 59 yrs (range, 18-87); and 46% men. Of 365 patients, 260 had KRAS mutation alone; 105 patients had 130 additional aberrations: PI3KCA, n=45 (39%); p53, n=29 (25.2%); PTEN, n=22 (19%); other, n=34 (29%). Of 260 patients, 159 were treated and evaluable for response. Outcomes in patients with KRAS mutation alone or with KRAS and additional molecular aberrations are shown in the Table. Conclusions: Keeping in mind that the number of patients was small, our results demonstrate heterogeneity in outcomes of patients with KRAS mutations. Combination studies of MEK inhibitors with other drugs may have improved antitumor activity. [Table: see text]
Internal mammary node biopsy for breast cancer patients: Issues for discussion and our practice.
Authors: He Qingqing 
Published: March 2020

e22089 Background: The aims of this study was to determine the clinical implications of internal mammary node biopsy as staging, treatment with radiotherapy and systemic treatment and a prognostic factor in patients with breast cancer. Methods: Internal mammary node biopsy via intercostal space was performed in 344 cases of breast cancer. Anatomical location of internal mammary nodes were recorded. Pathological status of internal mammary node were detected by H and E stains. Results: Internal mammary node biopsy was successfully finished in 344 patients.There were 162 cases (48.26%) with positive axillary nodes, while the internal mammary nodes were involved in 72 cases (20.93%).53 patients (32.72%) had regional metastases in both the axillary and internal mammary lymph nodes.19 (5.52%) patients had internal mammary node metastasis but no axillary node metastases. PN stage migration was seen in 72 patients with a positive internal mammary node. There was no statistic relation between internal mammary nodes metastases and tumor location (X2 =0.48, P>0.05). There was no complication such as pneumothorax or haemorrhagia. Conclusions: The approach used is a reliable surgical technique for removing lymph node from intercostal space. Without exploring internal mammary nodes status, pN stage was incomplete. Internal mammary node biopsy enables treatment to be better adjusted to the needs of the individual patient. Using internal mammary node biopsy, patients with a negative internal mammary node can be prevented from radiation to internal mammary nodal areas. This leads to optimization of treatment.
An analysis of preoperatively HE4 and CA125 in matched samples of patients (pts) with benign disease and borderline ovarian tumors (BOT) with and without invasive implants (InvImp).
Authors: Nassir Mani , Braicu Elena Ioana , Richter Rolf , Chekerov Radoslav , van Gorp Toon , Timmerman Dirk , Vergote Ignace , Sehouli Jalid 
Published: March 2020

e22102 Background: Presence of InvImp, quality of surgical staging and residual tumor mass were shown to be major prognostic factors for BOT. Currently, there are no biomarkers that can predict the various types of BOT. Aim of our study was to assess the value of individual CA125 and HE4 values, and the combination of CA125 and HE4 according to the ROMA algorithm for detecting BOT, and for predicting the presence of InvImp. Methods: BOT pts with InvImp (n=14) were matched by age and histology and compared to consecutive pts with benign disease and BOT without InvImp (1 to 4 to 1, respectively). Blood was collected prior surgery. HE4 and CA125 were determined using ELISA. The performance of HE4 and CA125 were analyzed using the receiver operator characteristic (ROC) and logistic regression. Results: HE4 and CA125 were increased in BOT with InvImp (median=73.85pM and 49.5IU/dl) compared with benign diseases and BOT without InvImp (median values: 48pM and 18.5IU/dl, and 61.45pM and 26.5IU/dl, respectively). HE4 and CA125 expression were significantly increased in BOT with InvImp compared to benign diseases (p=0.029 and 0.004, respectively) but not to BOT without InvImp. Furthermore we grouped BOT without InvImp together with benign diseases and compared them with BOT with InvImp. HE4 and CA125 cut off values of 65pM and 60IU/dl, respectively were independent predictive factors for the presence of InvImp (p=0.018, OR=5.32, 95%CI 1.33-21.20 and p=0.031, OR=4.83, 95%CI=1.16-20.13, respectively). ROMA performed better than HE4 or CA125 alone (p=0.002, RR=9.17, 95%CI=2.31-36.36). The OR of a high ROMA score were 0.082 (95%CI: 0.02-0.34; p=0.001) for benign diseases and 0.27 (95%CI: 0.05-1.42; p=0.123) for BOT without InvImp compared to BOT with InvImp. Conclusions: The ROMA score can not predict sufficiently InvImp in BOT. Further multicenter and larger prospective studies are needed.
Use of nanocurcumin to inhibit proliferation and metastases of hepatocellular carcinoma via NF-κB mediated matrix metalloproteinase-9 downregulation.
Authors: Xu Yang , Hu Bo , Anders Robert , Maitra Anirban , Fan Jia 
Published: March 2020

e22103 Background: Curcumin regulates the expression and secretion of MMPs, and has potent anti-cancer properties in several human cancer cell lines and animal carcinogenesis models. In this study we try to investigate the effects of polymeric nanoparticle encapsulated formulation of curcumin– nanocurcumin (NC) on Hepatocellular carcinoma (HCC) in vitro and in vivo. Methods: The effects of NC alone and in combination with sorafenib (SO) were investigated on HCC cell lines, Huh7 and MHCCLM3 in vitro by using proliferation and invasion assay, western blot, qRT-PCR, enzyme-linked immunosorbent assay and immunohistochemistry staining, and the subcutaneous and orthotopic HCC xenograft nude mice models (MHCCLM3) were used to evaluate primary tumor growth and metastasis after treatments. Results: NC alone (or combined with SO)inhibited HCC cell proliferation (p<0.05) and invasion in vitro (p<0.01), and remarkably decreased both the subcutaneous and orthotopic primary tumor growth and lung metastases in vivo. NC and/or SO could down-regulating the expressions of Matrix Metalloproteinase-9 (MMP9), p-ERK1 and NF-kB/p65 (p<0.05). Conclusions: NC showed potent anti-invasion and metastasis properties in HCC via NF-κB mediated MMP9 down-regulation, which may provide a new strategy to the treatment of HCC patients and prevention of tumor recurrence after operation.
Capturing and molecular analysis of tumor cells isolated from ascites fluid to predict response to treatment.
Authors: Krahn Thomas , Jeffers Michael , Von Hoff Daniel D. , Seetharam Mahesh , Liu Xinjun , Kim Phillip Sangwook , Singh Sharat 
Published: March 2020

e22110 Background: As access to tumor tissue if often limited in clinical studies, we are exploring technologies to capture tumor cells from body fluids with the aim to use the profile of pathway activation to predict response to treatment in early clinical trials. Methods: Tumor cells were captured from ascites fluid collected from an ovarian cancer patient via immunomagnetic enrichment. Isolated tumor cells were characterized for panel of signal transduction proteins at base line and after the treatment with PI3K inhibitor and/or MEK inhibitor alone or in combination. Comprehensive functional pathway modulation was determined using multiplexed Collaborative Enzyme Enhanced Reactive-immunoassay (CEER) to evaluate the treatment efficacy. Results: Sufficient numbers of tumor cells were present in ascites fluid for immunomagnetic enrichment and for subsequent functional pathway analysis. Comprehensive pathway modulations (HER1, HER2, HER3, cMET, IGF1R, PDK1, PI3K, AKT, PRAS40, RPS6, ERK, MEK and RSK) were determined with tumor cells using CEER. Pathway modulation upon in vitro drug treatment revealed insufficient targets as well as downstream signal protein inhibition against single agent PI3Ki or MEKi treatment. When these cells were treated with both compounds however, a dramatic target/pathway inhibition was observed. Conclusions: Viable, stimulatable tumor cells can be isolated in high number from ascites fluid and routine pathway analysis can be achieved in clinical setting. As pathway redundancy is a common feature in most solid tumor, a comprehensive in vitro analysis of pathway against various targeted drugs using tumor cells isolated from easily obtainable biological fluid (ascites, plural fluid, etc.) may guide clinicians in selecting the most effective targeted drug combination. Significant differences can be detected between single and combination treatment. Further studies need to be done to validate these findings.
Impact of antiangiogenic treatments on exhausted PD-1+ T lymphocytes in colorectal cancer.
Authors: Pernot Simon , Terme Magali , Marcheteau Elie , Voron Thibault , Colussi Orianne , Tartour Eric , Taïeb Julien 
Published: March 2020

e22121 Background: Tumors develop immunosuppressive mechanisms to escape the immune system. Among these mechanisms, T lymphocytes can express inhibitory molecules such as Program Death-1 (PD-1) protein which impair their activation and their effector functions. Multi-target anti-angiogenic tyrosine kinase inhibitors (TKI) that are routinely used as first- or second-line treatment of cancer patients, have been shown to modulate immunosuppressive mechanisms especially regulatory T cells. However, the role of specific VEGF/VEGFR blockade on PD-1 expression by T lymphocytes has not been studied. Methods: PD-1 expression on T lymphocytes has been analyzed by flow cytometry in a mouse model of colorectal cancer (CT26) treated by anti-angiogenic molecules targeting the VEGF-A/VEGFR axis and in the peripheral blood of metastatic colorectal cancer patients. Results: Sunitinib that directly targets VEGFR, PDGFR, c-kit, but also anti-VEGF-A antibody (the mouse orthologue of bevacizumab) decrease PD-1 expression on T lymphocytes infiltrating the tumors. Interestingly, anti-angiogenic treatments decrease the percentage of lymphocytes expressing not only PD-1 but also Tim-3 suggesting that the most exhausted T cells are targeted by anti-angiogenic treatments. Administration of masitinib, a TKI acting on KIT, PDGFR and FAK but not on the VEGF/VEGF-R pathway, was not able to modulate PD-1 expression on T cells. Finally, anti-VEGF-A treatment (bevacizumab) associated with chemotherapy decreases the proportion of PD-1+ CD4+T cells in the peripheral blood of metastatic colorectal cancer patients. Conclusions: These results show that anti-angiogenic treatments targeting VEGFA/VEGFR decrease PD-1-expressing T lymphocytes in colorectal cancer. These results suggest that VEGF-A could be involved in PD-1 expression and maybe in the induction of T lymphocyte exhaustion in colorectal cancer. We and others have shown that anti-angiogenic molecules could modulate other immunosuppressive populations such as regulatory T cells and myeloid suppressive cells, anti-angiogenic molecules might be efficiently associated with immunotherapeutic strategies in colorectal cancer.
A comparative proteomic approach for identification of putative biomarkers of neoadjuvant chemotherapy resistance in breast cancer.
Authors: Hussain Tasadooq , Scaife Lucy , Hodgkinson Victoria , Agarwal Vijay , Mahapatra Tapan , Kneeshaw Peter John , McManus Penelope Louis , Lind Michael , Drew Philip , Cawkwell Lynn 
Published: March 2020

e22123 Background: Neoadjuvant chemotherapy is a standard treatment for locally advanced breast cancer however chemoresistance can be a major obstacle in ER+ cancers. Using comparative proteomic approaches (antibody microarray/AbMA and 2D-PAGE with MALDI-TOF/TOF MS) to investigate a pilot series of breast cancer samples we recently identified 14-3-3 theta/tau, tBID and BcL-XL as putative biomarkers of response to neoadjuvant chemotherapy (Hodgkinson et al. J Prot 2012, 75:1276-1283 and 75:2745-2752). Here we aimed to analyse further samples using the AbMA approach and to re-analyse the combined data. Methods: Samples from chemoresistant and chemosensitive breast cancers were selected following anthracycline-taxane chemotherapy and 4 experiments were performed using ductal ER+ tumours. Differential protein expression was compared between chemoresistant and chemosensitive samples using the Panorama XPRESS Profiler725 AbMA kit. The combined data from 9 AbMA assays and 3 2D-PAGE/MS experiments was then analysed using Ingenuity Pathway Analysis (IPA; Ingenuity Systems). Results: 89 differentially expressed proteins (DEPs) were seen in the 4 further AbMA experiments. Sixteen proteins (DR4, E2F6, ILK, MeCP2, MyD88, PI19INK4d, PRMT2, ID, FANCD2, FAKpTyr577, Pinin, Zyxin, 14-3-3 theta/tau, BcL-xL, Pancytokeratin and RIP) were found in at least 2/4 experiments. In the combined dataset (12 experiments from 2 proteomic platforms), 8 DEPs were seen in at least 3 experiments. These were 14-3-3 theta, 14-3-3 epsilon, 14-3-3 gamma, Bcl-xl, Bid, Phosphokinase B, Vimentin and FAK. 121 DEPs from the combined data were analysed using IPA; 12 DEPs were mapped onto the PI3K/AKT pathway. Conclusions: We have identified at least 8 proteins which could play a role in chemoresistance and clinical validation of these putative biomarkers is currently underway.