bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oscillatory synchrony between head direction cells recorded bilaterally in the anterodorsal thalamic nuclei
Authors: Butler William N. , Taube Jeffrey S. 
Published: March 2017

The head direction (HD) circuit is a complex interconnected network of brain regions ranging from the brain stem to the cortex. Recent work found that HD cells corecorded ipsilaterally in the anterodorsal nucleus (ADN) of the thalamus displayed coordinated firing patterns. A high-frequency oscillation pattern (130–160 Hz) was visible in the cross-correlograms of these HD cell pairs. Spectral analysis further found that the power of this oscillation was greatest at 0 ms and decreased at greater lags, and demonstrated that there was greater synchrony between HD cells with similar preferred firing directions. Here, we demonstrate that the same high-frequency synchrony exists in HD cell pairs recorded contralaterally from one another in the bilateral ADN. When we examined the cross-correlograms of HD cells that were corecorded bilaterally, we observed the same high-frequency (~150- to 200-Hz) oscillatory relationship. The strength of this synchrony was similar to the synchrony seen in ipsilateral HD cell pairs, and the degree of synchrony in each cross-correlogram was dependent on the difference in tuning between the two cells. Additionally, the frequency rate of this oscillation appeared to be independent of the firing rates of the two cross-correlated cells. Taken together, these results imply that the left and right thalamic HD network are functionally related despite an absence of direct anatomical projections. However, anatomical tracing has found that each of the lateral mammillary nuclei (LMN) project bilaterally to both of the ADN, suggesting the LMN may be responsible for the functional connectivity observed between the two ADN. NEW & NOTEWORTHY This study used bilateral recording electrodes to examine whether head direction cells recorded simultaneously in both the left and right thalamus show coordinated firing. Cross-correlations of the cells’ spike trains revealed a high-frequency oscillatory pattern similar to that seen in cross-correlations between pairs of ipsilateral head direction cells, demonstrating that the bilateral thalamic head direction signals may be part of a single unified network.
Abstract A07: Detection of structural variants and recurrent breakpoint genes in colorectal adenoma-to-carcinoma progression
Authors: Broek Evert van den , Dijkstra Maurits J.J. , Voorham Quirinus J.M. , Carvalho Beatriz , Wiel Mark A. van de , Abeln Sanne , Meijer Gerrit A. , Fijneman Remond J.A. 
Published: March 2017

Abstract
Background and Aim: The transition of pre-malignant colorectal adenomas (CRAs) into malignant colorectal carcinomas (CRCs) is accompanied by accumulation of somatic genetic alterations. The contribution of small nucleotide variants (SNVs, such as gene point mutations) and numerical DNA copy number aberrations (CNAs, such as gains and losses of large chromosomal segments) in tumor genomes has been studied extensively. In contrast, studies that systematically detect recurrent structural variants (SVs, such as chromosomal breaks) across large series of clinically well-defined samples are scarce. We recently developed “GeneBreak”, a computational method to identify genes that are recurrently affected by the genomic location of CNA-associated chromosomal breaks, and demonstrated high prevalence and clinical relevance of recurrent breakpoint genes in advanced CRCs (PLoS One 2015;10(9):e0138141). Using a similar approach, the present study aimed to determine what recurrent breakpoint genes contribute to colorectal adenoma-to-carcinoma progression.
Methods: Differences in somatic CNA-associated gene breakpoint frequencies in 466 CRC and 118 CRA samples were examined using high-resolution array-comparative genomic hybridization (aCGH) profiles. Pearson's Chi-square statistic was applied to determine differences in gene breakpoint frequencies between CRC and CRA samples.
Results: In total 21 recurrent breakpoint genes were more frequently affected in CRCs compared to CRAs (p&lt;0.05). MACROD2 was affected by chromosomal breakpoints in 40% of CRCs while not being affected in CRAs. The frequencies of SVs in the other 20 recurrent breakpoint genes ranged from 5% to 29% in CRCs, and from 0% to 2% in CRAs.
Conclusion: We identified 21 recurrent breakpoint genes that are frequently affected by SVs in CRCs but not in CRAs. Additional studies are needed to further elaborate the biological and clinical role of these 21 candidate driver genes for colorectal tumor progression.
Citation Format: Evert van den Broek, Maurits J.J. Dijkstra, Quirinus J.M. Voorham, Beatriz Carvalho, Mark A. van de Wiel, Sanne Abeln, Gerrit A. Meijer, Remond J.A. Fijneman. Detection of structural variants and recurrent breakpoint genes in colorectal adenoma-to-carcinoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A07.
Abstract A08: Extensive subclonal mutations in human colorectal cancers detected by Duplex Sequencing
Authors: Fox Edward John Paul , Schmitt Michael W. , Reid-Bayliss Kate S. , Beckman Robert A. , Loeb Lawrence A. 
Published: March 2017

Abstract
The accumulation of somatic mutations is a defining hallmark of cancer. The genomes of solid tumors contain thousands of mutations that are present in most or all of the malignant cells in that tumor. In addition to these clonal mutations, subclonal mutations, those occurring only in a fraction of malignant cells, likely contribute to the phenotypic and morphologic heterogeneity of cancer cells within a tumor. The extent of subclonal mutations in cancer, however, has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 5% of cells. Here, we apply the highly accurate Duplex Sequencing methodology to quantify the extent of subclonal mutations in colorectal cancer (CRC) and paired normal mucosa. By sequencing known CRC driver and non-driver genes, we find that colorectal cancers without known DNA repair deficits harbor an extensive complement of subclonal mutations, in addition to the large number of clonal mutations previously identified. We show that normal colonic mucosa also accumulates substantial numbers of subclonal mutations in an age-dependent manner. The frequency of tumor-associated subclonal mutations, however, does not correlate with age, and has a spectrum distinct from that seen in normal tissue, indicating different mechanisms of mutation accumulation are operative in normal and tumor tissue. The frequency of tumor cells harboring unique subclonal mutations is so high that it is likely that every possible neutral somatic point mutation is present by the time a tumor is clinically detectable. We propose that these subclonal mutations likely accumulate in a series of punctuated bursts, making it highly likely that resistant subclones will emerge during chemotherapy.
Citation Format: Edward John Paul Fox, Michael W. Schmitt, Kate S. Reid-Bayliss, Robert A. Beckman, Lawrence A. Loeb. Extensive subclonal mutations in human colorectal cancers detected by Duplex Sequencing. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A08.
Abstract A19: Silencing LEF1 decreases the resistance of colorectal cancer cell lines to 5-FU as common chemotherapeutic drug
Authors: Teimoori-Toolabi Ladan , Fakhr Elham , Zare Fatemeh 
Published: March 2017

Abstract
Wnt signaling pathway is assumed to be the most important pathway activated in colorectal cancer. As this pathway in addition to Notch and hedgehog signaling pathway is responsible for the maintenance of stem cells in the population of cancerous cells, it could be predicted that by silencing this pathway the resistance of cancerous cells to chemotherapeutic drugs would be decreased. In this regard we tried to silence LEF1 as an important component of this pathway in two colorectal cancer cell lines and see the response of transfected cells to 5-flurouracil.
Oligonucleotide for silencing LEF1 was constructed and inserted into pSilencer Neo2.1 (Invitrogen). Thereafter these constructed were stably transfected to HCT116 and SW480 as colorectal cancer cell lines after treating the transfected cells with G418 for 21 days. Response of these cells to 5-flurouracil as a common chemotherapeutic drug was studied by MTT proliferation assay. The expression of LEF1 in transfected and non-transfected cells was also studied by Quantitative PCR. Cell cycle analysis was done by staining the cells with PI and analyzing them by flowcytometry instrument.
While the expression of LEF1 in SW480 transfected with pSilencer-antiLEF1 reduced to 0.004 in comparison to non-transfected cells in HCT116 cells transfected with pSilencer-anti LEF1 this value was 0.000002 in comparison to non-transfected cells.
Whereas the LC50 of 5-Flurouracil on non-transfected HCT116 and SW480 for 5-FU were 0.55 ng/µl and 1.45 ng/µl respectively. These values in transfected cells reduced to 0.18 and 0.1 ng/µl respectively. The percentages of proliferating cells (G2+S) stably transfected cells reduced to 30% and 32% in comparison to 39% and 45% in SW480 and HCT116 cell lines respectively.
These findings showed that silencing LEF1 as a main component of wnt signaling pathway sensitizes HCT116 and SW480 cells to 5-flurouracil. The difference between sensitizing strength may be due to mutations in other components of wnt signaling pathway or mutations in other genes like p53 and k-ras which is dissimilar between HCT116 and SW480 cells. This modality can be considered as sensitizing agents adjuvant to other chemotherapeutic drugs like 5-FU.
Note: This abstract was not presented at the conference.
Citation Format: Ladan Teimoori-Toolabi, Elham Fakhr, Fatemeh Zare. Silencing LEF1 decreases the resistance of colorectal cancer cell lines to 5-FU as common chemotherapeutic drug. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A19.
Abstract B06: Cathepsin B expression in colorectal cancer in Middle East population: Potential value as a tumor biomarker for late stages
Authors: Abdulla Maha 
Published: March 2017

Abstract
Objective: To investigate Cathepsin B (CTSB) expression in colorectal cancer (CRC) tissues and serum, the association of CTSB expression with tumor stages and metastasis and targeting CTSB by nanoparticles for potential CRC therapeutics.
Methods: CTSB expression was determined in 100 pairs of CRC tumor and adjacent normal tissue using quantitative PCR for mRNA levels. Serum CTSB levels were evaluated in 95 patients and 20 healthy control using enzyme-linked immunosorbant assay (ELISA) technique. Detection of Cathepsin B protein expression in tissues was done using immunohistochemistry and western blotting. Cathepsin B protein expression was inhibited using cobalt oxide nanoparticles in human colorectal cancer cells.
Results: Greater than 90% of tumors had detectable CTSB protein expression with significant increase staining in tumors compared with matched normal colon (p=0.006). The relative levels of CTSB mRNA in tumor samples and adjacent normal colorectal tissue were 0.04 ± 0.06 and 0.01 ± 0.02 respectively. The mRNA expression in early stage CRC compared to late stage CRC was 0.05 ± 0.04 and 0.02 ± 0.01, respectively. Increased mRNA expression was seen in the advanced stages with lymph node metastases compared to control P=0.002. CTSB was significantly higher in sera of patients with lymph node metastasis compared to early and late stage primary tumors. A subset of 40 paired tissue extracts were analyzed by western blotting. This also revealed consistent increase of CTSB protein level in tumor tissue. Treatment of human CRC cell HT-29 with increasing concentrations of cobalt oxide nanoparticles resulted in significant decrease of CTSB expression.
Conclusion: These findings thus indicate that CTSB may be an important prognostic biomarker for early stage CRC and lymph node metastasis in Middle East populations. Monitoring serum CTSB in CRC patient may predict and diagnose lymph node metastasis. Furthermore CTSB may represent a potential target for nanoparticle-based drugs in the treatment of colorectal cancer.
Citation Format: Maha Abdulla. Cathepsin B expression in colorectal cancer in Middle East population: Potential value as a tumor biomarker for late stages. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B06.
Abstract B08: Potential biomarkers for colorectal cancer diagnosis and prognosis
Authors: Mansour Hicham , Bouarourou Noureddine , Roperch Jean Pierre , Habib Fouazi , Said Mourad 
Published: March 2017

Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. It harbors several genetic and epigenetic alterations, which makes finding suitable biomarkers a challenge. CRC Cell lines are invaluable biomedical research tools for drug screening and biomarker discovery. Two emblematic cell lines for CRC were extensively used, HT29 and HCT116. We performed the whole transcriptome sequencing of these two cell lines and two normal epithelial cell lines, CR1780 and CRL18, derived from the colon as control. A methylation quantification of downregulated genes enables to screen potential biomarkers, which could be used as potential biomarkers for CRC diagnosis and prognosis.
Method: Total RNA was extracted from HT29, HCT116, CR1780 and CRL18 using RNeasy Mini Kit (Qiagen). mRNA libraries were generated using TruSeq Stranded mRNA Library Prep Kit (Illumina), and high-throughput sequencing were performed using Illumina systems (Hiseq and Miseq). All reads were filtered for high-quality reads (≥Q30, adapters trimming and broken pair-reads removing). Reads alignment and genes profiling analysis were done with CLCbio software. Selected genes downregulated with p-value &lt;0.001 in cancer cell lines versus normal cell lines, were evaluated for methylation in DNA extracted from tumors and autologous normal tissues from CRC patients.
Results: The transcriptome analysis reveals 741 different splice variants are downregulated in both cancer cell lines HT29 and HCT116, when compared to the two normal cell lines, CR1780 and CRL18 (p-value &lt;0.001). 10 relevant downregulated genes were selected, ACTG2, THY1, IGFBP3, WNT2, RAB32, SPARC, COL1A, MMP2, IGFBP3 and VIM. Interestingly, all the splice variants (10) of Vim, 7 of ATG2, 4 of THY1 and 2 of IGFBP3 were dramatically downregulated. Methylation quantification demonstrates the hypermethylation of all these 10 downregulated genes, in the tumors compared to matched normal tissues.
Conclusion. At the level of mRNA expression and methylation, this study enables to screen potential biomarkers for CRC diagnosis and prognosis.
Citation Format: Hicham Mansour, Noureddine Bouarourou, Jean Pierre Roperch, Fouazi Habib, Mourad Said. Potential biomarkers for colorectal cancer diagnosis and prognosis. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B08.
Abstract B15: Anti-metastatic activity of RGD-specific cadherin-17-targeting monoclonal antibodies in colorectal cancer
Authors: Bartolomé Rubén , Torres Sofia , Escudero-Paniagua Beatriz , Aizpurua Carmen , Calviño Eva , Imbaud Juan I. , Casal Ignacio 
Published: March 2017

Abstract
Most colorectal cancer deaths occur as a consequence of late diagnosis and the appearance of metastasis. We demonstrated that a RGD motif present in liver-intestine cadherin, also known as cadherin 17 (CDH17), plays a critical role in the liver metastasis of colorectal cancer by interacting with α2β1 integrin. CDH17 is able to induce a conformational change in β1 integrin to promote a high affinity conformation. This change is dependent of the RGD motif present in domain 6 of CDH17. The same activation was observed after cell exposition to 9 amino acid peptides containing the RGD motif and the flanking sequences from CDH17. Commercial antibodies anti-CDH17 did not cause any effect on β1 integrin activation. Here, we have used peptides containing the RGD motif and their flanking sequences in CDH17 to retrieve four highly selective monoclonal antibodies with anti-metastatic activity. Only CDH17 RGD-specific monoclonal antibodies inhibited β1 integrin activation in colorectal cancer cells. This inhibition provoked a significant reduction in cell adhesion and proliferation of metastatic cells. In addition, the treatment with these four anti-cadherin RGD antibodies impaired the activation of FAK, JNK and ERK kinases, which are critical for cell adhesion and proliferation. Moreover, RGD-specific monoclonal antibodies were able to cause a significant increase in mouse survival after intra-splenic injection together with highly metastatic cells, as determined by Kaplan-Meier survival analysis and log-rank curves. However, this effect on survival was different for each monoclonal antibody, suggesting a relevant impact of the RGD binding orientation in antibody recognition. As a conclusion, we propose that blocking the interaction between RGD cadherins and α2β1 integrin with highly selective monoclonal antibodies constitutes a promising therapy against colon cancer progression and liver metastasis.
Citation Format: Rubén Bartolomé, Sofia Torres, Beatriz Escudero-Paniagua, Carmen Aizpurua, Eva Calviño, Juan I. Imbaud, Ignacio Casal. Anti-metastatic activity of RGD-specific cadherin-17-targeting monoclonal antibodies in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B15.
Abstract B16: Activation of NRF2 and adaptive resistance to chemotherapy
Authors: Clinton Sarah A. , Barbour Karen W. , Berger Franklin G. 
Published: March 2017

Abstract
Nuclear factor-erythroid-2-related factor 2 (NRF2), a member of the cap ‘n’ collar family of bZIP transcription factors, confers protection against oxidative and electrophilic stress. NRF2 is of great interest in cancer research, due to its role in response to chemotherapy, including the class of drugs targeting thymidylate synthase (TYMS). It has long been known that inhibition of TYMS leads to depletion of thymidine levels and the onset of programmed cell death, deriving from the enzyme's function as the sole de novo source of thymidine for DNA replication and repair. Exposing cells to TYMS inhibitors such as fluoropyrimidine antimetabolites (5-fluorouracil, or FUra; 5'-fluoro-2'-deoxyuridine, or FdUrd), as well as anti-folate analogs (raltitrexed, or RTX), induce intracellular concentrations of reactive oxygen species, which are a primary cause of drug-mediated toxicity. This prompted our focus on assessing the impact of NRF2 on cellular response to TYMS inhibitors. Using human colon tumor-derived cell line HCT116, we have shown by gene expression profiling that drug exposure induces expression of a number of genes that are modulated by NRF2. Quantitative PCR assays of several colon tumor cell lines verified that FUra, FdUrd, and RTX induce transcription of several genes known to be NRF2-targets, including AKR1B10, ALDH3A1, HSPB8, HMOX1, and SERPINE1, among others. Such induction mirrors that in response to the known NRF2 activator tert-butylhydroquinone (tBHQ). NRF2 protein concentration and nuclear localization are increased by FdUrd treatment, though not to the same extent as with tBHQ. Reporter gene constructs were used to show that both FdUrd and tBHQ induce transcription mediated by the NRF2-binding antioxidant response element (ARE). Furthermore, chromatin-immunoprecipitation experiments revealed that TYMS inhibitors promote occupancy of the ARE regions of several genes by NRF2; again, tBHQ had a much greater effect. Further analysis showed an association between gene induction by TYMS inhibitors and patterns of histone acetylation within the NRF2-binding ARE regions. Finally, we observed that increases in the apoptotic index following exposure to TYMS inhibitors were greater in cells in which the transcription factor was subjected to siRNA-mediated “knockdown” or CRISPR/Cas9-mediated “knockout”, indicating that reduced NRF2 expression sensitizes cells to TYMS inhibitors. Overall, we conclude that TYMS inhibitors activate NRF2 and its downstream target genes, thereby constraining drug response. Reducing such activation of NRF2 or its consequences may be an effective strategy to sensitizing tumor cells to chemotherapy.
Citation Format: Sarah A. Clinton, Karen W. Barbour, Franklin G. Berger. Activation of NRF2 and adaptive resistance to chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B16.