bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Prediction of Disease Progression in Small Cell Lung Cancer: Toward Model-Based Personalized Medicine in Oncology
Authors: Buil-Bruna Núria , Sahota Tarjinder , López-Picazo José-María , Moreno-Jiménez Marta , Martín-Algarra Salvador , Ribba Benjamin , Trocóniz Iñaki F. 
Published: May 2015

Abstract
Predictive biomarkers can play a key role in individualized disease monitoring. Unfortunately, the use of biomarkers in clinical settings has thus far been limited. We have previously shown that mechanism-based pharmacokinetic/pharmacodynamic modeling enables integration of nonvalidated biomarker data to provide predictive model-based biomarkers for response classification. The biomarker model we developed incorporates an underlying latent variable (disease) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment. Here, we show that by integrating CT scan data, the population model can be expanded to include patient outcome. Moreover, we show that in conjunction with routine medical monitoring data, the population model can support accurate individual predictions of outcome. Our combined model predicts that a change in disease of 29.2% (relative standard error 20%) between two consecutive CT scans (i.e., 6–8 weeks) gives a probability of disease progression of 50%. We apply this framework to an external dataset containing biomarker data from 22 small cell lung cancer patients (four patients progressing during follow-up). Using only data up until the end of treatment (a total of 137 lactate dehydrogenase and 77 neuron-specific enolase observations), the statistical framework prospectively identified 75% of the individuals as having a predictable outcome in follow-up visits. This included two of the four patients who eventually progressed. In all identified individuals, the model-predicted outcomes matched the observed outcomes. This framework allows at risk patients to be identified early and therapeutic intervention/monitoring to be adjusted individually, which may improve overall patient survival. Cancer Res; 75(12); 2416–25. ©2015 AACR.
Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding
Authors: Goldstein Michael , Kastan Michael B. 
Published: May 2015

Abstract
The product of the Brca1 tumor-suppressor gene is involved in multiple aspects of the cellular DNA damage response (DDR), including activation of cell-cycle arrests and DNA double-stranded break (DSB) repair by homologous recombination. Prior reports demonstrated that BRCA1 recruitment to areas of DNA breakage depended on RAP80 and the RNF8/RNF168 E3 ubiquitin ligases. Here, we extend these findings by showing that RAP80 is only required for the binding of BRCA1 to regions flanking the DSB, whereas BRCA1 binding directly to DNA breaks requires Nijmegen breakage syndrome 1 (NBS1). These differential recruitment mechanisms differentially affect BRCA1 functions: (i) RAP80-dependent recruitment of BRCA1 to chromatin flanking DNA breaks is required for BRCA1 phosphorylation at serine 1387 and 1423 by ATM and, consequently, for the activation of S and G2 checkpoints; and (ii) BRCA1 interaction with NBS1 upon DSB induction results in an NBS1-dependent recruitment of BRCA1 directly to the DNA break and is required for nonhomologous end-joining repair. Together, these findings illustrate that spatially distinct fractions of BRCA1 exist at the DSB site, which are recruited by different mechanisms and execute different functions in the DDR. Cancer Res; 75(13); 2699–707. ©2015 AACR.
Abstract 3424: Deciphering the genomic heterogeneity and evolution in malignant melanoma by genomic profiling of clonal tumor populations
Authors: Lorber Thomas , Dietsche Tanja , Perrina Valeria , Barret Michael , Glatz Kathrin , Ruiz Christian , Bubendorf Lukas 
Published: May 2015

Abstract
Background
With the recent improvements in genomic analysis tools, research groups all over the world are intensively deep-sequencing different tumor entities, including malignant melanomas. However, most of these studies are using only a single biopsy per patient, providing only limited insights into genomic tumor evolution. In this study, we performed genomic profiling of sorted clonal tumor populations from several specimens per patient in order to infer genomic heterogeneity in malignant melanomas and genomic evolution during tumor progression.
Methods
A multi-parameter sorting approach was used to flow-sort multiple biopsies from individual melanoma patients. Therefore nuclei were extracted from frozen and FFPE tissues and sorted according to DNA ploidy. SOX10 was used as an additional melanoma parameter to ensure sorting of pure tumor populations. Resulting clonal tumor populations were genomically characterized by usage of high resolution aCGH and deep-sequencing with NGS technologies.
Results
Array CGH and NGS performed on flow-sorted clonal tumor populations (DNA and SOX10) revealed the clonal relationship between multiple tumor biopsies from individual patients. The tumor marker SOX10 allowed us to uncover and sort pure tumor populations, excluding the risk of contribution of non-neoplastic cells in downstream analysis with aCGH and NGS. Taken together the information of ploidy, aCGH and NGS data, we were able to detect chromosome imbalances and allelic frequencies from these populations. Our approach allows us to track the evolution of clonal populations across time and organs and in the context of therapeutic interventions.
Conclusions
Human malignant melanomas are composed of different clonal populations with population-specific genomic aberrations and mutations. The use of SOX10 allowed unraveling of pure tumor populations within the diploid peaks, which would have been obscured by the use of DNA content alone. NGS and aCGH helped to characterize these sorted clonal tumor populations. Further bioinformatic analyses of these sorted clonal tumor populations are fundamental for the understanding of the clonal relationship and genomic heterogeneity and their potential impact on metastasis and therapy response in malignant melanoma.
Citation Format: Thomas Lorber, Tanja Dietsche, Valeria Perrina, Michael Barret, Kathrin Glatz, Christian Ruiz, Lukas Bubendorf. Deciphering the genomic heterogeneity and evolution in malignant melanoma by genomic profiling of clonal tumor populations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3424. doi:10.1158/1538-7445.AM2014-3424
Abstract 3430: Recurrent somatic mutations of nitric oxide synthase NOS3, netrin receptor UNC5C and DNA repair genes in muscle-invasive bladder carcinoma
Authors: Yap Kai Lee , Kiyotani Kazuma , Tamura Kenji , Jang Miran , Montoya Magdeline , Ganshert Cory , Fujioka Tomoaki , Steinberg Gary , O'Donnell Peter , Nakamura Yusuke 
Published: May 2015

Abstract
Bladder cancer is the fourth most common cancer type in males and approximately 72,500 individuals were diagnosed in the United States in 2012. Patients with superficial (low-grade papillary) tumors generally have a good prognosis with a 5-year survival rate exceeding 90%, but those with muscle-invasive or locally advanced disease at surgical resection have a significant risk of recurrence with 5-year survival rates of 30-60%. The systemic chemotherapy options for bladder cancer are very limited, and no new drugs have been approved in the United States for metastatic bladder cancer in over 20 years. Although a number of newer, molecularly targeting drugs have been developed and approved for multiple cancer types in the last two decades, no such drug has been developed for the treatment of bladder cancer. This is likely due, in part, to the relatively limited molecular understanding of invasive bladder cancers and lack of knowledge about potential genetic drivers of invasive forms of the disease. Hence, it is of priority to discover novel genetic pathways involved in the carcinogenesis of muscle-invasive bladder cancer for the assessment of risk stratification and for the development of novel drugs. We analyzed exomes of 43 muscle-invasive bladder carcinomas and identified two novel significantly mutated genes, NOS3 (18.6%) and UNC5C (16.3%), in addition to previously reported frequently mutated genes like TP53 (37.2%) and KDM6A (18.6%). Both NOS3 and UNC5C are known to be involved in the apoptotic pathways, with NOS3 encoding for endothelial nitric oxide synthase (eNOS), and UNC5C for netrin receptor, a member of the dependence receptor family. When we correlated the mutational profiles with clinicopathological outcomes by stratifying patients according to disease recurrence status and observing for specific clustering of genetic mutations, we found that somatic mutations in six DNA repair genes (ATM, ERCC2, FANCD2, RAD51AP1, PALB2, BRCA2) were significantly associated with enhanced recurrence-free survival (hazard ratio of 0.091 with 95% CI of 0.018 to 0.45; P=0.0034) even after adjustment for pathologic TN staging, suggestive of their mutations as favorable prognostic events in bladder cancer.
Citation Format: Kai Lee Yap, Kazuma Kiyotani, Kenji Tamura, Miran Jang, Magdeline Montoya, Cory Ganshert, Tomoaki Fujioka, Gary Steinberg, Peter O'Donnell, Yusuke Nakamura. Recurrent somatic mutations of nitric oxide synthase NOS3, netrin receptor UNC5C and DNA repair genes in muscle-invasive bladder carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3430. doi:10.1158/1538-7445.AM2014-3430
Abstract 3436: Ameloblastoma driver mutations revealed by next-generation sequencing of formalin-fixed paraffin-embedded specimens
Authors: McClary Andrew C. , Sweeney Robert T. , Biscocho Jewison , Myers Benjamin R. , Neahring Lila , Kwei Kevin A. , Qu Kunbin , Gong Xue , Ng Tony , Jones Carol D. , Varma Sushama , Odegaard Justin I. , Rubin Brian , Troxell Megan L. , Pelham Robert J. , Zehnder James L. , Beachy Philip A. , Pollack Jonathan R. , West Robert B. 
Published: May 2015

Abstract
Rare cancer types are not only understudied, but are typically represented by formalin-fixed paraffin-embedded (FFPE) (rather than freshly-frozen) specimens that are suboptimal for genomic analysis. Ameloblastoma is one such rare tumor type, thought to arise from ameloblasts, the cells that deposit enamel during tooth development. Though typically benign, ameloblastomas are locally destructive to the jaw and face, and new non-surgical interventions are needed. To discover novel driver mutations and therapeutic targets, we optimized methods and performed whole-transcriptome sequencing and/or targeted exon sequencing (TruSeq Cancer Panel) of 8 FFPE cases. Identified mutations were verified, and then evaluated on a larger, independent set of 21 FFPE cases by PCR and Sanger sequencing. From the analysis, we identified recurrent somatic mutations in three key developmental or signaling pathways, including Hedgehog, fibroblast growth factor, and MAP kinase pathways. Functional interrogation of a novel Hedgehog pathway mutation confirmed increased basal pathway activity, and defined the response profile to various pharmacologic Hedgehog inhibitors. Together, our results define new ameloblastoma drivers and nominate new molecularly-directed therapies for this rare but disfiguring disease. More generally, our findings validate a robust approach for discovering driver mutations in rare cancers.
Citation Format: Andrew C. McClary, Robert T. Sweeney, Jewison Biscocho, Benjamin R. Myers, Lila Neahring, Kevin A. Kwei, Kunbin Qu, Xue Gong, Tony Ng, Carol D. Jones, Sushama Varma, Justin I. Odegaard, Brian Rubin, Megan L. Troxell, Robert J. Pelham, James L. Zehnder, Philip A. Beachy, Jonathan R. Pollack, Robert B. West. Ameloblastoma driver mutations revealed by next-generation sequencing of formalin-fixed paraffin-embedded specimens. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3436. doi:10.1158/1538-7445.AM2014-3436
Abstract 344: Silencing RBBP6 (retinoblastoma binding protein 6) sensitizes breast cancer cells to staurosporine and camptothecin-induced cell death
Authors: Motadi Lesetja Raymond , Moela Pontsho , Choene Mpho S. 
Published: May 2015

Abstract
Retinoblastoma Binding Protein 6 (RBBP6) is a multi-domain protein that uses its ring finger domain to interact with p53 and pRb tumour suppressor genes. The mechanism by which RBBP6 uses to degrade p53 is still unknown; nonetheless it is well known that RBBP6 promotes cell proliferation in several cancers by negatively regulating p53 via its E3 ubiquitin ligase activity (Ntwasa, 2008). Degradation of p53 by RBBP6 may compromise p53-mediated apoptosis in breast cancer.
This study is intended to investigate, the potential applications of RNA interference (RNAi) to block RBBP6 expression, as well as its subsequent effect on cell growth and apoptosis. To achieve these methodologies the following techniques were used: RT-PCR, western blotting, xCELLigence system and flow cytometry. Our studies indicate that the knockdown of RBBP6 expression by siRNA modulates p53 gene involved in cell death pathways and apoptosis, showing statistically significant gene expression differences. RBBP6 siRNA significantly reduced cell index (CI) compared to the control samples and we observed an inhibition of cellular proliferation in the interval of between 24 and 48 h, as shown in the data obtained by dynamic evaluation using the xCELLigence System. These results were further confirmed by flow cytometer which showed some apoptotic activity. About 20.7% increase in apoptosis was observed in cells co-treated with RBBP6 siRNA and camptothecin when compared to camptothecin-only whereas in siRBBP6 and Staurosporine treated there was only 8.8% increase in apoptosis. These findings suggest that silencing RBBP6 may be a novel strategy to promote staurosporine- and camptothecin-induced apoptosis in breast cancer cells.
Citation Format: Lesetja Raymond Motadi, Pontsho Moela, Mpho S. Choene. Silencing RBBP6 (retinoblastoma binding protein 6) sensitizes breast cancer cells to staurosporine and camptothecin-induced cell death. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 344. doi:10.1158/1538-7445.AM2014-344
Abstract 3445: The role of the truncated product of the neuregulin 4 gene in cancer and normal tissues
Authors: Alatsatianos Markella J. , Blackburn Edith , Gullick William 
Published: May 2015

Abstract
The Epidermal Growth Factor Receptor (EGFR) family consists of a group of four transmembrane proteins, EGFR, the Human Epidermal Growth Factor 2 (HER2), HER3 and HER4 that are each involved in cell-signalling. They are activated by ligands, which include the neuregulin (NRG) family of proteins. These proteins are produced as various splice variants from four genes, NRG1-4. Although NRG1 has been extensively investigated, not much is known about the other neuregulins. Thus far, the NRG4 gene has been found to encode five proteins, NRG4 A1, NRG4 A2, NRG4 B1, NRG4 B2 and NRG4 B3. NRG4s B1-3 are truncated structures, which either prematurely terminate as in NRG4s B1 and B2, or have an additional 21 amino acids as in NRG4 B3. Little is known about the structure and function of the NRG4 B3. Previous studies have suggested that it has a different disulphide bond arrangement than that of the other EGF-like ligands. In this study, we have surveyed the expression of NRG4 B3 in breast, lung and colorectal cancers, and found that it is expressed at variable levels. Nuclear magnetic resonance spectroscopy of re-folded NRG4 B3 suggests it has a largely unfolded structure very different from the typical EGF-like molecules. It also has distinct properties in that it is a weak agonist for HER4 signaling and inhibits rather than promotes cell motility in various model systems. Taken together, this suggests that it may have a distinct role in normal and malignant tissues differing in properties to typical EGF-like proteins.
Citation Format: Markella J. Alatsatianos, Edith Blackburn, William Gullick. The role of the truncated product of the neuregulin 4 gene in cancer and normal tissues. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3445. doi:10.1158/1538-7445.AM2014-3445
Abstract 3450: Internalization and recycling of RET receptor tyrosine kinase isoforms
Authors: Crupi Mathieu Joseph François , Richardson Douglas S. , Mulligan Lois M. 
Published: May 2015

Abstract
The RET (REarranged in Transfection) receptor tyrosine kinase is crucial for the normal development of the kidneys and enteric nervous system, as well as the regulation of neural-crest cell behaviours, including migration, proliferation, differentiation and survival. RET is also a potent contributor to clinically challenging cancers. Activating mutations in RET can lead to multiple endocrine neoplasia type 2, a cancer syndrome characterized by medullary thyroid carcinoma. Increased activation of wildtype RET receptors has been linked to aggressive breast cancers, and enhanced invasion and perineural spread in pancreatic carcinoma. Two distinct isoforms of the growth factor receptor arise through alternative splicing of the 3’ exons, and are termed RET9 and RET51 to denote the number of amino acids in each C-terminal tail. These isoforms induce unique transphosphorylation patterns on intracellular tyrosine residues, differentially bind downstream signalling proteins, and possess different intrinsic abilities to cause cellular transformation. Here, we explore the differential subcellular localization and trafficking of the two isoforms in human cell line models to better understand RET-mediated cancers. We have observed that RET51 is efficiently matured and localized to the cell membrane, while immature RET9 matures more slowly, leading to lower relative expression on the plasma membrane. Subsequent to RET activation, both isoforms at the cell surface are internalized through AP2-adaptor interactions and the clathrin coated-pit pathway into endosomes. Although RET51 is internalized more rapidly than RET9, a portion of RET51 molecules recycles back to the plasma membrane, maintaining high expression levels at the cell surface. We have shown that RET51 interacts with the sorting protein GGA3, which may allow the long isoform to travel back to the cell surface. Recycling prevents efficient degradation of RET51, allowing for prolonged downstream signaling relative to RET9. Since RET51 has a longer residency time in an endosomal compartment, where sustained Erk1/2 signaling promotes mitogenesis, this may in part explain the greater transforming potential of RET51. Together, our data suggest that differences in RET isoform subcellular localization and trafficking would lead to differences in signal transduction and may in part explain the functional differences observed between RET isoforms.
Citation Format: Mathieu Joseph François Crupi, Douglas S. Richardson, Lois M. Mulligan. Internalization and recycling of RET receptor tyrosine kinase isoforms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3450. doi:10.1158/1538-7445.AM2014-3450
Abstract 3453: Autophagic regulation of the Met receptor tyrosine kinase in breast cancer
Authors: Bell Emily S. , Zuo Dongmei , Park Morag 
Published: May 2015

Abstract
The Met receptor tyrosine kinase (RTK) and its ligand, hepatocyte growth factor (HGF), are potent mediators of epithelial-mesenchymal transition and an invasive growth program. The HGF-Met signaling axis plays a significant role in the development or progression of many human cancers, and elevated Met expression is associated with poor prognosis and the basal subtype in breast cancer. Met signaling is regulated temporally and spatially through endocytic trafficking to degradative or recycling compartments, and delayed Met trafficking to the degradative pathway promotes enhanced cell migration, adhesion-independent growth and tumorigenesis. It is now recognized that autophagy, an intracellular degradative process, utilizes the endocytic system in both formation and maturation of double-membraned autophagosomes. Autophagy can have both tumor promoting and tumor suppressor roles in different contexts or stages of disease. We hypothesized that reprogramming of endocytic membrane system to support an autophagic starvation response may alter Met RTK trafficking, and therefore modulate tumorigenic signaling. To test this, we utilized MDA-MB-231 and BT-549 triple-negative breast cancer cell lines, as well as Hela cells, as models to study the trafficking and signaling of the Met RTK under conditions of autophagic stimulation or inhibition. Following HGF stimulation and receptor internalization, Met engages with core autophagic machinery in a starvation-dependent manner. Increased autophagosome formation decreases Met recycling to the plasma membrane, which can be rescued by shRNA-mediated knockdown of genes required for autophagy initiation. We demonstrate that the autophagic process negatively regulates signaling of Met through the PI3K/Akt and MAPK pathways and decreases Met-dependent cellular responses. These findings identify Met RTK regulation as a potential tumor-suppressive function of autophagy.
Citation Format: Emily S. Bell, Dongmei Zuo, Morag Park. Autophagic regulation of the Met receptor tyrosine kinase in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3453. doi:10.1158/1538-7445.AM2014-3453