bluuebunny/crossref_metadata_2025_split huggingface dataset:
The real-world use of regorafenib for metastatic colorectal cancer: multicentre analysis of treatment pattern and outcomes in Hong Kong
Authors: Lam Ka-On , Lee Kin-Chung , Chiu Joanne , Lee Victor Ho-Fun , Leung Roland , Choy T S , Yau Thomas 
Published: November 2016

ABSTRACTPurpose of the studyTo evaluate the benefits and tolerability of regorafenib in the real-world setting, we performed a multicentre analysis in Hong Kong.Study designIndividual patient data were retrieved from three leading oncology centres in Hong Kong for analyses. All patients with metastatic colorectal cancer (mCRC) treated with regorafenib after failure of all standard systemic options were included.ResultsFrom July 2013 to December 2015, 45 consecutive patients treated with regorafenib for mCRC were analysed. The median age was 63. Twenty patients were started at 160 mg, while the other 25 patients were started at a lower dose. The median progression-free survival was 15.6 weeks (95% CI 13.1 to 18.1 weeks) and the median overall survival was 30.4 weeks (95% CI 16.6 to 44.3 weeks). Among the 31 evaluable patients, only 1 patient (3.2%) achieved partial response and another 10 patients (32.3%) had stable disease. The commonest grade 3 non-haematological adverse event (AE) was hand–foot skin reaction (26.7%) and the commonest grade 3 or 4 haematological AE was anaemia (8.9%). Notably, patients who were started on a lower dose of regorafenib had significantly lower risk of grade 3 treatment-emergent AEs. Overall, 78.3% of the patients had dose reduction during the first and second cycles. Patients older than 65 years were more likely to experience cycle suspension and require dose reduction.ConclusionsOur study confirmed the efficacy and tolerability of regorafenib in the real-world setting. It also suggested that individualised dosing of regorafenib in patients with mCRC might result in better clinical outcomes.
What is the reliability of non-trained investigators in recognising structural MRI lesions of sacroiliac joints in patients with recent inflammatory back pain? Results of the DESIR cohort
Authors: Jacquemin Charlotte , Rubio Vargas Roxana , van den Berg Rosaline , Thévenin Fabrice , Lenczner Gregory , Reijnierse Monique , Ferkal Salah , Le Corvoisier Philippe , Rahmouni Alain , Loeuille Damien , Feydy Antoine , Dougados Maxime , van der Heijde Désirée , Claudepierre Pascal 
Published: November 2016

ObjectiveThe objective of this study was to evaluate the reliability of recognising structural lesions on MRI (erosions, fatty lesions, ankylosis) of the sacroiliac joints (MRI-SIJ) in clinical practice compared to a central reading in patients with a possible recent axial spondyloarthritis (axSpA).MethodsPatients aged 18–50 years, with recent (<3 years) and chronic (≥3 months) inflammatory back pain, suggestive of axSpA were included in the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort. MRI-SIJ structural lesions were scored by non-trained local readers, and by two trained central readers. Local readers scored each SIJ as normal, doubtful or definite lesions. Central readers scored separately each type of lesion. The central reading (mean of the two central readers’ scores) was the external standard. Agreement (κ) was calculated first between local (3 definitions of a positive MRI-SIJ) and central readings (9 definitions), and then between the two central readers.Results664/708 patients with complete available images were included. Agreements between local and central readings were overall ‘fair’, except when considering at least 2 or 3 fatty lesions and at least 3 erosions and/or fatty lesions where agreement was ‘moderate’. Agreement between central readers was similar. MRI-SIJ was positive for 52.6% of patients according to central reading (at least 1 structural lesion) and for 35.4% of patients according to local reading (at least unilateral ‘doubtful‘ or ‘definite’ structural lesions).ConclusionsAgreement on a positive structural MRI-SIJ was fair to moderate between local and central readings, as well as between central readers. The reliability improved when fatty lesions were considered.Trial registration numberNCTO 164 8907.
Spaces and places: an historical overview of the development of geology in Austria (Habsburg Monarchy) in the eighteenth and nineteenth centuries
Authors: Klemun Marianne 
Published: November 2016

Abstract
Geology as a discipline emerged in Austria between the eighteenth and nineteenth centuries from mineralogy and geognosy, two sciences dominated by descriptive rather than theoretical approaches. Austria, in this context, refers to the conglomerate of different states under the Habsburg Monarchy that existed until 1918. Two key aspects shaped the development of geology and the establishment of public institutions: mining industries and natural history collections. As a result of their close relation, the k.k. Geologische Reichsanstalt (Imperial Geological Survey) was founded in Vienna in 1849, which had repercussions for the entire empire. The Reichsanstalt carried out a geological survey of all the territories of the Habsburg Monarchy, resulting in a unifying geological map published in 1867. Geology was triggered and accelerated not least by the industrialization processes of the nineteenth century. From the 1850s, geology no longer focused only on the empire and its provinces, but took a global perspective. From 1862 a growing number of university chairs for geology were established, making the ‘new’ academic discipline visible. The internationally outstanding research work of Eduard Suess contributed to this success story.
History of a discussion: selected aspects of the Earth expansion v. plate tectonics theories
Authors: Cwojdzinski Stefan 
Published: November 2016

Abstract
A global tensional system of mid-ocean ridges was discovered at the end of the 1950s. All the world's oceans were proved to be young Mesozoic–Cenozoic structures and these new ideas in geotectonics led directly to the theories of ocean floor spreading and plate tectonics. The development of the idea of ocean floor spreading proved to be a crucial turning point in modern geotectonics. These facts could suggest the expansion of the Earth. However, the view that invoked Wegener's theory of continental drift – plate tectonics – which assumed a constant size for the Earth, remained the most prevalent idea. From this point of view, plate tectonics is just a hypothesis for a non-expanding Earth. The followers of plate tectonics believe that the drift of the continents relies on their movement upon the asthenosphere. New oceanic crust has to be consumed in the so-called subduction zones, compensating for the growth of the Earth. If the process of the opening of the oceans is a unidirectional global process – and it is not compensated for – then the Earth will increase in size. The process of the widening of new oceans, such as the Atlantic, Arctic and Indian oceans, should be simultaneous with the shrinking of the Palaeo-Pacific Ocean. If the Pacific Ocean expands, then the expansion of the Earth is inevitable.
Prospective, Multicenter Clinical Trial of Everolimus as Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214)
Authors: Treon Steven P. , Meid Kirsten , Tripsas Christina , Heffner Leonard T. , Eradat Herbert , Badros Ashraf Z. , Xu Lian , Hunter Zachary R. , Yang Guang , Patterson Christopher J. , Gustine Joshua , Castillo Jorge J. , Matous Jeffrey , Ghobrial Irene M. 
Published: November 2016

Abstract
Purpose: Everolimus inhibits mTOR, a component of PI3K/AKT prosurvival signaling triggered by MYD88 and CXCR4-activating mutations in Waldenstrom macroglobulinemia.
Experimental design: We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated Waldenstrom macroglobulinemia patients. Intended therapy consisted of everolimus (10 mg/day) until progression or unacceptable toxicity. Dose deescalation was permitted. The study was registered at www.clinicaltrials.gov (NCT00976248).
Results: At best response, median serum IgM levels declined from 4,440 to 1,360 mg/dL (P &lt; 0.0001), median hemoglobin rose from 10.8 to 12 g/dL (P = 0.001), and median bone marrow disease burden declined from 75% to 52.5% in serially biopsied patients. The ORR and major response rates were 72.7% and 60.6%, respectively. Among genotyped patients, nonresponders associated with wild-type MYD88 and mutated CXCR4 status. Median time to response was 4 weeks. Discordance between serum IgM levels and bone marrow disease burden was remarkable. With a median follow-up of 13.1 (range, 1.6–64.6 months), the median time to progression was 21 months for all patients and 33 months for major responders. Discontinuation of everolimus led to rapid serum IgM rebound in 7 patients and symptomatic hyperviscosity in 2 patients. Toxicity led to treatment discontinuation in 27% of patients, including 18% for pneumonitis.
Conclusions: Everolimus is active in previously untreated Waldenstrom macroglobulinemia. IgM discordance is common, and treatment cessation can often lead to rapid serum IgM rebound. Pneumonitis also appears more pronounced in untreated versus previously treated Waldenstrom macroglobulinemia patients. The risks and benefits of everolimus should be carefully weighed against other primary Waldenstrom macroglobulinemia therapy options. Clin Cancer Res; 23(10); 2400–4. ©2016 AACR.
ASP5878, a Novel Inhibitor of FGFR1, 2, 3, and 4, Inhibits the Growth of FGF19-Expressing Hepatocellular Carcinoma
Authors: Futami Takashi , Okada Hidetsugu , Kihara Rumi , Kawase Tatsuya , Nakayama Ayako , Suzuki Tomoyuki , Kameda Minoru , Shindoh Nobuaki , Terasaka Tadashi , Hirano Masaaki , Kuromitsu Sadao 
Published: November 2016

Abstract
Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19–expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, and JHH-7. In the Hep3B2.1-7 cell line, ASP5878 inhibited the phosphorylation of fibroblast growth factor receptor 4 and its downstream signaling molecules as well as induced apoptosis. Oral administration of ASP5878 at 3 mg/kg induced sustained tumor regression in a subcutaneous xenograft mouse model using Hep3B2.1-7. In HuH-7, an orthotopic xenograft mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival of the mice. These results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing fibroblast growth factor 19. Mol Cancer Ther; 16(1); 68–75. ©2016 AACR.
Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma
Authors: Haak Andrew J. , Appleton Kathryn M. , Lisabeth Erika M. , Misek Sean A. , Ji Yajing , Wade Susan M. , Bell Jessica L. , Rockwell Cheryl E. , Airik Merlin , Krook Melanie A. , Larsen Scott D. , Verhaegen Monique , Lawlor Elizabeth R. , Neubig Richard R. 
Published: November 2016

Abstract
Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small-molecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971–mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell-cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared with the low RhoC–expressing SK-Mel-19. Furthermore, pharmacologic inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics. Mol Cancer Ther; 16(1); 193–204. ©2016 AACR.
Abstract A10: A Cdk4-dependent phosphorylation threshold regulates the cell cycle entry decision
Authors: Kaulich Manuel , Dowdy Steven 
Published: November 2016

Abstract
Cyclin-dependent kinases (Cdk's) are major cell cycle regulators and uncontrolled cell cycle entry is a hallmark of cancer. Cyclin D, the regulatory subunit of Cdk4, is misregulated in about 75% of human malignancies, leading to hyperactive Cdk4 and uncontrolled cell cycle entry. In sharp contrast, the total loss of Cyclin D-mediated activity results in permanent cell cycle arrest. Several functions of Cdk4 during cell cycle entry have been identified; however, the underlying mechanism for cell cycle arrest upon its inactivation remains unanswered. Here we employed CRISPR/Cas9 and rAAV-mediated gene editing to visualize Restriction Point passage in highly synchronized single cells and find that cyclin D:Cdk4/6 complexes perform a critical switch-like function that results in activation of cyclin E:Cdk2 complexes. Taken together, our data indicate that while cyclin E:Cdk2 is the rate-limiting step for transition across the Restriction Point, it is dependent on cyclin D:Cdk4/6 phosphorylation of an as of yet unknown molecule.
Citation Format: Manuel Kaulich, Steven Dowdy. A Cdk4-dependent phosphorylation threshold regulates the cell cycle entry decision. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A10.
Abstract A13: A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation
Authors: Parker Danitra , Mitra Kasturi 
Published: November 2016

Abstract
Cyclin E is indispensable for release from quiescence. However, the regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynamin related protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-cell-density environments elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events. Ref. JCS,(2015), 128, 4171-4182.
Citation Format: Danitra Parker, Kasturi Mitra. A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A13.
Abstract A18: G1 cell cycle arrest is required for invasive behavior
Authors: Kohrman Abraham Q. , Chandhok Mana , Zhang Wan , Matus David Q. 
Published: November 2016

Abstract
The ability for a cell to breach the surrounding basement membrane and adopt an invasive phenotype is a critical, but poorly understood step in the progression of cancer. Like many aspects of cancer cell behavior, the genetic programs that regulate invasive behavior are likely shared with normal cell biological processes, as invasion occurs during embryonic development and immune surveillance. Due to difficulties of studying this dynamic behavior in vivo, elucidating the genetic and epigenetic controls of cell invasive activity has been difficult. Our laboratory uses a unique in vivo model to examine cell invasion that combines functional genomic and genetic tools with single-cell high resolution visual analyses. We examine anchor cell (AC) invasion into the vulval epithelium during the larval development of the model roundworm, C. elegans. Our data functionally links G1 cell cycle arrest to acquisition of invasive behavior. Previously we have identified that a single transcription factor, the conserved nuclear hormone receptor nhr-67 (NR2E1/TLX) is required in the AC to prevent the invasive AC from entering the cell cycle. NHR-67 maintains the AC in G1 cell cycle arrest, in part through upregulation of the cyclin-dependent kinase inhibitor cki-1 (p21CIP1/p27Kip1). Loss of nhr-67 results in non-invasive mitotic ACs that fail to express matrix metalloproteinases (MMPs) and actin regulators or form invadopodia, F-actin rich membrane-localized protrusions that are required for invasion. Strikingly, AC invasion can be rescued through induction of G1 arrest, preventing cell division and promoting differentiation. Downstream of G1 arrest, the AC requires the activity of the conserved histone deacetylase HDA-1, a key regulator of cell differentiation, to regulate the expression of pro-invasive genes and localize invadopodia. Through loss-of-function RNA interference (RNAi) screening, we have identified new cell cycle regulatory components (lin-35/RB, skr-2/SKP1, cdc-14/CDC14A, cul-1/ Cullin-1 and cul-4/ Cullin-4B) and epigenetic modifiers (let-418/Mi-2/CHD3 and Swi/snf-components) that function with cki-1 and hda-1, respectively, to maintain G1 cell cycle arrest and differentiate the invasive phenotype. Together our results suggest that the acquisition of the invasive phenotype is a post-mitotic differentiated state, which may help explain the paradoxical reports that the invasive fronts of many metastatic cancers are non-proliferative.
Citation Format: Abraham Q. Kohrman, Mana Chandhok, Wan Zhang, David Q. Matus. G1 cell cycle arrest is required for invasive behavior. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A18.
Abstract B24: Ataxia-telangiectasia and Rad3-related (ATR) phosphorylation as a pharmacodynamic biomarker of ATR activation in solid tumor tissue models
Authors: Wilsker Deborah , Marrero Allison M. , Dull Angie , Pfister Thomas D. , Lawrence Scott M. , Carter John , Gottholm-Ahalt Michelle , Hollingshead Melinda , Doroshow James , Parchment Ralph E. , Kinders Robert J. 
Published: November 2016

Abstract
Inhibitors of checkpoint kinases, such as ATR, Chk1 or Wee1, in combination with cytotoxic agents could enhance therapeutic efficacy compared to monotherapy, and these combination approaches are currently being extensively explored. The presence of replicative stress or deregulated S-phase in cancer has been recognized as a rationale for the use of ATR and Chk1 inhibitors with chemotherapy and efforts are underway to define genetic determinants that sensitize cancer cells to ATR inhibition. Pharmacodynamic (PD) biomarkers of drug activity are valuable tools in clinical trials using targeted agents to determine whether each investigational agent is acting upon its intended target, the expected intracellular signaling pathways are modulated, and the dosage regimen and sequencing are optimal. In addition, investigations of the potential effects of cell cycle distribution within the tumor (in animal models) on drug efficacy may point to alternative dosing regimens. The first clinical trials evaluating inhibitors of the ataxia telangiectasia and Rad3-related kinase (ATR) in combination with cytotoxic agents are enrolling patients. The current method for quantifying ATR inhibition used in preclinical in vitro and in vivo models is via indirect measurement of downstream effector proteins, such as phosphorylated Chk1, rather than measurement of direct target engagement. We propose that an immunofluorescence microscopy assay of ATR autophosphorylation status as a biomarker of DNA damage activation combined with measurement of the downstream effector proteins will reveal more specific information about target engagement and intended PD effect than would be obtained from a single-biomarker assay. Here we propose that the measurement of ATR pT1989, Chk1 pS345 and γH2AX by validated quantitative immunofluorescence assays will be useful in PD evaluation of tumor responses in clinical trials as a biomarker for ATR pathway activation or inhibition. In addition, evaluation of the variability of expression of activated ATR in tumor models of different histologies may provide valuable insight into tumor types likely to be sensitive to ATR inhibitors.
Citation Format: Deborah Wilsker, Allison M. Marrero, Angie Dull, Thomas D. Pfister, Scott M. Lawrence, John Carter, Michelle Gottholm-Ahalt, Melinda Hollingshead, James Doroshow, Ralph E. Parchment, Robert J. Kinders. Ataxia-telangiectasia and Rad3-related (ATR) phosphorylation as a pharmacodynamic biomarker of ATR activation in solid tumor tissue models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B24.