Abstract
Prostate cancer (PC) is prevalent in both indolent and lethal forms. Although many PC patients diagnosed today have organ-confined disease curable by prostatectomy or radiation therapy, ...20-30% of PCs will relapse to lethal disease within 5-years of treatment. Relatively little attention has been paid to distinguishing the molecular characteristics of proven lethal metastatic PC from non-lethal cancers. A better understanding of the origins and evolution of lethal cancers should allow screening and treatment to be better tailored to the needs of each patient. To this end, we performed an integrative molecular profiling of a lethal PC from one patient (A21). High-coverage whole genome sequence, transcriptome sequence, and methylation analysis was performed on 9 anatomically separate metastases obtained by autopsy, and targeted sequencing was performed in multiple cancerous and noncancerous foci within the radical prostatectomy specimen removed 5 years prior to death. Molecular results were analyzed in relation to detailed clinical data. Integrated whole genome sequence analysis revealed convergent evolution of AR gene amplification events, and inception of p.L702H mutation in the AR present only in liver metastases. In addition, the analysis showed parallel increases in AR regulated transcripts in the liver metastases, suggesting a dominant effect by the mutation. Mutation of PI3/PI4 kinase member PIK3CG was found in all metastases but in no primary tumor foci studied. The study demonstrated the power of an integrated approach to interrogate clonal evolution of cancer suggesting that such studies are valuable on the individual level and could lead the way towards personalized treatment. In the individual studied, cessation of corticosteroid treatment and/or therapeutic manipulation of PI3K/AKT/mTOR activity theoretically could have provided a personalized benefit. These findings suggest that similar integrated analysis in large cohorts of patients with metastatic cancer could accelerate progress in establishing effective personalized cancer medicine.
Citation Format: Heini M.L. Kallio, Matti Annala, Kati Kivinummi, Gunilla Högnäs, Gunes Gundem, David C. Wedge, Peter Van Loo, Holger Heyn, Michael R. Emmert-Buck, William B. Isaacs, Manel Esteller, Ultan McDermott, Matti Nykter, Tapio Visakorpi, G. Steven Bova. Clonal evolution of a lethal prostate cancer: Integrated whole genome analysis case study. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3883. doi:10.1158/1538-7445.AM2015-3883
This study investigates whether temporal features in speech can predict the perceived proficiency level in Finnish learners of Swedish. In so doing, seven expert raters assessed speech samples ...produced by upper secondary school students using the revised CEFR scale for phonological control. The effect of temporal features was studied with a cumulative link mixed model, and the assessments were further analyzed to study inter-rater variation. The results indicate that articulation rate and certain types of disfluencies in speech can predict the perceived proficiency level. Furthermore, assessors seem to weigh temporal features differently depending on the speech type and their individual focus.
Fluency in L2 Learning and Use Pekka Lintunen, Maarit Mutta, Pauliina Peltonen / Pekka Lintunen, Maarit Mutta, Pauliina Peltonen
Multilingual Matters eBooks,
2019, 2019-12-06, Letnik:
138
eBook
Odprti dostop
This book brings together theoretical and empirical approaches to second language (L2) fluency and provides a state-of-the-art overview of current research on the topic. The strength of the volume ...lies in its interdisciplinarity: the chapters approach fluency from non-traditional starting points and go beyond disciplinary boundaries in their contributions. The volume includes chapters investigating fluency from an L2 perspective and integrates perspectives from related fields, such as psycholinguistics, sign language studies and L2 assessment. The book extends the common foci and approaches of fluency studies and offers new perspectives that enable readers to evaluate critically existing paradigms and models. This encourages the development of more comprehensive frameworks and directs future L2 fluency research into new areas of L2 learning and use.
Abstract
Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the ...formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones. In this study, we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer.
Citation Format: Gunes Gundem, Peter Van Loo, Barbara Kremeyer, Ludmil B. Alexandrov, Jose M.C. Tubio, Elli Papaemmanuil, Daniel S. Brewer, Heini Kallio, Gunilla Högnäs, Matti Annala, Kati Kivinummi, Victoria Goody, Calli Latimer, Sarah O'Meara, Kevin J. Dawson, William Isaacs, Michael R. Emmert-Buck, Matti Nykter, Christopher Foster, Zsofia Kote-Jarai, Douglas Easton, Hayley C. Whitaker, David E. Neal, Colin S. Cooper, Rosalind A. Eeles, Tapio Visakorpi, Peter J. Campbell, Ultan McDermott, David C. Wedge, G. S. Bova. The evolutionary history of lethal metastatic prostate cancer. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2015-956
Of the thirteen active carbonic anhydrase (CA) isozymes, CA IX and XII have been linked to carcinogenesis. It has been suggested that these membrane-bound CAs participate in cancer cell invasion, ...which is facilitated by an acidic tumor cell environment. Since active cell migration is a characteristic feature of embryonic development, we set out to explore whether these isozymes are expressed in mouse embryos of different ages. The studies were focused on organogenesis stage.
Immunohistochemistry demonstrated that both CA IX and XII are present in several tissues of the developing mouse embryo during organogenesis. Staining for CA IX revealed a relatively wide distribution pattern with moderate signals in the brain, lung, pancreas and liver and weak signals in the kidney and stomach. The expression pattern of CA XII in the embryonic tissues was also relatively broad, although the intensity of immunostaining was weak in most tissues. The CA XII-positive tissues included the brain, where the most prominent staining was seen in the choroid plexus, and the stomach, pancreas, liver and kidney.
Membrane-bound CA isozymes IX and XII are expressed in various tissues during mouse organogenesis. These enzymes may regulate ion and pH homeostasis within the developing embryo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study investigated human raters’ perceptions of automated assessment of oral language skills. The raters (n = 37) participated in three assessment rounds organized by the DigiTala research ...project using Moodle and Zoom. The raters assessed Finnish and Swedish learners’ speech samples using one holistic and five analytical rating scales created in the project. After the assessment, the raters responded to a questionnaire that included Likert-scale and open-ended questions. Numerical responses were analyzed with descriptive statistics, open responses with content analysis. The raters think that automated scoring could support human rating. The assessment rounds were carried out successfully. The selected dimensions proved to be essential parts of the speaking performances. The results will benefit those working on automated assessment and oral language assessment.
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