Pancreatic Cancer - Early Detection, Prognostic Factors, and Treatment

Background: Pancreatic cancer is the fourth leading cause of cancer-related death. Only about 6% of patients are alive 5 years after diagnosis. One reason for this low survival rate is that most patients are diagnosed at a late stage, when the tumor has spread to surrounding tissues or distant organs. Less than 20% of cases are diagnosed at an early stage that allows them to undergo potentially curative surgery. However, even for patients with a tumor that has been surgically removed, local and systemic recurrence is common and the median survival is only 17-23 months. This underscores the importance to identify factors that can predict postresection survival. With technical advances and centralization of care, pancreatic surgery has become a safe procedure. The future optimal treatment for pancreatic cancer is dependent on increased understanding of tumor biology and development of individualized and systemic treatment. Previous experimental studies have reported that mucins, especially the MUC4 mucin, may confer resistance to the chemotherapeutic agent gemcitabine and may serve as targets for the development of novel types of intervention. Aim: The aim of the thesis was to investigate strategies to improve management of pancreatic cancer, with special reference to early detection, prognostic factors, and treatment. Methods: In paper I, 27 prospectively collected serum samples from resectable pancreatic cancer (n=9), benign pancreatic disease (n=9), and healthy controls (n=9) were analyzed by high definition mass spectrometry (HDMSE). In paper II, an artificial neural network (ANN) model was constructed on 84 pancreatic cancer patients undergoing surgical resection. In paper III, we investigated the effects of transition from a low- to a high volume-center for pancreaticoduodenectomy in 221 patients. In paper IV, the grade of concordance in terms of MUC4 expression was examined in 17 tissue sections from primary pancreatic cancer and matched lymph node metastases. In paper V, pancreatic xenograft tumors were generated in 15 immunodeficient mice by subcutaneous injection of MUC4+ human pancreatic cancer cell lines; Capan-1, HPAF-II, or CD18/HPAF. In paper VI, a 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened against Capan-1 (MUC4+) and Panc-1 (MUC4-) cells, followed by high content screening of protein expression. Results/Conclusion: 134 differentially expressed serum proteins were identified, of which 40 proteins showed a significant up-regulation in the pancreatic cancer group. Pancreatic disease link associations could be made for BAZ2A, CDK13, DAPK1, DST, EXOSC3, INHBE, KAT2B, KIF20B, SMC1B, and SPAG5, by pathway network linkages to p53, the most frequently altered tumor suppressor in pancreatic cancer (I). An ANN survival model was developed, identifying 7 risk factors. The C-index for the model was 0.79, and it performed significantly better than the Cox regression (II). We experienced improved surgical results for pancreaticoduodenectomy after the transition to a high-volume center (≥25 procedures/year), including decreased operative duration, blood loss, hemorrhagic complications, reoperations, and hospital stay. There was also a tendency toward reduced operative mortality, from 4% to 0% (III). MUC4 positivity was detected in most primary pancreatic cancer tissues, as well as in matched metastatic lymph nodes (15/17 vs. 14/17), with a high concordance level (82%) (IV). The tumor incidence was 100% in the xenograft model. The median MUC4 count was found to be highest in Capan-1 tumors. α-SMA and collagen extent were also highest in Capan-1 tumors (V). Apicidin (a histone deacetylase inhibitor) had potent antiproliferative activity against Capan-1 cells and significantly reduced the expression of MUC4 and its transcription factor HNF4α. The combined treatment of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells (VI)

Promises and potential pitfalls of a ‘cognitive neuroscience of mathematics learning'

The present commentary discusses the papers of the special issue on ‘cognitive neuroscience and mathematics learning' with respect to methodological and theoretical constraints of using neuroscientific methods to study educationally relevant processes associated with mathematics learning. A special focus is laid on the relevance of subject populations, methodological limitations of current neuroimaging methods and theoretical questions concerning the relationship between the well-studied neural correlates of numerical magnitude processing and the less-investigated neural processes underlying higher level mathematical skills, such as algebraic reasonin

A million is more than a thousand: Children\u27s acquisition of very large number words

Very large numbers words such as “hundred,” “thousand,” “million,” “billion,” and “trillion” pose a learning problem for children because they are sparse in everyday speech and children\u27s experience with extremely large quantities is scarce. In this study, we examine when children acquire the relative ordering of very large number words as a first step toward understanding their acquisition. In Study 1, a hundred and twenty-five 5–8-year-olds participated in a verbal number comparison task involving very large number words. We found that children can judge which of two very large numbers is more as early as age 6, prior to entering first grade. In Study 2, we provided a descriptive analysis on the usage of very large number words using the CHILDES database. We found that the relative frequency of large number words does not change across the years, with “hundred” uttered more frequently than others by an order of magnitude. We also found that adults were more likely to use large number words to reference units of quantification for money, weight, and time, than for discrete, physical entities. Together, these results show that children construct a numerical scale for large number words prior to learning their precise cardinal meanings, and highlight how frequency and context may support their acquisition. Our results have pedagogical implications and highlight a need to investigate how children acquire meanings for number words that reference quantities beyond our everyday experience

Are specific learning disorders truly specific, and are they disorders?

© 2019 The Authors Specific learning disorders, such as dyslexia and dyscalculia, are frequently studied to inform our understanding of cognitive development, genetic mechanisms and brain function. In this Opinion Paper, we discuss limitations of this research approach, including the use of arbitrary criteria to select groups of children, heterogeneity within groups and overlap between domains of learning. By drawing on evidence from cognitive science, neuroscience and genetics, we propose an alternative, dimensional framework. We argue that we need to overcome the problems associated with a categorical approach by taking into account interacting factors at multiple levels of analysis that are associated with overlapping rather than entirely distinct domains of learning. We conclude that this research strategy will allow for a richer understanding of learning and development

Why numerical symbols count in the development of mathematical skills: evidence from brain and behaviour

Numerical skills measured prior to school entry are predictive of mathematics achievement longitudinally. It is therefore important that young children start school with strong mathematical foundations. Here we review evidence from behavior and neuroimaging that highlights numerical symbol knowledge as a key mediator between informal and formal mathematical competencies. We argue that future research should aim to elucidate cognitive and neuronal mechanisms underpinning the acquisition of symbolic knowledge. Furthermore, multiple aspects of numerical symbol knowledge, such as identification, cardinality, and ordinality, should be emphasized in preschool childcare environment

Probing the nature of deficits in the ‘Approximate Number System’ in children with persistent Developmental Dyscalculia

In the present study we examined whether children with Developmental Dyscalculia (DD) exhibit a deficit in the so-called \u27Approximate Number System\u27 (ANS). To do so, we examined a group of elementary school children who demonstrated persistent low math achievement over 4 years and compared them to typically developing (TD), aged-matched controls. The integrity of the ANS was measured using the Panamath (www.panamath.org) non-symbolic numerical discrimination test. Children with DD demonstrated imprecise ANS acuity indexed by larger Weber fraction (w) compared to TD controls. Given recent findings showing that non-symbolic numerical discrimination is affected by visual parameters, we went further and investigated whether children performed differently on trials on which number of dots and their overall area were either congruent or incongruent with each other. This analysis revealed that differences in w were only found between DD and TD children on the incongruent trials. In addition, visuo-spatial working memory strongly predicts individual differences in ANS acuity (w) during the incongruent trials. Thus the purported ANS deficit in DD can be explained by a difficulty in extracting number from an array of dots when area is anti-correlated with number. These data highlight the role of visuo-spatial working memory during the extraction process, and demonstrate that close attention needs to be paid to perceptual processes invoked by tasks thought to represent measures of the ANS

Differences between literates and illiterates on symbolic but not nonsymbolic numerical magnitude processing

The study of numerical magnitude processing provides a unique opportunity to examine interactions between phylogenetically ancient systems of semantic representations and those that are the product of enculturation. While nonsymbolic representations of numerical magnitude are processed similarly by humans and nonhuman animals, symbolic representations of numerical magnitude (e. g., Hindu-Arabic numerals) are culturally invented symbols that are uniquely human. Here, we report a comparison of symbolic and nonsymbolic numerical magnitude processing in two groups of participants who differ substantially in their level of literacy. In this study, level of literacy is used as an index of level of school-based numeracy skill. The data from these groups demonstrate that while the processing of nonsymbolic numerical magnitude (numerical distance effect) is unaffected by an individual\u27s level of literacy, the processing of Hindu-Arabic numerals differs between literate and illiterate individuals who live in a literature culture and have limited symbolic recognition skills. These findings reveal that nonsymbolic numerical magnitude processing is unaffected by enculturation, while the processing of numerical symbols is modulated by literacy. © 2011 Psychonomic Society, Inc