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1.  Examining Eye Movements in Visual Search through Clusters of Objects in a Circular Array 
Participants were asked to search for a complete O in an array consisting of eight clusters of four Landolt Cs (i.e., Os with a gap) arranged in a ring. The size of the gap in the Cs varied from cluster to cluster but was held constant within a cluster. The manual response time data were consistent with a serial self-terminating search. More importantly, eye movement data supported a serial processing model as (a) clusters were fixated serially (either clockwise or counterclockwise) on most trials and (b) fixation times on a cluster reflected processing time on that cluster and were unaffected by the gap size of either the prior or succeeding cluster. Furthermore, the pattern of fixation times on a cluster was similar to the pattern of response times in a secondary task where a single cluster was presented at fixation. These data extend the findings of Williams and Pollatsek (2007) in which search was through a linear sequence of clusters, and indicate that a serial search pattern through clusters of these kinds of objects is not confined to reading-like linear arrays.
doi:10.1080/20445911.2013.865630
PMCID: PMC3919660  PMID: 24527204
Eye Movements; Visual Search; Clusters
2.  Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients 
Background
Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed.
Methods
We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients.
Results
We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b.
Conclusions
In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype.
doi:10.1186/s13045-014-0051-y
PMCID: PMC4223626  PMID: 25023966
Adult T-cell acute lymphoblastic leukemia; BCL11b; Outcome; Standard risk; Expression; Mutation
3.  Using E-Z Reader to Examine Word Skipping During Reading 
The question of why readers sometimes skip words has important theoretical implications for our understanding of perception, cognition, and oculomotor control during reading (Drieghe, Rayner, & Pollatsek, 2005). In this article, the E-Z Reader model of eye-movement control in reading (Reichle, 2011) was used to examine the behavioral consequences of word skipping on fixation durations. The simulations suggest that skipping “cost”, or inflated fixation durations immediately prior to skips, is modulated by the lexical properties of the upcoming word (i.e., longer fixations before skipping infrequent and/or long words; Kliegl & Engbert, 2005), but that contrary to previous claims (e.g., Reichle & Laurent, 2006), “accidental” skips due to motor error also produce skipping cost. In contrast, the cost associated with having skipped a word was not modulated by that word’s properties. These simulations suggest that skipping behavior is even more complicated than previously assumed, and that further empirical research is needed to understand the causal link between skipping and its associated cost.
doi:10.1037/a0030910
PMCID: PMC3832990  PMID: 23206168
4.  Using E-Z Reader to examine the concurrent development of eye-movement control and reading skill 
Developmental review : DR  2013;33(2):110-149.
Compared to skilled adult readers, children typically make more fixations that are longer in duration, shorter saccades, and more regressions, thus reading more slowly (Blythe & Joseph, 2011). Recent attempts to understand the reasons for these differences have discovered some similarities (e.g., children and adults target their saccades similarly; Joseph, Liversedge, Blythe, White, & Rayner, 2009) and some differences (e.g., children’s fixation durations are more affected by lexical variables; Blythe, Liversedge, Joseph, White, & Rayner, 2009) that have yet to be explained. In this article, the E-Z Reader model of eye-movement control in reading (Reichle, 2011; Reichle, Pollatsek, Fisher, & Rayner, 1998) is used to simulate various eye-movement phenomena in adults vs. children in order to evaluate hypotheses about the concurrent development of reading skill and eye-movement behavior. These simulations suggest that the primary difference between children and adults is their rate of lexical processing, and that different rates of (post-lexical) language processing may also contribute to some phenomena (e.g., children’s slower detection of semantic anomalies; Joseph et al., 2008). The theoretical implications of this hypothesis are discussed, including possible alternative accounts of these developmental changes, how reading skill and eye movements change across the entire lifespan (e.g., college-aged vs. older readers), and individual differences in reading ability.
doi:10.1016/j.dr.2013.03.001
PMCID: PMC3774954  PMID: 24058229
Computer model; Eye movements; E-Z Reader; Lexical access; Reading; Reading skill
5.  Single-Subject Experimental Design for Evidence-Based Practice 
Purpose
Single-subject experimental designs (SSEDs) represent an important tool in the development and implementation of evidence-based practice in communication sciences and disorders. The purpose of this article is to review the strategies and tactics of SSEDs and their application in speech-language pathology research.
Method
The authors discuss the requirements of each design, followed by advantages and disadvantages. The logic and methods for evaluating effects in SSED are reviewed as well as contemporary issues regarding data analysis with SSED data sets. Examples of challenges in executing SSEDs are included. Specific exemplars of how SSEDs have been used in speech-language pathology research are provided throughout.
Conclusion
SSED studies provide a flexible alternative to traditional group designs in the development and identification of evidence-based practice in the field of communication sciences and disorders.
doi:10.1044/1058-0360(2012/11-0036)
PMCID: PMC3992321  PMID: 23071200
single-subject experimental designs; tutorial; research methods; evidence-based practice
6.  Direct lexical control of eye movements in reading: Evidence from a survival analysis of fixation durations 
Cognitive psychology  2012;65(2):177-206.
Participants’ eye movements were monitored in an experiment that manipulated the frequency of target words (high vs. low) as well as their availability for parafoveal processing during fixations on the pre-target word (valid vs. invalid preview). The influence of the word-frequency by preview validity manipulation on the distributions of first fixation duration was examined by using ex-Gaussian fitting as well as a novel survival analysis technique which provided precise estimates of the timing of the first discernible influence of word frequency on first fixation duration. Using this technique, we found a significant influence of word frequency on fixation duration in normal reading (valid preview) as early as 145 ms from the start of fixation. We also demonstrated an equally rapid non-lexical influence on first fixation duration as a function of initial landing position (location) on target words. The time-course of frequency effects, but not location effects was strongly influenced by preview validity, demonstrating the crucial role of parafoveal processing in enabling direct lexical control of reading fixation times. Implications for models of eye-movement control are discussed.
doi:10.1016/j.cogpsych.2012.03.001
PMCID: PMC3565237  PMID: 22542804
Eye movements; Reading; Lexical processing; Word frequency; Parafoveal preview; Direct control; Initial landing position; Fixation location; Fixation duration
7.  The Emergence of Frequency Effects in Eye Movements 
Cognition  2012;123(1):185-189.
A visual search experiment employed strings of Landolt Cs to examine how the gap size of and frequency of exposure to distractor strings affected eye movements. Increases in gap size were associated with shorter first-fixation durations, gaze durations, and total times, as well as fewer fixations. Importantly, both the number and duration of fixations decreased with repeated exposures. The findings provide evidence for the role of cognition in guiding eye-movements, and a potential explanation for word-frequency effects observed in reading.
doi:10.1016/j.cognition.2011.12.011
PMCID: PMC3278573  PMID: 22264379
eye-movement control; word frequency effects; reading; visual search
8.  Eye movements in reading versus nonreading tasks: Using E-Z Reader to understand the role of word/stimulus familiarity 
Visual cognition  2012;20(4-5):360-390.
In this article, we extend our previous work (Reichle, Pollatsek, & Rayner, 2012) using the principles of the E-Z Reader model to examine the factors that determine when and where the eyes move in both reading and non-reading tasks, and in particular the role that word/stimulus familiarity plays in determining when the eyes move from one word/stimulus to the next. In doing this, we first provide a brief overview of E-Z Reader, including its assumption that word familiarity is the “engine” driving eye movements during reading. We then review the theoretical considerations that motivated this assumption, as well as recent empirical evidence supporting its validity. We also report the results of three new simulations that were intended to demonstrate the utility of the familiarity check in three tasks: (1) reading; (2) searching for a target word in embedded in text; and (3) searching for the letter O in linear arrays of Landolt Cs. The results of these simulations suggest that the familiarity check always improves task efficiency by speeding its rate of performance. We provide several arguments as to why this conclusion is not likely to be true for the two non-reading tasks, and in the final section of the paper, we provide a fourth simulation to test the hypothesis that problems associated with the mis-identification of words may also curtail the too liberal use of word familiarity.
doi:10.1080/13506285.2012.667006
PMCID: PMC3374660  PMID: 22707910
9.  Neurophysiological constraints on the eye-mind link 
Several current computational models of eye-movement control in reading posit a tight link between the eye and mind, with lexical processing directly triggering most “decisions” about when to start programming a saccade to move the eyes from one word to the next. One potential problem with this theoretical assumption, however, is that it may violate neurophysiological constraints imposed by the time required to encode visual information, complete some amount of lexical processing, and then program a saccade. In this article, we review what has been learned about these timing constraints from studies using ERP and MEG. On the basis of this review, it would appear that the temporal constraints are too severe to permit direct lexical control of eye movements without a significant amount of parafoveal processing (i.e., pre-processing of word n+1 from word n). This conclusion underscores the degree to which the perceptual, cognitive, and motor processes involved in reading must be highly coordinated to support skilled reading, a par excellence example of a task requiring visual-cognitive expertise.
doi:10.3389/fnhum.2013.00361
PMCID: PMC3710954  PMID: 23874281
ERP; MEG; computational models; reading; saccades
10.  Parafoveal preview during reading: Effects of sentence position 
Two experiments examined parafoveal preview for words located in the middle of sentences and at sentence boundaries. Parafoveal processing was shown to occur for words at sentence-initial, mid-sentence, and sentence-final positions. Both Experiments 1 and 2 showed reduced effects of preview on regressions out for sentence-initial words. In addition, Experiment 2 showed reduced preview effects on first-pass reading times for sentence-initial words. These effects of sentence position on preview could result from reduced parafoveal processing for sentence-initial words, or other processes specific to word reading at sentence boundaries. In addition to the effects of preview, the experiments also demonstrate variability in the effects of sentence wrap-up on different reading measures, indicating that the presence and time course of wrap-up effects may be modulated by text-specific factors. We also report simulations of Experiment 2 using version 10 of E-Z Reader (Reichle, Warren, & McConnell, 2009), designed to explore the possible mechanisms underlying parafoveal preview at sentence boundaries.
doi:10.1037/a0022190
PMCID: PMC3140553  PMID: 21500948
reading; eye movements; E-Z Reader; parafoveal preview; wrap-up effects
11.  The Influence of Climatic Seasonality on the Diversity of Different Tropical Pollinator Groups 
PLoS ONE  2011;6(11):e27115.
Tropical South America is rich in different groups of pollinators, but the biotic and abiotic factors determining the geographical distribution of their species richness are poorly understood. We analyzed the species richness of three groups of pollinators (bees and wasps, butterflies, hummingbirds) in six tropical forests in the Bolivian lowlands along a gradient of climatic seasonality and precipitation ranging from 410 mm to 6250 mm. At each site, we sampled the three pollinator groups and their food plants twice for 16 days in both the dry and rainy seasons. The richness of the pollinator groups was related to climatic factors by linear regressions. Differences in species numbers between pollinator groups were analyzed by Wilcoxon tests for matched pairs and the proportion in species numbers between pollinator groups by correlation analyses. Species richness of hummingbirds was most closely correlated to the continuous availability of food, that of bees and wasps to the number of food plant species and flowers, and that of butterflies to air temperature. Only the species number of butterflies differed significantly between seasons. We were not able to find shifts in the proportion of species numbers of the different groups of pollinators along the study gradient. Thus, we conclude that the diversity of pollinator guilds is determined by group-specific factors and that the constant proportions in species numbers of the different pollinator groups constitute a general pattern.
doi:10.1371/journal.pone.0027115
PMCID: PMC3206942  PMID: 22073268
12.  Models of the Reading Process 
Reading is a complex skill involving the orchestration of a number of components. Researchers often talk about a “model of reading” when talking about only one aspect of the reading process (for example, models of word identification are often referred to as “models of reading”). Here, we review prominent models that are designed to account for (1) word identification, (2) syntactic parsing, (3) discourse representations, and (4) how certain aspects of language processing (e.g., word identification), in conjunction with other constraints (e g., limited visual acuity, saccadic error, etc.), guide readers’ eyes. Unfortunately, it is the case that these various models addressing specific aspects of the reading process seldom make contact with models dealing with other aspects of reading. Thus, for example, the models of word identification seldom make contact with models of eye movement control, and vice versa. While this may be unfortunate in some ways, it is quite understandable in other ways because reading itself is a very complex process. We discuss prototypical models of aspects of the reading process in the order mentioned above. We do not review all possible models, but rather focus on those we view as being representative and most highly recognized.
doi:10.1002/wcs.68
PMCID: PMC3001687  PMID: 21170142
13.  Lexical and Post-Lexical Complexity Effects on Eye Movements in Reading 
The current study investigated how a post-lexical complexity manipulation followed by a lexical complexity manipulation affects eye movements during reading. Both manipulations caused disruption in all measures on the manipulated words, but the patterns of spill-over differed. Critically, the effects of the two kinds of manipulations did not interact, and there was no evidence that post-lexical processing difficulty delayed lexical processing on the next word (c.f. Henderson & Ferreira, 1990). This suggests that post-lexical processing of one word and lexical processing of the next can proceed independently and likely in parallel. This finding is consistent with the assumptions of the E-Z Reader model of eye movement control in reading (Reichle, Warren, & McConnell, 2009).
PMCID: PMC3097123  PMID: 21603125
Reading; sentence complexity; eye movements; E-Z Reader; word frequency
14.  Renal function during rofecoxib therapy in patients with metastatic cancer: retrospective analysis of a prospective phase II trial 
BMC Research Notes  2011;4:2.
Background
Angiostatic/antiinflammatory therapy with COX-II inhibitors and pioglitazone seems to be a well tolerated and promising regimen in patients with metastatic cancer. COX-II inhibitors may have less gastrointestinal side effects than conventional non-steroidal antiinflammatory drugs, but their impact on renal function seems to be similar.
Methods
87 patients with metastatic/advanced cancer were treated up to 12 months (mean 19.5 weeks) with rofecoxib, pioglitazone and either capecitabine (group A with gastrointestinal and urological cancer, n = 50) or trofosfamide (group B with non-gastrointestinal/non-urological cancer, n = 37) and followed for further 6 months.
Results
Baseline serum creatinine concentration was 0.81 ± 0.28 mg/dl, and increased by about 0.15 mg/dl during months 1-3. Accordingly estimated glomerular filtration rate (eGFR) decreased from 90.3 ml/min ± 3.6 ml/min at baseline by about 10 ml/min during months 1-3. Renal function decreased in 75 patients (86%) in the first month (p < 0.0001). This decrease went along with clinical signs of volume expansion. Renal function tended to recover after discontinuation of the study medication.
Conclusions
Therapy with rofecoxib in an antiangiogenic/antiinflammatory setting results in a decrease of renal function in nearly every patient.
Trial registration number
German Clinical Trials Register DRKS: DRKS00000119
doi:10.1186/1756-0500-4-2
PMCID: PMC3038926  PMID: 21208422
15.  Eye Movements and Non-Canonical Reading: Comments on Kennedy and Pynte (2008) 
Vision research  2008;49(17):2232-2236.
Kennedy and Pynte (2008) presented data that they suggested pose problems for models of eye movement control in reading in which words are encoded serially. They focus on situations in which pairs of words are fixated out of order (i.e., the first word is skipped and the second fixated prior to a regression back to the first word). We strongly disagree with their claims and contest their arguments. We argue that their data set was obtained selectively and the events they believe are problematic do not occur frequently during reading. Furthermore, we do not consider that Kennedy and Pynte’s arguments pose serious difficulties for serial models of reading such as E-Z Reader.
doi:10.1016/j.visres.2008.10.013
PMCID: PMC2746070  PMID: 19000705
16.  Investigating the causes of wrap-up effects: Evidence from eye movements and E-Z Reader 
Cognition  2009;111(1):132-137.
Wrap-up effects in reading have traditionally been thought to reflect increased processing associated with intra- and inter-clause integration (Just & Carpenter, 1980; Rayner, Kambe & Duffy, 2000; cf. Hirotani, Frazier, & Rayner, 2006). We report an eye-tracking experiment with a strong manipulation of integrative complexity at a critical word that was either sentence-final, ended a comma-marked clause, or was not comma marked. Although both complexity and punctuation each had reliable effects, they did not interact in any eye-movement measure. These results and simulations using the E-Z Reader model of eye-movement control (Reichle, Warren, & McConnell, 2009) suggest that traditional accounts of clause wrap-up are incomplete.
doi:10.1016/j.cognition.2008.12.011
PMCID: PMC2682724  PMID: 19215911
17.  Principles of Modular Tumor Therapy 
Cancer Microenvironment  2009;2(Suppl 1):227-237.
Nature is interwoven with communication and is represented and reproduced through communication acts. The central question is how may multimodal modularly acting and less toxic therapy approaches, defined as modular therapies, induce an objective response or even a continuous complete remission, although single stimulatory or inhibitingly acting drugs neither exert mono-activity in the respective metastatic tumor type nor are they directed to potentially ‘tumor-specific’ targets. Modularity in the present context is a formal pragmatic communicative systems concept, describing the degree to which systems objects (cells, pathways etc.) may be communicatively separated in a virtual continuum, and recombined and rededicated to alter validity and denotation of communication processes in the tumor. Intentional knowledge, discharging in reductionist therapies, disregards the risk-absorbing background knowledge of the tumor’s living world including the holistic communication processes, which we rely on in every therapy. At first, this knowledge constitutes the validity of informative intercellular processes, which is the prerequisite for therapeutic success. All communication-relevant steps, such as intentions, understandings, and the appreciation of messages, may be modulated simultaneously, even with a high grade of specificity. Thus, modular therapy approaches including risk-absorbing and validity-modifying background knowledge may overcome reductionist idealizations. Modular therapies show modular events assembled by the tumor’s living world as an additional evolution-constituting dimension. This way, modular knowledge may be acquired from the environment, either incidentally or constitutionally. The new communicatively defined modular coherency of environment, i.e. the tumor-associated microenvironment, and tumor cells open novel ways for the scientific community in ‘translational medicine’.
doi:10.1007/s12307-009-0023-x
PMCID: PMC2756340  PMID: 19593676
Evolution; Inflammation; Metastatic tumor; Personalized therapy; Systems assessment tools; Systems biology
18.  Lost in the Sauce The Effects of Alcohol on Mind Wandering? 
Psychological science  2009;20(6):747-752.
Alcohol consumption alters consciousness in ways that make drinking both alluring and hazardous. Recent advances in the study of consciousness using a mind-wandering paradigm permit a rigorous examination of the effects of alcohol on experiential consciousness and metaconsciousness. Fifty-four male social drinkers consumed alcohol (0.82 g/kg) or a placebo beverage and then performed a mind-wandering reading task. This task indexed both self-caught and probe-caught zone-outs to distinguish between mind wandering inside and outside of awareness. Compared with participants who drank the placebo, those who drank alcohol were significantly more likely to report that they were zoning out when probed. After this increase in mind wandering was accounted for, alcohol also lowered the probability of catching oneself zoning out. The results suggest that alcohol increases mind wandering while simultaneously reducing the likelihood of noticing one's mind wandering. Findings are discussed with regard to theories of alcohol and theories of consciousness.
doi:10.1111/j.1467-9280.2009.02351.x
PMCID: PMC2724753  PMID: 19422627
19.  Serial or Parallel? Using Depth-of-Processing to Examine Attention Allocation During Reading 
Vision research  2008;48(17):1831-1836.
This paper presents an experiment investigating attention allocation in four tasks requiring varied degrees of lexical processing of 1-4 simultaneously displayed words. Response times and eye movements were only modestly affected by the number of words in the asterisk-detection task but increased markedly with the number of words in the letter-detection, rhyme-judgment, and semantic-judgment tasks, suggesting that attention may not be serial for tasks that do not require significant lexical processing (e.g., detecting visual features), but is approximately serial for tasks that do (e.g., retrieving word meanings). The implications of these results for models of readers’ eye movements are discussed.
doi:10.1016/j.visres.2008.05.007
PMCID: PMC2581815  PMID: 18602657
20.  Immediate and Delayed Effects of Word Frequency and Word Length on Eye Movements in Reading: A Reversed Delayed Effect of Word Length 
Three experiments examined the effects in sentence reading of varying the frequency and length of an adjective on (a) fixations on the adjective and (b) fixations on the following noun. The gaze duration on the adjective was longer for low frequency than for high frequency adjectives and longer for long adjectives than for short adjectives. This contrasted with the spillover effects: Gaze durations on the noun were longer when adjectives were low frequency but were actually shorter when the adjectives were long. The latter effect, which seems anomalous, can be explained by three mechanisms: (a) Fixations on the noun are less optimal after short adjectives because of less optimal targeting; (b) shorter adjectives are more difficult to process because they have more neighbors; and (c) prior fixations before skips are less advantageous places to extract parafoveal information. The viability of these hypotheses as explanations of this reverse length effect on the noun was examined in simulations using an updated version of the E-Z Reader model
doi:10.1037/0096-1523.34.3.726
PMCID: PMC2715992  PMID: 18505334
reading; eye movements; attention; models; E-Z Reader
21.  Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma 
PPAR Research  2009;2010:848645.
Using tissue microarrays (TMAs) we studied COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on clinicopathological correlations and the outcome of patients with malignant melanoma (MM). TMA-1 contained normal and tumor tissues (n = 3448) from 47 organs including skin neoplasms (n = 323); TMA-2 88 primary MM, 101 metastases, and 161 benign nevi. Based on a biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy metastases of 36 patients participating in a randomized trial with metastatic (stage IV) melanoma were investigated using TMA-3. COX2/PPARG immunoreactivity significantly increased from nevi to primary MM and metastases; COX2 positivity was associated with advanced Clark levels and shorter recurrence-free survival. Patients with PPARG-positive metastases and biomodulatory metronomic chemotherapy alone or combined with COX2/PPARG-targeting showed a significantly prolonged progression-free survival. Regarding primary MM, COX2 expression indicates an increased risk of tumor recurrence. In metastatic MM, PPARG expression may be a predicitive marker for response to biomodulatory stroma-targeted therapy.
doi:10.1155/2010/848645
PMCID: PMC2712952  PMID: 19639032
22.  Principles of Modular Tumor Therapy 
Cancer Microenvironment  2009;2(Suppl 1):227-237.
Nature is interwoven with communication and is represented and reproduced through communication acts. The central question is how may multimodal modularly acting and less toxic therapy approaches, defined as modular therapies, induce an objective response or even a continuous complete remission, although single stimulatory or inhibitingly acting drugs neither exert mono-activity in the respective metastatic tumor type nor are they directed to potentially ‘tumor-specific’ targets. Modularity in the present context is a formal pragmatic communicative systems concept, describing the degree to which systems objects (cells, pathways etc.) may be communicatively separated in a virtual continuum, and recombined and rededicated to alter validity and denotation of communication processes in the tumor. Intentional knowledge, discharging in reductionist therapies, disregards the risk-absorbing background knowledge of the tumor’s living world including the holistic communication processes, which we rely on in every therapy. At first, this knowledge constitutes the validity of informative intercellular processes, which is the prerequisite for therapeutic success. All communication-relevant steps, such as intentions, understandings, and the appreciation of messages, may be modulated simultaneously, even with a high grade of specificity. Thus, modular therapy approaches including risk-absorbing and validity-modifying background knowledge may overcome reductionist idealizations. Modular therapies show modular events assembled by the tumor’s living world as an additional evolution-constituting dimension. This way, modular knowledge may be acquired from the environment, either incidentally or constitutionally. The new communicatively defined modular coherency of environment, i.e. the tumor-associated microenvironment, and tumor cells open novel ways for the scientific community in ‘translational medicine’.
doi:10.1007/s12307-009-0023-x
PMCID: PMC2756340  PMID: 19593676
Evolution; Inflammation; Metastatic tumor; Personalized therapy; Systems assessment tools; Systems biology
24.  Systems Biology: A Therapeutic Target for Tumor Therapy 
Cancer Microenvironment  2008;1(1):159-170.
Tumor-related activities that seem to be operationally induced by the division of function, such as inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodeling, cell proliferation rate, apoptosis, coagulation effects, present itself from a systems perspective as an enhancement of complexity. We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects, as adjustable sizes to therapeutically modulate the tumor systems’ stability, homeostasis, and robustness. We performed a retrospective analysis of recently published data on 224 patients with advanced and heavily pre-treated (10% to 63%) vascular sarcoma, melanoma, renal clear cell, cholangiocellular, carcinoma, hormone-refractory prostate cancer, and multivisceral Langerhans’ cell histiocytosis enrolled in nine multi-center phase II trials (11 centers). Each patient received a multi-targeted systems-directed therapy that consisted of metronomic low-dose chemotherapy, a COX-2 inhibitor, combined with one or two transcription modulators, pioglitazone +/− dexamethasone or IFN-alpha. These treatment schedules may attenuate the metastatic potential, tumor-associated inflammation, may exert site-specific activities, and induce long-term disease stabilization followed by prolonged objective response (3% to 48%) despite poor monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies’ systems biological activity. Understanding systems biology as adjustable size may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way: Comparatively high efficacy at moderate toxicity. Structured systems-directed therapies in metastatic cancer may get a source for detecting the topology of tumor-associated complex aggregated action effects as adjustable sizes available for targeted biomodulatory therapies.
doi:10.1007/s12307-008-0012-5
PMCID: PMC2654356  PMID: 19308694
Systems biology; Tumor microenvironment; Transcription factors; Pioglitazone; PPARs; Dexamethasone; Interferon-alpha; COX-2 inhibitor; Metronomic low dose chemotherapy
25.  Enantioselective Synthesis of α-tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates 
Chiral α-tertiary hydroxyaldehydes are very versatile building blocks in synthetic chemistry. Herein, we reported the first examples of a catalytic asymmetric protocol for the synthesis of such compounds from readily available α-halo or α-hydroxy ketones or enol silyl ethers with excellent yields and enantioselectivity. Its synthetic utility is demonstrated in the short, efficient formal synthesis of (S)-oxybutynin. In this process, the chiral ligand controls with the regioselectivity as well as enantioselectivity.
doi:10.1021/ja067342a
PMCID: PMC2533583  PMID: 17212401

Results 1-25 (34)