Dysfunctional Modulation Research Articles

Dysfunctional miRNA-Mediated Regulation in Chromophobe Renal Cell Carcinoma.

Past research on pathogenesis of a complex disease suggests that differentially expressed message RNAs (mRNAs) can be noted as biomarkers of a disease. However, significant miRNA-mediated regulation change might also be more deep underlying cause of a disease. In this study, a miRNA-mediated regulation module is defined based on GO terms (Gene Ontology terms) from which dysfunctional modules are identified as the suspected cause of a disease. A miRNA-mediated regulation module contains mRNAs annotated to a GO term and MicroRNAs (miRNAs) which regulate the mRNAs. Based on the miRNA-mediated regulation coefficients estimated from the expression profiles of the mRNA and the miRNAs, a SW (single regulation-weight) value is then designed to evaluate the miRNA-mediated regulation change of an mRNA, and the modules with significantly differential SW values are thus identified as dysfunctional modules. The approach is applied to Chromophobe renal cell carcinoma and it identifies 70 dysfunctional miRNA-mediated regulation modules from initial 4381 modules. The identified dysfunctional modules are detected to be comprehensive reflection of chromophobe renal cell carcinoma. The proposed approach suggests that accumulated alteration in miRNA-mediated regulation might cause functional alterations, which further cause a disease. Moreover, this approach can also be used to identify diffentially miRNA-mediated regulated mRNAs showing more comprehensive underlying association with a disease than differentially expressed mRNAs.

Terapeutic Potential of Microencapsulated Sertoli Cells in Huntington Disease.

Immune dysfunction, promoted by pro-inflammatory cytokines, plays a pivotal role in neurodegeneration associated with Huntington's disease. The aim of this study was to investigate the emerging immunoregulatory and antiinflammatory properties of Sertoli cells in Huntington's disease. The experimental R6/2 mouse model of Huntington's disease was treated by a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells and lifespan, motor performance and striatal inflammatory pattern have been evaluated. The results of this study demonstrated that a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells uniquely improved performances and extended the life expectancy of R6/2 Huntington's disease mice, by immune dysfunction modulation in brain. This study highlights the immunomodulatory and trophic role of Sertoli cells that could be of help in the treatment of neurodegenerative disorders.

Deciphering the Potential Pharmaceutical Mechanism of Chinese Traditional Medicine (Gui-Zhi-Shao-Yao-Zhi-Mu) on Rheumatoid Arthritis.

Gui-Zhi-Shao-Yao-Zhi-Mu (GSZ) decoction is a Traditional Chinese Medicine (TCM) formula commonly used for the treatment of Rheumatoid Arthritis (RA). The therapeutic effect of GSZ for RA treatment is supported by our clinical retrospective study. To uncover the potential mechanism underlying GSZ formula, we identified 1,327 targets of 673 compounds from 9 herbs that involve in Fc epsilon RI signaling pathway and regulation of immunoglobulin production. Comparison between formula targets with 79 RA drug targets and 675 RA disease genes showed that formula targets covered 31.6% RA drug targets and 19.9% RA disease genes. Formula specific targets presented expression patterns highly similar to the disease genes and drug targets based on the expression profiles of RA samples. Investigation of 10 inferred gene clusters from expression profiles with a target association network revealed that formula specific targets directly or indirectly interacted with disease genes that were essential for immune related biological processes (e.g. inflammatory responses, treatment response of rheumatoid arthritis, etc.). Our result indicated that GSZ disrupted the RA disease dysfunction modules and restored homeostasis in the human body. The systemic approach to infer therapeutic mechanisms of GSZ for RA treatment provides a new insight in the understanding of this TCM formula.

A computational method for clinically relevant cancer stratification and driver mutation module discovery using personal genomics profiles.

BackgroundPersonalized genomics instability, e.g., somatic mutations, is believed to contribute to the heterogeneous drug responses in patient cohorts. However, it is difficult to discover personalized driver mutations that are predictive of drug sensitivity owing to diverse and complex mutations of individual patients. To circumvent this problem, a novel computational method is presented to discover potential drug sensitivity relevant cancer subtypes and identify driver mutation modules of individual subtypes by coupling differentially expressed genes (DEGs) based subtyping analysis with the driver mutation network analysis.ResultsThe proposed method was applied to breast cancer and lung cancer samples available from The Cancer Genome Atlas (TCGA). Cancer subtypes were uncovered with significantly different survival rates, and more interestingly, distinct driver mutation modules were also discovered among different subtypes, indicating the potential mechanism of heterogeneous drug sensitivity.ConclusionsThe research findings can be used to help guide the repurposing of known drugs and their combinations in order to target these dysfunctional modules and their downstream signaling effectively for achieving personalized or precision medicine treatment.

Dysfunctional modulation of default mode network activity in attention-deficit/hyperactivity disorder.

The state regulation deficit model posits that individuals with attention-deficit/hyperactivity disorder (ADHD) have difficulty applying mental effort effectively under suboptimal conditions such as very fast and very slow event rates (ERs). ADHD is also associated with diminished suppression of default mode network (DMN) activity and related performance deficits on tasks requiring effortful engagement. The current study builds on these 2 literatures to test the hypothesis that failure to modulate DMN activity in ADHD might be especially pronounced at ER extremes. Nineteen adults with ADHD and 20 individuals without any neuropsychiatric condition successfully completed a simple target detection task under 3 ER conditions (2-, 4-, and 8-s interstimulus intervals) inside the scanner. Task-related DMN deactivations were compared between 2 groups. There was a differential effect of ER on DMN activity for individuals with ADHD compared to controls. Individuals with ADHD displayed excessive DMN activity at the fast and slow, but not at the moderate ER. The results indicate that DMN attenuation in ADHD is disrupted in suboptimal energetic states where additional effort is required to optimize task engagement. DMN dysregulation may be an important element of the neurobiological underpinnings of state regulation deficits in ADHD.

Increased somatic sensations are associated with reduced limb ownership

ObjectiveMedically unexplained symptoms (MUS) are increasingly being thought of as resulting from dysfunctional modulation of interoceptive sensory signals by top-down cognitive processes. The current study investigated whether individuals with a tendency toward MUS would be more susceptible to visual illusions that suggest tactile sensation on the skin in the absence of any actual somatosensory input. MethodParticipants viewed real-time-mediated reality video images of their own hand, either un-manipulated or digitally altered to display moving pixelated ‘static’ effect, the crawling skin illusion. The strength of various physical sensations during each condition were rated on a numeric scale and compared to standard measures of somatoform dissociation (Somatoform Dissociation Questionnaire 20). ResultsParticipants reporting a higher degree of somatoform dissociation were found to be more susceptible to somatic sensations across all conditions. Interestingly, participants who reported more visually induced somatosensory sensations also felt less ownership over their digitally presented hands. ConclusionThese findings support the proposed link between MUS and disturbances in body representation, and suggest that an over-reliance on top-down knowledge may interfere with current sensory inputs, contributing to symptom formation and maintenance in susceptible individuals.

Abstract 115: Telomerase modulation in a human cancer stem cell syndrome with loss of TGF-β signaling is a promising treatment strategy in liver and gastrointestinal cancers

Abstract Background: Beckwith-Wiedemann syndrome (BWS) is a hereditary human cancer stem cell syndrome with an 800 fold risk of multiple cancers, is currently linked to deregulated imprinting at chromosome 11p15, IGF2, CDKN1C and others. Yet, causal molecular defects and genetic models of this overgrowth syndrome have remained elusive to date in the majority of cases. CCCTC-Binding Factor CTCF is a highly conserved zinc finger protein that has diverse regulatory functions, including transcriptional ctivation/repression/imprinting of molecules such as TERT, IGF-2 and c-Myc. Recent studies demonstrate a high frequency of TERT promoter mutations in early stage of multiple cancers, suggesting that these promoter mutations may function as driver events that contribute to oncogenesis through TERT deregulation. However, telomerase remains a challenge to target effectively. We have recently discovered identified a mouse model for BWS with loss of TGF-β signaling with multiple liver and GI cancers. CTCF expression is markedly decreased, with concomitantly high TERT levels in these cancers. Therefore, we hypothesize that TGF-β/β2SP/Smad3/ signaling regulates CTCF and TERT regulation. Rescuing TGF-β signaling may successfully reduce tumor burden with inhibition of telomerase. Materials & Methods: Generation of β2SP+/-/Smad3+/- mice and genotype analysis. Database of Genomics (COSMIC) and transcriptomics (TCGA) were analyzed. BWS tumors and mice liver, pancreas and stomach tissue specimens were immunostained with anti-TERT antibody. ChIP assays were to demonstrate the recruitment of β2SP/Smad3/CTCF at the promoter of TERT. Results: (1) β2SP+/-/Smad3+/- heterozygote mice spontaneously develop visceromegaly, multiple cancers, phenocopy a hereditary human cancer stem cell syndrome BWS. (2) Genomics and transcriptomics analyses revealed aberrant TGF-β signaling in β2SP+/-/Smad3+/- mice and human BWS. (3) Increased TERT expression in β2SP+/-/Smad3+/- mice is similar to that observed in human BWS. (4) CTCF levels are markedly decreased in β2SP+/-/Smad3+/- mice tissues. (5) CTCF interacts with β2SP/Smad3 in cell nucleus in a TGF-β-dependent manner. (6) TGF-β promotes the complex of β2SP/Smad3/CTCF at TERT promoter region. Conclusions: Loss of TGF-β signaling pathway leads to dysfunctional chromosome modulation through TERT deregulation. Smad3/β2SP/CTCF complex regulates TERT transcriptional activity. Our results provide a better mechanistic understanding of this dysfunctional stem cells cancer syndrome. Importantly, this study may lead to identify new treatment strategies and functional markers for the early detecting lethal cancers. Citation Format: Jian Chen, Jiun-Sheng Chen, Zhixing Yao, Wilma Jogunoori, Bibhuti Mishra, Lopa Mishra. Telomerase modulation in a human cancer stem cell syndrome with loss of TGF-β signaling is a promising treatment strategy in liver and gastrointestinal cancers. [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 115. doi:10.1158/1538-7445.AM2014-115

Toward a Definition of Affective Instability

Affective instability is a psychophysiological symptom observed in some psychopathologies. It is a complex construct that encompasses (1) primary emotions, or affects, and secondary emotions, with each category having its own characteristics, amplitude, and duration, (2) rapid shifting from neutral or valenced affect to intense affect, and (3) dysfunctional modulation of emotions. Affective instability is often confused with mood lability, as in bipolar disorders, as well as with other terms. To clarify the concept, we searched databases for the term affective instability and read related articles on the topic. In this article we situate the term within the current affective nomenclature and human emotional experience, explore its psychophysiological features, and place it within the context of psychopathology. We explain why the term can potentially be confused with mood pathology and then define affective instability as an inherited temperamental trait modulated by developmental experience.

Suggestion and Pain in Migraine: A Study by Laser Evoked Potentials

Belief and expectation are part of placebo effect. Migraine patients are characterized by a dysfunctional modulation of pain processing, though a clear placebo effect emerges in clinical trials. The aim of the study was to evaluate the effect of visual and verbal suggestion on subjective pain sensation and cortical responses evoked by CO2 painful laser stimuli in migraine without aura patients vs healthy controls. Twenty-six patients were recorded during the inter-ictal phase and compared to 26 sex and age-matched controls. The right hand and the right supraorbital zone were stimulated during a not conditioned and a conditioned task, where laser stimuli were delivered after a verbal and visual cues of decreased (D), increased (I) or basal (B) intensity, which was left unmodified during the entire task. In control subjects pain rating changed, according to the announced intensity, while in migraine patients the basal hyper-algesia remained unmodified. The N1 and N2 amplitudes tended to change coherently with the stimulus cue in controls, while an opposite paradoxical increase in decreasing condition emerged in migraine. The P2 amplitude modulation was also reduced in migraine, differently from controls. The altered pattern of pain rating and N2 amplitude modulation concurred with frequency of migraine, disability and allodynia. In controls suggestion influenced cortical pain processing and subjective pain rating, while in migraine a peculiar pattern of cortical activation contrasted external cues in order to maintain the basal hyper-algesia. This scarce influence of induced suggestion on pain experience seemed to characterize patients with more severe migraine and central sensitization.

Identifying disease genes and module biomarkers by differential interactions

A complex disease is generally caused by the mutation of multiple genes or by the dysfunction of multiple biological processes. Systematic identification of causal disease genes and module biomarkers can provide insights into the mechanisms underlying complex diseases, and help develop efficient therapies or effective drugs. In this paper, we present a novel approach to predict disease genes and identify dysfunctional networks or modules, based on the analysis of differential interactions between disease and control samples, in contrast to the analysis of differential gene or protein expressions widely adopted in existing methods. As an example, we applied our method to the study of three-stage microarray data for gastric cancer. We identified network modules or module biomarkers that include a set of genes related to gastric cancer, implying the predictive power of our method. The results on holdout validation data sets show that our identified module can serve as an effective module biomarker for accurately detecting or diagnosing gastric cancer, thereby validating the efficiency of our method. We proposed a new approach to detect module biomarkers for diseases, and the results on gastric cancer demonstrated that the differential interactions are useful to detect dysfunctional modules in the molecular interaction network, which in turn can be used as robust module biomarkers.

Identification of dysfunctional modules and disease genes in congenital heart disease by a network-based approach

BackgroundThe incidence of congenital heart disease (CHD) is continuously increasing among infants born alive nowadays, making it one of the leading causes of infant morbidity worldwide. Various studies suggest that both genetic and environmental factors lead to CHD, and therefore identifying its candidate genes and disease-markers has been one of the central topics in CHD research. By using the high-throughput genomic data of CHD which are available recently, network-based methods provide powerful alternatives of systematic analysis of complex diseases and identification of dysfunctional modules and candidate disease genes.ResultsIn this paper, by modeling the information flow from source disease genes to targets of differentially expressed genes via a context-specific protein-protein interaction network, we extracted dysfunctional modules which were then validated by various types of measurements and independent datasets. Network topology analysis of these modules revealed major and auxiliary pathways and cellular processes in CHD, demonstrating the biological usefulness of the identified modules. We also prioritized a list of candidate CHD genes from these modules using a guilt-by-association approach, which are well supported by various kinds of literature and experimental evidence.ConclusionsWe provided a network-based analysis to detect dysfunctional modules and disease genes of CHD by modeling the information transmission from source disease genes to targets of differentially expressed genes. Our method resulted in 12 modules from the constructed CHD subnetwork. We further identified and prioritized candidate disease genes of CHD from these dysfunctional modules. In conclusion, module analysis not only revealed several important findings with regard to the underlying molecular mechanisms of CHD, but also suggested the distinct network properties of causal disease genes which lead to identification of candidate CHD genes.

Dysfunctional Endogenous Pain Modulation (EPM) in Patients With Functional Dyspepsia (FD) and Its Clinical Relevance

Dysfunctional Endogenous Pain Modulation (EPM) in Patients With Functional Dyspepsia (FD) and Its Clinical Relevance

CS03-03 - Sleep and sleep disorders in somatoform pain disorder

IntroductionSomatoform pain disorder (SPD) is frequently associated with sleep disorders, specifically restless legs syndrome and insomnia, which in turn lowers the pain threshold and worsens pain.ObjectivesThe aim of the present study was to investigate differences in wake-EEG by low-resolution electromagnetic tomography (LORETA) and objective and subjective sleep and awakening quality in SPD patients as compared with controls and study acute and chronic effects of trazodone CR on these variables and pain measures.MethodsFifteen patients with SPD (F45.4) and co-morbid insomnia (F51.0) were compared with 15 controls and participated in a single-blind, placebo-controlled, cross-over study on the acute effect of 100 mg trazodone CR, followed by a six-week open titration period. Statistics involved clinical, EEG-LORETA, PSG and psychometry.ResultsLORETA showed reduced power, mainly in the beta band in almost all pain matrix areas (SI, SII, ACC, SMA, PFC, PPC, insula, amygdala, hippocampus). PSG demonstrated a lack of deep sleep and increased arousals and stage shifts, with opposite changes induced by trazodone after acute and chronic therapy. Improvement of sleep was associated with improvement of pain, evaluated by visual-analog scales.ConclusionOur LORETA findings demonstrate a dysfunctional pain modulation in SPD. Trazodone induced changes in subjective and objective sleep and awakening quality that were opposite to the differences between SPD patients and controls (key-lock principle) and associated with pain improvement.

Dysfunctional modulation of emotional interference in the medial prefrontal cortex in patients with schizophrenia

Patients with schizophrenia have impairment in cognitive-emotional interaction that is reflected in delusion formation and poor social functioning. Although monitoring deficits in the anterior cingulate have been observed in schizophrenia, the involvement of the affective division of the anterior cingulate implicated in cognitive modulation of emotional processing has not been directly addressed in schizophrenia. In this study, we examined the function of the affective division of the anterior cingulate and the related neural systems by using a modified emotional Stroop fMRI paradigm. Fourteen patients with schizophrenia and fourteen healthy controls performed an emotional appraisal task with semantically relevant emotional interferences during fMRI scanning. The patients with schizophrenia were significantly less efficient than the healthy controls during the emotional incongruence trials. When emotionally incongruent trials were compared to congruent trials, relative deactivations of the subgenual cingulate gyrus and the ventromedial prefrontal cortex observed in the healthy controls were not found in the patient group and activities of these regions inversely correlated with emotional interference to performance efficiency and response accuracy respectively in the patient group. In addition, relative activation in the dorsolateral prefrontal cortex was observed only in the patient group. These findings suggest that deficit in cognitive modulation over emotional interference in patients with schizophrenia may be explained by failure in suppressing the affective division of the anterior cingulate despite attentional effort. This may provide evidence for the failure in suppressing the bottom-up processing of emotion during cognitive-emotional interaction in schizophrenia.

Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.

The complexity in intracellular signaling mechanisms relevant for the conquest of many diseases resides at different levels of organization with scales ranging from the subatomic realm relevant to catalytic functions of enzymes to the mesoscopic realm relevant to the cooperative association of molecular assemblies and membrane processes. Consequently, the challenge of representing and quantifying functional or dysfunctional modules within the networks remains due to the current limitations in our understanding of mesoscopic biology, i.e., how the components assemble into functional molecular ensembles. A multiscale approach is necessary to treat a hierarchy of interactions ranging from molecular (nm, ns) to signaling (microm, ms) length and time scales, which necessitates the development and application of specialized modeling tools. Complementary to multiscale experimentation (encompassing structural biology, mechanistic enzymology, cell biology, and single molecule studies) multiscale modeling offers a powerful and quantitative alternative for the study of functional intracellular signaling modules. Here, we describe the application of a multiscale approach to signaling mediated by the ErbB1 receptor which constitutes a network hub for the cell's proliferative, migratory, and survival programs. Through our multiscale model, we mechanistically describe how point-mutations in the ErbB1 receptor can profoundly alter signaling characteristics leading to the onset of oncogenic transformations. Specifically, we describe how the point mutations induce cascading fragility mechanisms at the molecular scale as well as at the scale of the signaling network to preferentially activate the survival factor Akt. We provide a quantitative explanation for how the hallmark of preferential Akt activation in cell-lines harboring the constitutively active mutant ErbB1 receptors causes these cell-lines to be addicted to ErbB1-mediated generation of survival signals. Consequently, inhibition of ErbB1 activity leads to a remarkable therapeutic response in the addicted cell lines.

Trait anger and blood pressure recovery following acute pain: Evidence for opioid-mediated effects

Previous work has suggested that positive associations between trait anger (TRANG) and pain sensitivity are due to dysfunctional endogenous opioid analgesic systems. In this study, we examined whether TRANG is associated with impaired opioid modulation of blood pressure (BP) recovery. A total of 46 pain-free normotensive controls and 69 normotensive chronic low back pain (LBP) sufferers received opioid blockade (8mg naloxone IV) or placebo in randomized, counterbalanced order in separate sessions. During each, participants underwent a 1-min finger pressure pain task followed by an ischemic forearm pain task. Opioid blockade impaired post-pain BP recovery in controls but not LBP participants (ps < .001). In controls, low TRANG was associated with blockade-induced recovery impairments, with no blockade effect in high TRANG participants. In LBP participants, blockade did not alter recovery regardless of TRANG (interaction ps < .05). Results support dysfunctional opioid modulation of BP recovery in healthy high TRANG controls and further suggest chronic pain-related impairments in opioid-mediated cardiovascular recovery.

Trait anger and blood pressure recovery following acute pain: evidence for opioid-mediated effects

Previous work has suggested that positive associations between trait anger (TRANG) and pain sensitivity are due to dysfunctional endogenous opioid analgesic systems. In this study, we examined whether TRANG is associated with impaired opioid modulation of blood pressure (BP) recovery. A total of 46 pain-free normotensive controls and 69 normotensive chronic low back pain (LBP) sufferers received opioid blockade (8 mg naloxone i.v.) or placebo in randomized, counterbalanced order in separate sessions. During each, participants underwent a 1-min finger pressure pain task followed by an ischemic forearm pain task. Opioid blockade impaired post-pain BP recovery in controls but not LBP participants (ps < .001). In controls, low TRANG was associated with blockade-induced recovery impairments, with no blockade effect in high TRANG participants. In LBP participants, blockade did not alter recovery regardless of TRANG (interaction ps < .05). Results support dysfunctional opioid modulation of BP recovery in healthy high TRANG controls and further suggest chronic pain-related impairments in opioid-mediated cardiovascular recovery.

Underconstrained thalamic activation + underconstrained top-down modulation of cortical input processing = underconstrained perceptions

Behrendt &amp; Young's (B&amp;Y's) theory offers a potentially important perspective on the neurobiology of schizophrenia, but it remains incomplete. In addition to bottom-up contributions, such as those associated with disturbances in sensory constraints on cognitive processes, a comprehensive model requires the integration of the consequences of abnormal top-down modulation of input processing for the evolution of “underconstrained” perceptions. Dysfunctional cholinergic modulation of input functions represents a necessary mechanism for the generation of false perceptions.

Cerebrospinal fluid studies in the Rett syndrome: Biogenic amines and β-endorphins

The etiology of the Rett syndrome (RS) is unknown. Reduced function of biogenic amines has been described. Symptoms of central apnea, hyperventilation, hypothermia, peripheral analgesia, muscle rigidity, myoclonic jerks, hand stereotypy and seizures occur in RS and have been suggested as a result of elevated central beta-endorphins. It was hypothesized that a dysfunctional modulation of endogenous opiate systems and biogenic amines may be present. Cerebrospinal fluid (CSF) from 12 girls with RS was studied for beta-endorphin immunoreactivity, and biogenic amines. Lactates and pyruvate levels were measured. Eleven of the 12 girls had elevated beta-endorphin immunoreactivity in CSF, 4 girls had reduced biogenic amines and 6 girls had elevated pyruvate and lactate levels. Whether the elevated beta-endorphin immunoreactivity is a primary disorder or is a result of secondary feedback mechanisms is unknown. Naltrexone, an antiopioid drug, may reduce symptoms.