NCOA3 is a selective co-activator of estrogen receptor α-mediated transactivation of PLAC1 in MCF-7 breast cancer cells.

BACKGROUND: The placenta-specific 1 (PLAC1) gene encodes a membrane-associated protein which is selectively expressed in the placental syncytiotrophoblast and in murine fetal tissues during embryonic development. In contrast to its transcriptional repression in all other adult normal tissues, PLAC1 is frequently activated and highly expressed in a variety of human cancers, in particular breast cancer, where it associates with estrogen receptor α (ERα) positivity. In a previous study, we showed that ERα-signaling in breast cancer cells transactivates PLAC1 expression in a non-classical pathway. As the members of the p160/nuclear receptor co-activator (NCOA) family, NCOA1, NCOA2 and NCOA3 are known to be overexpressed in breast cancer and essentially involved in estrogen-mediated cancer cell proliferation we asked if these proteins are involved in the ERα-mediated transactivation of PLAC1 in breast cancer cells. METHODS: Applying quantitative real-time RT-PCR (qRT-PCR), Western Blot analysis and chromatin immunoprecipitation, we analyzed the involvement of NCOA1, NCOA2, NCOA3 in the ERα-mediated transactivation of PLAC1 in the breast cancer cell lines MCF-7 and SK-BR-3. RNAi-mediated silencing of NCOA3, qRT-PCR, Western blot analysis and ERα activation assays were used to examine the role of NCOA3 in the ERα-mediated regulation of PLAC1 in further detail. Transcript expression of NCOA3 and PLAC1 in 48 human breast cancer samples was examined by qRT-PCR and statistical analysis was performed using Student's t-test. RESULTS: We detected selective recruitment of NCOA3 but not NCOA1 or NCOA2 to the PLAC1 promoter only in ERα-positive MCF-7 cells but not in ERα-negative SK-BR-3 breast cancer cells. In addition, we demonstrate that silencing of NCOA3 results in a remarkable decrease of PLAC1 expression levels in MCF-7 cells which cannot be restored by treatment with estradiol (E2). Moreover, significant higher transcript levels of PLAC1 were found only in ERα-positive human breast cancer samples which also show a NCOA3 overexpression. CONCLUSIONS: In this study, we identified NCOA3 as a selective co-activator of ERα-mediated transactivation of PLAC1 in MCF-7 breast cancer cells. Our data introduce PLAC1 as novel target gene of NCOA3 in breast cancer, supporting the important role of both factors in breast cancer biology.

Confidence-based somatic mutation evaluation and prioritization.

Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set.

Converging theories on dreaming: Between Freud, predictive processing, and psychedelic research.

Dreams are still an enigma of human cognition, studied extensively in psychoanalysis and neuroscience. According to the Freudian dream theory and Solms' modifications of the unconscious derived from it, the fundamental task of meeting our emotional needs is guided by the principle of homeostasis. Our innate value system generates conscious feelings of pleasure and unpleasure, resulting in the behavior of approaching or withdrawing from the world of objects. Based on these experiences, a hierarchical generative model of predictions (priors) about the world is constantly created and modified, with the aim to optimize the meeting of our needs by reducing prediction error, as described in the predictive processing model of cognition. Growing evidence from neuroimaging supports this theory. The same hierarchical functioning of the brain is in place during sleep and dreaming, with some important modifications like a lack of sensual and motor perception and action. Another characteristic of dreaming is the predominance of primary process thinking, an associative, non-rational cognitive style, which can be found in similar altered states of consciousness like the effect of psychedelics. Mental events that do not successfully fulfill an emotional need will cause a prediction error, leading to conscious attention and adaptation of the priors that incorrectly predicted the event. However, this is not the case for repressed priors (RPs), which are defined by the inability to become reconsolidated or removed, despite ongoing error signal production. We hypothesize that Solms' RPs correspond with the conflictual complexes, as described by Moser in his dream formation theory. Thus, in dreams and dream-like states, these unconscious RPs might become accessible in symbolic and non-declarative forms that the subject is able to feel and make sense of. Finally, we present the similarities between dreaming and the psychedelic state. Insights from psychedelic research could be used to inform dream research and related therapeutic interventions, and vice versa. We propose further empirical research questions and methods and finally present our ongoing trial "Biological Functions of Dreaming" to test the hypothesis that dreaming predicts intact sleep architecture and memory consolidation, via a lesion model with stroke patients who lost the ability to dream.

Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia.

BACKGROUND: Early dysfunction of the brain reward system in schizophrenia might be already recognized in the prodromal phase of this illness. We used functional magnetic resonance imaging to assess the blood oxygen level-dependent response in the ventral striatum (VS) of subjects with ultra-high risk for psychosis during the presentation of reward-indicating and loss-indicating stimuli. METHODS: Thirteen prodromal patients (mean age: 25.5 ± 4.6 years) and 13 age-matched healthy volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus will gain money, avoid losing money or have no consequence. RESULTS: Compared with the neutral condition, anticipation of reward loss-avoidance elicited significant activation of the VS in both healthy subjects and subjects with ultra-high risk for psychosis, but there was only a statistical tendency for less activation during loss-avoidance anticipation in prodromal compared to healthy subjects. DISCUSSION: This study provides a first weak hint, as revealed by functional magnetic resonance imaging, for impaired activation of a central area of the mesolimbic dopaminergic brain reward system, the VS, already in subjects with ultra-high risk for psychosis, which is in line with results of patients with full-blown schizophrenic psychosis. This pilot study has, however, strong limitations, and its results need to be replicated first before they can be used e.g. for early recognition of patients in the schizophrenic prodrome.

Processing Individually Distinctive Schematic-Faces Supports Proto-Arithmetical Counting in the Young Domestic Chicken.

A key signature of small-number processing is the difficulty in discriminating between three and four objects, as reported in infants and animals. Five-day-old chicks overcome this limit if individually distinctive features characterize each object. In this study, we have investigated whether processing individually different face-like objects can also support discrimination between three and four objects. Chicks were reared with seven face-like stimuli and tested in the proto-arithmetic comparison 1 + 1 + 1 vs. 1 + 1 + 1 + 1. Birds reared and tested with all different faces discriminated and approached the larger group (Exp. 1), whereas new birds reared and tested with seven identical copies of one same face failed (Exp. 2). The presence at test of individually different faces allowed discrimination even when chicks were reared with copies of one face (Exp. 3). To clarify the role of the previous experience of at least one specific arrangement of facial features, in Experiment 4, featureless faces were employed during rearing. During testing, chicks were unable to discriminate between three and four individually distinct faces. Results highlight the importance of having experienced at least one "face" in prompting individual processing and proto-arithmetical calculation later during testing. We speculate that mechanisms effective at the non-symbolic level may positively affect numerical performance.

Chorea in systemic lupus erythematosus.

BACKGROUND: Chorea is recognized as one of the neurologic manifestations of systemic lupus erythematosus (SLE). Most reports show an association between chorea and antiphospholipid (aPL) antibodies in SLE patients. OBJECTIVES: The objective of this study was to describe the association of aPL antibodies with lupus chorea and its possible role in the pathogenesis of chorea. METHODS: We made a retrospective review of all cases of lupus chorea between 1989 and 2007 in a tertiary care center in Mexico City. RESULTS: We found 7 episodes of chorea in 5 patients with SLE. In 2 patients (3 episodes), chorea was associated with cerebral ischemia; one of these cases had positive anticardiolipin (aCL) immunoglobulin G (IgG) antibodies, whereas the other was diagnosed as having vascular lipohyalinosis as the probable cause of cerebral ischemia. In 3 patients (4 episodes), an immune-mediated mechanism was suspected; these cases had negative aPL at the onset of chorea, but IgM aCL antibodies became positive later. CONCLUSIONS: In most episodes, chorea seems to be immunologically mediated and was associated with a later appearance of IgM aCL antibodies. Chorea in patients with lupus may also be caused by cerebral ischemia, and in some cases, it may be associated with IgG aCL antibodies.

Using routine MRI data of depressed patients to predict individual responses to electroconvulsive therapy.

Electroconvulsive therapy (ECT) is one of the most effective treatments in cases of severe and treatment resistant major depression. 60-80% of patients respond to ECT, but the procedure is demanding and robust prediction of ECT responses would be of great clinical value. Predictions based on neuroimaging data have recently come into focus, but still face methodological and practical limitations that are hampering the translation into clinical practice. In this retrospective study, we investigated the feasibility of ECT response prediction using structural magnetic resonance imaging (sMRI) data that was collected during ECT routine examinations. We applied machine learning techniques to predict individual treatment outcomes in a cohort of N = 71 ECT patients, N = 39 of which responded to the treatment. SMRI-based classification of ECT responders and non-responders reached an accuracy of 69% (sensitivity: 67%; specificity: 72%). Classification on additionally investigated clinical variables had no predictive power. Since dichotomisation of patients into ECT responders and non-responders is debatable due to many patients only showing a partial response, we additionally performed a post-hoc regression-based prediction analysis on continuous symptom improvements. This analysis yielded a significant relationship between true and predicted treatment outcomes and might be a promising alternative to dichotomization of patients. Based on our results, we argue that the prediction of individual ECT responses based on routine sMRI holds promise to overcome important limitations that are currently hampering the translation of such treatment biomarkers into everyday clinical practice. Finally, we discuss how the results of such predictive data analysis could best support the clinician's decision on whether a patient should be treated with ECT.

Selective activation of trophoblast-specific PLAC1 in breast cancer by CCAAT/enhancer-binding protein beta (C/EBPbeta) isoform 2.

The trophoblast-specific gene PLAC1 (placenta-specific 1) is ectopically expressed in a wide range of human malignancies, most frequently in breast cancer, and is essentially involved in cancer cell proliferation, migration, and invasion. Here we show that basal activity of the PLAC1 promoter is selectively controlled by ubiquitous transcription factor SP1 and isoform 2 of CCAAT/enhancer-binding protein beta that we found to be selectively expressed in placental tissue and cancer cells. Binding of both factors to their respective elements within the PLAC1 promoter was essential to attain full promoter activity. Estrogen receptor alpha (ERalpha) signaling further augmented transcription and translation of PLAC1 and most likely accounts for the positive correlation between PLAC1 expression levels and the ERalpha status we observed in primary breast cancer specimens. DNA affinity precipitation and chromatin immunoprecipitation assays revealed that transactivation of the PLAC1 promoter by ligand-activated ERalpha is based on a nonclassical pathway independent of estrogen-response elements, by tethering of ERalpha to DNA-bound CCAAT/enhancer-binding protein beta-2, and SP1. Our findings provide first insight into a novel and hitherto unknown regulatory mechanism governing selective activation of trophoblast-specific gene expression in breast cancer.

In vivo evidence of htid suppressive activity on ErbB-2 in breast cancers over expressing the receptor.

BACKGROUND: Htid encoded proteins are physiological partners of a wide spectrum of molecules relevant to neoplastic transformation. One of the molecular ligands of the cytosolic hTid-L and hTid-I forms is the ErbB-2 receptor variably over expressed in diverse solid tumors. Altered ErbB-2 signalling is associated with an unfavourable prognosis in about 30% of human breast malignancies. METHODS: We evaluated htid and HER-2 expression by quantitative real time PCR in tumors of different TNMG status and by immunohistochemistry in a cohort of breast tumors of the Luminal A, B, HER-2 and triple negative subtype. RESULTS: The RT-PCR analysis revealed that aberrant expression of all three htid forms correlates with malignant transformation. Furthermore, elevated hTid-L expression can be associated with less aggressive tumors. The immunohistochemical testing revealed that tumors of the luminal A subtype are characterized by a high level of htid (81%). In contrast htid expression is significantly lower in tumors of the Luminal B (20%) and HER-2 (18%) subtype over expressing the receptor and in the triple negative (40%) more aggressive malignancies. A statistically significant inverse correlation between htid and ErbB-2 expression was found in human breast (p < 0,0001) and non-mammary tumors (p < 0,007), and in transgenic mice carrying the rat HER-2/neu oncogene. CONCLUSIONS: Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.

Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance.

The efficacy of psychedelic-assisted therapies for mental disorders has been attributed to the lasting change from experiential avoidance to acceptance that these treatments appear to facilitate. This article presents a conceptual model that specifies potential psychological mechanisms underlying such change, and that shows substantial parallels between psychedelic therapy and cognitive behavioral therapy: We propose that in the carefully controlled context of psychedelic therapy as applied in contemporary clinical research, psychedelic-induced belief relaxation can increase motivation for acceptance via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective information and become revised accordingly, which may explain long-term increases in acceptance and corresponding reductions in psychopathology. Open research questions and implications for clinical practice are discussed.

PLAC1 is essential for FGF7/FGFRIIIb-induced Akt-mediated cancer cell proliferation.

PLAC1 (placenta enriched 1) is a mammalian trophoblast-specific protein. Aberrant expression of PLAC1 is observed in various human cancers, where it is involved in the motility, migration, and invasion of tumor cells, which are associated with the phosphoinositide 3-kinase (PI3K)/AKT pathway. We previously demonstrated that AKT activation mediates the downstream effects of PLAC1; however, the molecular mechanisms of PLAC1-induced AKT-mediated tumor-related processes are unclear. We studied human choriocarcinoma and breast cancer cell lines to explore the localization and receptor-ligand interactions, as well as the downstream effects of PLAC1. We show secretion and adherence of PLAC1 to the extracellular matrix, where it forms a trimeric complex with fibroblast growth factor 7 (FGF7) and its receptor, FGF receptor 2 IIIb (FGFR2IIIb). We further show that PLAC1 signaling via FGFR2IIIb activates AKT phosphorylation in cancer cell lines. As the FGF pathway is of major interest in anticancer therapeutic strategies, these data further promote PLAC1 as a promising anticancer drug target.

Selective activation of tumor growth-promoting Ca2+ channel MS4A12 in colon cancer by caudal type homeobox transcription factor CDX2.

Colon cancer-associated MS4A12 is a novel colon-specific component of store-operated Ca2+ (SOC) entry sensitizing cells for epidermal growth factor (EGF)-mediated effects on proliferation and chemotaxis. In the present study, we investigated regulation of the MS4A12 promoter to understand the mechanisms responsible for strict transcriptional restriction of this gene to the colonic epithelial cell lineage. DNA-binding assays and luciferase reporter assays showed that MS4A12 promoter activity is governed by a single CDX homeobox transcription factor binding element. RNA interference (RNAi)-mediated silencing of intestine-specific transcription factors CDX1 and CDX2 and chromatin immunoprecipitation (ChIP) in LoVo and SW48 colon cancer cells revealed that MS4A12 transcript and protein expression is essentially dependent on the presence of endogenous CDX2. In summary, our findings provide a rationale for colon-specific expression of MS4A12. Moreover, this is the first report establishing CDX2 as transactivator of tumor growth-promoting gene expression in colon cancer, adding to untangle the complex and conflicting biological functions of CDX2 in colon cancer and supporting MS4A12 as important factor for normal colonic development as well as for the biology and treatment of colon cancer.

Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development.

PURPOSE: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer. EXPERIMENTAL DESIGN: We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage-specific cell surface molecules and to validate them as therapeutic antibody targets. RESULTS: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP-responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells. CONCLUSIONS: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.

A placenta-specific gene ectopically activated in many human cancers is essentially involved in malignant cell processes.

The identification and functional characterization of tumor-specific genes is a prerequisite for the development of targeted cancer therapies. Using an integrated data mining and experimental validation approach for the discovery of new targets for antibody therapy of cancer, we identified PLAC1. PLAC1 is a placenta-specific gene with no detectable expression in any other normal human tissue. However, it is frequently aberrantly activated and highly expressed in a variety of tumor types, in particular breast cancer. RNAi-mediated silencing of PLAC1 in MCF-7 and BT-549 breast cancer cells profoundly impairs motility, migration, and invasion and induces a G1-S cell cycle block with nearly complete abrogation of proliferation. Knockdown of PLAC1 is associated with decreased expression of cyclin D1 and reduced phosphorylation of AKT kinase. Moreover, PLAC1 is localized on the surface of cancer cells and is accessible for antibodies which antagonize biological functions of this molecule. These features, in summary, make PLAC1 an attractive candidate for targeted immunotherapeutic approaches.

The emerging role of γδ T cells in cancer immunotherapy.

The recent successes of chimeric antigen receptor T cells in the treatment of hematological malignancies have clearly led to an explosion in the field of adoptive cell therapy for cancer. Current efforts are focused on the translation of this exciting technology to the treatment of solid tumors and the development of allogeneic 'off-the-shelf' therapies. γδ T cells are currently gaining considerable attention in this field as their unique biology and established role in cancer immunosurveillance place them in a unique position to potentially overcome these challenges in adoptive cell therapy. Here, we review the relevant aspects of the function of γδ T cells in cancer immunity, and summarize clinical observations and clinical trial results that highlight their emerging role as a platform for the development of safe and effective cancer immunotherapies.

In silico strategy for detection of target candidates for antibody therapy of solid tumors.

In contrast to earlier attempts for the identification of target candidates suitable for monoclonal antibody (mAb) based cancer therapies we concentrated on highly selective lineage-specific genes additionally preserved or even overexpressed in orthotopic cancers. In a script aided workflow we reduced all human entries of the RefSeq mRNA database to those encoding transmembrane domain bearing gene products and subjected them to BLAST analysis against the human EST database. All BLAST results were validated in a gene centric way allowing two types of data curation prior to expression profiling of matching ESTs in selected healthy tissues: (i) exclusion of questionable ESTs arising e.g. from genomic contamination and (ii) elimination of erroneously predicted mRNAs as well as transcripts with only weak EST coverage. The impact of such stringent input control on accuracy of prediction is underlined by RT-PCR confirmation of predicted tissue distribution patterns for a number of selected candidates.

Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine.

RATIONALE: High blockade of dopamine D2 receptors in the ventral striatum including the nucleus accumbens may interfere with reward anticipation and cause secondary negative symptoms such as apathy or anhedonia. This may not be the case with newer neuroleptics such as olanzapine, which show less dopamine D2 receptor blockade and a faster off-rate from the receptor. OBJECTIVES: We used functional magnetic resonance imaging to assess the blood oxygenation level dependent response in the ventral striatum of schizophrenics medicated with typical neuroleptics (T1) and after switching them to olanzapine (T2) and of healthy control subjects at corresponding time points during reward anticipation. MATERIALS AND METHODS: Ten schizophrenics, while medicated with typical neuroleptics (T1) and after having been switched to olanzapine (T2), and ten matched healthy volunteers participated in a monetary incentive delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus would either result in monetary gain or have no consequence. RESULTS: During reward anticipation, healthy volunteers showed significantly higher ventral striatal activation compared to schizophrenic patients treated with typical neuroleptics but not olanzapine, which was reflected in a significant interaction between group and session. In patients treated with typical neuroleptics, but not with olanzapine, decreased left ventral striatal activation was correlated with negative symptoms. CONCLUSIONS: Failure to activate the ventral striatum during reward anticipation was pharmacologically state-dependent and observed only in patients treated with typical neuroleptics but not with olanzapine, which may indicate that this drug did not induce secondary negative symptoms via interference with reward anticipation.

Regional patterns and clinical correlates of basal ganglia morphology in non-medicated schizophrenia.

Although structural changes of the basal ganglia are widely implicated in schizophrenia, prior findings in chronically medicated patients show that these changes relate to particular antipsychotic treatments. In unmedicated schizophrenia, local alterations in morphological parameters and their relationships with clinical measures remain unknown. Novel surface-based anatomical modelling methods were applied to magnetic resonance imaging data to examine regional changes in the shape and volume of the caudate, the putamen and the nucleus accumbens in 21 patients (19 males/2 females; mean age=30.7+/-7.3) who were either antipsychotic-naïve or antipsychotic-free for at least 1 year and 21 healthy comparison subjects (19 males/2 females; mean age=31.1+/-8.2). Clinical relationships of striatal morphology were based on exploratory analyses. Left and right global putamen volumes were significantly smaller in patients than controls; no significant global volume effects were observed for the caudate and the nucleus accumbens. However, surface deformation mapping results showed localized volume changes prominent bilaterally in medial/lateral anterior regions of the caudate, as well as in anterior and midposterior regions of the putamen, pronounced on the medial surface. A significant positive correlation was observed between right anterior putamen surface contractions and affective flattening, a core negative symptom of schizophrenia. The diagnostic effects of local surface deformations mostly pronounced in the associative striatum, as well as the correlation between anterior putamen morphology and affective flattening in unmedicated schizophrenia suggest disease-specific neuroanatomical abnormalities and distinct cortical-striatal dysconnectivity patterns relevant to altered executive control, motor planning, along with abnormalities of emotional processing.

Switching schizophrenia patients from typical neuroleptics to olanzapine: effects on BOLD response during attention and working memory.

Dysfunctional activation of the dorsolateral prefrontal cortex (DLPFC) during working memory (WM) in schizophrenia patients has repeatedly been observed, however little is known about specific medication effects on the modulation of DLPFC activation. We measured activation of DLPFC during a WM task in a longitudinal fMRI study in ten schizophrenia patients first when they received conventional antipsychotics (T1) and a second time after they had been switched to olanzapine (T2). A healthy control group matched for age, handedness and gender was investigated at two corresponding time points. We analyzed the fMRI data with SPM5 in a 2 x 2 x 2 design (group x session x task). Schizophrenia patients showed fewer correct responses compared to healthy controls at both time points. The fMRI data revealed a significant group by task interaction in the bilateral DLPFC and the right parietal cortex, indicating a reduced BOLD response in the patient group. After switching to olanzapine, schizophrenia patients displayed a significant increase in the BOLD response during the 0-back condition in the DLPFC. This study showed that switching patients from conventional neuroleptics to olanzapine did not significantly alter the frontal or parietal BOLD response during working memory task. However, medication status had influences on the activation during attentional task (0-back), emphasizing the importance of baseline selection in pharmacological fMRI studies.

Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor.

Recently, we identified htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs [l(2)tid], as a direct molecular ligand of the adenomatous polyposis coli (APC) tumor suppressor. The gene encodes three cytosolic (Tid50, Tid48 and Tid46) and three mitochondrial (Tid43, Tid40 and Tid38) proteins. In the colorectal epithelium the cytosolic forms hTid50/hTid48 interact under physiological conditions with the N-terminal region of APC. This complex which associates with additional proteins such as Hsp70, Hsc70, Actin, Dvl and Axin defines a novel physiological state of APC unrelated to beta-catenin degradation. Here we show that the expression of the genes htid-1 and APC was altered in colorectal tumors. These changes concerned both the localization and the expression level of all three htid-1 splice variants and of APC. Furthermore, we showed that the protein products of the two tumor suppressors co-localized in the basal and apical region of normal colon epithelia and that loss of differentiation capacity of colorectal cancers correlated with a shift in their expression patterns from compartmentalized to diffuse cytoplasmic. These findings support our hypothesis that the building of the multi-component complex mentioned above is associated with the maintenance of the polarity of cells and tissues. In addition, we provide evidence that colon cancer progression correlates with up-regulation of htid-1 and its ligand Hsp70. Since the Tid proteins are members of the DnaJ-like protein family, an essential component of the Hsp70/Hsc70 chaperone machinery, our findings describe a novel, causal link between the function of chaperone machines, APC-mediated Wg/Wnt signaling and tumor development.