Mutations in the transcription factor FOXO1 mimic positive selection signals to promote germinal center B cell expansion and lymphomagenesis.

The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting this regulatory axis in GC-derived B cell non-Hodgkin lymphomas (B-NHLs) contribute to lymphomagenesis. Examination of primary B-NHL tissues revealed that FOXO1 mutations and PI3K pathway activity were not directly correlated. Human B cell lines bearing FOXO1 mutations exhibited hyperactivation of PI3K and Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) signaling, and increased cell survival under stress conditions as a result of alterations in FOXO1 transcriptional affinities and activation of transcriptional programs characteristic of GC-positive selection. When modeled in mice, FOXO1 mutations conferred competitive advantage to B cells in response to key T-dependent immune signals, disrupting GC homeostasis. FOXO1 mutant transcriptional signatures were prevalent in human B-NHL and predicted poor clinical outcomes. Thus, rather than enforcing FOXO1 constitutive activity, FOXO1 mutations enable co-option of GC-positive selection programs during the pathogenesis of GC-derived lymphomas.

Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma.

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.

Super-enhancer hypermutation alters oncogene expression in B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets1-5. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.

KMT2D acetylation by CREBBP reveals a cooperative functional interaction at enhancers in normal and malignant germinal center B cells.

Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)-specific haploinsufficiency of Crebbp and Kmt2d synergizes in vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, supporting a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.

The Emergence of Tuning to Global Shape Properties of Radial Frequency Patterns in the Ventral Visual Pathway.

Radial frequency (RF) patterns, created by sinusoidal modulations of a circle's radius, are processed globally when RF is low. These closed shapes therefore offer a useful way to interrogate the human visual system for global processing of curvature. RF patterns elicit greater responses than those to radial gratings in V4 and more anterior face-selective regions of the ventral visual pathway. This is largely consistent with work on nonhuman primates showing curvature processing emerges in V4, but is evident also higher up the ventral visual stream. Rather than contrasting RF patterns with other stimuli, we presented them at varied frequencies in a regimen that allowed tunings to RF to be derived from 8 human participants (3 female). We found tuning to low RF in lateral occipital areas and to some extent in V4. In a control experiment, we added a high-frequency ripple to the stimuli disrupting the local contour. Low-frequency tuning to these stimuli remained in the ventral visual stream, underscoring its role in global processing of shape curvature. We then used representational similarity analysis to show that, in lateral occipital areas, the neural representation was related to stimulus similarity, when it was computed with a model that captured how stimuli are perceived. We therefore show that global processing of shape curvature emerges in the ventral visual stream as early as V4, but is found more strongly in lateral occipital regions, which exhibit responses and representations that relate well to perception.SIGNIFICANCE STATEMENT We show that tuning to low radial frequencies, known to engage global shape processing mechanisms, was localized to lateral occipital regions. When low-level stimulus properties were accounted for such tuning emerged in V4 and LO2 in addition to the object-selective region LO. We also documented representations of global shape properties in lateral occipital regions, and these representations were predicted well by a proxy of the perceptual difference between the stimuli.

The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program.

The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression.

Prediction of knee pain improvement over two years for knee osteoarthritis using a dynamic nomogram based on MRI-derived radiomics: a proof-of-concept study.

OBJECTIVES: To develop and validate a nomogram to detect improved knee pain in osteoarthritis (OA) by integrating magnetic resonance imaging (MRI) radiomics signature of subchondral bone and clinical characteristics. METHODS: Participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. The primary outcome was 20% improvement of knee pain score over 2 years in participants administrated either vitamin D or placebo. Radiomics features of subchondral bone and clinical characteristics from 216 participants were extracted and analyzed. The participants were randomly split into the training and validation cohorts at a ratio of 8:2. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate radiomics signatures. The optimal radiomics signature and clinical indicators were fitted into a nomogram using multivariable logistic regression model. RESULTS: The nomogram showed favorable discrimination performance [AUCtraining, 0.79 (95% CI: 0.72-0.79), AUCvalidation, 0.83 (95% CI: 0.70-0.96)] as well as a good calibration. Additional contributing value of fusion radiomics signature to the nomogram was statistically significant (NRI, 0.23; IDI, 0.14, P < 0.001 in training cohort and NRI, 0.29; IDI, 0.18, P < 0.05 in validating cohort). Decision curve analysis confirmed the clinical usefulness of nomogram. CONCLUSION: The radiomics-based nomogram comprising the MR radiomics signature and clinical variables achieves a favorable predictive efficacy and accuracy in differentiating improvement in knee pain among OA patients. This proof-of-concept study provides a promising way to predict clinically meaningful outcomes.

Pharmacist-Driven Therapeutic Infliximab Monitoring at the Point of Care Using Rapidly Assessed Drug Levels in Patients with Inflammatory Bowel Disease.

BACKGROUND: Therapeutic monitoring of infliximab is limited by the time lag between drug-level measurement and dose adjustment, along with the cost of dose escalation. Strategies for dose reduction in stable patients on maintenance infliximab at supratherapeutic levels are uncertain. This study determined the feasibility of a pharmacist-driven strategy for immediate dose adjustment using a sliding scale at the point of care in stable patients with inflammatory bowel disease on maintenance therapy. METHODS: Adult patients with stable disease undergoing maintenance therapy with infliximab infusions, 5 mg/kg every 8 weeks, were prospectively studied. Trough drug levels were assessed by a rapid assay (and later by ELISA) at all infusions for up to 12 months with immediate but quantitatively small dose adjustment according to a sliding scale targeting a therapeutic range of 3-7 mcg/mL. Disease activity was assessed both clinically and biochemically. RESULTS: The rapid assay and ELISA detected similar infliximab levels, and the strategy added approximately 30 minutes to the duration of infusion events. Only 20% of 48 patients (77% with Crohn disease) had baseline trough infliximab concentrations within the therapeutic range. This value increased 3-fold after 24 and 48 weeks of interventions. One in 2 patients had baseline supratherapeutic levels, and most were brought into the therapeutic range without a discernible impact on disease activity by 1 dose adjustment, but 2 or 3 adjustments were generally needed for 29% of patients with subtherapeutic levels. Overall, drug costs were reduced by 4%. CONCLUSIONS: Immediate dose adjustment after infliximab rapid assay performed by a pharmacist using a sliding scale is a feasible strategy. Supratherapeutic infliximab levels can be safely and quickly brought into the therapeutic range using small dose adjustments without affecting disease activity, offsetting (at least partly) costs associated with dose escalation.

Burden of osteoarthritis in India and its states, 1990-2019: findings from the Global Burden of disease study 2019.

OBJECTIVE: To describe the burden of osteoarthritis (OA) in India from 1990 to 2019. DESIGN: Data from Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 were used. The burden of OA -knee OA, hip OA, hand OA, and other OA- was estimated for India and its states from 1990 to 2019 through a systematic analysis of prevalence, incidence, years lived with disability (YLD), and disability-adjusted life years (DALY) using methods reported in GBD 2019 study. RESULT: Around 23.46 million individuals in India had OA in 1990; this increased to 62.35 million in 2019. The age-standardised prevalence of OA increased from 4,895 (95% uncertainty interval (UI):4,420-5,447) in 1990-5313 (95%UI:4,799-5,898) in 2019, per 100,000 persons. Similarly, DALYs due to OA increased from 0.79 million (95%UI:0.40-1.55) to 2.12 million (95%UI:1.07-4.23); while age-standardised DALYs increased from 164 (95%UI:83-325) to 180 (95%UI:91-361) per 100,000 persons from 1990 to 2019. OA was the 20th most common cause of YLDs in India in 2019, accounting for 1.48% (95%UI:0.88-2.78) of all YLDs; increasing from 23rd most common cause in 1990 (1.25%(95%UI:0.74-2.34)). Knee OA was the most common form of OA, followed by hand OA. The prevalence, incidence, and DALYs for OA and knee OA were consistently higher in females than males. CONCLUSION: The burden and impact of OA in India are substantial and is increasing. Adopting suitable control and preventive community measures to reduce modifiable risk factors (obesity, injuries, occupational stress) are needed to reduce the current and future burden of OA in India.

Association between osteoarthritis-related serum biochemical markers over 11 years and knee MRI-based imaging biomarkers in middle-aged adults.

OBJECTIVE: To describe the associations between osteoarthritis (OA)-related biochemical markers (COMP, MMP-3, HA) and MRI-based imaging biomarkers in middle-aged adults over 10-13 years. METHODS: Blood serum samples collected during the Childhood Determinants of Adult Health (CDAH)-1 study (year:2004-06; n = 156) and 10-13 year follow-up at CDAH-3 (n = 167) were analysed for COMP, MMP-3, and HA using non-isotopic ELISA. Knee MRI scans obtained during the CDAH-knee study (year:2008-10; n = 313) were assessed for cartilage volume and thickness, subchondral bone area, cartilage defects, and BML. RESULTS: In a multivariable linear regression model describing the association of baseline biochemical markers with MRI-markers (assessed after 4-years), we found a significant negative association of standardised COMP with medial femorotibial compartment cartilage thickness (ß:-0.070; 95%CI:-0.138,-0.001), and standardised MMP-3 with patellar cartilage volume (ß:-141.548; 95%CI:-254.917,-28.179) and total bone area (ß:-0.729; 95%CI:-1.340,-0.118). In multivariable Tobit regression model, there was a significant association of MRI-markers with biochemical markers (assessed after 6-9 years); a significant negative association of patellar cartilage volume (ß:-0.001; 95%CI:-0.002,-0.00004), and total bone area (ß:-0.158; 95%CI-0.307,-0.010) with MMP-3, and total cartilage volume (ß:-0.001; 95%CI:-0.001,-0.0001) and total bone area (ß:-0.373; 95%CI:-0.636,-0.111) with COMP. No significant associations were observed between MRI-based imaging biomarkers and HA. CONCLUSION: COMP and MMP-3 levels were negatively associated with knee cartilage thickness and volume assessed 4-years later, respectively. Knee cartilage volume and bone area were negatively associated with COMP and MMP-3 levels assessed 6-9 years later. These results suggest that OA-related biochemical markers and MRI-markers are interrelated in early OA.

Asymmetries between achromatic and chromatic extraction of 3D motion signals.

Motion in depth (MID) can be cued by high-resolution changes in binocular disparity over time (CD), and low-resolution interocular velocity differences (IOVD). Computational differences between these two mechanisms suggest that they may be implemented in visual pathways with different spatial and temporal resolutions. Here, we used fMRI to examine how achromatic and S-cone signals contribute to human MID perception. Both CD and IOVD stimuli evoked responses in a widespread network that included early visual areas, parts of the dorsal and ventral streams, and motion-selective area hMT+. Crucially, however, we measured an interaction between MID type and chromaticity. fMRI CD responses were largely driven by achromatic stimuli, but IOVD responses were better driven by isoluminant S-cone inputs. In our psychophysical experiments, when S-cone and achromatic stimuli were matched for perceived contrast, participants were equally sensitive to the MID in achromatic and S-cone IOVD stimuli. In comparison, they were relatively insensitive to S-cone CD. These findings provide evidence that MID mechanisms asymmetrically draw on information in precortical pathways. An early opponent motion signal optimally conveyed by the S-cone pathway may provide a substantial contribution to the IOVD mechanism.

Neural markers of suppression in impaired binocular vision.

Even after conventional patching treatment, individuals with a history of amblyopia typically lack good stereo vision. This is often attributed to atypical suppression between the eyes, yet the specific mechanism is still unclear. Guided by computational models of binocular vision, we tested explicit predictions about how neural responses to contrast might differ in individuals with impaired binocular vision. Participants with a history of amblyopia (N = 25), and control participants with typical visual development (N = 19) took part in the study. Neural responses to different combinations of contrast in the left and right eyes, were measured using both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Stimuli were sinusoidal gratings with a spatial frequency of 3c/deg, flickering at 4 Hz. In the fMRI experiment, we also ran population receptive field and retinotopic mapping sequences, and a phase-encoded localiser stimulus, to identify voxels in primary visual cortex (V1) sensitive to the main stimulus. Neural responses in both modalities increased monotonically with stimulus contrast. When measured with EEG, responses were attenuated in the weaker eye, consistent with a fixed tonic suppression of that eye. When measured with fMRI, a low contrast stimulus in the weaker eye substantially reduced the response to a high contrast stimulus in the stronger eye. This effect was stronger than when the stimulus-eye pairings were reversed, consistent with unbalanced dynamic suppression between the eyes. Measuring neural responses using different methods leads to different conclusions about visual differences in individuals with impaired binocular vision. Both of the atypical suppression effects may relate to binocular perceptual deficits, e.g. in stereopsis, and we anticipate that these measures could be informative for monitoring the progress of treatments aimed at recovering binocular vision.

The cross-sectional and longitudinal associations of dietary patterns with knee symptoms and MRI detected structure in patients with knee osteoarthritis.

OBJECTIVES: To examine the cross-sectional and longitudinal associations of dietary patterns with knee symptoms and structures in patients with knee osteoarthritis (OA). METHODS: Participants with symptomatic knee OA were recruited from a randomised, placebo-controlled trial conducted in Tasmania (N = 259) and Victoria (N = 133). Diet was assessed by the Anti-Cancer Council of Victoria food frequency questionnaire. Factor analysis was used to identify dietary patterns. Knee symptoms were assessed using Western Ontario and McMaster Universities Arthritis Index (WOMAC) and structures using MRI. Multivariable linear regressions were used to examine associations. RESULTS: Three dietary patterns ("high-fat", "healthy" and "mixed") were identified in whole sample. Participants with higher "healthy pattern" score had lower total WOMAC, pain, function and stiffness scores at baseline but the associations were not significant over 24 months. Three ("western", "vegetable and meat" and "mediterranean") and two ("processed" and "vegetable") patterns were identified in Tasmania and Victoria, respectively. Cross-sectionally, only "mediterranean pattern" and "vegetable pattern" scores were significantly and negatively associated with total WOMAC or function scores. Longitudinally, participants with higher "western pattern" had worsening function (ß: 0.35, 95%CI: 0.03, 0.67) and total WOMAC (ß: 0.40, 95%CI: 0.07, 0.72) scores; furthermore, "vegetable pattern" was associated with decreased WOMAC stiffness score (ß: -0.47, 95%CI: -0.93, -0.02). In contrast, dietary patterns were largely not associated with structural changes. CONCLUSION: Some healthy dietary patterns were associated with reduced joint symptoms but dietary patterns were not associated with joint structure in this sample with knee OA. Further studies are required to confirm these findings.

The interactions between MRI-detected osteophytes and bone marrow lesions or effusion-synovitis on knee symptom progression: an exploratory study.

OBJECTIVES: To investigate the longitudinal association between MRI-detected osteophyte scores and progression of knee symptoms, and whether the association was modified in the presence of bone marrow lesions (BMLs) or effusion-synovitis. METHODS: Data from Vitamin D Effects on Osteoarthritis (VIDEO) study, a randomized, double-blinded and placebo-controlled clinical trial in symptomatic knee osteoarthritis (OA) patients, were analyzed as an exploratory study. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess knee symptoms. Osteophytes, BMLs and effusion-synovitis were measured using MRI. RESULTS: 334 participants with MRI information and WOMAC score (baseline and follow-up) were included in the analyses, with 24.3% of them having knee pain increased 2 years later. Statistically significant interactions were found between MRI-detected osteophytes and BMLs or effusion-synovitis on increased knee symptoms. In participants with BMLs, higher baseline scores of MRI-detected osteophytes in most compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and effusion-synovitis. In participants with effusion-synovitis, higher baseline scores of MRI-detected osteophytes in almost all the compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and BMLs. In contrast, MRI-detected osteophyte scores were generally not associated with knee symptom progression in participants without baseline BMLs or effusion-synovitis. CONCLUSIONS: MRI-detected OPs are associated with increased total knee pain, weight-bearing knee pain, stiffness and physical dysfunction in participants presenting BMLs or effusion-synovitis, but not in participants lacking BMLs or effusion-synovitis. This suggests they could interact with bone or synovial abnormalities to induce symptoms in knee OA.

Effects of fiber intake on intestinal pH, transit, and predicted oral mesalamine delivery in patients with ulcerative colitis.

BACKGROUND AND AIM: Limited data are available on the effects of fermentable fiber in altering intestinal pH and transit to predict efficacy-based delivery profiles of pH-dependent mesalamine coatings in ulcerative colitis (UC). This study aimed to examine regional pH and transit after acute changes in fermentable fiber intake in quiescent UC patients and their effects on drug release systems. METHODS: In a randomized, double-blind study, 18 patients with quiescent UC and 10 healthy controls were supplied meals high (13 g) or low (≤ 2 g) in fermentable fiber and subsequently ingested a wireless pH-motility capsule. After a ≥ 3-day washout, they crossed over to the other diet. Measurements of intestinal pH and transit were used to predict drug release for the various pH-dependent coatings. RESULTS: Increasing fermentable fiber intake lowered overall (median 6.2 [6.1-6.7] vs low: 6.9 [range or interquartile range: 6.4-7.4]; P = 0.01) and distal pH (7.8 [7.3-8.1] vs 8.2 [8.0-8.5]; P = 0.04) in controls. In UC patients, only cecal pH was decreased (high: 5.1 [4.8-5.5] vs low: 5.5 [5.3-5.7]; P < 0.01). Colonic transit in the UC cohort varied widely after a low-fiber intake but tended to normalize after the high fermentable fiber intake. Hypothetical coating dissolution profiles were heterogeneous in UC patients, with a multi-matrix delayed release system having the highest likelihood of patients (20-40%) with incomplete dissolution, and predominant small intestinal dissolution predicted for Eudragit L (94% patients) and S (44-69%). CONCLUSIONS: Patients with quiescent UC have abnormalities in intestinal pH and transit in response to acute changes in fermentable fiber intake. These have potentially detrimental effects on predicted luminal release patterns of pH-dependent 5-aminosalicylic acid release systems.

Triple visual hemifield maps in a case of optic chiasm hypoplasia.

In humans, each hemisphere comprises an overlay of two visuotopic maps of the contralateral visual field, one from each eye. Is the capacity of the visual cortex limited to these two maps or are plastic mechanisms available to host more maps? We determined the cortical organization of the visual field maps in a rare individual with chiasma hypoplasia, where visual cortex plasticity is challenged to accommodate three hemifield maps. Using high-resolution fMRI at 7T and diffusion-weighted MRI at 3T, we found three hemiretinal inputs, instead of the normal two, to converge onto the left hemisphere. fMRI-based population receptive field mapping of the left V1-V3 at 3T revealed three superimposed hemifield representations in the left visual cortex, i.e. two representations of opposing visual hemifields from the left eye and one right hemifield representation from the right eye. We conclude that developmental plasticity including the re-wiring of local intra- and cortico-cortical connections is pivotal to support the coexistence and functioning of three hemifield maps within one hemisphere.

Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia.

Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.

Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application.

Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.

Population receptive field (pRF) measurements of chromatic responses in human visual cortex using fMRI.

The spatial sensitivity of the human visual system depends on stimulus color: achromatic gratings can be resolved at relatively high spatial frequencies while sensitivity to isoluminant color contrast tends to be more low-pass. Models of early spatial vision often assume that the receptive field size of pattern-sensitive neurons is correlated with their spatial frequency sensitivity - larger receptive fields are typically associated with lower optimal spatial frequency. A strong prediction of this model is that neurons coding isoluminant chromatic patterns should have, on average, a larger receptive field size than neurons sensitive to achromatic patterns. Here, we test this assumption using functional magnetic resonance imaging (fMRI). We show that while spatial frequency sensitivity depends on chromaticity in the manner predicted by behavioral measurements, population receptive field (pRF) size measurements show no such dependency. At any given eccentricity, the mean pRF size for neuronal populations driven by luminance, opponent red/green and S-cone isolating contrast, are identical. Changes in pRF size (for example, an increase with eccentricity and visual area hierarchy) are also identical across the three chromatic conditions. These results suggest that fMRI measurements of receptive field size and spatial resolution can be decoupled under some circumstances - potentially reflecting a fundamental dissociation between these parameters at the level of neuronal populations.