Search

Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

Theoretical models assert that the brain's interoceptive network links external stimuli with their interoceptive consequences, thereby supporting later recall of these associations to guide the selection of healthy behaviors. If these accounts are correct, previously reported interoceptive abnormalities in major depressive disorder (MDD) should lead to altered recall of associations between external stimuli and their interoceptive (somatic) consequences. To date, the processes underlying interoceptive recall have never been experimentally investigated.We designed and implemented the Interoceptive Encoding and Recall task to compare interoceptive and exteroceptive recall among subjects with MDD (n = 24) and healthy comparison subjects (n = 21). During the encoding phase, subjects learned to pair neutral visual cues (geometric shapes) with aversive interoceptive and exteroceptive stimuli. Later, while undergoing functional magnetic resonance imaging, subjects were prompted to recall the stimulus associated with each shape.Interoceptive recall, relative to exteroceptive recall, was associated with bilateral mid-to-posterior insula activation. Relative to the healthy control participants, participants with depression exhibited marked hypoactivation of the right dorsal mid-insula during interoceptive recall.In healthy control subjects, simply recalling a stimulus associated with a previous interoceptive challenge activated a key region in the brain's interoceptive network. Although previous research has linked MDD with aberrant processing of interoceptive stimuli, the current study is the first to demonstrate that individuals with MDD exhibit decreased insula activity while recalling interoceptive memories. It is possible that insula hypoactivation during interoceptive recall may affect the representation of prior interoceptive experiences in ways that contribute to depressive symptomology and the relationship between depression and systemic health.

Changes in food-cue neural reactivity associated with behavioral and surgical weight loss interventions have been reported. Resting functional connectivity represents tonic neural activity that may contribute to weight loss success. This study explores whether intervention type is associated with differences in functional connectivity after weight loss.Fifteen participants with obesity were recruited prior to adjustable gastric banding surgery. Thirteen demographically matched participants with obesity were selected from a separate behavioral diet intervention. Resting-state functional magnetic resonance imaging was collected 3 months after surgery/behavioral intervention. ANOVA was used to examine post-weight loss differences between the two groups in connectivity to seed regions previously identified as showing differential cue-reactivity after weight loss.Following weight loss, behavioral dieters exhibited increased connectivity between left precuneus/superior parietal lobule (SPL) and bilateral insula pre- to postmeal and bariatric patients exhibited decreased connectivity between these regions pre- to postmeal (P(corrected)0.05).Behavioral dieters showed increased connectivity pre- to postmeal between a region associated with processing of self-referent information (precuneus/SPL) and a region associated with interoception (insula) whereas bariatric patients showed decreased connectivity between these regions. This may reflect increased attention to hunger signals following surgical procedures and increased attention to satiety signals following behavioral diet interventions.

Objective Obese children demonstrate less activation in prefrontal regions associated with self-control and inhibition when presented with food cues and advertisements. The current study evaluates the differences between obese and healthy weight children in resting-state functional connectivity to these brain regions. Design and Methods Seed regions in bilateral middle frontal gyri were chosen based on previous task-based analysis showing differences between obese and healthy weight children’s responses to food-associated stimuli. Functional connectivity to these seed regions was measured in resting-state scans collected in obese and lean children undergoing fMRI. Results Obese children exhibited greater resting-state functional connectivity than healthy weight children between the left middle frontal gyrus and reward-related regions in the left ventromedial prefrontal cortex, as well as the left lateral OFC. Conclusion Previously published results demonstrate that obese children exhibit less activity in brain regions associated with self-control when viewing motivationally salient food advertisements. Here we show that obese children also have tonically greater input to these self-control regions from reward neurocircuitry. The greater functional connectivity between reward and self-control regions, in conjunction with weaker activation of self-control neurocircuitry, may render these children more susceptible to food advertisements, placing them at elevated risk for over-feeding and obesity.

This article briefly examines special treatment centers in the United States set up to provide services to child abusing families. Australian efforts to contend with child abuse are also mentioned. (CM)