Neuroinflammation, particularly in the dorsolateral prefrontal cortex, is well-established in a subset of people with schizophrenia, with significant increases in inflammatory markers including several cytokines. Yet the cause(s) of cortical inflammation in schizophrenia remains unknown. Clues as to potential microenvironmental triggers and/or intracellular deficits in immunoregulation may be gleaned from looking further upstream of effector immune molecules to transcription factors that control inflammatory gene expression. Here, we focus on the ‘master immune regulator’ nuclear factor kappa B (NF-κB) and review evidence in support of NF-κB dysregulation causing or contributing to neuroinflammation in patients. We discuss the utility of ‘immune biotyping’ as a tool to analyse immune-related transcripts and proteins in patient tissue, and the insights into cortical NF-κB in schizophrenia revealed by immune biotyping compared to studies treating patients as a single, homogenous group. Though the ubiquitous nature of NF-κB presents several hurdles for drug development, targeting this key immunoregulator with novel or repurposed therapeutics in schizophrenia is a relatively underexplored area that could aid in reducing symptoms of patients with active neuroinflammation.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β₂-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β₂-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β₂-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β₂-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Cancer patients with non-central nervous system tumors often suffer from cognitive impairment. While chemotherapy has long been attributed as the cause of these memory, learning and concentration difficulties, we recently observed cognitive impairment in cancer patients prior to treatment. This suggests the cancer alone may be sufficient to induce cognitive impairment, however the mechanisms are unknown. Here, we show that we can experimentally replicate the clinical phenomenon of cancer-associated cognitive impairment and we identify inflammation as a causal mechanism. We demonstrate that a peripheral tumor is sufficient to induce memory loss. Using an othotopic mouse model of breast cancer, we found that mice with 4T1.2 or EO771 mammary tumors had significantly poorer memory than mice without tumors. Memory impairment was independent of cancer-induced sickness behavior, which was only observed during the later stage of cancer progression in mice with high metastatic burden. Tumor-secreted factors were sufficient to induce memory impairment and pro-inflammatory cytokines were elevated in the plasma of tumor-bearing mice. Oral treatment with low-dose aspirin completely blocked tumor-induced memory impairment without affecting tumor-induced sickness or tumor growth, demonstrating a causal role for inflammation in cognitive impairment. These findings suggest that anti-inflammatories may be a safe and readily translatable strategy that could be used to prevent cancer-associated cognitive impairment in patients.

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (bothp < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined ‘high inflammation’ individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying ‘high inflammation’ compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (allp < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (allp < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Diets of children and adolescents on the autism spectrum often differ when compared to their non‐autistic peers. Most dietary studies have been limited by small sample sizes and rarely assess the heterogeneity of autism. Addressing this gap, this study compared the anthropometrics, dietary composition, dietary quality, and food variety of 154 Australian children and adolescents on the spectrum and 213 non‐autistic children (71 siblings and 142 unrelated controls). Beyond the case‐control approach, within‐group comparisons assessed the influence of autism clinical presentations and sensory processing styles on body mass index (BMI) and measures of dietary intake among those on the spectrum. In this word first study of diet that included between‐group comparisons with non‐autistic peers (siblings and an unrelated comparison group) and within‐autism group comparisons, we found that children on the spectrum consumed limited variety and lower quality of food and non‐autistic siblings also ate comparably higher levels of energy‐dense, nutrient poor food, and less diary. This may be due to autistic traits influencing family's diets or shared sensory sensitivities driving dietary intake. Within the autism group, higher autistic traits were associated with lower BMIs and a specific dietary pattern higher in simple carbohydrates and lower in unprocessed protein. Contrastingly, greater sensitivity to sensory stimuli was associated with a healthier diet. Increased age was linked to more varied diets but also diets higher in saturated fats and energy‐dense, nutrient poor foods. Overall, this research highlights that potential mediators of dietary intake, such as familial influences, autistic traits, sensory processing styles, age and sex, need to be considered when assessing diet in the autistic population.Lay Summary: In this study of dietary differences linked to autism, children, and teenagers on the spectrum ate fewer different foods and were less likely to eat recommended amounts of fruits and vegetables when compared to non‐autistic siblings and unrelated children and teenagers. There were also family differences, in that those on the spectrum and their siblings ate more unhealthy foods and less dairy. Among those on the spectrum, dietary differences were linked to age, sex, autistic traits and sensory processing styles.

Disruption of circadian rhythms occurs in rotating shift-work, jetlag, and in individuals with irregular sleep schedules. Circadian disruption is known to alter inflammatory responses and impair immune function. However, there is limited understanding of how circadian disruption modulates cancer-induced inflammation. Inflammation is a hallmark of cancer and is linked to worse prognosis and impaired brain function in cancer patients. Here, we investigated the effect of circadian disruption on cancer-induced inflammation in an orthotopic breast cancer model. Using a validated chronic jetlag protocol that advances the light-cycle by 8 ​h every 2 days to disrupt circadian rhythms, we found that circadian disruption alters cancer-induced inflammation in a tissue-specific manner, increasing inflammation in the body and brain while decreasing inflammation within the tumor tissue. Circadian disruption did not affect inflammation in mice without tumors, suggesting that the impact of circadian disruption may be particularly detrimental in the context of underlying inflammatory conditions, such as cancer. Importantly, circadian disruption did not affect tumor burden, suggesting that increased inflammation was not a result of increased cancer progression. Overall, these findings identify the importance of healthy circadian rhythms for limiting cancer-induced inflammation.