Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.

Summary To characterize somatic alterations in colorectal carcinoma (CRC), we conducted genome-scale analysis of 276 samples, analyzing exome sequence, DNA copy number, promoter methylation, mRNA and microRNA expression. A subset (97) underwent low-depth-of-coverage whole-genome sequencing. 16% of CRC have hypermutation, three quarters of which have the expected high microsatellite instability (MSI), usually with hypermethylation and MLH1 silencing, but one quarter has somatic mismatch repair gene mutations. Excluding hypermutated cancers, colon and rectum cancers have remarkably similar patterns of genomic alteration. Twenty-four genes are significantly mutated. In addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9, and FAM123B/WTX. Recurrent copy number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive CRC and important role for MYC-directed transcriptional activation and repression.

Objective To understand how researchers experience working in academia and the effects these experiences have on their mental health and well-being, through synthesizing published qualitative data. Method A systematic review and qualitative meta-synthesis was conducted to gain a comprehensive overview of what is currently known about academic researchers’ mental health and well-being. Relevant papers were identified through searching electronic databases, Google Scholar, and citation tracking. The quality of the included studies was assessed and the data was synthesised using reflexive thematic analysis. Results 26 papers were identified and included in this review. Academic researchers’ experiences were captured under seven key themes. Job insecurity coupled with the high expectations set by the academic system left researchers at risk of poor mental health and well-being. Access to peer support networks, opportunities for career progression, and mentorship can help mitigate the stress associated with the academic job role, however, under-represented groups in academia are at risk of unequal access to resources, support, and opportunities. Conclusion To improve researchers’ well-being at work, scientific/academic practice and the system’s concept of what a successful researcher should look like, needs to change. Further high-quality qualitative research is needed to better understand how systemic change, including tackling inequality and introducing better support systems, can be brought about more immediately and effectively. Further research is also needed to better understand the experiences and support needs of post-doctoral and more senior researchers, as there is a paucity of literature in this area. Trial registration The review protocol was registered on PROSPERO (CRD42021232480).

Cognitive impairments have been reported in Idiopathic Intracranial Hypertension (IIH), however evidence supporting these deficits are scarce and contributing factors have not been defined. Using a case-control prospective study, we identified multiple domains of deficiency in a cohort of 66 female adult IIH patients. We identified significantly impaired attention networks (executive function) and sustained attention compared to a body mass index and age matched control group of 25 healthy female participants. We aimed to investigate how cognitive function changed over time and demonstrated that deficits were not permanent. Participants exhibited improvement in several domains including executive function, sustained attention and verbal short-term memory over 12 months follow up. Improved cognition over time was associated with reduction in intracranial pressure but not body weight. We then evaluated cognition before and after a lumbar puncture with acute reduction in intracranial pressure and noted significant improvement in sustained attention to response task performance. The impact of comorbidities (headache, depression, adiposity and obstructive sleep apnoea) was also explored. We observed that body mass index and the obesity associated cytokine interleukin-6 (serum and CSF) were not associated with cognitive performance. Headache severity during cognitive testing, co-morbid depression and markers of obstructive sleep apnoea were adversely associated with cognitive performance. Dysregulation of the cortisol generating enzyme 11β hydroxysteroid dehydrogenase type 1 has been observed in IIH. Elevated cortisol has been associated with impaired cognition. Here we utilised liquid chromatography-tandem mass spectrometry for multi-steroid profiling in serum and CSF in IIH patients. We noted that reduction in the serum cortisol:cortisone ratio in those undergoing bariatric surgery at 12 months was associated with improving verbal working memory. The clinical relevance of cognitive deficits was noted in their significant association with impaired reliability to perform visual field tests, the cornerstone of monitoring vision in IIH. Our findings propose that cognitive impairment should be accepted as a clinical manifestation of IIH and impairs the ability to reliably perform visual field testing. Importantly cognitive deficits can improve over time and with reduction of intracranial pressure. Treating comorbid depression, obstructive sleep apnoea and headache could improve cognitive performance in IIH.