Functional network changes and cognitive control in schizophrenia

Cognitive control is a cognitive and neural mechanism that contributes to managing the complex demands of day-to-day life. Studies have suggested that functional impairments in cognitive control associated brain circuitry contribute to a broad range of higher cognitive deficits in schizophrenia. To examine this issue, we assessed functional connectivity networks in healthy adults and individuals with schizophrenia performing tasks from two distinct cognitive domains that varied in demands for cognitive control, the RiSE episodic memory task and DPX goal maintenance task. We characterized general and cognitive control-specific effects of schizophrenia on functional connectivity within an expanded frontal parietal network (FPN) and quantified network topology properties using graph analysis. Using the network based statistic (NBS), we observed greater network functional connectivity in cognitive control demanding conditions during both tasks in both groups in the FPN, and demonstrated cognitive control FPN specificity against a task independent auditory network. NBS analyses also revealed widespread connectivity deficits in schizophrenia patients across all tasks. Furthermore, quantitative changes in network topology associated with diagnostic status and task demand were observed. The present findings, in an analysis that was limited to correct trials only, ensuring that subjects are on task, provide critical insights into network connections crucial for cognitive control and the manner in which brain networks reorganize to support such control. Impairments in this mechanism are present in schizophrenia and these results highlight how cognitive control deficits contribute to the pathophysiology of this illness

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Optimum surgical intervention for low-grade haemorrhoids is unknown. Haemorrhoidal artery ligation (HAL) has been proposed as an efficacious, safe therapy while rubber band ligation (RBL) is a commonly used outpatient treatment. We compared recurrence after HAL versus RBL in patients with grade II-III haemorrhoids. METHODS: This multicentre, open-label, parallel group, randomised controlled trial included patients from 17 acute UK NHS trusts. We screened patients aged 18 years or older presenting with grade II-III haemorrhoids. We excluded patients who had previously received any haemorrhoid surgery, more than one injection treatment for haemorrhoids, or more than one RBL procedure within 3 years before recruitment. Eligible patients were randomly assigned (in a 1:1 ratio) to either RBL or HAL with Doppler. Randomisation was computer-generated and stratified by centre with blocks of random sizes. Allocation concealment was achieved using a web-based system. The study was open-label with no masking of participants, clinicians, or research staff. The primary outcome was recurrence at 1 year, derived from the patient's self-reported assessment in combination with resource use from their general practitioner and hospital records. Recurrence was analysed in patients who had undergone one of the interventions and been followed up for at least 1 year. This study is registered with the ISRCTN registry, ISRCTN41394716. FINDINGS: From Sept 9, 2012, to May 6, 2014, of 969 patients screened, 185 were randomly assigned to the HAL group and 187 to the RBL group. Of these participants, 337 had primary outcome data (176 in the RBL group and 161 in the HAL group). At 1 year post-procedure, 87 (49%) of 176 patients in the RBL group and 48 (30%) of 161 patients in the HAL group had haemorrhoid recurrence (adjusted odds ratio [aOR] 2·23, 95% CI 1·42-3·51; p=0·0005). The main reason for this difference was the number of extra procedures required to achieve improvement (57 [32%] participants in the RBL group and 23 [14%] participants in the HAL group had a subsequent procedure for haemorrhoids). The mean pain 1 day after procedure was 3·4 (SD 2·8) in the RBL group and 4·6 (2·8) in the HAL group (difference -1·2, 95% CI -1·8 to -0·5; p=0·0002); at day 7 the scores were 1·6 (2·3) in the RBL group and 3·1 (2·4) in the HAL group (difference -1·5, -2·0 to -1·0; p<0·0001). Pain scores did not differ between groups at 21 days and 6 weeks. 15 individuals reported serious adverse events requiring hospital admission. One patient in the RBL group had a pre-existing rectal tumour. Of the remaining 14 serious adverse events, 12 (7%) were among participants treated with HAL and two (1%) were in those treated with RBL. Six patients had pain (one treated with RBL, five treated with HAL), three had bleeding not requiring transfusion (one treated with RBL, two treated with HAL), two in the HAL group had urinary retention, two in the HAL group had vasovagal upset, and one in the HAL group had possible sepsis (treated with antibiotics). INTERPRETATION: Although recurrence after HAL was lower than a single RBL, HAL was more painful than RBL. The difference in recurrence was due to the need for repeat bandings in the RBL group. Patients (and health commissioners) might prefer such a course of RBL to the more invasive HAL. FUNDING: NIHR Health Technology Assessment programme

Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF-MEK-ERK Pathway in Cancer

The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF inhibitor and MEK inhibitor (trametinib) is significantly more active in patients with BRAF mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of ERK. Such adaptive changes in tumor cell signaling networks allows bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR and many receptor tyrosine kinases such as EGFR and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses

Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition

BACKGROUND: Most novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors are associated with cardiotoxicity, whereas others appear to be cardiosafe. The basis for this distinction is unclear, as are the molecular effects of kinase inhibitors in the heart. METHODS AND RESULTS: We administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multitargeted kinase inhibitors), or erlotinib (a cardiosafe epidermal growth factor receptor inhibitor) to mice daily for 2 weeks. We then compared the effects of these 3 kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all 3 kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using in vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective signal transducer and activator of transcription 3 pathway, as co-treatment with erlotinib and a signal transducer and activator of transcription inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation. CONCLUSIONS: Collectively our findings indicate that preclinical kinome and transcriptome profiling may predict the cardiotoxicity of novel kinase inhibitors, and suggest caution for the proposed therapeutic strategy of combined signal transducer and activator of transcription/epidermal growth factor receptor inhibition for cancer treatment

Deep Extragalactic VIsible Legacy Survey (DEVILS): SED fitting in the D10-COSMOS field and the evolution of the stellar mass function and SFR–M⋆ relation

We present catalogues of stellar masses, star formation rates (SFRs), and ancillary stellar population parameters for galaxies spanning 0 \u3c z \u3c 9 from the Deep Extragalactic VIsible Legacy Survey (DEVILS). DEVILS is a deep spectroscopic redshift survey with very high completeness, covering several premier deep fields including COSMOS (D10). Our stellar mass and SFR estimates are self-consistently derived using the spectral energy distribution (SED) modelling code PROSPECT, using well-motivated parametrizations for dust attenuation, star formation histories, and metallicity evolution. We show how these improvements, and especially our physically motivated assumptions about metallicity evolution, have an appreciable systematic effect on the inferred stellar masses, at the level of ∼0.2 dex. To illustrate the scientific value of these data, we map the evolving galaxy stellar mass function (SMF) and the SFR–M⋆ relation for 0 \u3c z \u3c 4.25. In agreement with past studies, we find that most of the evolution in the SMF is driven by the characteristic density parameter, with little evolution in the characteristic mass and low-mass slopes. Where the SFR–M⋆ relation is indistinguishable from a power law at z \u3e 2.6, we see evidence of a bend in the relation at low redshifts (z \u3c 0.45). This suggests evolution in both the normalization and shape of the SFR–M⋆ relation since cosmic noon. It is significant that we only clearly see this bend when combining our new DEVILS measurements with consistently derived values for lower redshift galaxies from the Galaxy And Mass Assembly (GAMA) survey: this shows the power of having consistent treatment for galaxies at all redshifts

Deep Extragalactic VIsible Legacy Survey (DEVILS): SED Fitting in the D10-COSMOS Field and the Evolution of the Stellar Mass Function and SFR-M⋆M_\star relation

We present catalogues of stellar masses, star formation rates, and ancillary stellar population parameters for galaxies spanning $0<z<9$ from the Deep Extragalactic VIsible Legacy Survey (DEVILS). DEVILS is a deep spectroscopic redshift survey with very high completeness, covering several premier deep fields including COSMOS (D10). Our stellar mass and star formation rate estimates are self-consistently derived using the spectral energy distribution (SED) modeling code ProSpect, using well-motivated parameterisations for dust attenuation, star formation histories, and metallicity evolution. We show how these improvements, and especially our physically motivated assumptions about metallicity evolution, have an appreciable systematic effect on the inferred stellar masses, at the level of $\sim$0.2 dex. To illustrate the scientific value of these data, we map the evolving galaxy stellar mass function (SMF) for $0<z<5$ and the SFR-$M_\star$ relation for $0<z<9$. In agreement with past studies, we find that most of the evolution in the SMF is driven by the characteristic density parameter, with little evolution in the characteristic mass and low-mass slopes. Where the SFR-$M_\star$ relation is indistinguishable from a power-law at $z>2.6$, we see evidence of a bend in the relation at low redshifts ($z<0.45$). This suggests evolution in both the normalisation and shape of the SFR-$M_\star$ relation since cosmic noon. It is significant that we only clearly see this bend when combining our new DEVILS measurements with consistently derived values for lower redshift galaxies from the Galaxy And Mass Assembly (GAMA) survey: this shows the power of having consistent treatment for galaxies at all redshifts.Comment: Submitted for publication in MNRA

SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2

Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression

Galaxy and Mass Assembly (GAMA): The Weak Environmental Dependence of Quasar Activity at 0.1< z <0.35

Understanding the connection between nuclear activity and galaxy environment remains critical in constraining models of galaxy evolution. By exploiting extensive catalogued data from the Galaxy and Mass Assembly (GAMA) survey, we identify a representative sample of 205 quasars at 0.1 < z < 0.35 and establish a comparison sample of galaxies, closely matched to the quasar sample in terms of both stellar mass and redshift. On scales <1 Mpc, the galaxy number counts and group membership of quasars appear entirely consistent with those of the matched galaxy sample. Despite this, we find that quasars are ∼1.5 times more likely to be classified as the group center, indicating a potential link between quasar activity and cold gas flows or galaxy interactions associated with rich group environments. On scales of ∼a few Mpc, the clustering strength of both samples are statistically consistent and beyond 10 Mpc we find no evidence that quasars trace large scale structures any more than the galaxy control sample. Both populations are found to prefer intermediate-density sheets and filaments to either very high-or very low-density environments. This weak dependence of quasar activity on galaxy environment supports a paradigm in which quasars represent a phase in the lifetime Corresponding author: Clare F. Wethers [email protected] 2 Wethers et al. of all massive galaxies and in which secular processes and a group-centric location are the dominant trigger of quasars at low redshift