Major depressive disorder (MDD) is characterized by alterations in brain function that are identifiable also during the brain's 'resting state'. One functional network that is disrupted in this ...disorder is the default mode network (DMN), a set of large-scale connected brain regions that oscillate with low-frequency fluctuations and are more active during rest relative to a goal-directed task. Recent studies support the idea that the DMN is not a unitary system, but rather is composed of smaller and distinct functional subsystems that interact with each other. The functional relevance of these subsystems in depression, however, is unclear.
Here, we investigated the functional connectivity of distinct DMN subsystems and their interplay in depression using resting-state functional magnetic resonance imaging.
We show that patients with MDD exhibit increased within-network connectivity in posterior, ventral and core DMN subsystems along with reduced interplay from the anterior to the ventral DMN subsystems.
These data suggest that MDD is characterized by alterations of subsystems within the DMN as well as of their interactions. Our findings highlight a critical role of DMN circuitry in the pathophysiology of MDD, thus suggesting these subsystems as potential therapeutic targets.
Adults with psychotic disorders have dysconnectivity in critical brain networks, including the default mode (DM) and the cingulo-opercular (CO) networks. However, it is unknown whether such deficits ...are present in youth with less severe symptoms. We conducted a multivariate connectome-wide association study examining dysconnectivity with resting state functional magnetic resonance imaging in a population-based cohort of 188 youths aged 8-22 years with psychosis-spectrum (PS) symptoms and 204 typically developing (TD) comparators. We found evidence for multi-focal dysconnectivity in PS youths, implicating the bilateral anterior cingulate, frontal pole, medial temporal lobe, opercular cortex and right orbitofrontal cortex. Follow-up seed-based and network-level analyses demonstrated that these results were driven by hyper-connectivity among DM regions and diminished connectivity among CO regions, as well as diminished coupling between frontal and DM regions. Collectively, these results provide novel evidence for functional dysconnectivity in PS youths, which show marked correspondence to abnormalities reported in adults with established psychotic disorders.
Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection ...is limited to the K-Ras 'hotspot' codons 12 and 13.
Colorectal tumours (n=106) were screened for additional K-Ras mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual K-Ras mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate K-Ras gene amplification.
Four additional K-Ras mutations (Leu(19)Phe (1 out of 106 tumours), Lys(117)Asn (1 out of 106), Ala(146)Thr (7 out of 106) and Arg(164)Gln (1 out of 106)) were identified. Lys(117)Asn and Ala(146)Thr had phenotypes similar to the hotspot mutations, whereas Leu(19)Phe had an attenuated phenotype and the Arg(164)Gln mutation was phenotypically equivalent to wt K-Ras. We additionally identified a new K-Ras gene amplification event, present in approximately 2% of tumours.
The identification of mutations outwith previously described hotspot codons increases the K-Ras mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with EGFR-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual K-Ras mutations.
Abstract
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics ...and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.
We present a measurement of the volumetric rate of superluminous supernovae (SLSNe) at z ~ 1.0, measured using archival data from the first four years of the Canada-France-Hawaii Telescope Supernova ...Legacy Survey (SNLS). We develop a method for the photometric classification of SLSNe to construct our sample. Our sample includes two previously spectroscopically identified objects, and a further new candidate selected using our classification technique. We use the point-source recovery efficiencies from Perrett et al. and a Monte Carlo approach to calculate the rate based on our SLSN sample. We find that the three identified SLSNe from SNLS give a rate of 91... SNe yr super( -1) Gpc super( -3) at a volume-weighted redshift of z = 1.13. This is equivalent to 2.2...x10 super( -4) of the volumetric core-collapse supernova rate at the same redshift. When combined with other rate measurements from the literature, we show that the rate of SLSNe increases with redshift in a manner consistent with that of the cosmic star formation history. We also estimate the rate of ultra-long gamma-ray bursts based on the events discovered by the Swift satellite, and show that it is comparable to the rate of SLSNe, providing further evidence of a possible connection between these two classes of events. We also examine the host galaxies of the SLSNe discovered in SNLS, and find them to be consistent with the stellar-mass distribution of other published samples of SLSNe. (ProQuest: ... denotes formulae/symbols omitted.)
Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.
We evaluated infection-related complications that were grade ...≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.
Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n= 389), followed by ear (n= 151), bloodstream (n= 147), and gastrointestinal tract (n= 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n= 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1–9.9 years at diagnosis was associated with febrile neutropenia (P= 0.002) during induction and febrile neutropenia and documented infection (both P< 0.001) during later continuation. White race was associated with documented infection (P= 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P< 0.001) and documented infections (P= 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P< 0.001).
The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.
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