During metastasis, invading cells produce various actin-based membrane protrusions that promote directional migration and proteolysis of extracellular matrix (ECM). Observations of actin staining ...within thin, tubulin-based microtentacle (McTN) protrusions in suspended MDA-MB-231 tumor cells, prompted an investigation of whether McTNs are structural or functional analogs of invadopodia. We show here that MDA-MB-231 cells are capable of producing invadopodia and McTNs, both of which contain F-actin. Invadopodium formation was enhanced by the expression of a constitutively active c-Src kinase, and repressed by the expression of dominant-negative, catalytically inactive form of c-Src. In contrast, expression of inactive c-Src significantly increased McTN formation. Direct inhibition of c-Src with the SU6656 inhibitor compound also significantly enhanced McTN formation, but suppressed invadopodia, including the appearance of F-actin cores and phospho-cortactin foci, as well as completely blocking focal degradation of ECM. In addition, silencing of Tks5 in Src-transformed fibroblasts blocked invadopodia without affecting McTNs. Genetic modification of c-Src activity that promoted McTN formation augmented capillary retention of circulating tumor cells in vivo and rapid re-attachment of suspended cells in vitro, even though invadopodia were strongly suppressed. These results indicate that McTNs are capable of enhancing tumor cell reattachment, even in the absence of Tks5 and active Src, and define separate cytoskeletal mechanisms and functions for McTNs and invadopodia.
Aims
To evaluate the effectiveness of automated symptom and side effect monitoring on quality of life among individuals with symptomatic diabetic peripheral neuropathy.
Methods
We conducted a ...pragmatic, cluster randomized controlled trial (July 2014 to July 2016) within a large healthcare system. We randomized 1834 primary care physicians and prospectively recruited from their lists 1270 individuals with neuropathy who were newly prescribed medications for their symptoms. Intervention participants received automated telephone‐based symptom and side effect monitoring with physician feedback over 6 months. The control group received usual care plus three non‐interactive diabetes educational calls. Our primary outcomes were quality of life (EQ‐5D) and select symptoms (e.g. pain) measured 4–8 weeks after starting medication and again 8 months after baseline. Process outcomes included receiving a clinically effective dose and communication between individuals with neuropathy and their primary care provider over 12 months. Interviewers collecting outcome data were blinded to intervention assignment.
Results
Some 1252 participants completed the baseline measures mean age (sd): 67 (11.7), 53% female, 57% white, 8% Asian, 13% black, 20% Hispanic. In total, 1179 participants (93%) completed follow‐up (619 control, 560 intervention). Quality of life scores (intervention: 0.658 ± 0.094; control: 0.653 ± 0.092) and symptom severity were similar at baseline. The intervention had no effect on primary EQ‐5D: −0.002 (95% CI −0.01, 0.01), P = 0.623; pain: 0.295 (−0.75, 1.34), P = 0.579; sleep disruption: 0.342 (−0.18, 0.86), P = 0.196; lower extremity functioning: −0.079 (−1.27, 1.11), P = 0.896; depression: −0.462 (−1.24, 0.32); P = 0.247 or process outcomes.
Conclusions
Automated telephone monitoring and feedback alone were not effective at improving quality of life or symptoms for people with symptomatic diabetic peripheral neuropathy.
Trial Registration: ClinicalTrials.gov (NCT02056431).
What's new?
Frequent communication between individuals with diabetic peripheral neuropathy and primary care providers about symptoms and medication side effects is critical to optimizing medication dosing to treat painful diabetic peripheral neuropathy. Yet, there are considerable barriers to effective communication.
This cluster randomized controlled trial found that a brief intervention to automatically monitor person‐reported data on symptoms and side effects, and provide the information to physicians via an electronic health record was not effective in improving the outcomes valued by individuals with neuropathy.
Alerts alone are unlikely to change provider behaviour related to treatment intensification. More intensive interventions focused on individual activation or provider education may be more effective in changing prescribing behaviour and improving outcomes.
Background
Renal transplant recipients (RTRs) are at increased risk of keratinocyte cancer (KC), especially cutaneous squamous cell carcinoma (cSCC). Previous studies identified a genetic variant of ...the Methylenetetrahydrofolate Reductase (MTHFR) gene, C677T, which conferred a risk for diagnosis of cSCC in Irish RTRs.
Objective
We sought to find further genetic variation in MTHFR and overlap genes that may be associated with a diagnosis of KC in RTRs.
Methods
Genotyping of a combined RTR population (n = 821) from two centres, Ireland (n = 546) and the USA (n = 275), was performed. This included 290 RTRs with KC and 444 without. Eleven single nucleotide polymorphisms (SNPs) in the MTHFR gene and seven in the overlap gene MTHFR Chloride transport protein 6 (CLCN6) were evaluated and association explored by time to event analysis (from transplant to first KC) using Cox proportional hazards model.
Results
Polymorphism at MTHFR CLCN6 (rs9651118) was significantly associated with KC in RTRs (HR 1.50, 95% CI 1.17–1.91, p < 0.00061) and cSCC (HR 1.63, 95% CI 1.14–2.34, p = 0.007). A separate SNP, MTHFR C677T, was also significantly associated with KC in the Irish population (HR 1.31, 95% CI 1.05–1.63, p = 0.016), but not American RTRs.
Conclusions
We report the association of a SNP in the MTHFR overlap gene, CLCN6 and KC in a combined RTR population. While the exact function of CLCN6 is not known, it is proposed to be involved in folate availability. Future applications could include incorporation in a polygenic risk score for KC in RTRs to help identify those at increased risk beyond traditional risk factor assessment.
Time from date of transplant to development of keratinocyte skin cancer (Irish cohort n = 500) CLCN6. CC (usual) allele is solid line and heterozygous or homozygous variants for the MTHFR CLCN6 (rs9651118) polymorphism are indicated here by the broken lines.
To investigate the occurrence of status epilepticus and seizure clusters, and the duration until first seizure at epilepsy monitoring units in the United States.
The authors examined the inpatient ...video-EEG monitoring reports of 514 consecutive patients admitted to five comprehensive epilepsy centers during the year 2000. Time to first seizure, seizure clustering, and seizure duration were ascertained from reports and entered into a database.
In 169 admissions with complex partial seizures (CPSs) or secondarily generalized tonic-clonic (2GTC) seizures, there were 5 (3.0%) patients with status epilepticus, 30 (17.8%) with 4-hour seizure clusters, and 82 (48.5%) with 24-hour seizure clusters. There were no statistically significant differences between centers, except that seizure clusters were observed to be less common at the one center with a formal drug withdrawal protocol. The average time to CPS or 2GTC seizure was 2.1 days; the average number of days to nonepileptic event was 1.2 days (p = 0.001).
Although status epilepticus is uncommon at epilepsy monitoring units, clusters of seizures are common. Intensive monitoring with drug withdrawal must be performed in a highly supervised, hospitalized setting. Inpatient video-EEG monitoring is efficient, with recording of the first epileptic or nonepileptic events in 2 days or less.
Prior to the launch of NuSTAR, it was not feasible to spatially resolve the hard (E > 10 keV) emission from galaxies beyond the Local Group. The combined NuSTAR data set, comprised of three ~165 ks ...observations, allows spatial characterization of the hard X-ray emission in the galaxy NGC 253 for the first time. As a follow up to our initial study of its nuclear region, we present the first results concerning the full galaxy from simultaneous NuSTAR, Chandra, and Very Long Baseline Array monitoring of the local starburst galaxy NGC 253. Above ~10 keV, nearly all the emission is concentrated within 100" of the galactic center, produced almost exclusively by three nuclear sources, an off-nuclear ultraluminous X-ray source (ULX), and a pulsar candidate that we identify for the first time in these observations. We detect 21 distinct sources in energy bands up to 25 keV, mostly consisting of intermediate state black hole X-ray binaries. The global X-ray emission of the galaxy-dominated by the off-nuclear ULX and nuclear sources, which are also likely ULXs-falls steeply (photon index > ~3) above lOkeV, consistent with other NuSTAR-observed ULXs, and no significant excess above the background is detected at E > 40 keV. We report upper limits on diffuse inverse Compton emission for a range of spatial models. For the most extended morphologies considered, these hard X-ray constraints disfavor a dominant inverse Compton component to explain the gamma -ray emission detected with Fermi and H.E.S.S. If NGC 253 is typical of starburst galaxies at higher redshift, their contribution to the E > 10 keV cosmic X-ray background is < 1%.
Loss of PTEN tumor suppressor enhances metastatic risk in breast cancer, although the underlying mechanisms are poorly defined. We report that homozygous deletion of PTEN in mammary epithelial cells ...induces tubulin-based microtentacles (McTNs) that facilitate cell reattachment and homotypic aggregation. Treatment with contractility-modulating drugs showed that McTNs in PTEN(-/-) cells are suppressible by controlling the actin cytoskeleton. Because outward microtubule extension is counteracted by actin cortical contraction, increased activity of actin-severing proteins could release constraints on McTN formation in PTEN(-/-) cells. One such actin-severing protein, cofilin, is activated in detached PTEN(-/-) cells that could weaken the actin cortex to promote McTNs. Expression of wild-type cofilin, an activated mutant (S3A), and an inactive mutant (S3E) demonstrated that altering cofilin phosphorylation directly affects McTNs formation. Chemical inhibition of PI3K did not reduce McTNs or inactivate cofilin in PTEN(-/-) cells. Additionally, knock-in expression of the two most common PI3K-activating mutations observed in human cancer patients did not increase McTNs or activate cofilin. PTEN loss and PI3K activation also caused differential activation of the cofilin regulators, LIM-kinase1 (LIMK) and Slingshot-1L (SSH). Furthermore, McTNs were suppressed and cofilin was inactivated by restoration of PTEN in the PTEN(-/-) cells, indicating that both the elevation of McTNs and the activation of cofilin are specific results arising from PTEN loss. These data identify a novel mechanism by which PTEN loss could remodel the cortical actin network to facilitate McTNs that promote tumor cell reattachment and aggregation. Using isogenic MCF-10A PTEN(-/-) and PIK3CA mutants, we have further demonstrated that there are clear differences in activation of cofilin, LIMK and SSH between PTEN loss and PI3K activation, providing a new evidence that these mutations yield distinct cytoskeletal phenotypes, which could have an impact on tumor biology.
We report NuSTAR observations of a sample of six X-ray weak broad absorption line (BAL) quasars. These targets, at z = 0.148-1.223, are among the optically brightest and most luminous BAL quasars ...known at z < 1.3. However, their rest-frame approximately 2 keV luminosities are 14 to >330 times weaker than expected for typical quasars. Our results from a pilot NuSTAR study of two low-redshift BAL quasars, a Chandra stacking analysis of a sample of high-redshift BAL quasars, and a NuSTAR spectral analysis of the local BAL quasar Mrk 231 have already suggested the existence of intrinsically X-ray weak BAL quasars, i.e., quasars not emitting X-rays at the level expected from their optical/UV emission. The aim of the current program is to extend the search for such extraordinary objects. Three of the six new targets are weakly detected by NuSTAR with lap45 counts in the 3-24 keV band, and the other three are not detected. The hard X-ray (8-24 keV) weakness observed by NuSTAR requires Compton-thick absorption if these objects have nominal underlying X-ray emission. However, a soft stacked effective photon index (Gamma sub(eff) approximately 1.8) for this sample disfavors Compton-thick absorption in general. The uniform hard X-ray weakness observed by NuSTAR for this and the pilot samples selected with <10 keV weakness also suggests that the X-ray weakness is intrinsic in at least some of the targets. We conclude that the NuSTAR observations have likely discovered a significant population (gap33%) of intrinsically X-ray weak objects among the BAL quasars with significantly weak <10 keV emission. We suggest that intrinsically X-ray weak quasars might be preferentially observed as BAL quasars.
Black hole feedback in the luminous quasar PDS 456 Nardini, E.; Reeves, J. N.; Gofford, J. ...
Science (American Association for the Advancement of Science),
02/2015, Letnik:
347, Številka:
6224
Journal Article
Recenzirano
Odprti dostop
The evolution of galaxies is connected to the growth of supermassive black holes in their centers. During the quasar phase, a huge luminosity is released as matter falls onto the black hole, and ...radiation-driven winds can transfer most of this energy back to the host galaxy. Over five different epochs, we detected the signatures of a nearly spherical stream of highly ionized gas in the broadband x-ray spectra of the luminous quasar PDS 456. This persistent wind is expelled at relativistic speeds from the inner accretion disk, and its wide aperture suggests an effective coupling with the ambient gas. The outflow's kinetic power larger than 1046 ergs per second is enough to provide the feedback required by models of black hole and host galaxy coevolution.
Front-end ASIC for germanium strip detectors Wulf, E.A.; Hou, W.; De Geronimo, G. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2020, Letnik:
954
Journal Article
Recenzirano
The characteristics of a recently developed front-end application specific integrated circuit (ASIC) designed for high-purity germanium (HPGe) strip detectors are detailed. The ASIC contains 32 ...channels, and can instrument either cathode or anode signals from the HPGe detector. The channels provide low-noise charge amplification, four shaping times, four gain ranges, trimmable discrimination for each channel, time to analog output, and peak detectors with analog memory. The channels process events in parallel, and the ASIC emits a logical-OR of the internal discriminators for external control. Each channel contains a time-to-analog circuit to allow the depth of interaction in a detector to be determined. The ASIC has a small noise slope, allowing it to maintain germanium energy resolution at the large, 30 pF, input capacitance of a germanium strip detector connected through the cryostat by a kapton flex cable. The ASIC sparsifies the triggered channels for low deadtime readout. Each channel dissipates 6.2 mW and covers an energy range up to 4 MeV in HPGe. Measurements demonstrate an equivalent noise charge (ENC) of 260 electrons at an input capacitance of 32.5 pF with a slope of 6.4 electrons/pF for a peaking time of 2μs.
We present results from three nearly simultaneous Nuclear Spectroscopic Telescope Array (NuSTAR) and Chandra monitoring observations between 2012 September 2 and 2012 November 16 of the local ...star-forming galaxy NGC 253. The 3-40 keV intensity of the inner ~20 arcsec (~400 pc) nuclear region, as measured by NuSTAR, varied by a factor of ~2 across the three monitoring observations. We make use of the variability to measure the spectra of this single hard X-ray source when it was in bright states. The spectra are well described by an absorbed (H sub(H) approximately 1.6 x 10 super(23) cm super(-2)) broken power-law model with spectral slopes and break energies that are typical of ultraluminous X-ray sources (ULXs), but not active galactic nuclei (AGNs). Future NuSTAR and Chandra monitoring would be well equipped to break the degeneracy between the AGN and ULX nature of the 2003 source, if again caught in a high state.
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