Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome

Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis

AbstractTo determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state

Crustal structure across the Grand Banks–Newfoundland Basin Continental Margin – II. Results from a seismic reflection profile

Author Posting. © Blackwell, 2006. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 167 (2006): 157-170, doi:10.1111/j.1365-246X.2006.02989.x.New multi-channel seismic (MCS) reflection data were collected over a 565km transect covering the non-volcanic rifted margin of the central eastern Grand Banks and the Newfoundland Basin in the northwestern Atlantic. Three major crustal zones are interpreted from west to east over the seaward 350-km of the profile: (1) continental crust; (2) transitional basement; (3) oceanic crust. Continental crust thins over a wide zone (~160 km) by forming a large rift basin (Carson Basin) and seaward fault block, together with a series of smaller fault blocks eastward beneath the Salar and Newfoundland basins. Analysis of selected previous reflection profiles (Lithoprobe 85-4, 85-2 and Conrad NB-1) indicates that prominent landward-dipping reflections observed under the continental slope are a regional phenomenon. They define the landward edge of a deep serpentinized mantle layer, which underlies both extended continental crust and transitional basement. The 80-km-wide transitional basement is defined landward by a basement high that may consist of serpentinized peridotite and seaward by a pair of basement highs of unknown crustal origin. Flat and unreflective transitional basement most likely is exhumed, serpentinized mantle, although our results do not exclude the possibility of anomalously thinned oceanic crust. A Moho reflection below interpreted oceanic crust is first observed landward of magnetic anomaly M4, 230 km from the shelf break. Extrapolation of ages from chron M0 to the edge of interpreted oceanic crust suggests that the onset of seafloor spreading was ~138Ma (Valanginian) in the south (southern Newfoundland Basin) to ~125Ma (Barremian-Aptian boundary) in the north (Flemish Cap), comparable to those proposed for the conjugate margins.This work was funded by NSF grants OCE-9819053 and OCE-0326714 to Woods Hole Oceanographic Institution, NSERC (Canada) and the Danish Research Council. B. Tucholke also acknowledges support from the Henry Bryant Bigelow Chair in Oceanography at Woods Hole Oceanographic Institution

Crustal structure across the Grand Banks–Newfoundland Basin Continental Margin – I. Results from a seismic refraction profile

Author Posting. © Blackwell, 2006. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 167 (2006): 127-156, doi:10.1111/j.1365-246X.2006.02988.x.A P-wave velocity model along a 565-km-long profile across the Grand Banks/Newfoundland basin rifted margin is presented. Continental crust ~36-kmthick beneath the Grand Banks is divided into upper (5.8-6.25 km/s), middle (6.3- 6.53 km/s) and lower crust (6.77-6.9 km/s), consistent with velocity structure of Avalon zone Appalachian crust. Syn-rift sediment sequences 6-7-km thick occur in two primary layers within the Jeanne d’Arc and the Carson basins (~3 km/s in upper layer; ~5 km/s in lower layer). Abrupt crustal thinning (Moho dip ~ 35º) beneath the Carson basin and more gradual thinning seaward forms a 170-km-wide zone of rifted continental crust. Within this zone, lower and middle continental crust thin preferentially seaward until they are completely removed, while very thin (<3 km) upper crust continues ~60 km farther seaward. Adjacent to the continental crust, high velocity gradients (0.5-1.5 s-1) define an 80-km-wide zone of transitional basement that can be interpreted as exhumed, serpentinized mantle or anomalously thin oceanic crust, based on its velocity model alone. We prefer the exhumed-mantle interpretation after considering the non-reflective character of the basement and the low amplitude of associated magnetic anomalies, which are atypical of oceanic crust. Beneath both the transitional basement and thin (<6 km) continental crust, a 200-kmwide zone with reduced mantle velocities (7.6-7.9 km/s) is observed, which is interpreted as partially (<10%) serpentinized mantle. Seaward of the transitional basement, 2- to 6-km-thick crust with layer 2 (4.5-6.3 km/s) and layer 3 (6.3-7.2 km/s) velocities is interpreted as oceanic crust. Comparison of our crustal model with profile IAM-9 across the Iberia Abyssal Plain on the conjugate Iberia margin suggests asymmetrical continental breakup in which a wider zone of extended continental crust has been left on the Newfoundland side.This research was supported by National Science Foundation (NSF) grants OCE-9819053 and OCE-0326714, by the National Sciences and Engineering Research Council of Canada (NSERC), and by the Danish National Research Foundation. B. Tucholke also acknowledges support from the Henry Bryant Bigelow Chair in Oceanography from Woods Hole Oceanographic Institution

A deep seismic investigation of the Flemish Cap margin: implications for the origin of deep reflectivity and evidence for asymmetric break-up between Newfoundland and Iberia

Author Posting. © Blacwell, 2006. This article is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 164 (2006): 501–515, doi:10.1111/j.1365-246X.2006.02800.x.Seismic reflection and refraction data were acquired along the southeast margin of Flemish Cap at a position conjugate to drilling and geophysical surveys across the Galicia Bank margin. The data document first-order asymmetry during final break-up between Newfoundland and Iberia. An abrupt necking profile of continental crust observed off Flemish Cap contrasts strongly with gradual tapering on the conjugate margin. There is no evidence beneath Flemish Cap for a final phase of continental extension that resulted in thin continental crust underlain by a strong 'S'-like reflection, which indicates that this mode of extension occurred only on the Galicia Bank margin. Compelling evidence for a broad zone of exhumed mantle or for peridotite ridges is also lacking along the Flemish Cap margin. Instead, anomalously thin, 3–4-km-thick oceanic crust is observed. This crust is highly tectonized and broken up by high-angle normal faulting. The thin crust and rift structures that resemble the abandoned spreading centre in the Labrador sea suggest that initial seafloor spreading was affected by processes observed in present-day ultra-slow spreading environments. Landwards, Flemish Cap is underlain by a highly reflective lower crust. The reflectivity most likely originates from older Palaeozoic orogenic structures that are unrelated to extension and break-up tectonics.This work was supported by the Danish National Research Foundation, U.S. National Science Foundation grants OCE-9819053 and OCE-0326714, and the Natural Science and Engineering Research Council of Canada. Additional support for Hopper was provided by the German Research Foundation grant MO-961/4-1. Tucholke also acknowledges support from Henry Bryant Bigelow Chair in Oceanography at Woods Hole Oceanographic Institution

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Persistence of fermentative process to phenolic toxicity in groundwater

The fermentation process is an important component in the biodegradation of organic compounds in natural and contaminated systems. Comparing with terminal electron-accepting processes (TEAPs), however, research on fermentation processes has to some extent been ignored in the past decades, particularly on the persistence of fermentation process in the presence of toxic organic pollutants. Both field and laboratory studies, presented here, showed that microbial processes in a groundwater-based system exhibited a differential inhibitory response to toxicity of phenolic compounds from coal tar distillation, thus resulting in the accumulation of volatile fatty acids (VFAs) and hydrogen. This indicated that fermentation processes could be more resistant to phenol toxicity than the subsequent TEAPs such as methanogenesis and sulfate reduction, thus providing us with more options for enhancing bioremediation processes

Biodegradation processes in a laboratory-scale groundwater contaminant plume assessed by fluorescence imaging and microbial analysis

Flow reactors containing quartz sand colonized with biofilm were set up as physical model aquifers to allow degrading plumes of acetate or phenol to be formed from a point source. A noninvasive fluorescent tracer technique was combined with chemical and biological sampling in order to quantify transport and biodegradation processes. Chemical analysis of samples showed a substantial decrease in carbon concentration between the injection and outflow resulting primarily from dilution but also from biodegradation. Two-dimensional imaging of the aqueous oxygen [O2(aq)] concentration field quantified the depletion of O2(aq) within the contaminant plume and provided evidence for microbial respiration associated with biodegradation of the carbon source. Combined microbiological, chemical, and O2(aq) imaging data indicated that biodegradation was greatest at the plume fringe. DNA profiles of bacterial communities were assessed by temperature gradient gel electrophoresis, which revealed that diversity was limited and that community changes observed depended on the carbon source used. Spatial variation in activity within the plume could be quantitatively accounted for by the changes observed in active cell numbers rather than differences in community structure, the total biomass present, or the increased enzyme activity of individual cells. Numerical simulations and comparisons with the experimental data were used to test conceptual models of plume processes. Results demonstrated that plume behavior was best described by growth and decay of active biomass as a single functional group of organisms represented by active cell counts