1,179 research outputs found
Cell–substrate adhesion drives Scar/WAVE activation and phosphorylation by a Ste20-family kinase, which controls pseudopod lifetime
The Scar/WAVE complex is the principal catalyst of pseudopod and lamellipod formation. Here we show that Scar/WAVE’s proline-rich domain is polyphosphorylated after the complex is activated. Blocking Scar/WAVE activation stops phosphorylation in both Dictyostelium and mammalian cells, implying that phosphorylation modulates pseudopods after they have been formed, rather than controlling whether they are initiated. Unexpectedly, phosphorylation is not promoted by chemotactic signaling but is greatly stimulated by cell:substrate adhesion and diminished when cells deadhere. Phosphorylation-deficient or phosphomimetic Scar/WAVE mutants are both normally functional and rescue the phenotype of knockout cells, demonstrating that phosphorylation is dispensable for activation and actin regulation. However, pseudopods and patches of phosphorylation-deficient Scar/WAVE last substantially longer in mutants, altering the dynamics and size of pseudopods and lamellipods and thus changing migration speed. Scar/WAVE phosphorylation does not require ERK2 in Dictyostelium or mammalian cells. However, the MAPKKK homologue SepA contributes substantially—sepA mutants have less steady-state phosphorylation, which does not increase in response to adhesion. The mutants also behave similarly to cells expressing phosphorylation-deficient Scar, with longer-lived pseudopods and patches of Scar recruitment. We conclude that pseudopod engagement with substratum is more important than extracellular signals at regulating Scar/WAVE’s activity and that phosphorylation acts as a pseudopod timer by promoting Scar/WAVE turnover
Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression.
OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA).
BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection.
METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (\u3c12 \u3emonths) or long-term (\u3e30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes (eg, recurrence pattern and early cancer-specific mortality) were determined.
RESULTS: Loss of SMAD4 expression in pancreatic adenocarcinoma was identified in 40 of 127 patients (32%). SMAD4 loss occurred in 27% of patients who experienced isolated local recurrence, 33% of patients with a distant recurrence, 33% of patients who experienced local and distant site recurrences, and 25% of patients who were without evidence of recurrence (Fisher exact, P = 0.9). In a multivariate analysis, the presence of regional lymph node metastases was the only factor associated with the development of distant metastases (odds ratio = 4.7, P = 0.02). SMAD4 was neither associated with recurrence pattern (odds ratio = 0.9, P = 0.9) nor associated with early death (odds ratio = 0.5, P = 0.15).
CONCLUSIONS: Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected PDA
Human α2β1HI CD133+VE epithelial prostate stem cells express low levels of active androgen receptor
Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis
Long-term outcomes for women after obstetric fistula repair in Lilongwe, Malawi: a qualitative study
Background Obstetric fistula affects a woman’s life physically, psychosocially, and economically. Although surgery can repair the physical damage of fistula, the devastating consequences that affect a woman’s quality of life may persist when she reintegrates into her community. This qualitative study assessed long-term outcomes among women who underwent obstetric fistula repair in Malawi. We explored three domains: overall quality of life before and after repair, fertility and pregnancy outcomes after repair, and understanding of fistula. Methods In-depth interviews were conducted in Chichewa with 20 women from seven districts across Central Malawi. All women were interviewed 1 to 2 years after surgical repair for obstetric fistula at the Fistula Care Centre in Lilongwe, Malawi. Interviews were independently coded and analyzed using content analysis. Results About half of women were married and nine of 20 women reported some degree of urinary incontinence. With the exception of relationship challenges, women’s concerns before and after repair were different. Additionally, repair had resolved many of the concerns women had before repair. However, challenges, both directly and indirectly related to fistula, persisted. Improvements in quality of life at the individual level included feelings of freedom, confidence and personal growth, and improved income-earning ability. Interpersonal quality of life improvements included improved relationships with family and friends, reduced stigma, and increased participation with their communities. Nearly half of women desired future pregnancies, but many were uncertain about their ability to bear children and feared additional pregnancies could cause fistula recurrence. Most women were well informed about fistula development but myths about witchcraft and fear of delivery were present. Nearly all women would recommend fistula repair to other women, and many were advocates in their communities. Conclusions Nearly all women believed their quality of life had improved at the individual and interpersonal levels since fistula repair, even among women who continued to have urinary incontinence. Contrary to other studies, women reported they were welcomed back by their communities and had limited challenges when reintegrating. Despite the overall improvements in quality of life, many continued to have relationship problems and were concerned about future fertility. These issues need to be further explored in other studies
A comprehensive study on the relationship between image quality and imaging dose in low-dose cone beam CT
While compressed sensing (CS) based reconstructions have been developed for
low-dose CBCT, a clear understanding on the relationship between the image
quality and imaging dose at low dose levels is needed. In this paper, we
qualitatively investigate this subject in a comprehensive manner with extensive
experimental and simulation studies. The basic idea is to plot image quality
and imaging dose together as functions of number of projections and mAs per
projection over the whole clinically relevant range. A clear understanding on
the tradeoff between image quality and dose can be achieved and optimal
low-dose CBCT scan protocols can be developed for various imaging tasks in
IGRT. Main findings of this work include: 1) Under the CS framework, image
quality has little degradation over a large dose range, and the degradation
becomes evident when the dose < 100 total mAs. A dose < 40 total mAs leads to a
dramatic image degradation. Optimal low-dose CBCT scan protocols likely fall in
the dose range of 40-100 total mAs, depending on the specific IGRT
applications. 2) Among different scan protocols at a constant low-dose level,
the super sparse-view reconstruction with projection number less than 50 is the
most challenging case, even with strong regularization. Better image quality
can be acquired with other low mAs protocols. 3) The optimal scan protocol is
the combination of a medium number of projections and a medium level of
mAs/view. This is more evident when the dose is around 72.8 total mAs or below
and when the ROI is a low-contrast or high-resolution object. Based on our
results, the optimal number of projections is around 90 to 120. 4) The
clinically acceptable lowest dose level is task dependent. In our study,
72.8mAs is a safe dose level for visualizing low-contrast objects, while 12.2
total mAs is sufficient for detecting high-contrast objects of diameter greater
than 3 mm.Comment: 19 pages, 12 figures, submitted to Physics in Medicine and Biolog
Prognostic significance of T-cell–inflamed gene expression profile and PD-L1 expression in patients with esophageal cancer
PURPOSE: The ability of the T‐cell–inflamed gene expression profile (GEP) to predict clinical outcome in esophageal cancer (EC) is unknown. This retrospective observational study assessed the prognostic value of GEP and programmed death ligand 1 (PD‐L1) expression in patients with EC treated in routine clinical practice. METHODS: Tumor samples of 294 patients from three centers in Denmark, South Korea, and the United States, collected between 2005 and 2017, were included. T‐cell–inflamed GEP score was defined as non‐low or low using a cutoff of −1.54. A combined positive score (CPS) ≥10 was defined as PD‐L1 expression positivity. Associations between overall survival (OS) and GEP status and PD‐L1 expression were explored by Cox proportional hazards models adjusting for age, sex, histology, stage, and performance status. RESULTS: Median age was 65 years; 63% of patients had adenocarcinoma (AC) and 37% had squamous cell carcinoma (SCC). Thirty‐six percent of tumors were GEP non‐low, with higher prevalence in AC (46%) than SCC (18%). Twenty‐one percent were PD‐L1–positive: 32% in South Korean samples versus 16% in non‐Asian samples and 26% in SCC versus 18% in AC. GEP scores and PD‐L1 CPS were weakly correlated (Spearman’s R = 0.363). OS was not significantly associated with GEP status (non‐low vs low; adjusted hazard ratio, 0.91 [95% CI, 0.69–1.19]) or PD‐L1 expression status. CONCLUSION: Neither GEP nor PD‐L1 expression was a prognostic marker in Asian and non‐Asian patients with EC
Synthesis of freestanding HfO2 nanostructures
Two new methods for synthesizing nanostructured HfO2 have been developed. The first method entails exposing HfTe2 powders to air. This simple process resulted in the formation of nanometer scale crystallites of HfO2. The second method involved a two-step heating process by which macroscopic, freestanding nanosheets of HfO2 were formed as a byproduct during the synthesis of HfTe2. These highly two-dimensional sheets had side lengths measuring up to several millimeters and were stable enough to be manipulated with tweezers and other instruments. The thickness of the sheets ranged from a few to a few hundred nanometers. The thinnest sheets appeared transparent when viewed in a scanning electron microscope. It was found that the presence of Mn enhanced the formation of HfO2 by exposure to ambient conditions and was necessary for the formation of the large scale nanosheets. These results present new routes to create freestanding nanostructured hafnium dioxide
A population of luminous accreting black holes with hidden mergers
Major galaxy mergers are thought to play an important part in fuelling the
growth of supermassive black holes. However, observational support for this
hypothesis is mixed, with some studies showing a correlation between merging
galaxies and luminous quasars and others showing no such association. Recent
observations have shown that a black hole is likely to become heavily obscured
behind merger-driven gas and dust, even in the early stages of the merger, when
the galaxies are well separated (5 to 40 kiloparsecs). Merger simulations
further suggest that such obscuration and black-hole accretion peaks in the
final merger stage, when the two galactic nuclei are closely separated (less
than 3 kiloparsecs). Resolving this final stage requires a combination of
high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray
observations to detect highly obscured sources. However, large numbers of
obscured luminous accreting supermassive black holes have been recently
detected nearby (distances below 250 megaparsecs) in X-ray observations. Here
we report high-resolution infrared observations of hard-X-ray-selected black
holes and the discovery of obscured nuclear mergers, the parent populations of
supermassive-black-hole mergers. We find that obscured luminous black holes
(bolometric luminosity higher than 2x10^44 ergs per second) show a significant
(P<0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a
sample of inactive galaxies with matching stellar masses and star formation
rates (1.1 per cent), in agreement with theoretical predictions. Using
hydrodynamic simulations, we confirm that the excess of nuclear mergers is
indeed strongest for gas-rich major-merger hosts of obscured luminous black
holes in this final stage.Comment: To appear in the 8 November 2018 issue of Nature. This is the
authors' version of the wor
Diaphragm as an anatomic surrogate for lung tumor motion
Lung tumor motion due to respiration poses a challenge in the application of
modern three-dimensional conformal radiotherapy. Direct tracking of the lung
tumor during radiation therapy is very difficult without implanted fiducial
markers. Indirect tracking relies on the correlation of the tumor's motion and
the surrogate's motion. The present paper presents an analysis of the
correlation between the tumor motion and the diaphragm motion in order to
evaluate the potential use of diaphragm as a surrogate for tumor motion. We
have analyzed the correlation between diaphragm motion and superior-inferior
lung tumor motion in 32 fluoroscopic image sequences from 10 lung cancer
patients. A simple linear model and a more complex linear model that accounts
for phase delays between the two motions have been used. Results show that the
diaphragm is a good surrogate for tumor motion prediction for most patients,
resulting in an average correlation factor of 0.94 and 0.98 with each model
respectively. The model that accounts for delays leads to an average
localization prediction error of 0.8mm and an error at the 95% confidence level
of 2.1mm. However, for one patient studied, the correlation is much weaker
compared to other patients. This indicates that, before using diaphragm for
lung tumor prediction, the correlation should be examined on a
patient-by-patient basis.Comment: Accepted by Physics in Medicine and Biolog
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