Background: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using ...next‐generation sequencing‐based whole miRNome sequencing and quantitative polymerase chain reaction‐based validation analysis. In this study, we examined the mechanism of action of miR‐139‐5p, one of the downregulated miRNAs identified in the panel.
Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR‐139 (dichotomized around the median) using the Kaplan‐Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR‐139 to confirm its targets as well as examine pathways through which miR‐139 may function using cell‐based assays.
Results: Low miR‐139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR‐139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR‐139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR‐139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33‐0.82). Overexpression of miR‐139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR‐139 based on multiple miRNA‐binding sites in 3′‐untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR‐139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR‐139 treatment, which was reversed by the addition of miR‐139 antagomir. Examination of the molecular mechanism of growth inhibition by miR‐139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21.
Conclusions: miR‐139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.
Among patients with cancer, prior research suggests that patients with mental illness may have reduced survival. The objective was to assess the impact of psychiatric utilisation (PU) prior to cancer ...diagnosis on survival outcomes.
All residents of Ontario diagnosed with one of the top 10 malignancies (1997-2014) were included. The primary exposure was psychiatric utilisation gradient (PUG) score in 5 years prior to cancer: 0: none, 1: outpatient, 2: emergency department, 3: hospital admission. A multivariable, cause-specific hazard model was used to assess the effect of PUG score on cancer-specific mortality (CSM), and a Cox proportional hazard model for effect on all-cause mortality (ACM).
A toal of 676,125 patients were included: 359,465 (53.2%) with PUG 0, 304,559 (45.0%) PUG 1, 7901 (1.2%) PUG 2, and 4200 (0.6%) PUG 3. Increasing PUG score was independently associated with worse CSM, with an effect gradient across the intensity of pre-diagnosis PU (vs PUG 0): PUG 1 h 1.05 (95% CI 1.04-1.06), PUG 2 h 1.36 (95% CI 1.30-1.42), and PUG 3 h 1.73 (95% CI 1.63-1.84). Increasing PUG score was also associated with worse ACM.
Pre-cancer diagnosis PU is independently associated with worse CSM and ACM following diagnosis among patients with solid organ malignancies.
In direct methanol fuel cells (DMFCs), the optimum characteristics of ion-exchange membranes are investigated at high concentrations of methanol feed up to 7
M by modifying the diffusion coefficient ...and the ionic conductivity of the polyelectrolyte material. A Nafion membrane is modified by the incorporation of layered double hydroxide (LDH) nanoplatelets with different Mg
2+:Al
3+ ratios. When the feed concentration of methanol is lower than 3
M, the DMFC is controlled by the ionic conductivity of the polyelectrolyte membrane because methanol cross-over is not relatively significant. When the feed concentration is high, however, the diffusion coefficient of methanol is the key factor that determines the performance of the fuel cell. This is due to a high concentration gradient of methanol across the polyelectrolyte membrane. The open-circuit voltage is increased by the decreased diffusion coefficient in LDH/Nafion nanocomposite membranes at methanol feed concentrations up to 7
M; apparently because methanol cross-over is suppressed by the incorporation of LDH. The maximum power density of the DMFC is determined by the two competing transport processes of ion conduction and methanol diffusion, especially at a relatively high methanol concentration, that can provide optimum operating conditions in the membrane.
A new biomimetic linear actuator named Antagonistically Driven Linear Actuator (ANTLA) that could be directly employed in both macro and microscale of robotic applications is introduced in the ...present work. The presented actuator provides cost effectiveness and simple fabrication process thanks to its plain construction. In addition to producing basic bidirectional rectilinear motions, the actuator is able to modulate its compliance that might be one of the critical elements of the actuator functionality for the biomimetic applications. For the test, the proposed actuator concept is fabricated and assembled in a microscale robot that generates annelid motion.
Combining a nanocomposite technique and the electrospinning process, a robust dual-porosity scaffold structure was developed for a facile transport of metabolic nutrients and wastes through the ...nano-sized pores and for the cell implantation and blood vessel invasion through the micro-sized pores. The montmorillonite (MMT) nano-sized platelets were incorporated into poly(
L-lactic acid) (PLLA) solution, which was subsequently electrospun and mechanically entangled by a cold compression molding process for a robust 3-dimensional scaffold structure. Using a salt leaching/gas forming method, micro-sized pores were developed in the electrospun fiber bundles giving a dual-porosity scaffold structure. Compared with the pristine PLLA scaffold, the developed nanocomposite fibrous scaffold structure exhibited increased strength and improved structural integrity during the biodegradation process. The nanocomposite scaffold systems also exhibited many tiny pinholes desirably generated on the scaffold walls without serious fragmentation during biodegradation reactions.
Basin-scale planning is needed to minimize impacts in mega-diverse rivers
The world's most biodiverse river basins—the Amazon, Congo, and Mekong—are experiencing an unprecedented boom in construction ...of hydropower dams. These projects address important energy needs, but advocates often overestimate economic benefits and underestimate far-reaching effects on biodiversity and critically important fisheries. Powerful new analytical tools and high-resolution environmental data can clarify trade-offs between engineering and environmental goals and can enable governments and funding institutions to compare alternative sites for dam building. Current site-specific assessment protocols largely ignore cumulative impacts on hydrology and ecosystem services as ever more dams are constructed within a watershed (
1
). To achieve true sustainability, assessments of new projects must go beyond local impacts by accounting for synergies with existing dams, as well as land cover changes and likely climatic shifts (
2
,
3
). We call for more sophisticated and holistic hydropower planning, including validation of technologies intended to mitigate environmental impacts. Should anything less be required when tampering with the world's great river ecosystems?
A
bstract
The exclusive photoproduction reactions
γp
→
J/ψ
(1
S
)
p
and
γp
→
ψ
(2
S
)
p
have been measured at an
ep
centre-of-mass energy of 318 GeV with the ZEUS detector at HERA using an integrated ...luminosity of 373 pb
−
1
. The measurement was made in the kinematic range 30
< W <
180 GeV,
Q
2
<
1 GeV
2
and |
t
|
<
1 GeV
2
, where
W
is the photon-proton centre-of-mass energy,
Q
2
is the photon virtuality and
t
is the squared four-momentum transfer at the proton vertex. The decay channels used were
J/ψ
(1
S
)
→ μ
+
μ
−
,
ψ
(2
S
)
→ μ
+
μ
−
and
ψ
(2
S
)
→ J/ψ
(1
S
)
π
+
π
−
with subsequent decay
J/ψ
(1
S
)
→ μ
+
μ
−
. The ratio of the production cross sections,
R
=
σ
ψ
(2
S
)
/σ
J/ψ
(1
S
)
, has been measured as a function of
W
and |
t
| and compared to previous data in photoproduction and deep inelastic scattering and with predictions of QCD-inspired models of exclusive vector-meson production, which are in reasonable agreement with the data.
Purpose To our knowledge the role of magnetic resonance imaging as a first line screening test for prostate cancer is unknown. We performed a pilot study to evaluate the feasibility of prostate ...magnetic resonance imaging as the primary screening test for prostate cancer. Materials and Methods We recruited unselected men from the general population. Prostate multiparametric magnetic resonance imaging and random or targeted biopsies were performed in all patients, in addition to prostate specific antigen testing. We compared the performance of prostate magnetic resonance imaging and prostate specific antigen test results to predict prostate cancer. Results Of the 47 recruited patients 18 (38.3%) had cancer while 29 (61.7%) had no evidence of cancer. The adjusted OR of prostate cancer was significantly higher for magnetic resonance imaging score than for prostate specific antigen level (2.7, 95% CI 1.4–5.4, p = 0.004 vs 1.1, 95% CI 0.9–1.4, p = 0.21). Among the 30 patients with a normal prostate specific antigen (less than 4.0 ng/ml) the positive predictive value in those with a magnetic resonance imaging score of 4 or more was 66.7% (6 of 9) and the negative predictive value in those with a magnetic resonance imaging score of 3 or less was 85.7% (18 of 21, p = 0.004). Conclusions In this pilot study we determined the feasibility of using multiparametric prostate magnetic resonance imaging as the primary screening test for prostate cancer. Initial results showed that prostate magnetic resonance imaging was better to predict prostate cancer than prostate specific antigen in an unselected sample of the general population.
Biological complexity leads to significant variation in the survival of patients with stage I non-small-cell lung cancer (NSCLC). DNA damage response (DDR) pathways play a critical role in ...maintaining genomic stability and in the progression of NSCLC. Therefore, the development of a prognostic biomarker focusing on DDR pathways is an intriguing issue.
Expression of several proteins (ATM, ATMpS1981, γH2AX, 53BP1, 53BP1pS25, Chk2, Chk2pT68, MDC1, MDC1pS964, BRCA1pS1423, and ERCC1) and overall survival were investigated in 889 pathological stage I NSCLC patients.
Low expression of BRCA1pS1423 or ERCC1 was significantly associated with worse survival in the whole cohort of patients. Analysis performed based on histology revealed that low expression of γH2AX, Chk2pT68, or ERCC1 was a poor prognostic factor in squamous cell carcinoma patients adjusted hazard ratio (aHR), Cox P: 1.544, 0.012 for γH2AX; 1.624, 0.010 for Chk2pT68; 1.569, 0.011 for ERCC1. The analysis of the interaction between two proteins showed that this effect was more pronounced in squamous cell carcinoma patients. However, these effects were not detected in adenocarcinoma patients.
The proteins involved in DDR pathways exhibited differential expression between squamous cell carcinoma and adenocarcinoma and were important determinants of survival in stage I squamous cell carcinoma patients.
Growing evidence suggests that managers select financial policies partially by mimicking policies of peer firms. We find that these peer effects in capital structure choice are unique to firms ...operating under weak external corporate governance. Cross-sectional tests suggest that this finding is best explained by a quiet life hypothesis in which managers may be able to avoid the effort required to optimize financial policies and the scrutiny of market participants. Leverage ratios of mimicking firms display less sensitivity to a profitability shock. Finally, mimicking correlates to higher financing costs and lower future profitability, especially if it results in high leverage.
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