Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) (also called VEGFR-3) is activated by its specific ligand, VEGF-C, which promotes cancer progression. The VEGF-C/VEGFR-3 axis is ...expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumours. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, activation of the VEGF-C/VEGFR-3 axis in several types of solid tumours enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis. In this review, we discuss the novel function and molecular mechanism of the VEGF-C/VEGFR-3 axis in cancer progression.
We devise and implement quasi-Monte Carlo methods for computing the expectations of nonlinear functionals of solutions of a class of elliptic partial differential equations with random coefficients. ...Our motivation comes from fluid flow in random porous media, where relevant functionals include the fluid pressure/velocity at any point in space or the breakthrough time of a pollution plume being transported by the velocity field. Our emphasis is on situations where a very large number of random variables is needed to model the coefficient field. As an alternative to classical Monte Carlo, we here employ quasi-Monte Carlo methods, which use deterministically chosen sample points in an appropriate (usually high-dimensional) parameter space. Each realization of the PDE solution requires a finite element (FE) approximation in space, and this is done using a realization of the coefficient field restricted to a suitable regular spatial grid (not necessarily the same as the FE grid). In the statistically homogeneous case the corresponding covariance matrix can be diagonalized and the required coefficient realizations can be computed efficiently using FFT. In this way we avoid the use of a truncated Karhunen–Loève expansion, but introduce high nominal dimension in parameter space. Numerical experiments with 2-dimensional rough random fields, high variance and small length scale are reported, showing that the quasi-Monte Carlo method consistently outperforms the Monte Carlo method, with a smaller error and a noticeably better than
O
(
N
-
1
/
2
)
convergence rate, where
N is the number of samples. Moreover, the rate of convergence of the quasi-Monte Carlo method does not appear to degrade as the nominal dimension increases. Examples with dimension as high as 10
6 are reported.
Summary
We examined the effect of blood pressure lowering drugs on BMD using data from the Study of Women’s Health Across the Nation. Thiazide users had a slower decline in BMD compared to nonusers, ...while decline among ACE inhibitor and beta blocker users were similar to rates in nonusers.
Introduction
Several blood pressure lowering drugs may affect bone mineral density (BMD), leading to altered fracture risk. We examined the effect of blood pressure lowering drugs on BMD using data from the Study of Women’s Health Across the Nation.
Methods
We conducted a propensity score matched cohort study. Women were initiators of ACE inhibitors (ACEi), beta-blockers (BB), or thiazide diuretics (THZD). Their annualized BMD changes during the 14 years of observation were compared with nonusers.
Results
Among the 2312 eligible women, we found 69 ACEi, 71 BB, and 74 THZD users who were matched by a propensity score with the same number of nonusers. THZD users had a slower annual percent decline in BMD compared to nonusers at the femoral neck (FN) (−0.28 % vs −0.88 %;
p
= 0.008) and the spine (−0.74 % vs −1.0 %;
p
= 0.34), albeit not statistically significant. Annual percent changes in BMD among ACEi and BB users were similar to rates in nonusers. In comparison with BB, THZD use was associated with a trend toward less annualized BMD loss at the spine (−0.35 % vs −0.60 %;
p
= 0.08) and a similar trend at the FN (−0.39 % vs −0.64 %;
p
= 0.08); in comparisons with ACEi, THZD was also associated with less loss at the FN (−0.48 % vs −0.82 %;
p
= 0.02), but not at the spine (−0.40 % vs −0.56 %;
p
= 0.23).
Conclusions
Neither ACEi nor BB was associated with improvements in BMD. THZD use was associated with less annualized loss of BMD compared with nonusers, as well as compared with ACEi and BB.
Objective
We aimed at studying the role of the most deregulated miR‐99a, identifying its downstream targets, and exploring the clinical potential of miR‐99a and its target(s) in oral cancer.
Subjects ...and Methods
Following confirmation of miR‐99a deregulation in nine oral lines and 26 pairwise clinical specimens, miR‐99a‐manipulated oral cancer cells were subjected to cell proliferation, migration, invasion, and in vivo murine metastasis assays. We characterized putative miR‐99a target(s) using luciferase reporter assays and genetic manipulation. The inverse relation of miR‐99a and its target(s) was examined in clinical specimens using real‐time PCR and Western blot analysis.
Results
MiR‐99a down‐regulation was confirmed both in tested oral cancer cell lines and clinical specimens. Ectopic miR‐99a expression inhibited oral cancer cell migration and invasion. Anti‐miR‐99a, silencing miR‐99a functions, had the opposite effect. Myotubularin‐related protein 3 (MTMR3) with one evolutionarily conserved seed region in the 3′‐untranslated region was a novel miR‐99a target. Depleting MTMR3 expression significantly reduced cell proliferation, migration, or invasion. There was an inverse expression of miR‐99a and MTMR3 protein in oral cancer lines and clinical specimens.
Conclusion
miR‐99a repressed oral cancer cell migration and invasion partly through decreasing MTMR3 expression. MTMR3 may serve as a therapeutic target for oral cancer treatment.
Summary
Background Wound healing is a dynamic and complicated process in which inflammation, re‐epithelialization and angiogenesis play important roles. Intriguingly, all three processes have been ...found to be defective during diabetic wound healing conditions. One common denominator associated with regulation of these events is human β‐defensin‐2 (hBD2). It has been shown that skin wounding induces cutaneous hBD2 expression, and diabetic wounds have been associated with inadequate hBD expression.
Objectives The current study was launched to explore the effects of a high‐glucose environment on cultured human keratinocytes.
Methods Human keratinocytes were exposed to indicated culture conditions. The mRNA and protein levels of hBD2 were determined, and activation of relevant pathways was evaluated. The small interference RNA approach was used to validate the functional role of the proposed pathway on hBD2 expression.
Results We showed that high‐glucose cultivated keratinocytes expressed reduced levels of hBD2 and phosphorylated signal transducer and activator of transcription (pSTAT)‐1 constitutively. In addition, pSTAT‐1 signalling is critically involved in hBD2 expression. Formation of advanced glycation endproducts, a direct consequence of a high‐glucose environment, involves constitutive downregulation of pSTAT‐1 and hBD2. The addition of interleukin‐1β, an important cytokine during the cutaneous wound healing process, enabled the upregulation of hBD2 expression of both normal‐ and high‐glucose cultivated keratinocytes, but the absolute levels of hBD2 were still significantly lower in the high‐glucose‐treated group.
Conclusions As hBD2 plays multifaceted roles during the wound healing process, the inadequate expression of hBD2 during diabetic conditions contributes to impaired wound healing.
Across the planet, outbreaks of bacterial illnesses pose major health risks and raise concerns. Photodynamic, photothermal, and metal ion release effects of transition metal-based nanocomposites ...(TMNs) were recently shown to be highly effective in reducing bacterial resistance and upsurges in outbreaks. Surface plasmonic resonance, photonics, crystal structures, and optical properties of TMNs have been used to regulate metal ion release, produce oxidative stress, and generate heat for bactericidal applications. The superior properties of TMNs provide a chance to investigate and improve their antimicrobial actions, perhaps leading to therapeutic interventions. In this review, we discuss three alternative antibacterial strategies based on TMNs of photodynamic therapy, photothermal therapy, and metal ion release and their mechanistic actions. The scientific community has made significant efforts to address the safety, effectiveness, toxicity, and biocompatibility of these metallic nanostructures; significant achievements and trends have been highlighted in this review. The combination of therapies together has borne significant results to counter antimicrobial resistance (4-log reduction). These three antimicrobial pathways are separated into subcategories based on recent successes, highlighting potential needs and challenges in medical, environmental, and allied industries.
We consider the forward problem of uncertainty quantification for the generalised Dirichlet eigenvalue problem for a coercive second order partial differential operator with random coefficients, ...motivated by problems in structural mechanics, photonic crystals and neutron diffusion. The PDE coefficients are assumed to be uniformly bounded random fields, represented as infinite series parametrised by uniformly distributed i.i.d. random variables. The expectation of the fundamental eigenvalue of this problem is computed by (a) truncating the infinite series which define the coefficients; (b) approximating the resulting truncated problem using lowest order conforming finite elements and a sparse matrix eigenvalue solver; and (c) approximating the resulting finite (but high dimensional) integral by a randomly shifted quasi-Monte Carlo lattice rule, with specially chosen generating vector. We prove error estimates for the combined error, which depend on the truncation dimension
s
, the finite element mesh diameter
h
, and the number of quasi-Monte Carlo samples
N
. Under suitable regularity assumptions, our bounds are of the particular form
O
(
h
2
+
N
-
1
+
δ
)
, where
δ
>
0
is arbitrary and the hidden constant is independent of the truncation dimension, which needs to grow as
h
→
0
and
N
→
∞
. As for the analogous PDE source problem, the conditions under which our error bounds hold depend on a parameter
p
∈
(
0
,
1
)
representing the summability of the terms in the series expansions of the coefficients. Although the eigenvalue problem is nonlinear, which means it is generally considered harder than the source problem, in almost all cases (
p
≠
1
) we obtain error bounds that converge at the same rate as the corresponding rate for the source problem. The proof involves a detailed study of the regularity of the fundamental eigenvalue as a function of the random parameters. As a key intermediate result in the analysis, we prove that the spectral gap (between the fundamental and the second eigenvalues) is uniformly positive over all realisations of the random problem.
Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent ...research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood.
In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse.
Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae.
Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.
We present formulas that allow us to decompose a function ƒ of d variables into a sum of 2 d terms f u indexed by subsets u of {1,. . . , d}, where each term f u depends only on the variables with ...indices in u. The decomposition depends on the choice of d commuting projections $\{ P_j \} _j^d = 1$ , where P j (ƒ ) does not depend on the variable x j . We present an explicit formula for f u , which is new even for the ANOVA and anchored decompositions; both are special cases of the general decomposition. We show that the decomposition is minimal in the following sense: if f is expressible as a sum in which there is no term that depends on all of the variables indexed by the subset z, then, for every choice of $\{ P_j \} _j^d = 1$ , the terms f u = 0 for all subsets u containing z. Furthermore, in a reproducing kernel Hubert space setting, we give sufficient conditions for the terms f u to be mutually orthogonal.
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