HIF-transcribed p53 chaperones HIF-1α

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation

Intravesical Treatments of Bladder Cancer: Review

For bladder cancer, intravesical chemo/immunotherapy is widely used as adjuvant therapies after surgical transurethal resection, while systemic therapy is typically reserved for higher stage, muscle-invading, or metastatic diseases. The goal of intravesical therapy is to eradicate existing or residual tumors through direct cytoablation or immunostimulation. The unique properties of the urinary bladder render it a fertile ground for evaluating additional novel experimental approaches to regional therapy, including iontophoresis/electrophoresis, local hyperthermia, co-administration of permeation enhancers, bioadhesive carriers, magnetic-targeted particles and gene therapy. Furthermore, due to its unique anatomical properties, the drug concentration-time profiles in various layers of bladder tissues during and after intravesical therapy can be described by mathematical models comprised of drug disposition and transport kinetic parameters. The drug delivery data, in turn, can be combined with the effective drug exposure to infer treatment efficacy and thereby assists the selection of optimal regimens. To our knowledge, intravesical therapy of bladder cancer represents the first example where computational pharmacological approach was used to design, and successfully predicted the outcome of, a randomized phase III trial (using mitomycin C). This review summarizes the pharmacological principles and the current status of intravesical therapy, and the application of computation to optimize the drug delivery to target sites and the treatment efficacy

On Lamb's plane problem in micropolar viscoelastic half-space with stretch

A study is made of Lamb's plane problem in micropolar viscoelastic half-space with stretch. The viscoelasticity is characterized by the rate-dependent theories of micro-viscoelasticity generalizing the classical Kelvin-Voigt theory. The displacement components, force stress, couple stress and vector first moment are obtained for a half-space subjected to an arbitrary normal load. Two particular cases of a horizontal force and a torque which are time harmonic have been considered. Several limiting cases are obtained as special cases of the present analysis

On Lamb’S Plane Problem In Micropolar Viscoelastic Half-Space With Stretch

A study is made of Lamb’s plane problem in micropolar viscoelastic halfspace with stretch. The viscoelasticity is characterized by the rate-dependent theories of micro-viscoelasticity generalizing the classical Kelvin-Voigt theory. The displacement components, force stress, couple stress and vector first moment are obtained for a half-space subjected to an arbitrary normal load. Two particular cases of a horizontal force and a torque which are time harmonic have been considered. Several limiting cases are obtained as special cases of the present analysis. © 1990, Hindawi Publishing Corporation. All rights reserved