IGF2 increases de novo steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

Effect of bone morphogenetic protein-4 (BMP-4) on the expression of Sox2, Oct-4 and c-Myc in human periodontal ligament cells during long-term culture

Recent studies demonstrated endogenous expression level of Sox2, Oct-4 and c-Myc is correlated with the pluripotency and successful induction of induced pluripotent stem cells (iPSCs). Periondontal ligament cells (PDLCs)have multi-lineage diferentiation capability and ability to maintain undifferentiated stage, which makes PDLCs a suitable cell source for tissue repair and regeneration. To elucidate the effect of in vitro culture condition on the stemness potential of PDLCs, we explored the cell growth, proliferation, cell cycle, and the expression of Sox2, Oct-4 and c-Myc in PDLCs from passage 1 to 7 with or without the addition of recombinant human BMP4(rhBMP4). Our results revealed that BMP-4 promoted cell growth and proliferation, arrested PDLCs in S phase of cell cycle and upregulated PI value. It was revealed that without the addition of rhBMP4, the expression of Sox2, Oct-4 and c-Myc in PDLCs only maintained nucleus location until passage 3, then lost nucleus location subsequently. The mRNA expression in PDLCs further confirmed that the level of Sox2 and Oct-4 peaked at passage 3, then decreased afterwards, whereas c-Myc maintained consistently upregulation along passages. after the treatment with rhBMP4, the expression of Sox2, Oct-4 and c-Myc in PDLCs maintained nucleus location even at passage 7 and the mRNA expression of Sox2 and Oct-4 significantly upregulated at passage 5 and 7. These results demonstrated that addition of rhBMP-4 in the culture media could improve the current culture condition for PDLCs to maintain in an undifferentiated stage.

Dying in hospital: medical failure or natural outcomes?

The purpose of this study was to describe patterns of medical and nursing practice in the care of patients dying of oncological and hematological malignancies in the acute care setting in Australia. A tool validated in a similar American study was used to study the medical records of 100 consecutive patients who died of oncological or hematological malignancies before August 1999 at The Canberra Hospital in the Australian Capital Territory. The three major indicators of patterns of end-of-life care were documentation of Do Not Resuscitate (DNR) orders, evidence that the patient was considered dying, and the presence of a palliative care intention. Findings were that 88 patients were documented DNR, 63 patients' records suggested that the patient was dying, and 74 patients had evidence of a palliative care plan. Forty-six patients were documented DNR 2 days or less prior to death and, of these, 12 were documented the day of death. Similar patterns emerged for days between considered dying and death, and between palliative care goals and death. Sixty patients had active treatment in progress at the time of death. The late implementation of end-of-life management plans and the lack of consistency within these plans suggested that patients were subjected to medical interventions and investigations up to the time of death. Implications for palliative care teams include the need to educate health care staff and to plan and implement policy regarding the management of dying patients in the acute care setting. Although the health care system in Australia has cultural differences when compared to the American context, this research suggests that the treatment imperative to prolong life is similar to that found in American-based studies.

Future-proofing our community for natural disaster requires more attention on men

Response to the "2011 Brisbane floods affected residents' health"

Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

Numerical simulation of red blood cells' deformation using SPH method

A numerical simulation method for the Red Blood Cells’ (RBC) deformation is presented in this study. The two-dimensional RBC membrane is modeled by the spring network, where the elastic stretch/compression energy and the bending energy are considered with the constraint of constant RBC surface area. Smoothed Particle Hydrodynamics (SPH) method is used to solve the Navier-Stokes equation coupled with the Plasma-RBC membrane and Cytoplasm- RBC membrane interaction. To verify the method, the motion of a single RBC is simulated in Poiseuille flow and compared with the results reported earlier. Typical motion and deformation mechanism of the RBC is observed.

Numerical simulation of red blood cells’ motion : a review

The micro-circulation of blood plays an important role in human body by providing oxygen and nutrients to the cells and removing carbon dioxide and wastes from the cells. This process is greatly affected by the rheological properties of the Red Blood Cells (RBCs). Changes in the rheological properties of the RBCs are caused by certain human diseases such as malaria and sickle cell diseases. Therefore it is important to understand the motion and deformation mechanism of RBCs in order to diagnose and treat this kind of diseases. Although, many methods have been developed to explore the behavior of the RBCs in micro-channels, they could not explain the deformation mechanism of the RBCs properly. Recently developed Particle Methods are employed to explain the RBCs’ behavior in micro-channels more comprehensively. The main objective of this study is to critically analyze the present methods, used to model the RBC behavior in micro-channels, in order to develop a computationally efficient particle based model to describe the complete behavior of the RBCs in micro-channels accurately and comprehensively

Natural convection of nanofluids in open rectangular cavity

An investigation of the effect of nano particles on natural convection of water based nanofluids contained in an open rectangular cavity is carried out numerically. The flow pattern and heat transfer characteristics are studied for different values of volume fraction in the range 0   0.2 , Rayleigh number in the range 9 1 Ra 10 and the nano particles with different thermo physical properties. It was found that for low Rayleigh numbers, heat transfer exhibits a decreasing trend for increasing values of volume fraction of oxide nanofluids, whereas for higher values of Rayleigh numbers, an increasing trend of heat transfer was observed due to increase in the volume fraction of nanofluids.

Finite volume approach of natural convection in a triangular enclosure with localized heating from below

In this study, natural convection heat transfer and buoyancy driven flows have been investigated in a right angled triangular enclosure. The heater located on the bottom wall while the inclined wall is colder and the remaining walls are maintained as adiabatic. Governing equations of natural convection are solved through the finite volume approach, in which buoyancy is modeled via the Boussinesq approximation. Effects of different parameters such as Rayleigh number, aspect ratio, prantdl number and heater location are considered. Results show that heat transfer increases when the heater is moved toward the right corner of the enclosure. It is also revealed that increasing the Rayleigh number, increases the strength of free convection regime and consequently increases the value of heat transfer rate. Moreover, larger aspect ratio enclosure has larger Nusselt number value. In order to have better insight, streamline and isotherms are shown.

Natural convection flow in a strong cross magnetic field with radiation

The problem of MHD natural convection boundary layer flow of an electrically conducting and optically dense gray viscous fluid along a heated vertical plate is analyzed in the presence of strong cross magnetic field with radiative heat transfer. In the analysis radiative heat flux is considered by adopting optically thick radiation limit. Attempt is made to obtain the solutions valid for liquid metals by taking Pr≪1. Boundary layer equations are transformed in to a convenient dimensionless form by using stream function formulation (SFF) and primitive variable formulation (PVF). Non-similar equations obtained from SFF are then simulated by implicit finite difference (Keller-box) method whereas parabolic partial differential equations obtained from PVF are integrated numerically by hiring direct finite difference method over the entire range of local Hartmann parameter, $xi$ . Further, asymptotic solutions are also obtained for large and small values of local Hartmann parameter $xi$ . A favorable agreement is found between the results for small, large and all values of $xi$ . Numerical results are also demonstrated graphically by showing the effect of various physical parameters on shear stress, rate of heat transfer, velocity and temperature.

Natural convection flow with surface radiation along a vertical wavy surface

In this study, natural convection boundary layer flow of thermally radiating fluid along a heated vertical wavy surface is analyzed. Here, the radiative component of heat flux emulates the surface temperature. Governing equations are reduced to dimensionless form, subject to the appropriate transformation. Resulting dimensionless equations are transformed to a set of parabolic partial differential equations by using primitive variable formulation, which are then integrated numerically via iterative finite difference scheme. Emphasis has been given to low Prandtl number fluid. The numerical results obtained for the physical parameters, such as, surface radiation parameter, R, and radiative length parameter, ξ, are discussed in terms of local skin friction and Nusselt number coefficients. Comprehensive interpretation of velocity distribution is also given in the form of streamlines.

Conduction-radiation effect on natural convection flow in a fluid-saturated non-Darcy porous medium enclosed by non-isothermal walls

The effect of conduction-convection-radiation on natural convection flow of Newtonian optically thick gray fluid, confined in a non-Darcian porous media square cavity is numerically studied. For the gray fluid consideration is given to Rosseland diffusion approximation. Further assuming that (i) the temperature of the left vertical wall is varying linearly with height, (ii) cooled right vertical and top walls and (iii) the bottom wall is uniformly-heated. The governing equations are solved using the Alternate Direct Implicit method together with the Successive Over Relaxation technique. The investigation of the effect of governing parameters namely the Forschheimer resistance (Γ), the Planck constant (Rd), and the temperature difference (Δ), on flow pattern and heat transfer characteristics has been carried out. It was seen that the reduction of flow and heat transfer occurs as the Forschheimer resistance is increased. On the other hand both the strength of flow and heat transfer increases as the temperature ratio, Δ, is increased.