A Biomechanical Model of Tumor-Induced Intracranial Pressure and Edema in Brain Tissue

Brain tumor growth and tumor-induced edema result in increased intracranial pressure (ICP), which, in turn, is responsible for conditions as benign as headaches and vomiting or as severe as seizures, neurological damage, or even death. Therefore, it has been hypothesized that tracking ICP dynamics may offer improved prognostic potential in terms of early detection of brain cancer and better delimitation of the tumor boundary. However, translating such theory into clinical practice remains a challenge, in part because of an incomplete understanding of how ICP correlates with tumor grade. Here, we propose a multiphase mixture model that describes the biomechanical response of healthy brain tissue—in terms of changes in ICP and edema—to a growing tumor. The model captures ICP dynamics within the diseased brain and accounts for the ability/inability of healthy tissue to compensate for this pressure. We propose parameter regimes that distinguish brain tumors by grade, thereby providing critical insight into how ICP dynamics vary by severity of disease. In particular, we offer an explanation for clinically observed phenomena, such as a lack of symptoms in low-grade glioma patients versus a rapid onset of symptoms in those with malignant tumors. Our model also takes into account the effects tumor-derived proteases may have on ICP levels and the extent of tumor invasion. This work represents an important first step toward understanding the mechanisms that underlie the onset of edema and ICP in cancer-afflicted brains. Continued modeling effort in this direction has the potential to make an impact in the field of brain cancer diagnostics.     

Immunological effects of cancer chemotherapy in malignant melanoma

Summary The effects on the immune system of highdose cyclical combination chemotherapy were studied in nine patients with advanced malignant melanoma. Chemotherapy consisted of monthly cycles of dimethyl triazeno imidazole carboxamide 150 mg/m² i.v. daily from days 1–5, cyclophosphamide 1000 mg/m² i.v. on day 5, and vincristine 1.4 mg/m² i.v. on day 5.Immunological testing was carried out prior to treatment and at weekly intervals during the first month.B, T and non-B, non-T cell numbers all tended to fall early in the cycle as did the phytohaemagglutinin(PHA)-induced transformation and PHA-induced cytotoxicity to chicken red cells. Although PHA-induced transformation and cytotoxicity usually returned to normal by day 29, B and T cell numbers often remained subnormal. In contrast, levels for antibody-dependent, cell-mediated cytotoxicity (ADCC) were relatively stable throughout the cycle. Two patients with subsequent tumour response to therapy had rebound supranormal PHA transformations between weeks 1 and 3 of the first cycle. No other changes correlated with prognosis in individual patients.Analysis of the temporal relationships between PHA transformation, PHA-induced cytotoxicity, and ADCC supported the concept that the three assays reflect the function of separate mononuclear cell subpopulations.The stability of ADCC is of particular interest in view of other work suggesting that this function may be important in immune responses to tumours, including melanoma.Work was supported by grants from the National Health and Medical Research Council and the Western Australian Arthritis and Rheumatism Foundation, and the Cancer Council of Western Australia     

Ganglioside-Induced Neuritogenesis: Verification That Gangliosides Are the Active Agents, and Comparison of Molecular Species

Abstract: Gangliosides were previously reported to induce neuritogenesis in primary neuronal cultures and in some neurally derived cell lines. Because isolated gangliosides usually contain variable quantities of peptides, we investigated the possibility the neurite-stimulating activity could be caused by these contaminants. Ganglioside preparations from bovine brain and other sources were subjected to a three-step purification procedure that eliminated at least 95% of the contaminating peptides. These purfied preparations retained their capacity to induce extensive neurite growth in neuro-2A murine neuroblastoma. Proteolytic digestion and a number of additional procedures were used to reduce residual contamination further without loss of activity. Several crude ganglioside samples had negative effects on neurite development until freed of theri inhibitory factors, which were derived from the tissue and/or introduced during laboratory operations. This was particularly evident for bovine white matter gangliosides whose activity increased in proportion to peptide removal. When carefully purified, virtually all of 11 different gangliosides tested were highly active, with the possible exception of GM4, which demonstrated only moderate activity in a limited number of tests. All of the neutral glycolipids tested, as well as sulfatides and free sialic acid, were inactive.     

Bioerosion caused by foraging of the tropical chiton Acanthopleura gemmata at One Tree Reef, southern Great Barrier Reef

The bioerosive potential of the intertidal chiton Acanthopleura gemmata on One Tree Reef was determined by quantification of CaCO₃ in daily faecal pellet production of individuals transplanted into mesocosms after nocturnal-feeding forays. Mean bioerosive potential was estimated at 0.16 kg CaCO₃ chiton⁻¹ yr⁻¹. Bioerosion rates were estimated for populations on two distinct chiton habitats, reef margin (0.013 kg CaCO₃ m⁻² yr⁻¹) and beachrock platform (0.25 kg CaCO₃ m⁻² yr⁻¹). Chiton density on the platform was orders of magnitude greater than on the reef margin. The surface-lowering rate (0.16 mm m⁻² yr) due to bioerosion by the beachrock population is a substantial contribution to the total surface-lowering rate of 2 mm m⁻² yr⁻¹ previously reported for One Tree Reef across all erosive agents. At high densities, the contribution of A. gemmata to coral reef bioerosion budgets may be comparable to other important bioeroders such as echinoids and fish.     

Nucleotide sequence analysis of IS256 from the Staphylococcus aureus gentamicin-tobramycin-kanamycin-resistance transposon Tn4001

Resistance to the aminoglycosides gentamicin, tobramycin and kanamycin (GmTmKmR) in Australian clinical strains of Staphylococcus aureus is commonly carried on the composite transposon Tn4001. The resistance gene aacA-aphD of Tn4001, which encodes a bifunctional AAC(6')-APH(2") modifying enzyme, is flanked by two 1324-bp inverted repeats, IS256L and IS256R, that are identical in sequence. Analysis of the IS256 sequence revealed structural features characteristic of IS elements including 26-bp imperfect terminal inverted repeats and a single open reading frame with coding capacity for a 45.6 kDa protein. The nucleotide sequence of IS256 described here, together with the sequence of the aacA-aphD gene reported previously [Rouch et al., J. Gen. Microbiol. 133 (1987) 3039-3052], completes the entire sequence of Tn4001, which totals 4566 bp.     

Dung beetles ignore landmarks for straight-line orientation

Upon locating a suitable dung pile, ball-rolling dung beetles shape a piece of dung into a ball and roll it away in a straight line. This guarantees that they will not return to the dung pile, where they risk having their ball stolen by other beetles. Dung beetles are known to use celestial compass cues such as the sun, the moon and the pattern of polarised light formed around these light sources to roll their balls of dung along straight paths. Here, we investigate whether terrestrial landmarks have any influence on straight-line orientation in dung beetles. We find that the removal or re-arrangement of landmarks has no effect on the beetle’s orientation precision. Celestial compass cues dominate straight-line orientation in dung beetles so strongly that, under heavily overcast conditions or when prevented from seeing the sky, the beetles can no longer orient along straight paths. To our knowledge, this is the only animal with a visual compass system that ignores the extra orientation precision that landmarks can offer.     

Foundations for the future: A long‐term plan for Australian ecosystem science

Australia's ecosystems are the basis of our current and future prosperity, and our national well‐being. A strong and sustainable Australian ecosystem science enterprise is vital for understanding and securing these ecosystems in the face of current and future challenges. This Plan defines the vision and key directions for a national ecosystem science capability that will enable Australia to understand and effectively manage its ecosystems for decades to come. The Plan's underlying theme is that excellent science supports a range of activities, including public engagement, that enable us to understand and maintain healthy ecosystems. Those healthy ecosystems are the cornerstone of our social and economic well‐being. The vision guiding the development of this Plan is that in 20 years' time the status of Australian ecosystems and how they change will be widely reported and understood, and the prosperity and well‐being they provide will be secure. To enable this, Australia's national ecosystem science capability will be coordinated, collaborative and connected. The Plan is based on an extensive set of collaboratively generated proposals from national town hall meetings that also form the basis for its implementation. Some directions within the Plan are for the Australian ecosystem science community itself to implement, others will involve the users of ecosystem science and the groups that fund ecosystem science. We identify six equal priority areas for action to achieve our vision: (i) delivering maximum impact for Australia: enhancing relationships between scientists and end‐users; (ii) supporting long‐term research; (iii) enabling ecosystem surveillance; (iv) making the most of data resources; (v) inspiring a generation: empowering the public with knowledge and opportunities; (vi) facilitating coordination, collaboration and leadership. This shared vision will enable us to consolidate our current successes, overcome remaining barriers and establish the foundations to ensure Australian ecosystem science delivers for the future needs of Australia.     

Knockdown of human deubiquitinase PSMD14 induces cell cycle arrest and senescence

The PSMD14 (POH1, also known as Rpn11/MPR1/S13/CepP1) protein within the 19S complex (19S cap; PA700) is responsible for substrate deubiquitination during proteasomal degradation. The role of PSMD14 in cell proliferation and senescence was explored using siRNA knockdown in carcinoma cell lines. Our results reveal that down-regulation of PSMD14 by siRNA transfection had a considerable impact on cell viability causing cell arrest in the G0-G1 phase, ultimately leading to senescence. The molecular events associated with decreased cell proliferation, cell cycle arrest and senescence include down-regulation of cyclin B1-CDK1-CDC25C, down-regulation of cyclin D1 and up-regulation of p21^/Cip and p27^/Kip1. Most notably, phosphorylation of the retinoblastoma protein was markedly reduced in PSMD14 knockdown cells. A comparative study with PSMB5, a subunit of the 20S proteasome, revealed that PSMB5 and PSMD14 have different effects on cell cycle, senescence and associated molecular events. These data support the view that the 19S and 20S subunits of the proteasome have distinct biological functions and imply that targeting 19S and 20S would have distinct molecular consequences on tumor cells.