Tracing the role of human civilization in the globalization of plant pathogens

Acknowledgments. We apologize to all those colleagues whose work was not cited because of space restrictions.Peer reviewedPostprin

Immunodetection of nmt55/p54(nrb) isoforms in human breast cancer

BACKGROUND: We previously identified and characterized a novel 55 kDa nuclear protein, termed nmt55/p54(nrb), whose expression was decreased in a subset of human breast tumors. The objective of this study was to determine if this reduced expression in human breast tumors was attributed to the regulation of mRNA transcription or the presence of altered forms of this protein. RESULTS: Northern blot analysis and ribonuclease protection assay indicated that nmt55/p54(nrb) mRNA is expressed at varying levels in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) human breast tumors suggesting that reduced expression of nmt55/p54(nrb) protein in ER- tumors was not due to transcriptional regulation. To determine if multiple protein isoforms are expressed in breast cancer, we utilized Western blot and immunohistochemical analyses, which revealed the expression of an nmt55/p54(nrb) protein isoform in a subset of ER+ tumors. This subset of ER+ human breast tumors expressed an altered form of nmt55/p54(nrb) that was undetectable with an amino-terminal specific antibody suggesting that this isoform contains alterations or modifications within the amino terminal domain. CONCLUSIONS: Our study indicates that nmt55/p54(nrb) protein is post-transcriptionally regulated in human breast tumors leading to reduced expression in ER- tumors and the expression of an amino terminal altered isoform in a subset of ER+ tumors. The potential involvement of nmt55/p54(nrb) in RNA binding and pre-mRNA splicing may be important for normal cell growth and function; thus, loss or alteration of protein structure may contribute to tumor growth and progression

Routine prophylactic antibiotic use in the management of snakebite

BACKGROUND: Routine antibiotic prophylaxis following snakebite is not recommended but evidence suggests that it may be common practice in Zimbabwe. This study set out to determine and describe the extent of this practice at Parirenyatwa Hospital, a large teaching hospital in Zimbabwe METHODS: A retrospective case review (1996 to 1999 inclusive) of all cases of snakebite was undertaken at Parirenyatwa Hospital. Cases with a diagnosis of snakebite, presenting within 24 hours of the bite and with no complications or concurrent illness were defined as "routine prophylactic antibiotic use". RESULTS: From 78 cases which satisfied the inclusion criteria, 69 (88.5%) received antibiotics. Ten different antibiotics from 6 different classes were used with penicillins the most commonly prescribed (benzylpenicillin in 29% of cases, alone or in combination). Over 40% of antibiotics were given parenterally although all patients were conscious on admission. The total cost of antibiotics used was estimated at US$522.98. CONCLUSION: Routine prophylactic use of antibiotics in snakebite at Parirenyatwa Hospital is common practice. This may highlight the lack of a clearly defined policy leading to wasteful inappropriate antibiotic use which is costly and may promote bacterial antibiotic resistance. Further work is required to investigate the reasons for this practice and to design appropriate interventions to counter it

Vascular disrupting agents in clinical development

Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given

Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative

Background: The European NCI compounds programme, a joint initiative of the EORTC Research Branch, Cancer Research Campaign and the US National Cancer Institute, was initiated in 1993. The objective was to help the NCI in reducing the backlog of in vivo testing of potential anticancer compounds, synthesised in Europe that emerged from the NCI in vitro 60-cell screen. Methods: Over a period of more than twenty years the EORTC—Cancer Research Campaign panel reviewed ~2000 compounds of which 95 were selected for further evaluation. Selected compounds were stepwise developed with clear go/no go decision points using a pharmacologically directed programme. Results: This approach eliminated quickly compounds with unsuitable pharmacological properties. A few compounds went into Phase I clinical evaluation. The lessons learned and many of the principles outlined in the paper can easily be applied to current and future drug discovery and development programmes. Conclusions: Changes in the review panel, restrictions regarding numbers and types of compounds tested in the NCI in vitro screen and the appearance of targeted agents led to the discontinuation of the European NCI programme in 2017 and its transformation into an academic platform of excellence for anticancer drug discovery and development within the EORTC-PAMM group. This group remains open for advice and collaboration with interested parties in the field of cancer pharmacology

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

In a previous study, we used subcutaneous LY80 tumours (a subline of Yoshida sarcoma), Sato lung carcinoma, and methylcholanthrene-induced primary tumours, to demonstrate that a novel water-soluble combretastatin A-4 derivative, AC7700, abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour. In the present study, we investigated whether AC7700 acts in the same way against solid tumours growing in the liver, stomach, kidney, muscle, and lymph nodes. Tumour blood flow and the change in tumour blood flow induced by AC7700 were measured by the hydrogen clearance method. In a model of cancer chemotherapy against metastases, LY80 cells (2×106) were injected into the lateral tail vein, and AC7700 at 10 mg kg−1 was injected i.v. five times at intervals of 2 days, starting on day 7 after tumour cell injection. The number and size of tumours were compared with those in the control group. The change in tumour blood flow and the therapeutic effect of AC7700 on microtumours were observed directly by using Sato lung carcinoma implanted in a rat transparent chamber. AC7700 caused a marked decrease in the tumour blood flow of all LY80 tumours developing in various tissues and organs and growth of all tumours including lymph node metastases and microtumours was inhibited. In every tumour, tumour blood flow began to decrease immediately after AC7700 administration and reached a minimum at approximately 30 min after injection. In many tumour capillaries, blood flow completely stopped within 3 min after AC7700 administration. These results demonstrate that AC7700 is effective for tumours growing in various tissues and organs and for metastases. We conclude that tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer

Cholesterol and Lipoprotein Dynamics in a Hibernating Mammal

Hibernating mammals cease feeding during the winter and rely primarily on stored lipids to fuel alternating periods of torpor and arousal. How hibernators manage large fluxes of lipids and sterols over the annual hibernation cycle is poorly understood. The aim of this study was to investigate lipid and cholesterol transport and storage in ground squirrels studied in spring, summer, and several hibernation states. Cholesterol levels in total plasma, HDL and LDL particles were elevated in hibernators compared with spring or summer squirrels. Hibernation increased plasma apolipoprotein A-I expression and HDL particle size. Expression of cholesterol 7 alpha-hydroxylase was 13-fold lower in hibernators than in active season squirrels. Plasma triglycerides were reduced by fasting in spring but not summer squirrels. In hibernators plasma β-hydroxybutyrate was elevated during torpor whereas triglycerides were low relative to normothermic states. We conclude that the switch to a lipid-based metabolism during winter, coupled with reduced capacity to excrete cholesterol creates a closed system in which efficient use of lipoproteins is essential for survival

Effects of platinum/taxane based chemotherapy on acute perfusion in human pelvic tumours measured by dynamic MRI

Dynamic contrast enhanced MRI (DCE-MRI) is being used increasingly in clinical trials to demonstrate that vascular disruptive and antiangiogenic agents target tumour microcirculation. Significant reductions in DCE-MRI kinetic parameters are seen within 4–24 and 48 h of treatment with vascular disruptive and antiangiogenic agents, respectively. It is important to know whether cytotoxic agents also cause significant acute reductions in these parameters, for reliable interpretation of results. This study investigated changes in transfer constant (Ktrans) and the initial area under the gadolinium curve (IAUGC) following the first dose of chemotherapy in patients with mostly gynaecological tumours. A reproducibility analysis on 20 patients (using two scans performed on consecutive days) was used to determine the significance of DCE-MRI parameter changes 24 h after chemotherapy in 18 patients. In 11 patients who received platinum alone or with a taxane, there were no significant changes in Ktrans or IAUGC in either group or individual patient analyses. When the remaining seven patients (treated with a variety of agents including platinum and taxanes) were included (n=18), there were also no significant changes in Ktrans. Therefore, if combination therapy does show changes in DCE-MRI parameters then the effects can be attributed to antivascular therapy rather than chemotherapy