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PubMed2006

The quest for the universals of protein evolution.

The sequences of proteins change at dramatically different rates. Unraveling the association between this variability and cellular and ecological processes will enable a better understanding of protein function and evolution. Although weak associations of protein evolutionary rates with a plethora of variables have been reported, none withstands comparison with the effect of expression levels. A recent report by Drummond et al. suggests that the dominant role of expression levels in slowing the rate of protein evolution stems from selection for translation robustness.

Animals↗
PubMed2005

New horizons for (p)ppGpp in bacterial and plant physiology.

A hyperphosphorylated guanosine nucleotide, (p)ppGpp, was initially identified as the effector molecule responsible for the stringent response in Escherichia coli. However, a rapidly growing number of reports proves that (p)ppGpp-mediated regulation is conserved in many bacteria and even in plants. It is now clear that (p)ppGpp acts as a global regulator during physiological adaptation of the organism to a plethora of environmental conditions. Adaptation is not only essential for surviving periods of stress and nutrient exhaustion but also for the interaction of bacteria with their eukaryotic host, as observed during pathogenesis and symbiosis, and for bacterial multicellular behaviour. Recently, there have been several new discoveries about the effects of (p)ppGpp levels, balanced by RelA-SpoT homologue proteins, in diverse organisms.

Arabidopsis↗
PubMed2006

Thermophiles like hot T.

A plethora of mechanisms confer protein stability in thermophilic microorganisms and, recently, it was suggested that these mechanisms might be divided along evolutionary lines. Here, a multi-genome comparison shows that there is a statistically significant increase in the proportion of NTN codons correlated with increasing optimal growth temperature for both Bacteria and Archaea. NTN encodes exclusively non-polar, hydrophobic amino acids and indicates a common underlying use of hydrophobicity for stabilizing proteins in Bacteria and Archaea that transcends evolutionary origins. However, some microorganisms do not follow this trend, suggesting that alternate mechanisms (e.g. intracellular electrolytes) might be used for protein stabilization. These studies highlight the usefulness of large-scale comparative genomics to uncover novel relationships that are not immediately obvious from protein structure studies alone.

Amino Acid Sequence↗
PubMed2005

Techniques: high-throughput measurement of intracellular Ca(2+) -- back to basics.

High-throughput screening techniques continue to provide important tools to the pharmaceutical industry for the efficient identification of drug leads. However, high-throughput techniques are now being exploited to address a variety of pharmacological and cellular signaling research questions, including the regulation and role of intracellular Ca(2+) in a plethora of biological systems. Although an awareness of specific assay conditions is crucial for reliable and reproducible measurements of intracellular free Ca(2+) whichever system of study is used, the complex temporal nature of Ca(2+) signals has posed some unique limitations for its measurement in high-throughput mode. Progress in high-throughput design has overcome many of these limitations and will complement other technical approaches to understanding the underlying regulation and role of intracellular Ca(2+).

Animals↗
PubMed2006

Multilevel modulation of the mevalonate and protein-prenylation circuitries as a novel strategy for anticancer therapy.

The important role of the mevalonate and protein-prenylation circuitries in the process of carcinogenesis is increasingly being recognized. Accordingly, several enzymes within these pathways have been pharmacologically targeted for anticancer drug development. Despite promising activity in a plethora of preclinical models, clinical evaluation of these agents as monotherapy against various malignancies has been disappointing. Appropriate combinations of inhibitors of isoprenoid biosynthesis, inhibitors of prenylation and postprenylation modifications might be a more clinically effective strategy for anticancer therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Differential polyamine analogue effects in four human breast cancer cell lines.

Polyamine analogues have demonstrated anti-tumour activity in a number of solid tumour models. In the present study we compared the cytotoxicities of three polyamine analogues against four breast cancer cell lines. All cell lines are derived from tumours of women with breast cancer and, although we are sampling just a small number of tumours, they represent a spectrum of the genetic plethora of breast cancers. Cytotoxicity, over a dose range from 0.1 to 100 microM, was evaluated with three different cytotoxicity assays performed in 96-well plates. Comparing the effects of the analogues on polyamine pools with data from the cytotoxicity assays indicates that there was not a direct correlation between polyamine pool depletion and cytotoxicity. Flow cytometry was used to investigate analogue-induced cell death as measured by the appearance of a sub-G(1) peak. Induction of cell death by the analogues differed in the cell lines, however, cell death when induced was apoptotic, as demonstrated by detection of apoptotic bodies with immunofluorescence microscopy of propidium iodide-stained nuclei. Comparing the flow cytometry-derived data and the data from the cytotoxicity assays reveals that the analogues exert their effects by inhibiting cell growth and/or inducing cell death.

Antineoplastic Agents↗
PubMed2004

Chemical weapons: documented use and compounds on the horizon.

Man's inhumanity to man is expressed through a plethora of tools of modern warfare and terror. The use of chemical and biological weapons with the goals of assault, demoralisation and lethality has been documented in recent history, both on the battlefield and in urban terror against civilians. A general review of a few of the currently employed chemical weapons and biological toxins, along with a look at potential chemical weapons and tools of counter-terrorism, follows. While these weapons are fearsome elements, the dangers should be viewed in the context of the widespread availability and efficacy of conventional weapons.

Animals↗
PubMed2004

Challenges to environmental toxicology and epidemiology: where do we stand and which way do we go?

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.

Animals↗
PubMed2005

Oxygen carriers: a selected review.

The most common and widely transplanted tissue world wide is blood, which in 2000 resulted in the transfusion of 12.5 million units of blood in the US alone [Goodnough LT, Shander A, Brecher ME. Transfusion medicine: looking to the future. Lancet 2003;361:161-9]. The current use of donated blood products is relatively safe; however, there are inherent problems with allogeneic blood transfusions. The wide spread use of blood in procedures results in problems involving inadequate supply exacerbated in times of war and disasters and by the limited storage life of blood donations (30-42 days). Blood contamination due to patient pre-disposition, poor collection, sterilization, or storage is the second most common cause of death from transfusion in the US [Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: joint ASH and AABB educational session in transfusion medicine. Hematology (Am Soc Hematol Educ Program) 2003:575-89]. Blood is a complex tissue involved in a plethora of homeostatic roles, including immunity, wound healing and the transport of nourishment, electrolytes, hormones, vitamins, heat, oxygen and the removal of metabolic waste products. However, by far the principle role of blood transfusions is the replacement of red cell volume and the maintenance of oxygen levels within the circulation. Creation of investigational new drugs (INDs) which would function as oxygen carriers and prolong shelf life is now a very active arena of scientific research. Several such IND products are now in clinical trials. This article gives an easy to follow concise evaluation of major areas of focus and current testing for each type of blood substitution molecule.

Bacterial Infections↗
PubMedDate not supplied

Statins and cholesterol lowering after a cancer diagnosis: why not?

The pleiotropic effects of statins continue to garner attention. One area of interest that requires more attention is their potential, or that of another heart healthy agent, to impact favorably or inhibit the progression of numerous cancers, especially prostate cancer. Statins have accumulated a plethora of data in the area of general cancer cell line inhibition, and the potential to have a synergistic impact in patients receiving a variety of conventional treatments for a diversity of cancers is endorsed at least by laboratory and some preliminary small clinical studies. However, prostate cancer is unique compared to other cancers because, despite a high prevalence, some men choose watchful waiting or no treatment, especially if they are older and/or have a well-differentiated tumor. Thus, prostate cancer is a good candidate for the potential investigation of statins after diagnosis, with or without standard therapy. Regardless, because the number 1 or 2 cause of death in men with prostate cancer is cardiovascular disease than even in the worst-case scenario, these agents appear attractive for more immediate clinical study because they could impact a major cause of morbidity and mortality in these men. It is time to see the forest over the tree, and statins seem to have an argument as good as many other agents for allocating more money and time to test their ability as adjuvant therapy in a randomized trial or, in some cases, of nonaggressive disease as a potential monotherapy.

Anticarcinogenic Agents↗
PubMedDate not supplied

Nonclinical proarrhythmia models: predicting Torsades de Pointes.

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I(Kr) (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.

Animals↗
PubMed2004

Molecular and genetic regulation of testis descent and external genitalia development.

Testicular descent as a prerequisite for the production of mature spermatozoa and normal external genitalia morphogenesis, and therefore facilitating copulation and internal fertilization, are essential developmental steps in reproduction of vertebrate species. Cryptorchidism, the failure of testis descent, and feminization of external genitalia in the male, usually in the form of hypospadias, in which the opening of the urethra occurs along the ventral aspect of the penis, are the most frequent pediatric complications. Thus, elucidating the molecular mechanisms involved in the regulation of testis descent and the formation of external genitalia merits a special focus. Natural and transgenic rodent models have demonstrated both morphogenic processes to be under the control of a plethora of genetic factors with complex time-, space-, and dose-restricted expression pattern. The review elucidates the molecular mechanisms involved in the regulation of testis descent and the formation of external genitalia and, wherever possible, assesses the differences between these rodent animal models and other mammalian species, including human.

Androgens↗
PubMed2004

Smad2 and Smad3 coordinately regulate craniofacial and endodermal development.

Ligands of the transforming growth factor-beta (TGF-beta) superfamily are involved in numerous developmental and disease processes. TGF-beta, activins, and nodal ligands operate through the highly homologous Smad2 and Smad3 intracellular mediators. Smad2 mutants exhibit early embryonic lethality, while Smad3 mutants are viable, but show a plethora of postnatal phenotypes, including immune dysfunction and skeletal abnormalities. Previously, we have shown that the Smad2 and Smad3 genes function cooperatively during liver morphogenesis. Here we show that Smad2 and Smad3 are required at a full dosage for normal embryonic development. Animals lacking one allele of each gene exhibit a variably penetrant phenotype in which structures in the anterior and ventral midline are reduced or lost; additionally, we demonstrate that this craniofacial defect and the previously reported hepatic phenotypes are both due to defects in the definitive endoderm. A reduction of endodermal gene expression as well as a failure to displace the visceral endoderm occurs despite the formation of a normal foregut pocket. This precedes any defects in anterior patterning and likely causes the abnormalities observed in craniofacial and midline development, as well as hepatogenesis.

Animals↗
PubMed2006

RTK and TGF-beta signaling pathways genes in the sea urchin genome.

The Receptor Tyrosine kinase (RTK) and TGF-beta signaling pathways play essential roles during development in many organisms and regulate a plethora of cellular responses. From the genome sequence of Strongylocentrotus purpuratus, we have made an inventory of the genes encoding receptor tyrosine kinases and their ligands, and of the genes encoding cytokines of the TGF-beta superfamily and their downstream components. The sea urchin genome contains at least 20 genes coding for canonical receptor tyrosine kinases. Seventeen of the nineteen vertebrate RTK families are represented in the sea urchin. Fourteen of these RTK among which ALK, CCK4/PTK7, DDR, EGFR, EPH, LMR, MET/RON, MUSK, RET, ROR, ROS, RYK, TIE and TRK are present as single copy genes while pairs of related genes are present for VEGFR, FGFR and INSR. Similarly, nearly all the subfamilies of TGF-beta ligands identified in vertebrates are present in the sea urchin genome including the BMP, ADMP, GDF, Activin, Myostatin, Nodal and Lefty, as well as the TGF-beta sensu stricto that had not been characterized in invertebrates so far. Expression analysis indicates that the early expression of nodal, BMP2/4 and lefty is restricted to the oral ectoderm reflecting their role in providing positional information along the oral-aboral axis of the embryo. The coincidence between the emergence of TGF-beta-related factors such as Nodal and Lefty and the emergence of the deuterostome lineage strongly suggests that the ancestral function of Nodal could have been related to the secondary opening of the mouth which characterizes this clade, a hypothesis supported by functional data in the extant species. The sea urchin genome contains 6 genes encoding TGF-beta receptors and 4 genes encoding prototypical Smad proteins. Furthermore, most of the transcriptional activators and repressors shown to interact with Smads in vertebrates have orthologues in echinoderms. Finally, the sea urchin genome contains an almost complete repertoire of genes encoding extracellular modulators of BMP signaling including Chordin, Noggin, Sclerotin, SFRP, Gremlin, DAN and Twisted gastrulation. Taken together, these findings indicate that the sea urchin complement of genes of the RTK and TGF-beta signaling pathways is qualitatively very similar to the repertoire present in vertebrates, and that these genes are part of the common genetool kit for intercellular signaling of deuterostomes.

Amino Acid Sequence↗
PubMed2006

The UBX-regulated network in the haltere imaginal disc of D. melanogaster.

Hox proteins have been proposed to act at multiple levels within regulatory hierarchies and to directly control the expression of a plethora of target genes. However, for any specific Hox protein or tissue, very few direct in vivo-regulated target genes have been identified. Here, we have identified target genes of the Hox protein Ultrabithorax (UBX), which modifies the genetic regulatory network of the wing to generate the haltere, a modified hindwing. We used whole-genome microarrays and custom arrays including all predicted transcription factors and signaling molecules in the Drosophila melanogaster genome to identify differentially expressed genes in wing and haltere imaginal discs. To elucidate the regulation of selected genes in more detail, we isolated cis-regulatory elements (CREs) for genes that were specifically expressed in either the wing disc or haltere disc. We demonstrate that UBX binds directly to sites in one element, and these sites are critical for activation in the haltere disc. These results indicate that haltere and metathoracic segment morphology is not achieved merely by turning off the wing and mesothoracic development programs, but rather specific genes must also be activated to form these structures. The evolution of haltere morphology involved changes in UBX-regulated target genes, both positive and negative, throughout the wing genetic regulatory network.

Animals↗
PubMed2006

HIV-1 Nef protects human-monocyte-derived macrophages from HIV-1-induced apoptosis.

HIV-1 Nef is the regulatory protein expressed earliest and most abundantly in the infection cycle. Its expression has been correlated with a plethora of effects detectable either in producer, target, and bystander cells, as well as in the viral particles. Even if the relationship between Nef expression and apoptosis has been already matter of investigation in infected lymphocytes, whose resistance to HIV infection is however limited to few days, this remains to be investigated in cells that in vivo well resist the HIV cytopathic effect. In such an instance, we were interested in establishing whether Nef influences the apoptotic processes in primary human-monocyte-derived macrophages (MDM). High efficiency HIV-1 infection of MDM allowed us to establish that virus-expressed Nef strongly counteracts the HIV-1-induced apoptosis. The Nef mutant analysis suggested that this effect relies on the interaction with different protein partners and cell compartments. We also observed that the Nef protection to the HIV-1-induced apoptosis correlated with the hyper-phosphorylation and consequent inactivation of the pro-apoptotic Bad protein. On the basis of these results, we propose the Nef anti-apoptotic effect as a relevant part of the mechanism of the in vivo establishment of the HIV macrophage reservoirs.

Adult↗
PubMed2006

Parathyroid hormone-related protein in teleost fish.

A brief description is given of the discovery of PTHrP and the roles of the peptide in mammalian physiology. Next, the occurrence of PTHrP in the earliest vertebrates, sharks, skates and fishes, is reviewed and the calciotropic functions of PTHrP are addressed more specifically in fishes. Parathyroid hormone-related protein (PTHrP) is a hypercalcemic hormone in teleostean fishes, but also has para- and autocrine functions. After the isolation and identification of fish PTHrP and PTHrP receptors and the subsequent development of recombinant protein and a real-time quantitative PCR, a calciotropic role of PTHrP in fish physiology could be assessed. PTHrP influences calcium physiology via regulation of calcium mobilisation from internal sources (bone and scales) and via calcium uptake from the environment (water and diet). Continuous variations in the need for calcium and in the availability of environmental calcium require fast calciotropes to guarantee calcium balance, in which PTHrP is pivotal for the fish. PTHrP is essential in fish bone physiology, e.g. in mineralisation and calcium reabsorption from the scales. Moreover, PTHrP plays a role in vitellogenesis, cortisol production, regulation of renal Mrp2 activity and melatonin synthesis. The plethora of functions of PTHrP in fish concern endocrine, paracrine and autocrine (and possibly intracrine) functions; calciotropic actions of PTHrP at the organismal and cellular level are prominent in fish. The strong conservation of the pthrp gene in the vertebrate lineage and the N-terminal similarity of the coded proteins relates to the important role of PTHrP in calcium physiology that is of paramount importance to all physiological processes. Recent and ongoing studies will contribute to our rapidly expanding knowledge of the original physiological functions of PTHrP in teleost fish.

Animals↗
PubMed2005

Role of pegylated liposomal doxorubicin in ovarian cancer.

OBJECTIVES: Safe, effective treatments are needed for relapsed ovarian cancer. Goals include improving symptoms, enhancing quality of life, and prolonging survival. The plethora of agents currently available present difficult choices for physicians. The present effort seeks to examine the role of one of these agents, pegylated liposomal doxorubicin. METHODS: A roundtable meeting of experts in the management of ovarian carcinoma was held to build consensus around the present and future role of pegylated liposomal doxorubicin for ovarian cancer and other gynecologic malignancies. RESULTS: Pegylated liposomal doxorubicin is effective and well tolerated in relapsed ovarian cancer. When compared with topotecan in a phase III randomized trial, pegylated liposomal doxorubicin showed several advantages: improved quality of life, fewer severe adverse events, fewer dose modifications, less hematologic support, and lower total cost per patient. In platinum-sensitive patients, pegylated liposomal doxorubicin also produced a survival advantage. Results from prospective and retrospective studies further demonstrate the improved cardiac safety of pegylated liposomal doxorubicin compared to conventional anthracyclines. CONCLUSIONS: Based on survival and toxicity advantages and a once-monthly administration schedule, pegylated liposomal doxorubicin is the first-choice nonplatinum agent for relapsed ovarian cancer. Pegylated liposomal doxorubicin may also have clinical application in combination regimens for platinum-sensitive ovarian cancer, as consolidation/maintenance therapy for ovarian cancer, as a component of first-line therapy for ovarian cancer, and in the treatment of other gynecologic malignancies. Future clinical trials will further define and maximize the role of pegylated liposomal doxorubicin in the treatment of ovarian cancer and other gynecologic malignancies.

Antibiotics, Antineoplastic↗