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Vice Chair, Loyola University Chicago Stritch School of Medicine

Zinc appears to be absorbed by both passive diffusion and a saturable carrier-mediated process (Tacnet et al. Metallothionein may be involved in zinc homeostasis at higher zinc concentrations (Richards and Cousins, 1975; Hempe and Cousins, 1992). Metallothionein production is increased in response to an increase in zinc levels as well as by other heavy metals (Richards and Cousins, 1975; Cousins, 1985). The exact role of metallothionein in zinc absorption is not known, but it is thought to regulate zinc availability by sequestering it in the intestinal mucosal cells, thereby preventing absorption and providing an exit route for excess zinc as these cells are shed and excreted in the feces (Foulkes and McMullen, 1987). Evans (1976) proposed that zinc bound to ligands is transported into epithelial cells where the metal is transferred to the binding site on the plasma membrane. Metal-free albumin then interacts with the plasma membrane and removes zinc from the receptor site. The quantity of metal-free albumin available probably determines the amount of zinc removed from the epithelial cell, and thus regulates the quantity of zinc that enters the body. Several dietary factors can influence zinc absorption, including other trace elements. High levels of phytate or phosphate in the diet can decrease the amount of zinc absorbed (Pecoud et al. Oberleas (1996) suggested that the phytate in the food provided to test subjects complexes with endogenous zinc ions secreted from the pancreas, thus preventing its reabsorption and increasing fecal zinc elimination. In general, low molecular weight substances, such as amino acids, increase the absorption of zinc (Wapnir and Stiel, 1986). Imidazole, tryptophan, proline, and cysteine increased zinc absorption from various regions of the gastrointestinal tract. Wapnir and Stiel (1986) suggested that the increase was due to the presence of both mediated and non-mediated transport mechanisms for amino acids. Fractional absorption was significantly lower in young adult mice (70 days of age) and in adult mice (100 days of age) compared to weanling mice (1 day of age); fractional absorption in adolescent mice (20 days of age) was similar to that found in weanlings. Respiratory Tract Absorption Hamdi (1969) found elevated levels of zinc in the urine and blood of workers exposed to zinc oxide fumes, relative to non-exposed workers. Although this study did not estimate zinc absorption efficiency, it does provide evidence that zinc is absorbed following inhalation exposure. Similarly, Drinker and Drinker (1928) found elevated levels of zinc in the gall bladder, kidney, and pancreas of cats, rabbits, and rats exposed to airborne zinc oxide. Retention is reflective of deposition of zinc oxide in the lung rather than systemic absorption (Hirano et al. Species differences in retention have been observed; guinea pigs, rats, and rabbits retained 20, 12, and 5%, respectively, following nose-only exposure to 11. In humans, the highest concentrations of zinc have been found in bone, muscle, prostate, liver, and kidneys (Schroeder et al. Approximately 98% of serum zinc is bound to proteins; 85% is bound to albumin, 12% to "2-macroglobulin, and the remainder to amino acids (Giroux et al. In 8 erythrocytes, zinc is predominantly found as a component of carbonic anhydrase (87%) and Cu, Zn-superoxide dismutase (5. While small increases in tissue zinc levels relative to controls were reported, only occasionally were the differences statistically significant, and no pattern with increasing tissue zinc with time was noted. Exposure to 1200 ppm had no significant effect on tissue zinc levels relative to controls; the amount of stable zinc in liver, kidney, and bone was increased at 2400 ppm and higher, but reached a plateau (2400-7200 ppm; approximately 200-625 mg/kg-day). Exposure at the highest level (8400 ppm) caused additional increases in liver, kidney, and bone, as well as an increase in zinc level in the heart. Similar results for the accumulation of zinc in organs have been found in mice (He et al. In a series of animal experiments carried out by Drinker and Drinker (1928), the fate of inhaled zinc oxide from the lungs of animals (cats, rabbits and rats) was assessed. Increased zinc levels were found in the lungs, pancreas, liver, kidney, and gall bladder.

Secondly, there are mutations in the tumour suppressors, which are inhibitory components that normally act to inhibit proliferative signalling pathways. Thirdly, there are mutations in the signalling system that detect aberrant cells and remove them from the cell cycle by inducing either senescence or apoptosis. In order for a cancer cell to develop, it has to evade both the normal immune surveillance system and the internal control mechanisms that remove most cancer cells before they proliferate to form tumours. Therefore cancer arises from different combinations of activated oncogenes, inactivated tumour suppressor genes and the development of various anti-apoptotic mechanisms, which explains why therapeutic strategies have proven to be so difficult to devise, because cancer is a multifactorial disease and no two cancers are the same. Nevertheless, there clearly are well-defined cancer cell phenotypes that have proved very important in providing clues as to how a typical cancer cell develops. When this tight regulation on proliferation and apoptosis breaks down, the aberrant cell begins to proliferate and forms a large clone of cells that we recognize as a cancerous growth. Cells remain as a tight mass when the modifications are benign, but once they become malignant they migrate away to invade other regions of the body with disastrous consequences. The tumour cell microenvironment plays a special role in not only maintaining the tumour but may also contribute to the onset of metastasis. An important aspect of this microenvironment is the activation of tumour angiogenesis to provide the tumour with a supply of blood. A relationship between inflammation and cancer may also be a significant feature of the microenvironment in many C 2012 Portland Press Limited X p53 surveillance system switched off The proto-oncogenes that provide the positive signals to drive cells into the cell cycle are mutated into constitutively active oncogenes, whereas the tumour suppressors and the anti-proliferative signalling pathways are inactivated. In cancer, the cell-fate pathways of senescence, apoptosis and differentiation are also switched off by inactivation of the p53 surveillance system, thus leaving the developing cancer cells with no other option than to continue proliferating. Cancer depends on enhanced proliferation and decreased apoptosis the development of a cancer cell occurs through a series of discrete steps that gradually alter the normal signalling pathways that operate on the cell cycle network to control both cell proliferation and cell fate (primarily apoptosis). These signalling systems not only determine whether or not a cell should divide, but also decide on what happens to the two daughter cells once they exit the cell cycle after completing mitosis (Module 9: Figure cell cycle network). Emergence of a cancer cell signalsome depends on two major changes: there must be an increase in cell proliferation and a decrease in apoptosis (Module 12: Figure the cancer signalsome). Cancer cells begin to emerge when this genomic instability results in the accumulation of mutations in protooncogenes and tumour suppressors (Module 12: Figure cell cycle network and cancer). For example, one of the essential steps in the development of cancer is the expression of telomerase, which thus allows the emerging cancer cell to escape replicative senescence (Module 11: Figure senescence). Cancer is a multistep process because a number of signalling systems have to be altered in order to achieve both the increased growth potential and to switch off alternative non-proliferating cell fates. Cancer is a multistep process Almost all cancers are clonal in that they descend from a single abnormal cell that has undergone the multistep genetic modifications that enable it both to proliferate and to switch off other cell fates, such as differentiation, senescence and apoptosis. This transformation of cells with multiple potential fates into a cell that has a single-track proliferative fate depends upon multiple mutations dispersed throughout the many control systems that regulate the cell cycle network (Module 9: Figure cell cycle network). It has been estimated that between four and seven mutations are necessary for a cancer cell to develop. These multistep genetic changes occur relatively slowly as the cell gradually transforms into a cancer cell. Normal cell proliferation depends upon a number of positive and negative signalling systems that operate on the cell cycle network. Berridge r Module 12 r Signalling Defects and Disease 12 r48 exert both positive and negative control of the cell cycle. During the development of cancer, mutations occur in both these positive and negative signalling systems (Module 12: Figure cell cycle network and cancer). Mutations of the proto-oncogenes convert them into oncogenes that are constitutively activated to stimulate the cell cycle independently of growth factors. Inactivation of tumour suppressors removes their negative effects on cell cycle progression. Activation of proliferation alone will not lead to cancer, because the internal surveillance system mainly operated by p53 detects cells with abnormal growth potential and shunts them off towards either senescence or p53-induced apoptosis.

Many biological materials fall into the category of dangerous goods for shipping purposes. All individuals involved in the transport of dangerous goods or the preparation of dangerous goods for transport must be trained to do so properly and safely. In addition, the Biosafety Office requires safe transport of items within facilities and around campus. General guidelines for transport of Biological Materials on campus: Double contain the items in plastic leak-proof containers within sturdy outer packaging. Include absorbent material within the containers as well as padding to minimize movement of the container(s) within the outer packaging. Wipe the outer container with an appropriate disinfectant before removing it from the laboratory and apply a biohazard sticker if applicable. Training ensures successful shipments to the recipient since carriers or Federal regulators may open, delay or reject the shipment if not packaged/labeled correctly. In addition, violations of the shipping regulations may result in civil penalties of $250 - $27,500 per violation per day, and/or criminal penalties for willful violations, up to $500,000 and 5 years in jail. To register for the on-line Shipping and Transport of Biological Materials course send an email bso@ehs. All individuals involved in the transport of dangerous goods or the preparation of dangerous goods for transport must abide by the International Air Transport / International Civil Aviation and Dept. Biological Materials Under this Definition: Biological toxins Infectious substances Diagnostic specimens Biomedical waste Cultures Genetically Modified Organisms Other Regulated Biological Material: Plants Plant pests Insects Cell cultures Live animals Other Regulated Items Accompanying Biological Material Shipment: Dry ice Environmental pollutants (formalin) Alcohol Fixative solutions If shipping radioactives, call 392-7359. General guidelines Double contain the items in plastic leak-proof containers within sturdy outer packaging. Individuals transporting biohazardous agents should be knowledgeable about handling spills. These agents also require registration with the Biosafety Office by submission of a biological agent registration form and a copy of the current permit/notification and permit conditions that have been granted by that agency. The Principal Investigator is responsible for obtaining and maintaining valid permits. In addition, a permit is also required for the interstate movement of microorganisms infectious to livestock/poultry including bacteria, viruses, protozoa, fungi, arthropod vectors of livestock/poultry diseases, and tissues, blood, serum, or cells from known infected livestock/poultry. Note: A courtesy letter to the Florida Department of Agriculture and Consumer Services Division of Animal Industry is required for possession or use of any of the State of Florida reportable animal diseases. Fish & Wildlife Service issues permits under various wildlife laws and treaties at different offices at the national, regional, and/or wildlife port levels. Florida Department of Agriculture and Consumer Services A Division of Plant Industry Permit is required for the import into Florida of: arthropods, plant pathogens, nematodes, noxious weeds, genetically altered (insects, nematodes, plants, plant pests) organisms and biological control agents. Bioagent Export Control Export of Etiologic Agents of Humans, Animals, Plants and Related Materials is regulated by the U. A wide variety of etiologic agents of human, plant and animal diseases, including genetic material, and products which might be used for culture or production of biological agents, will require an export license. Furthermore disclosing (including oral or visual disclosure) of controlled information to a non-U. The registration is a means to initiate a risk assessment of the project, and to ensure that these materials are handled properly and disposed of appropriately. Project registration categories include Biological Agents, Recombinant and Synthetic Nucleic Acid Molecules, and Acute Toxins. Research use of human blood, cells, or other tissues that are known to be positive for any human disease agent Recombinant and Synthetic Nucleic Acid Registration Use of the materials listed below requires that the principal investigator complete and submit the Recombinant or Synthetic Nucleic Acid registration form for approval. An exception to the registration requirement is the use of purchased or transferred. Acute Toxin Registration Use of the following materials requires that the principal investigator complete and submit the Acute Toxin registration form for approval. A Standard Operating Procedure Template for documenting this information has been developed. Bacterial toxins: a table of lethal amounts; Microbiological Reviews 46:86-94 Stirpe, F. Project site listing: manufacture (if applicable) area, storage area, administration area, as well as laboratory.

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