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AEI currently utilizes a RIEGL VZ400 Terrestrial Laser Scanner on various job sites.  This proecss utilizes a high accuracy 3D terrestrial LiDAR unit.  The data collected will be brought into a feature extraction software, TopoDOT.  TopoDOT utilizes a variety of tools to identify adn quickly extrapolate features within pointcloud data.  All features can then be imported into an AutoCAD drawing file.  AEI can provide an accurate 3D pointcloud of terrain plus any existing building or structures.  The pointcloud can also be converted for Building Information Models.

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Allen Engineering is involved with the civil design and surveying for the new park in Palm Bay, Flordia.  This Regional Park will feature 150 full service campsite hookups and is scheduled to break ground in 2018.  We are extremely proud to be involved in this project.

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Allen Engineering is beginning its 21st year associated with the Space Coast Post of the Society of American Military Engineers (SAME).  During our 21 years, we have helped raise over $350,000 in scholarships and endowments.  We are extremely proud to be associated with SAME and its continued commitment to offer opportunities for students pursuing careers in the engineering field.


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By: Stephen R. Thompson, MD, MEd, FRCSC

  • Cooperating Associate Professor of Sports Medicine, University of Maine
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  • Deputy Editor, The Journal of Bone and Joint Surgery
  • Eastern Maine Medical Center Bangor, Maine
  • Cofounder and Codirector, Miller Review Course Part II, Denver , Colorado

A popular advance on this technique involves the use of radiolabels to arthritis relief for back pain 15 mg meloxicam for sale tag each bead arthritis medication lung damage cheap meloxicam 7.5mg without prescription, thus allowing a rapid handling of each bag arthritis can diet help buy discount meloxicam 7.5mg. More recent developments involve synthesis in multiwell plates on automated synthesizers degenerative arthritis in neck and spine generic meloxicam 15mg online. In general, the pharmaceutical industry has turned to this technique, using discrete molecules in a high-throughput format. This technique has been facilitated by the development of large-scale machine-based organic synthesizers. Gene technology has been developed to generate knockout mice that lack a specific protein of interest; however, the mouse must reach development without the aid of this protein and often this gene is required for proper development. Furthermore, it is often more desirable to study the biologic effect in a cell line before proceeding to an animal model. The most common, often used in the pharmaceutical industry, is high-throughput screening. This method often involves an automated assay based on affinity or some related in vitro cell-based or cell-free phenotype and a large library of chemical compounds. These chemicals may originate from a natural product isolation, combinatorial synthesis, or an in-house library grown over many years of chemical development. Such a library can be a great place to start to determine whether a molecule or class of molecules with affinity for either the receptor of interest or a closely related receptor from the same family has already been identified. In the case in which no known inhibitor exists for the class of receptor of study, or for identifying a novel inhibitor for a specific receptor, then access to chemical diversity is essential. Because this chapter is intended for a nonchemical audience, we discuss methods of buying chemical diversity. Once a natural peptide inhibitor is identified, peptidomimetic strategies can be used to identify nonpeptide inhibitors. The development of nonpeptide inhibitors is usually performed by the further analysis of molecules that mimic the functional nature of the peptide, yet eliminate the poor drug-like qualities of the peptides. One popular and potentially very powerful modification of peptides to improve function and biologic activity is the cyclization of the peptide, which results in a cyclic peptide with a limited number of ground-state conformations and a reduced susceptibility to proteases. However, the cyclization may result in locking the peptide in an inactive conformation, limiting the success of the method. For this reason, many individuals begin screening with cyclized libraries rather than cyclizing a linear peptide. This can even be achieved in phage display by using a randomized peptide sequence that is flanked by cysteine residues. Once the phage is secreted from the cell, the flanking cysteine residues form a disulfide bond and create a cyclic structure. Peptidomimetics has become one of the most studied areas of molecular recognition. It is often found that the product of nature lacks the specificity that is desired for therapeutic activity. Combinatorial chemistry offers the possibility of developing a more specific inhibitor using the chemical nature of the natural product as a good starting point for diversity. However, the modification of a natural product or the construction of a novel library based on a natural product is chemically intensive and usually requires collaboration with a chemistry laboratory or pharmaceutical company. The formula for diversity, in any library, can be described as the number of monomer units raised to the power of the number of variable positions. For example, if we chemically synthesize a heptapeptide library using all 20 natural amino acids, our library will contain 20 7 or 1. If we use phage display to create the same heptapeptide library, we must account for the redundancy of the genetic code and consider each codon as a monomer unit. Proper design of the library and use of the wobble position can reduce the required number of codons to 32, reducing the diversity to 32 7, or 3. The Mathematics of Chemical Diversity a It is important to consider the size and chemical diversity of the library. There is increasing data to suggest that it is more important for a library to be diverse than to be large. In all likelihood, the epitope is likely to be smaller than the total positions varied. Some phage display libraries contain 12 randomized amino acids, with no hope of containing that diversity. Yet these libraries are very useful for the identification of discontinuous epitopes within the same peptide. In summary, phage display offers the most accessible first entry into chemical diversity, but often it must be followed up with a synthetic library. A hit is defined as a molecule that shows activity in an assay below a certain activity level. High-throughput screening of chemical compounds emerged in the early 1990s to aid the rapid evaluation of the large chemical stocks that were being amassed in the pharmaceutical industry. The high-throughput assay is usually an in vitro assay, although it is not necessarily cell-free. Once a molecule has been identified as a hit, it is evaluated by a medicinal chemist who begins a synthetic effort to obtain a structure activity relationship for the molecule. If the activity of the initial hit can be optimized for in vitro activity, the molecule becomes a "lead" molecule. Although each pharmaceutical company and, indeed, each therapeutic target has different criteria for the categorization of a lead molecule, the development process is basically the same. Once a lead is identified, a series of in vivo tests and further development take place to determine whether the chemical lead has the proper pharmacologic properties and in vivo efficacy to become an actual drug. This approach involves the synthesis of secondary libraries, synthesized in a manner that allow the randomization of chemical functionality that was not, or could not be, addressed in the first library.

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In children arthritis in neck c6 cheap meloxicam 7.5 mg visa, esophageal perforation results most frequently from iatrogenic causes psoriatic arthritis medication side effects order meloxicam 15mg visa, but may also be caused by penetrating and blunt trauma arthritis knee exercises pdf purchase meloxicam 7.5mg fast delivery. Esophageal injury may also occur as a complication of foreign bodies or caustic ingestions hip arthritis definition purchase meloxicam 15 mg. In children with a history of button battery ingestion, ongoing progression of esophageal injury, even after the operative removal of the battery, has been reported. Progression of esophageal injury has been reported days to weeks after removal of esophageal button batteries, resulting in serious sequelae, including esophageal perforation and aortoesophageal fistula formation. Clinical features of esophageal perforation may include neck pain and/or stiffness, chest pain, epigastric pain, abdominal guarding, hematemesis, odynophagia, drooling, or dyspnea. Physical examination findings may include crepitus noted on palpation of the neck and/or chest wall, asymmetric breath sounds (which may indicate a concurrent pneumothorax), coarse lung sounds, wheezing, tachycardia, tachypnea, or signs of respiratory distress. Aspiration pneumonia is an infection of the lung parenchyma that develops as a sequela of inhaling foreign material, often due to oropharyngeal bacteria. Signs and symptoms include fever, cough, tachypnea, respiratory difficulty, and hypoxia; symptoms typically develop within 1 hour of an aspiration event. The girl in the vignette has had no recent history of choking, aspiration, or recent fevers. She is complaining of pain in her anterior neck, which is not a typical symptom of aspiration pneumonia. Bacterial tracheitis is an exudative bacterial infection involving the soft tissues of the trachea. Affected children may present with pain or difficulty with swallowing, fever, stridor, anterior neck pain, cough, drooling, signs of respiratory distress, or a toxic clinical appearance. Bacterial tracheitis may arise as a complication of viral croup, and should be suspected in children who significantly worsen over the clinical course of a croup infection. Although some of the symptoms displayed by the girl in the vignette may be seen in children with bacterial tracheitis, bloody emesis and the presence of subcutaneous crepitus over the anterior chest wall and neck would not be explained by this diagnosis. A Mallory-Weiss tear, or syndrome, is part of the differential diagnosis for children presenting with hematemesis. The girl in the vignette had acute onset of hematemesis that was not preceded by repeated vomiting and/or forceful retching; this is inconsistent with the clinical picture of Mallory-Weiss syndrome. In addition, the findings of drooling, neck/chest wall crepitus, wheezing, and respiratory distress in this patient cannot be explained by a diagnosis of Mallory-Weiss syndrome. Manifestations of spontaneous pneumothorax include the sudden onset of chest pain and shortness of breath. Physical examination findings include unilateral decreased breath sounds, decreased chest wall movement, and hyperresonance to percussion over the affected lung. Depending on the degree of the pneumothorax (and the presence or absence of tension pneumothorax), affected patients may present with respiratory distress, tachycardia, hypotension, or cyanosis. Spontaneous pneumothorax most commonly affects adolescents and adult men with a tall, thin body habitus. The girl in the vignette has no known risk factors for spontaneous pneumothorax, and her lung examination findings are not consistent with that expected in patients with pneumothorax. Button battery ingestion in children: a paradigm for management of severe pediatric foreign body ingestions. She has a complex medical history consisting of cyanotic congenital heart disease as a newborn, leading to a heart transplant when she was 2 years old. Her physical examination findings are unremarkable aside from a well-healed median sternotomy scar. Calcineurin inhibitors are commonly used in transplant recipients to prevent rejection. Current and recent medications need to be considered when monitoring a patient and considering the etiology of hypertension. Drugs frequently associated with hypertension include corticosteroids, decongestants, nonsteroidal antiinflammatory medications, herbal supplements, -adrenergic agonists, erythropoietin, cyclosporine, tacrolimus, and stimulants (attention-deficit disorder medications). Recent discontinuation of antihypertensive medications can also cause hypertension. Enalapril, mycophenolate mofetil, nystatin, and sulfamethoxazole/trimethoprim do not cause hypertension. His diet consists exclusively of "white foods," notably mashed potatoes, chicken nuggets, and plain macaroni. His physical examination shows an afebrile nonverbal child with diffuse extremity tenderness, without swelling or deformity. He has inflamed gums with mild bleeding, several bruises on his legs, and a hemorrhagic follicular rash on his buttocks. Laboratory findings include normal prothrombin and partial thromboplastin times; a mild microcytic anemia but an otherwise normal complete blood count; normal liver and renal functions; and normal alkaline phosphatase, calcium, and phosphorus levels. Once the diagnosis is confirmed, treatment consists of 100 mg of ascorbic acid (orally, intramuscularly, or intravenously) 3 times per day for 1 week, followed by 100 mg daily for several weeks until symptoms resolve and body stores are repleted. Hypovitaminosis C is rarely seen in developed countries today, though patients with severely restricted diets remain at risk. It has been seen most often in children with neurologic or neurobehavioral conditions such as cerebral palsy and autism. Adolescents with eating disorders, children undergoing dialysis (which removes vitamin C), children with inflammatory bowel disease, and patients receiving unsupplemented parenteral nutrition are also at risk. Vitamin C is involved in collagen synthesis, bone formation, iron absorption, folate metabolism, and neurotransmitter synthesis, among other functions.

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Clefts of the lip and palate are the most 5 common arthritis fruit diet buy generic meloxicam 15mg on line, but many other head and neck congenital deformities exist arthritis pain for dogs buy 15mg meloxicam with amex. In addition arthritis pain control order 7.5 mg meloxicam, the plastic surgeon treats injuries to arthritis knee swelling meloxicam 15mg otc the face, including fractures of craniofacial skeleton. Craniofacial surgery is a discipline developed to reposition and reshape the bones of the face and skull through inconspicuous incisions. Severe deformities of the cranium and face, which previously were uncorrectable or corrected with great difficulty, can now be better reconstructed employing these new techniques. Such deformities may result from a tumor resection, congenital defect, previous surgery, or previous injury. Treatment of tumors of the head and neck and reconstruction of these regions after the removal of these tumors is also within the scope of plastic surgery. Another area of expertise for the plastic surgeon is hand surgery, including the management of acute hand injuries, the correction of hand deformities and reconstruction of the hand. Microvascular surgery, a technique that allows the surgeon to connect blood vessels of one millimeter or less in diameter, is a necessary skill in hand surgery for reimplanting amputated parts or in moving large pieces of tissue from one part of the body to another. Defects of the body surface resulting from burns or from injuries, previous surgical treatment, or congenital deformities may also be treated by the plastic surgeon. One of the most common of such procedures is reconstruction of the breast following mastectomy. Breasts may also be reduced in size, increased in size, or changed in shape to improve the final aesthetic appearance. Operations of this type are sometimes cosmetic in purpose, but in cases where the patient has a significant asymmetry or surgical defect, the procedure serves important therapeutic purposes. Advances such as transplantation, microvascular surgery, fat grafting, and various medical devices have been spearheaded and advanced by plastic surgeons. The discipline requires meticulous attention to detail, sound judgment and technical expertise in performing the intricate and complex procedures associated with plastic surgery. In addition, plastic surgeons must possess a flexible approach that will enable them to work daily with a tremendous variety of surgical problems. Most importantly, the plastic surgeon must have creativity, curiosity, insight, and an understanding of human psychology. The first is through an integrated or categorical plastic surgery residency program. Programs are six years in duration; however, several programs also dedicate one or more years to research. The other route, known as the independent route, is to complete residency in general surgery, otolaryngology, urology, orthopedic surgery, or neurosurgery and then complete a three-year independent plastic surgery residency. After the completion of either the integrated or independent pathway, one is eligible to sit for the plastic surgery board examination. In addition, one can attain further training in a plastic surgery fellowship program. Fellowships are typically one year in duration and are offered for specialty training in hand surgery, craniofacial surgery, microsurgery, facial aesthetics, cosmetic surgery, body contouring surgery, and burn surgery. Traditionally, plastic surgeons have established their practices in large urban settings. However, there is an increasing need for more plastic surgeons in the smaller communities and rural areas of this country - many metropolitan areas with populations of 65,000 to 268,000 have no plastic surgeons, leaving many areas needing plastic surgery expertise. There are approximately 7,000 board certified plastic surgeons in the United States; many of those currently certified by the American Board of Plastic Surgery received certification in the past ten years. Despite this recent rapid growth, there are opportunities for plastic surgeons in community and academic practice. Plastic surgery is an old specialty with references that date back thousands of years. It has survived and flourished because it is a changing specialty built by imaginative, creative and innovative surgeons with a broad background and education. The future of this specialty is bright and will continue to progress because of students like you who choose to enter this special field. Students interested in plastic surgery can find more information from the following: 1) Nagarkar P, Pulikkottil B, Patel A, Rohrich R. Not so much that it may delight the eye, but that it might buoy up the spirit, and help the mind of the afflicted. Key historical figures and milestones are described in the long and illustrious history of the development of the modern innovative field of Plastic Surgery. The term "plastic" in plastic surgery comes from the Greek "plastikos" which translates to "moldable". Ancient plastic surgery has its origins in the management of wounds, with historical reference to sewing wound edges with fibers or wound edges approximated with insect mandibles. The first semblance to modern reconstruction is found in India with nasal reconstruction. Ancient cultures often punished adulterers, thieves and prisoners of war by mutilating their noses as a way of public shaming. He is often credited with descriptions of the first forehead flap for nasal reconstruction, but this is controversial and unknown as the first published report of the forehead flap appears to be in 1794 (figure 1). The middle ages also brought about the advent of western universities which ushered anatomical classes and cadaver dissections, and anatomists as surgeons. Andreas Vesalius publishes his anatomical treatise De Humani Corporis Fabrica (1543). French surgeon Ambrose Pare (1510-1590) compiled his works in Les Oeuvers, in which are described repair of cleft lip and cleft palate, in addition to disputing the practice of "wound cleansing" by hot cautery and pouring boiling oil into wounds.

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The committee notes in the Biology section that a very low radiation dose was reported to arthritis pain flare ups meloxicam 7.5 mg on line cause a reduction in transformation in vitro below a relatively high spontaneous transformation frequency zeel rheumatoid arthritis generic 15 mg meloxicam free shipping. However rheumatoid arthritis morning stiffness cheap 15mg meloxicam otc, problems and possible artifacts of the assay system employed are also discussed rheumatoid arthritis specialist new zealand purchase meloxicam 7.5 mg free shipping. When radioresistance is observed after doses that cause some cell lethality- for example, after chronic doses that continually eliminate cells from the population-the radioresistance that emerges may be caused either (1) by some inductive phenomenon or (2) by selecting for cells that are intrinsically radioresistant. Either process 1 or process 2 could occur as the radiosensitive cells are selectively killed and thus eliminated from the population as the chronic irradiation is delivered. In the end, an adaptive or hormetic response in the population may appear to have occurred, but this would be at the expense of eliminating the sensitive or weak components in the population. In chronic low-dose experiments with dogs (75 mGy/d for the duration of life), vital hematopoietic progenitors showed increased radioresistance along with renewed proliferative capacity (Seed and Kaspar 1992). Although one might interpret these observations as an adaptive effect at the cellular level, the exposed animal population experienced a high incidence of myeloid leukemia and related myeloproliferative disorders. The authors concluded that "the acquisition of radioresistance and associated repair functions under the strong selective and mutagenic pressure of chronic radiation is tied temporally and causally to leukemogenic transformation by the radiation exposure" (Seed and Kaspar 1992). The general thesis presented is that stress responses activated by low doses of radiation, particularly those that would increase immunological responses, are more beneficial than any deleterious effects that might result from the low doses of ionizing radiation. Although evidence for stimulatory effects from low doses has been presented, little if any evidence is offered concerning the ultimate deleterious effects that may occur. End points for these deleterious effects include mutations, chromosomal aberrations, oncogenic transformation, genomic instability, and cell lethality. These deleterious effects have been observed for cells irradiated in vivo as well as in vitro. Adaptive Response the radiation-adaptive response in mammalian cells was demonstrated initially in human lymphocyte experiments (Olivieri and others 1984) and has been associated in recent years with the older concept of radiation hormesis. A more extensive treatment of adaptive effects is discussed in another section of this report. Radiation adaptation, as it was initially observed in human lymphocytes, is a transient phenomenon that occurs in some (but not all) individuals when a conditioning radiation dose lowers the biological effect of a subsequent (usually higher) radiation exposure. In lymphocyte experiments, this reduction occurs under defined temporal conditions and at specific radiation dose levels and dose rates (Shadley and others 1987; Shadley and Wiencke 1989). However, priming doses less than 5 mGy or greater than ~200 mGy generally result in very little if any adaptation, and adaptation has not been reported for challenge doses of less than about 1000 mGy. Furthermore, the induction and magnitude of the adaptive response in human lymphocytes is highly variable (Bose and Olivieri 1989; Hain and others 1992; Vijayalaxmi and others 1995), with a great deal of heterogeneity demonstrated between different individuals (Upton 2000). Also, the adaptive response could not be induced when the lymphocytes were given the priming dose during G0. Statistical analyses of the distribution of deaths in these studies indicate control animals usually show a greater variance around the mean survival time than groups exposed to low doses of radiation. In addition, the longer-living irradiated animals generally have a reduced rate of intercurrent mortality from nonspecific and infectious diseases during their early adult life, followed by a greater mortality rate later in life. Since these investigations were conducted under conditions in which infectious diseases made a significant contribution to overall mortality, the interpretation of these studies with respect to radiationinduced cancer or other chronic diseases in human populations must be viewed with caution. For example, the cited data of Lorenz (1950) show a small difference in life span in mice exposed to 0. In a study by Covelli and colleagues (1989), a decrease in incidence of malignant lymphoma at low doses of radiation (46 and 52% age-adjusted incidence at X-ray exposures of 500 and 1000 mGy versus 57% incidence in control animals) shows a reduction in tumor incidence relative to the control frequency. After peaking at 60% lymphoma incidence (3000 mGy), the frequencies decline, "possibly due to cell inactivation becoming predominant at higher doses over the initial transforming events. In the Ishii study, the authors speculate that possible mechanisms may include augmentation of the immune system or initiation of an "adaptive response. Human populations, which have a wider spectrum of "spontaneous" tumors occurring at a lower incidence, may not be expected to respond to radiation in the same way as mouse strains with high lymphoma incidence. A positive association is one in which the rate of disease is higher among a group exposed to some substance or condition than among those not exposed, and a negative (or inverse) association is one in which the rate of disease is lower among the exposed group. If an association is judged to be causal, a positive association may be termed a causal effect and a negative association could be termed a protective effect. One type of epidemiologic study that has been used to evaluate the association between exposure to radiation and disease is the "ecologic" study in which data on populations, rather than data on individuals, are compared. Another example of an ecologic study is the evaluation of geographic areas with high background levels of radiation compared to areas with "normal" background levels. The fact that cancer rates in these high-background-radiation geographic regions are not elevated is sometimes cited as evidence against a linear no-threshold model (Jaworowowski 1995). It is also true that certain populations residing in highbackground areas, such as occur at high altitudes, have lower levels of health problems than those residing at lower altitudes. This observation has been interpreted by some as evidence for a hormetic effect of radiation. A protocol of 50 mGy three times a week gave a smaller (not statistically significant) decrease to 67. The mean survival time was significantly prolonged from 283 d for the control animals to 309 d with the three-exposure-per-week protocol and to 316 d with the twice-a-week protocol. This is not interpreted to mean that work per se reduces the risk of mortality, but rather that healthy persons start to work more often than unhealthy persons (Monson 1990).

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Work clarifying many details of this pathway in mammalian cells indicates that it controls the activation of cyclin B/cdk1 severe arthritis in neck and back buy meloxicam 7.5 mg low price, which is particularly important for regulating entry into mitosis (see rheumatoid arthritis medication options buy meloxicam 15mg. Phosphorylated cdc25 can be bound and arthritis rosehip treatment discount 15mg meloxicam visa, hence severe arthritis in upper back generic meloxicam 15 mg online, inactivated by interaction with 14-3-3 proteins (see. This checkpoint functions to prevent the metaphase to anaphase transition until all sister chromatid pairs are aligned and attached to the mitotic spindle apparatus (see M-Phase Entry and Exit, earlier in this chapter) (see. Abnormalities in this checkpoint can lead to gross changes in chromosome number, which is a common occurrence in cancer cells. Interestingly, p53 has been implicated in a spindle checkpoint in mouse cells, 103 which again demonstrates its importance in numerous aspects of cancer cell biology. Cellular Senescence Finally, it has been suggested that cellular senescence also represents a type of cell-cycle checkpoint that is activated when chromosomal telomeres become shortened to a critical point. This could be significant for tumorigenesis because tumor cells may have defective checkpoint-signaling pathways. Thus, in addition to expressing telomerase activity (see S Phase, earlier in this chapter), the loss of a growth inhibitory checkpoint signal to induce senescence could also contribute to the development of cellular immortality in tumor cells. However, one phenotypic abnormality that is virtually pathognomonic of all cancer cells is dysregulation of cell-cycle control. Rather, the growth abnormality in cancer cells appears to result from two factors: (1) lack of appropriate control responses to the signals that normally cause the cell to stop going through the cell cycle, and (2) lack of a cellular death program in response to appropriate stimuli or stresses. The transformation of a normal cell to a tumor cell appears to be dependent on mutations in gene products important in integrating extracellular and intracellular signals to the cell cycle and cell death machinery and on those gene products involved in directly controlling cell-cycle progression. Loss of either type of function would lead to loss of regulatory cell growth signals. An evolution has occurred over the past 25 years in our thinking about the nature of the growth abnormalities present in cancer cells. The discovery of oncogenes in the 1970s and their overexpression or increased activity in tumor cells led to the suggestion that the abnormality in tumor cells was the presence of too much of a signal that pushed the cell through the cell cycle. The discovery of tumor suppressor genes in the 1980s added to this model by suggesting that the growth abnormalities of tumor cells resulted from a combination of too few of the cell-cycle brakes (tumor suppressors) and too many of the cell-cycle accelerators (oncogenes). This model has been even further revised in the past several years with the recognition of the importance of cell death controls in maintaining appropriate numbers of cells in a given tissue. Changes in tissue cell number are dictated by the number of new cells generated by cellular proliferation and the number of cells lost to the tissue by cell death. The number of proliferating cells is controlled by a combination of the gene products driving the cell through the cycle (can be considered oncogenes in a simplified model) and the gene products that inhibit cell-cycle progression (considered tumor suppressor genes in a simplified model). In a simplified model, the number of cells dying in a tissue is a function of the relative activities of the gene products that block programmed cell death (antiapoptosis genes) and the gene products that enhance programmed cell death (apoptosis-enhancing genes). Thus, tumors may develop and malignant cells may continue to increase their numbers by acquiring mutations in genes that result in combinations of increased drive through the cell cycle (increased oncogene activity), decreased inhibition of cell-cycle progression (loss of tumor suppressor genes), increased antiapoptosis signals. Cell differentiation is also probably associated with slowing or stopping cell proliferation, and some abnormal gene products in malignancies that drive proliferation also appear to inhibit differentiation. The steady-state number of cells in a tissue is a function of the relative amount of cell proliferation and cell death. Cell proliferation is influenced by the balance of positive effects of oncogenes and negative effects of tumor suppressor genes. Cell death is influenced by the balance of positive and negative effects of proapoptotic and antiapoptotic gene products. Simplistically, cell number may be increased by increased activity of oncogenes or antiapoptotic genes or by decreased activity of tumor suppressor genes or proapoptotic genes. Oncogenes One formal definition for an oncogene is that the oncogene product contributes to malignant transformation either in vitro or in vivo. The concept used previously that oncogenes are gene products that enhance cell-cycle progression is not always true, but is useful for the discussion here. However, it is clear that many of the genes that have been classified as oncogenes are positive growth signals. Such signaling pathways were discussed previously as influencing the actual cell-cycle machinery, and it is easy to envision how activating mutations in any of these genes could lead to enhanced signals that inappropriately keep the cell going through the cell cycle. Positive signals directly involved in the cell-cycle machinery have been linked to oncogenesis by the observations of abnormally high levels of cyclin expression in certain tumor cells. It is easy to conceive how this would cause both increased genetic instability and decreased apoptosis and contribute to malignant transformation. Additionally, roles for p53 in controlling certain aspects of the progression from the G 2 phase of the cell through mitosis and chromosome segregation have been suggested. Thus, it is not at all surprising that this locus is so commonly mutated in human tumors. Apoptosis is a mode of cellular death that is an energy-dependent, programmed event (hence the name programmed cell death) that occurs in response to certain stimuli. Apoptosis is also a critical event in normal development and in normal tissue homeostasis, clearly playing a role, for example, in nervous system development and in lymphocyte selection processes in the immune system. Some of the gene products that control the cell cycle also appear to influence apoptosis tendencies. It has been suggested that apoptosis occurs when conflicting cell-cycle signals are simultaneously active in the cell or when survival signals coming from extracellular peptides are blocked. Some models also conceive of apoptosis as an integral part of the cell cycle, with apoptotic death being viewed as a type of permanent exit from the cycle, just as the G 0 quiescent phase is an exit from the cycle. It has also been suggested that apoptotic death is the natural default outcome for cycling cells unless a survival factor (hormone or growth factor) is present to keep the cell alive as it progresses through the cycle. Since responses to current antineoplastic therapies (chemotherapy and radiation therapy) are also likely to be affected by the apoptosis tendencies of cells, this process has obvious therapeutic implications.


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