Heidi Bauer MD, MS, MPH

• Associate Adjunct Professor, Epidemiology

https://publichealth.berkeley.edu/people/heidi-bauer/

Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment best treatment for pain from shingles discount benemid 500mg with visa. Transcription factors: their potential as targets for an individualized therapeutic approach to cancer pain treatment guidelines 2012 discount benemid 500mg with mastercard. We will discuss the difference between genetic instability arising in germline predisposition syndromes compared to genetic instability in sporadic cancers pain treatment in acute pancreatitis order benemid 500mg overnight delivery, and the meaning of these distinctions with regard to the ongoing debate over the necessity (or lack thereof) of genetic instability for the development and progression of all cancers pain medication for dogs advil best 500 mg benemid. Finally pain treatment devices benemid 500mg on-line, we offer an overview of some of the possible mechanisms through which sporadic cancers may become genetically unstable heel pain treatment video discount benemid 500 mg without prescription. It is widely quoted that most cancers exhibit some form of genetic instability at either the nucleotide or chromosome level. There has been much debate as to whether it is absolutely required for cancer development or whether the genetic instability is simply a byproduct/bystander effect of selection for some other crucial mechanism such as escape from apoptosis [4, 5]. We can gain crucial insight into the nature of genetic instability by comparing its perturbation in inherited and sporadic cancers. No further event is needed to cause genetic instability in the cancer: the defect is present in all cells, hugely increasing the chance of developing the cancer through selectively advantageous mutations. However, it is important to note that heterozygote germline carriers for recessive cancer predisposing syndromes are not generally at any higher risk than the normal population of developing cancer. The parallel mechanisms leading to sporadic cancers are illustrated from the bottom up. Perhaps we need to question whether or not it is fair to claim that most sporadic cancers display some form of genetic instability. It is important to point out that genetic instability is defined by an increase in rate (compared to normal) of generation and accumulation of mutations or changes in chromosome number or structure. The presence of large numbers of mutations or structural/numeric chromosomal changes provides no information regarding the rate at which they were generated nor whether they reflect a current state of genetic instability. The incidence of certain mutations that are selected for is necessarily much higher than would be predicted from the mutation rate alone. These are mostly based on mutations identified from a mixture of uncloned cells, where only mutations common to the majority of cells are detected (in contrast to the tumour, which is clonal) and so do not give valid estimates of the mutation rate [4]. There is, in fact, evidence that a sizeable proportion of at least some cancers do not display any form of genetic instability. This, in itself, argues strongly against a genetic requirement of instability for the development of cancer. Results from recent whole-genome and -exome sequencing of individual cancers provide some further insight. Without knowing the length of time each of those cancers has taken to manifest, it is hard to approximate a rate of mutation necessary to account for the observed numbers of mutations in any particular cancer. Further arguments against the requirement of genetic instability are supported by mathematical models, which show that genetic instability is not necessary for accumulation of the requisite number of mutations for a cancer to develop [15]. For example, lack of an increase in mutation rate (up to 1000 times higher in genetically unstable tumours) can be compensated for by a similar-fold increase in cell number such that the overall likelihood of accumulating each new mutation would be similar in a genetically stable tumour that has undergone clonal expansion [5]. Rather, there must be an advantage, such as escape from apoptosis, from which the initiating cell derives a selective advantage. Thus, even if genetic instability is present in a sporadic cancer, this may simply be a byproduct of the requirement for escape from apoptosis. Although the issue is key to understanding the role of genetic instability in cancer, this chapter will not further attempt to address the question of how common true genetic instability is in sporadic cancers, but rather to give an overview of the types of genetic instability that may occur, and the mechanisms that might give rise to them in both sporadic cancers and those arising as a result of germline mutations in key genes. It is significant that it is the only form of genetic instability seen in a range of both germline and sporadic cancers that can be explained through the inactivation of the key genes in the relevant pathway. Patients have an estimated 80% lifetime risk of developing colorectal cancer and an increased risk of developing a wide range of other malignancies including ovarian, gastric, brain, pancreatic, endometrial, biliary, small bowel, and urinary tract cancers [21]. This form of genetic instability in sporadic cancers has been described best in colorectal cancer and is found in up to 15% of sporadic colorectal tumours [23]. The two pathways differ in the mechanism by which damage is recognized but involve the same proteins for excision and resynthesis. Generally speaking, this pathway serves to repair and replace nucleotides with small chemical alterations. The form of genetic instability in cancers from these patients is not, however, clearly defined, with reports of both aneuploidy as well as near diploid karyotypes. While it is clear that each of these plays a role in the development and progression of sporadic cancers, their causative role in the development of genetic instability in sporadic cancers remains unproven. They are therefore listed here to give a more complete overview of the currently held views that might explain genetic instability in sporadic human cancers. The assumption for each of these is that, if they provide a mechanism through which the rate at which genetic, epigenetic, or chromosomal changes could be generated (albeit transiently in some circumstances), they could be considered as mechanisms contributing to genetic instability. Numerical changes can occur as a result of errors within mitotic control pathways regulating chromosome segregation and centrosome duplication. In yeast, more than 100 genes that can cause genetic instability at the level of the chromosome have been identified [43]. That these genes behave as typical tumour suppressor genes, requiring somatic inactivation of both copies of the relevant gene in sporadic cancers, may account for the low incidence of observed mutations in genes within these pathways in sporadic cancers. Almost half of all genes are predicted to contain a CpG rich region that fulfils the criteria of being a CpG island [45]. Thus, disruption of the epigenetic signature in cancer represents a theoretical alternative to genetic instability in providing a similar, heritable mechanism involved in the progression of cancer. There are also clear examples where precancerous lesions, such as colorectal adenomas, are not commonly aneuploid. Consequently, they are unable to maintain telomere length during replication and eventually undergo replicative cell senescence. It is unclear whether this is due to reactivation via re-expression of the catalytic subunit, or whether the cancers arose from a stem cell or early progenitor cell in which telomerase was already active. Conclusion It is now undisputed that cancer arises as a result of the sequential accumulation of genetic and epigenetic changes, each of which is selected for in a Darwinian evolutionary process because they provide a selective advantage to the developing cancer. It is also clear that disruptions of the mechanisms that have evolved to maintain the fidelity of the genome result in increased rates of mutation and can accelerate tumorigenesis. These observations have led some to hypothesize the existence of a mutator phenotype. The mutator hypothesis argues that genetic instability is present in precancerous lesions and drives tumour development by increasing the spontaneous mutation rate [70]. The key assumption with this argument is that spontaneous mutation rates are not high enough to give rise to the mutations that are selected for in the outgrowth of a cancer. The counter-argument is that mutation rates are large enough if selection is properly taken into account [4]. In hereditary cancers, genetic instability facilitates the accumulation of critical mutations in oncogenes and tumour suppressor genes, and these cancers almost certainly fulfil the requirements of the mutator hypothesis in that genetic instability occurs early in the development of the cancer and results in an increased rate of accumulation of spontaneous mutation. However, the germline cancer predisposition syndromes are almost always autosomal recessive and do not, in the heterozygous state, affect genome stability. The key issue with genetic and epigenetic changes that increase genetic instability is whether their selective advantage is due solely to their effect on mutation rate, or whether it is due to a more direct effect, and that the increase in mutation rate is a bystander effect. The rationale for the argument against the mutator hypothesis rests on the fundamentals of natural selection; any selective advantage must be conferred in the first change that does not yet increase the mutation rate. Exhaustive studies of sporadic cancers have failed Hypoxia Hypoxia is a common feature of developing cancers as they outgrow existing blood supply and before angiogenic stimuli lead to new vasculature. The low frequency of these mutations in sporadic cancers has confounded expectations and argues against the mutator hypothesis for sporadic cancers [4, 14]. This protective mechanism allows the cell to attempt repair, but in the event that the damage cannot be repaired, activation of apoptosis ensures that fidelity is retained. Experimental and theoretical evidence do not support the concept of genetic instability as a universal and required driving force for all cancers, but where it is evident in sporadic cancers, we still have some way to go before we fully understand the underlying mechanisms. Three classes of genes mutated in colorectal cancers with chromosomal instability. Clinicopathologic and molecular features of sporadic microsatellite- and chromosomal-stable colorectal cancers. Colorectal cancer without high microsatellite instability and chromosomal instability: an alternative genetic pathway to human colorectal cancer. Microsatellitestable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. Comparison of hypoxia-induced replication arrest with hydroxyurea and aphidicolin-induced arrest. Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. A multistep damage recognition mechanism for global genomic nucleotide excision repair. Xeroderma pigmentosum: a glimpse into nucleotide excision repair, genetic instability, and cancer. Breast cancer susceptibility: current knowledge and implications for genetic counselling. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Systematic genome instability screens in yeast and their potential relevance to cancer. The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle. Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer. In tumour cells this number may vary by a factor of two with substantial impact on the cellular radiosensitivity. Differences in the repair kinetics, especially in the final plateau, indicate defects either in damage response, chromatin organization, repair pathways, or repair regulation. Adapted from Springer Verlag, the Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies, 2009, pp. However, in many tumours this hierarchy is disturbed so that these two pathways are more active. The mechanisms leading to this cetuximab-mediated improved tumour control are not yet fully understood. However, an even stronger effect was seen for erlotinib, for which no cellular radiosensitization was seen. Probably, targeting of these two signalling pathways is more effective, because it cannot be compensated by other signalling cascades. Radiotherapy is combined with chemotherapy in an adjuvant or neo-adjuvant regimen but also may be given simultaneously. However, for most of the conventional drugs used there is rarely a synergistic effect observed but mostly only an additive effect, even for the often applied combination of radiation and cisplatin. When combined with external irradiation, tumour control is already achieved with fairly low doses. It should, however, be noted that a difference in repair capacity of 1% has already been shown to have a strong effect on cell survival [19]. This technique may also be applied for tumour tissue slides irradiated both in situ or ex-vivo [18, 20]. However, there are still numerous problems to be solved such as hypoxic regions as well as contamination by normal tissue before this technique can be used in a daily clinical routine. Substantial variations in the amount of repair proteins have been reported in tumours both intra- and inter-individually. It should, however, be considered that this technique only allows determination of the relative amount of the protein present. There are several studies showing an excellent correlation between a specific gene expression profile and tumour radiosensitivity [24, 25]. Chk1 und Chk2 In most tumours, the G1/S checkpoint is not active because p53 is mutated. There are several inhibitors available targeting either or both of these kinases which are already used in the clinics. Huge differences in cellular radiosensitivity due to only very small variations in double-strand break repair capacity. Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. Gene expression profiling to predict outcome after chemoradiation in head and neck cancer. At the top of the cellular organization, normal adult stem cells maintain tissues during homoeostasis and facilitate their regeneration, for example in response to infection or to cell loss due to injury or chemotherapy. Indeed, as early as 1937, Furth and Kahn could demonstrate that one single mouse leukaemic cell is able to seed and form a new tumour in a healthy recipient mouse. The clonality of human cancers assessed by genetic markers was also demonstrated later on, confirming that cancers can arise from one transformed initiating cellular clone [8].

Laxative: An agent that promotes peristalsis and evacuation of the bowel in a relatively slow manner (as opposed to a cathartic) pain breast treatment buy benemid 500 mg line. Leukotrienes are important in mediating certain allergic and inflammatory responses treatment pain when urinating purchase line benemid, especially in respiratory tissues back pain treatment yahoo answers buy benemid 500mg without prescription. This enzyme converts arachidonic acid into precursors that the cell uses to synthesize specific leukotrienes georgia pain treatment center canton ga discount benemid master card. Loading dose: Amount of drug administered at the onset of treatment to rapidly bring the amount of drug in the body to therapeutic levels pain treatment in cancer patients buy benemid discount. Lymphokines: Chemicals released from activated lymphocytes that help mediate various aspects of the immune response dna advanced pain treatment center west mifflin buy benemid 500 mg with mastercard. Malignancy: A term usually applied to cancerous tumors that tend to become progressively worse. Metabolite: the compound that is formed when the drug undergoes biotransformation and is chemically altered by some metabolic process. Muscarinic receptor: A primary class of cholinergic receptors that are named according to their affinity for the muscarine toxin. Certain cholinergic agonists and antagonists also have a relatively selective affinity for muscarinic receptors. Myxedema: the adult or acquired form of hypothyroidism characterized by decreased metabolic rate, lethargy, decreased mental alertness, weight gain, and other somatic changes. Nicotinic receptor: A primary class of cholinergic receptors, named according to their affinity for nicotine, as well as certain other cholinergic agonists and antagonists. On-off phenomenon: the fluctuation in response seen in certain patients with Parkinson disease, in which the effectiveness of medications may suddenly diminish at some point between dosages. Because these drugs are only used in a small patient population (usually less that 200,000 people), financial and other incentives are often provided by various sources to encourage a drug company to develop and market the drug. Orthostatic hypotension: A sudden fall in blood pressure that occurs when the patient stands erect; this is a frequent side effect of many medications. Parenteral administration: Administration of drugs by routes other than via the alimentary canal: by injection, transdermally, topically, and so on. Parkinson disease or parkinsonism: the clinical syndrome of bradykinesia, rigidity, resting tremor, and postural instability associated with neurotransmitter abnormalities within the basal ganglia. Pharmacodynamics: the study of how drugs affect the body-that is, the physiological and biochemical mechanisms of drug action. Pharmacogenetics: the study of the how genetic variability can influence drug responses and metabolism. Pharmacokinetics: the study of how the body handles drugs-that is, the manner in which drugs are absorbed, distributed, metabolized, and excreted. Pharmacological dose: An amount of drug given that is much greater than the amount of a similar substance produced within the body; this increased dose is used to exaggerate the beneficial effects normally provided by the endogenous compound. Pharmacotherapeutics: the study of how drugs are used in the prevention and treatment of disease. Pharmacy: the professional discipline dealing with the preparation and dispensing of medications. Physical dependence: A phenomenon that develops during prolonged use of addictive substances, signified by the onset of withdrawal symptoms when the drug is discontinued. Physiological dose: the amount of drug given that is roughly equivalent to the amount of a similar substance normally produced within the body; Glossar y 679 this dose is typically used to replace the endogenous substance the body is no longer able to produce. Potency: the dose of a drug that produces a given response in a specific amplitude. When two drugs are compared, the more potent drug will produce a given response at a lower dose. Progestins: the general term for the natural and synthetic female hormones, such as progesterone. Prostaglandin: A member of the family of 20-carbon fatty acid compounds (eicosanoids) formed from arachidonic acid by the cyclooxygenase enzyme. Prostaglandins help regulate normal cell activity and may help mediate certain pathological responses, including pain, inflammation, fever, and abnormal blood coagulation. Proton pump: An enzyme that moves hydrogen ions (protons) across the cell membrane. The gastric proton pump transports hydrogen ions into the stomach; drugs that inhibit this enzyme are known as proton pump inhibitors, and these drugs are used to reduce the formation and effects of excess gastric acid. Psychosis: A relatively severe form of mental illness characterized by marked thought disturbances and an impaired perception of reality. Receptor: the component of the cell (usually a protein) to which the drug binds, thus initiating a change in cell function. Salicylate: the chemical term commonly used to denote compounds such as aspirin that have anti-inflammatory, analgesic, antipyretic, and anticoagulant properties. Seizure: A sudden attack of symptoms usually associated with diseases such as epilepsy. Epileptic seizures are due to the random, uncontrolled firing of a group of cerebral neurons, which results in a variety of sensory and motor manifestations. These drugs can be used to enhance bone mineralization and to prevent certain cancers. Selective toxicity: A desired effect of antineoplastic and anti-infectious agents, wherein the drug kills the pathogenic organism or cells without damaging healthy tissues. Side effect: Any effect produced by a drug that occurs in addition to the principal therapeutic response. Spinal nerve block: Administration of local anesthesia into the spinal canal between the arachnoid membrane and the pia mater. Drugs in this class share a common -statin suffix at the end of their generic name. Status epilepticus: An emergency characterized by a rapid series of epileptic seizures that occur without any appreciable recovery between seizures. Steroid: the general term used to describe a group of hormones and their analogs that have a common chemical configuration but are divided into several categories depending on their primary physiological effects. Common types of steroids include the glucocorticoids (cortisone, prednisone, many others), mineralocorticoids (aldosterone), androgens/anabolic steroids (testosterone), and steroids related to female physiological function (estrogen, progesterone). Sublingual: Under the tongue; drugs administered sublingually are absorbed into the systemic circulation via the venous drainage from underneath the tongue. Sympatholytics: Drugs that inhibit or antagonize function within the sympathetic nervous system. Sympathomimetics: Drugs that facilitate or increase activity within the sympathetic nervous system. Tardive dyskinesia: A movement disorder characterized by involuntary, fragmented movements of the mouth, face, and jaw. This disorder may occur during the prolonged administration of antipsychotic drugs. Drug concentrations less than the lower end of this range will be ineffective, and concentrations greater than the upper end of this range will create excessive side effects. Thromboxanes are especially important in regulating platelet activity and blood clotting. Excessive thrombus formation (thrombosis) can be controlled by drugs that affect various aspects of the clotting mechanisms. Tolerance: the acquired phenomenon associated with some drugs, in which larger dosages of the drug are needed to achieve a given effect when the drug is used for prolonged periods. Vaccine: A substance typically consisting of a modified infectious microorganism that is administered to help prevent disease by stimulating the endogenous immune defense mechanisms against infection. Viscos upplementation: Injection of a polysaccharide (hyaluronan) into osteoarthritic joints to help restore the viscosity of synovial fluid. Volume of distribution (V d): A ratio used to estimate the distribution of a drug within the body relative to the total amount of fluid in the body. It is calculated as the amount of drug administered divided by the plasma concentration of the drug. Xanthine: A category of compounds that includes stimulants such as caffeine and theophylline. Listed here are some drug classes that contain groups of drugs that share a common suffix. Please note that some members of a drug class may have a suffix that is different from the one indicated; for instance, not all benzodiazepines end with -epam or -olam. Some antibiotics ending with -mycin or -rubicin are used as antineoplastics (Chapter 36). However, these regulatory networks are far too complex to serve as predictive model systems for our understanding of cell signalling processes, forcing us to adhere to easier directional pathways that describe the main signalling avenues that transmit environmental cues from the plasma membrane to the nucleus. In most cancer types several key regulators in signalling pathways are perturbed, and each of these perturbations provides the cancer cell with a small survival and growth advantage. The advent of large-scale sequencing revealed that there are on average 80 mutations that alter amino acid residues in signalling proteins in a typical cancer biopsy. These mutations are composed of few commonly mutated genes but the majority of mutations occur with low frequency resulting in a complex picture of the cancer genome landscape. Analysis of these mutations by statistical methods predicts that most of the detected mutations have probably little or no functional consequences. However, it has been estimated that nevertheless around 15 mutations contribute either to the initiation, progression, or maintenance of a tumour. In late-stage metastatic cancer, multiple distinct and spatially separated inactivating mutations of tumour-suppressor genes have been identified within a single tumour leading to a considerable degree of intra-tumour heterogeneity, further complicating molecular mechanisms that lead to deregulation of signalling in cancer and consequently the rational design of new therapeutic strategies that target signal transduction pathways. However, all cancers need to acquire a set of capabilities that are tightly controlled in normal cells. These hallmark capabilities lead to alterations in signalling that sustain growth factor-independent proliferation, evade growth suppression, suppress apoptotic mechanism and detection of cancer cells by the immune system, overcome the limited replication potential of somatic cells, guarantee sufficient nutrition supply by generating new blood vessel formation and by changing the cellular energy supply. These lead finally to the spread of the tumour in the body by inducing cell migration and metastasis. Here I review the principal regulatory mechanisms that control the main signalling pathways, with a particular focus on pathways that have been successfully targeted in cancer therapy. This pathway evolved very early in evolution to regulate growth, body size, and longevity as a response to nutrient supply. Depending on the mouse strain used, ErbB1-/- mice die at mid-gestation or shortly after birth. Endosomal trafficking is a key regulatory mechanism controlling receptor turnover. Once internalized, the clathrin-coated vesicles containing the receptor fuse with intracellular organelles known as the endosomes. Interestingly, the oncogenic activity of viral Cbl (v-Cbl) functions by stimulating the receptor recycling pathway. They interact with specific cytokine receptors which lacks intrinsic kinase activity. The C-terminal tripeptide "aaX" is subsequently cleaved by a prenyl-protein specific endoprotease and the new C-terminus is methylated by a methyltransferase completing the insertion cycle. Several regulatory and scaffolding proteins guarantee tight control of this signalling pathway. The scaffolding protein Raptor is regulated by phosphorylation and it facilitates substrate recruitment. The autophagic programme allows cells to recycle catabolites by organelle breakdown, which can be used for essential biosynthetic and metabolic processes promoting survival during starvation. During autophagy intracellular vesicles named autophagosomes engulf cellular organelles and fuse them with lysosomes. On the one hand, repressing autophagy may impair tumorigenesis by reducing the ability of cancer cells to survive under energy-poor conditions. Cyclin A and B accumulate during the cell cycle and are rapidly degraded at the onset of anaphase, mediating entry and exit from mitosis. Elimination of these sites is required for chromosome decondensation, reformation of the nuclear envelope, and cytokinesis. In addition, c-Myc, is frequently overexpressed in cancer and has a key role in regulating the cell cycle. Regulation of the cell cycle and mitosis the decision as to whether cells enter the cell cycle and proliferate is tightly controlled by mitogens that stimulate growth-promoting pathways that have been discussed above. A hallmark of cancer is that cells enter the cell cycle in the absence of mitogenic signals, leading to so-called unscheduled proliferation. To ensure proper timing and successful completion of each step, the eukaryotic cell cycle implements a number of checkpoints that includes the restriction point-a point of no return that commits cells to complete a division cycle even if mitogenic signals drop or, failing that, enter an apoptotic programme. They require the binding of activating cyclin cofactors, which stabilizes the active state of these kinases. From this point onwards the cell cycle progresses independently of mitogenic stimulation (restriction point) into S-phase. Wnt signalling Canonical Wnt signalling plays an important role in development, tissue homoeostasis, and dysfunction of this pathway has been implicated in the development of a cancer. The Wnt pathway has been discovered by the identification of the Int1 locus (Wnt1) as the factor required for mouse mammary tumour virus-driven tumorigenesis and by mutants in Drosophila melanogaster lacking wings (Wingless (Wg)). This complex translocates into the nucleus where it interacts with a number of transcription factors and co-activators regulating the expression of a large diversity of target genes. Loss of cadherin function results in increased cell mobility, a characteristic feature of mesenchymal cells. Snail and Slug also regulate expression of p63, a transcription factor of the p53 family required for development of epithelial structures and proper cell polarity. La Thangue Introduction to cell cycle control All cells arise by the division of existing cells.

Mineralocorticoids are involved primarily in the control of fluid and electrolyte balance pain medication for dogs for arthritis discount benemid 500 mg free shipping. Pharmacologically neck pain treatment exercise buy benemid now, natural and synthetic adrenal steroids are often used as replacement therapy to resolve a deficiency in adrenal cortex function pain treatment sickle cell order 500 mg benemid amex. Patients also take glucocorticoids primarily for their antiinflammatory and immunosuppressive effects on a diverse group of clinical problems arizona pain treatment center mcdowell benemid 500 mg line. These agents can be extremely beneficial in controlling the symptoms of various rheumatic and allergic disorders pain treatment of the bluegrass order benemid 500mg visa. Prolonged glucocorticoid use chiropractic treatment for shingles pain order cheapest benemid, however, is limited by a number of serious effects, such as adrenocortical suppression and breakdown of muscle, bone, and other tissues. Physical therapists and occupational therapists should be especially aware of the potential side effects of glucocorticoids. The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis. Gene profiling reveals a role for stress hormones in the molecular and behavioral response to food restriction. Blunted serum and enhanced salivary free cortisol concentrations in the chronic phase after aneurysmal subarachnoid haemorrhage-is stress the culprit Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs. The regulation of leucocyte transendothelial migration by endothelial signalling events. Comparison of surgical decompression and local steroid injection in the treatment of carpal tunnel syndrome: 2-year clinical results from a randomized trial. Efficacy comparisons of the intraarticular steroidal agents in the patients with knee osteoarthritis. Multiple pulley rupture following corticosteroid injection for trigger digit: case report. The effects of dexamethasone on human patellar tendon stem cells: implications for dexamethasone treatment of tendon injury. Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage them. Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case report and review of the literature. Duration of cortisol suppression following a single dose of dexamethasone in healthy volunteers: a randomised double-blind placebocontrolled trial. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions. Delineating the receptor mechanisms underlying the rapid vascular contractile effects of aldosterone and estradiol. Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine. Management of hyperkalaemia consequent to mineralocorticoidreceptor antagonist therapy. Exercise training prevents hyperinsulinemia, muscular glycogen loss and muscle atrophy induced by dexamethasone treatment. Role of exercise therapy in prevention of decline in aging muscle function: glucocorticoid myopathy and unloading. The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Non-genomic actions of aldosterone: from receptors and signals to membrane targets. Male hormones, such as testosterone, are usually referred to collectively as androgens. Androgens, estrogens, and progestins are classified as steroid hormones; their chemical structure is similar to those of the other primary steroid groups, the glucocorticoids and mineralocorticoids (see Chapter 29). In the female, the ovaries are the main sites of estrogen and progestin production. As discussed in Chapter 29, small amounts of sex-related hormones are also produced in the adrenal cortex in both sexes, which accounts for the fact that low testosterone levels are seen in females, and males produce small quantities of estrogen. However, under normal conditions, the amounts of sex-related hormones produced by the adrenal cortex are usually too small to produce significant physiological effects. In this chapter, we first discuss the physiological role of the male hormones and the pharmacological use of natural and synthetic androgens. We then address the physiological and pharmacological characteristics of the female hormones. There are several aspects of male and female hormones that should concern you as a physical therapist or occupational therapist. Rehabilitation patients may use these agents for approved purposes, such as female hormones as contraceptives. These agents may also be used for illicit reasons, such as the use of male hormones to enhance athletic performance. Hence, you should be aware of the therapeutic and potential toxic effects of these drugs. The seminiferous tubules are the convoluted ducts within the testes in which sperm production (spermatogenesis) takes place. Testosterone produced by the Leydig cells exerts a direct effect on the seminiferous tubules, as well as systemic effects on other physiological systems (see "Physiological Effects of Androgens"). For instance, growth hormone, thyroid hormones, insulin-like growth factor 1, and prolactin may also affect the functions of Leydig and Sertoli cells, thereby influencing the production and effects of testosterone. Testosterone enters the tubules to directly stimulate the production of sperm through an effect on protein synthesis within the tubule cells. Androgens and their synthetic derivatives are approved for administration in several clinical situations, ranging from common replacement therapy to rare hereditary disorders. Development of Male Characteristics the influence of testosterone on sexual differentiation begins in utero. In the fetus, the testes produce small amounts of testosterone that affect the development of the male reproductive organs. At the onset of puberty, a complex series of hormonal events stimulates the testes to begin to synthesize significant amounts of testosterone. The production of testosterone brings about the development of most of the physical characteristics associated with men. Most notable are increased body hair, increased skeletal muscle mass, voice change, and maturation of the external genitalia. These changes are all caused by the effect of androgenic steroids on their respective target tissues. Like other steroids, androgens exert their primary effects by entering the target cell and binding to a cytoplasmic receptor. The proteins produced then cause a change in cellular function, which is reflected as one of the maturational effects of the androgens. For instance, testosterone increases protein synthesis in skeletal muscle, thus increasing muscle mass at the onset of puberty. Increased muscle mass as it relates to androgen abuse in athletes is discussed in more detail under "Androgen Abuse" later in this chapter. Replacement Therapy Patients take testosterone and other androgens as replacement therapy when their endogenous production of testosterone is impaired. Physicians do not typically administer these agents as a primary treatment, but as adjuncts to more conventional treatments such as dietary supplementation and exercise. However, pharmacologists have developed erythropoietin-stimulating agents, such as darbepoetin and epoetin, to more directly treat anemia that occurs secondary to renal disease, cancer chemotherapy, and other anemic conditions. Certain androgens act on the liver to restore production of several clotting factors and to increase production of a glycoprotein, inhibiting the initial stages of the clotting sequence that leads to increased vascular permeability. Delayed Puberty Androgens administered on a short-term basis in selected adolescent males can mimic the characteristics normally associated with the onset of puberty (increased body mass, deepening voice, etc. Specific Agents the agents listed in Table 30-1 are the principal androgens approved for clinical use. Patients usually take the specific agents orally or intramuscularly, as indicated, to replace endogenous androgen production or to treat various medical problems such as catabolic states and anemias. Androgens can also be classified according to their relative androgenic and anabolic properties-that is, certain androgens are given primarily to mimic male sexual characteristics (androgenic effects), whereas other androgens are given primarily to enhance tissue metabolism (anabolic effects; see Table 30-1). This distinction is not absolute, however, because all compounds given to produce anabolism will also produce some androgenic effects. Many other androgenic and anabolic steroids exist and can be acquired relatively easily on the black market by individuals engaging in androgen abuse (see "Androgen Abuse"). Breast Cancer Androgens may be used to treat a limited number of hormone-sensitive tumors, such as certain cases of breast cancer in women. However, other drugs, such as the antiestrogens, have largely replaced the use of androgens in such cancers. We discuss the role of various hormones in the treatment of cancer in more detail in Chapter 36. Irregular menstrual periods and acne may also occur in women undergoing androgen therapy. In men, these drugs may produce bladder irritation, breast swelling and soreness, and frequent or prolonged erections. When used in children, androgens may cause accelerated sexual maturation and impairment of normal bone development due to premature closure of epiphyseal plates. In adults, most of the adverse effects are reversible, and symptoms will diminish once the agent is discontinued. However, a few effects-such as vocal changes in females-may persist even after the drugs are withdrawn. Skeletal changes are irreversible, and permanent growth impairment may occur if these drugs are used in children. Androgens may also increase the risk of prostate cancer, especially in older men who are susceptible to this disease. Hypertension may occur because of the salt-retaining and water-retaining effects of these drugs, and androgens can adversely affect plasma lipids. Although these hepatic and cardiovascular problems may occur during therapeutic androgen use, their incidence is even more prevalent when extremely large doses are used to enhance athletic performance (see "Androgen Abuse"). Antiandrogens Antiandrogens inhibit the synthesis or effects of endogenous androgen production. Finasteride (Propecia, Proscar) and dutasteride (Avodart) inhibit the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone accelerates the growth and development of the prostate gland; these antiandrogens may be helpful in attenuating this effect in conditions such as benign prostate hypertrophy. Flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Anandron, Nilandron) act as antagonists (blockers) of the cellular androgen receptor; these drugs are used to decrease hirsutism in women or to help treat prostate cancer. Also, researchers have documented that anabolic steroid abuse is occurring among the general athletic population, including younger athletes. Athletes engaging in androgen abuse usually obtain these drugs from various illicit but readily available sources. In addition, several different androgens are often taken simultaneously for a combined dose that is 10 to 100 times greater than the therapeutic dose. It has been known for some time that certain athletes have been self-administering large doses of androgens in an effort to increase muscle size and strength. Typically, androgen use is associated with athletes involved in strength and power activities such as weight lifting and bodybuilding and in certain sports such as football, baseball, and track and field. Androgen abuse, however, has infiltrated many aspects of athletic competition at both the amateur and professional levels. There also appears to be a contingent of men, women, and adolescents who are not athletes who take anabolic steroids to increase lean body mass to simply appear more muscular. Athletes often self-administer these drugs in cycles that last between 7 and 14 weeks, and the dosage of each drug is progressively increased during the cycle. An example of a dosing cycle using stacked anabolic steroids is shown in Table 30-3. To help control anabolic steroid abuse, many sporting federations have instituted drug testing at the time of a specific competition. To prevent detection, an athlete will employ a complex pattern of high-dosage androgen administration followed with washout periods. Washouts are scheduled a sufficient amount of time prior to the competition in order to eliminate the drug from the body before testing. The practice of planned schedules can be negated to some extent through randomized drug testing that subjects the athlete to testing at any point in the training period and at the time of the competition. Definitive answers to these questions are difficult because of the illicit nature of androgen abuse and because of the ethical and legal problems of administering large doses of androgens to healthy athletes as part of controlled research studies. The effects of androgens on athletic performance and the potential adverse effects of these drugs are discussed briefly here. Effects of Androgens on Athletic Performance There is little doubt that androgens can promote skeletal muscle growth and increase strength in people who do not synthesize meaningful amounts of endogenous androgens. The question has often been whether large amounts of exogenous androgens can increase muscle size, strength, and athletic performance in healthy men. In general, it appears that athletic men taking androgens during strength training may experience greater increments in lean body mass and muscle strength than athletes training without androgens. For instance, the anabolic effects of steroids cannot be isolated easily from the other factors that produce increments in strength and muscle size.

Autophagy as well as direct radiation-induced cell necrosis play a minor role in the inactivation of non-haematological tumour cells pain management treatment options discount 500 mg benemid amex. Direct cellular necrosis does not significantly contribute to radiation-induced cell kill pain treatment for ovarian cysts generic benemid 500mg fast delivery, but may play a role as an unregulated process of cell destruction due to ischaemia and inflammation opioid treatment guidelines journal of pain buy discount benemid on line. Apoptotic cell death plays a major role after irradiation of haematopoietic and lymphatic neoplasm and some normal tissues but only a minor role in the majority of solid tumours pain medication for dogs after dental surgery buy generic benemid online. Radiation-induced senescence is one of the central mechanisms in normal tissue reactions like fibrosis southern california pain treatment center order benemid us, as will be explained later pain treatment for lyme disease cheap benemid 500mg mastercard. While this may sound trivial, it certainly is not, given the severe limitations of imaging technologies to define small tumour extensions and microscopic disease, the motion of tumours and normal tissues during the treatment series and individual fractions, and changing anatomy during treatment. Adapted from Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology, Volume 108, Issue 3, Butof R et al. Only from such data can information on, for example, the radiosensitivity of a given tumour be derived. Frequently, lower doses are therefore prescribed to areas with low tumour burden, such as subclinical or microscopic residual disease, compared with macroscopic tumours of different volumes. This leads in clinical practice to relatively small differences in prescribed dose which, for example on tumour boards, are often found counterintuitive by oncologists not trained in radiobiological principles. Even if 90% of the tumour is resected, the radiation oncologist has to apply almost or exactly the same dose to the residual tumour, as if it has not been resected, because logarithmic cell kill 90% removal corresponds generally to about 2 fractions of 2 Gy. Thus, while the effect of macroscopic incomplete resection is small or nil, there may be added unwarranted treatment effects on normal tissues from surgery and radiotherapy. Notable exceptions include situations where due to (incomplete) resection, the radiation volume can be importantly reduced or critical normal tissues, such as the optic nerve, can be excluded altogether from the treatment volume. It is obvious that such approaches require detailed interdisciplinary discussion and treatment planning before administering therapy. On the other hand, because of the steep dose-response relationships, relatively small escalations in total dose to macroscopic tumours may lead to significant increase of local tumour control rates. This is one of the reasons underlying the enthusiasm of radiation oncologists toward highly conformal precision techniques because these may allow escalation of the total dose without exceeding (volume-dependent, see below) normal tissue tolerance. Regression of tumours after chemotherapy may not allow significant reduction of total radiation dose Another important clinical practice point originating from the exponential cell kill of radiation is that partial regression of tumours after drug treatment, even if impressive, usually does not allow a significant reduction in the radiation dose to the tumour. While the tumour in the upper panels was resistant to the treatment, no statement on resistance is possible for the second tumour. It should be noted, however, that particularly in the field of molecular targeted drugs many combinations with radiation have shown more pronounced tumour regression and longer growth delay but no impact on local tumour control. As it has been shown that novel drugs might also modulate the radiation response of normal tissues in both directions, it will be important carefully to investigate if the therapeutic window can be broadened by new approaches. However, one potential advantage of induction chemotherapy is that the radiation target volume may be reduced after response to the drugs. While lymphomas and germ cell tumours are often exquisitely radiosensitive, sarcomas and high-grade gliomas are usually highly radioresistant. The most frequent tumour entities, squamous cell or adenocarcinomas, range between these extremes [11]. In addition to these differences of radiosensitivity among tumour entities there is also vast heterogeneity of radiosensitivity between tumours of the same histology and size in different patients (intertumoral heterogeneity). Recent research indicates that even different subvolumes of the same tumour in the same patient may differ in radiosensitivity (intratumoral heterogeneity). It is obvious that knowledge of the radiosensitivity of individual tumours obtained from predictive tests before the start of treatment would provide an opportunity to better tailor the treatment to individual patients. Radiobiological mechanisms that may underlie differences in radiosensitivity of tumours of equal volume include: Radiation effects on normal tissues the radiosensitivity of organs at risk depends on the types of tissue of which they are composed, their structure, function, pre-existing defects, and remaining potential for compensation. In addition, the different parameters of radiotherapy, including beam quality, total dose, dose per fraction, time interval between fractions, dose per week, overall treatment time, volume irradiation, and spatial dose-distribution, have significant impact on radiation effects in normal tissues (as well as in tumours). The challenge of radiation treatment planning is to minimize the risk of normal tissue damage while fully covering the tumour. To facilitate this complex and dynamic process the radiation oncologist utilizes data derived from detailed long-term observation of irradiated patients. Through the use of appropriate radiobiological and biostatistical methodology, data with high spatial resolution on normal tissue effects are correlated with dose-volume-fractionation parameters under consideration of clinical parameters, for example on pre-existing damage. In general, it is useful to differentiate between two broad classes of normal tissue effects in radiotherapy, i. This can be clinically very important if the radiation doses applied cannot be further escalated because of risk of normal tissue complications and if at the same time no (or little) overlapping toxicities exist between the drugs and radiation for the dose-limiting normal tissue [12]. A large number of clinical trials have corroborated this strategy in the past decades, and simultaneous drug plus radiation treatment is today more the rule than the exception. Further exploitable mechanisms of combined radiochemotherapy include spatial cooperation. Early radiation-induced normal tissue reactions Early (or acute) normal tissue reactions occur during radiotherapy and usually resolve within weeks or a few months after treatment. The underlying radiobiological mechanism is the kill of stem or precursor cells with subsequent cell depletion in tissues with high turnover. Typical examples include haematological effects, mucositis, dermatitis, or hair loss. Incidence and severity and to some extent time of onset of early radiation-induced normal tissue reactions increase with: increasing total dose increased dose-intensity (weekly dose), i. For example, the risk of pneumonitis increases after both short overall treatment times and high doses per fraction. Consequential late effects Consequential late effects are defined as late effects occurring after particularly severe early normal tissue reactions and, while follow the radiobiology of early normal tissue reactions, show the typical time course and morphology of late normal tissue reactions. Late radiation-induced normal tissue reactions In contrast to early effects, late normal tissue reactions occur months or even years after completion of radiotherapy, and are usually irreversible and often even progressive. Fibrosis, for example, is often already fully expressed after one or few years, while coronary stenosis is an example of a late damage often occurring a decade or later after end of treatment. For a long time it has been assumed that, much as early normal tissue damage, late effects are caused by cellular depletion. Long turnover times of target cells were assumed to be the cause of clinical delay of damage. While this radiobiological mechanism remains part of the explanation of the clinical time course, it is now known that molecular events in cells, tissue and potentially even the whole organism cascade over long time intervals and contribute to the development of subclinical and overt late damage. Incidence and severity of late radiation-induced normal tissue reactions increase with: review whether these are expected based on the treatment plan or, if unexpected, will re-review the parameters of radiotherapy. The radiation oncologist also recommends supportive measures to ameliorate the symptoms as well as for skin care, nutrition, and pain control during treatment. Suspected late normal tissue damage also needs to be evaluated by the radiation oncologist because such damage occurs only in irradiated volumes and usually follows closely the biological effective radiation dose distribution. Not infrequently, radiation damage is assumed by other healthcare professionals to underlie a new lesion or symptom in a patient previously treated by radiotherapy, while this is judged to be extremely unlikely after expert review, necessitating further diagnostic evaluation. Last but not least, the radiation oncologist should be involved in cases of further treatment such as surgery (or even surgical dental care) when this affects pre-irradiated tissues. This enhances the pre-therapeutic assessment of the risk of complications, and frequently allows modification of the procedure. Even on histopathological exam it is not possible to determine if a tumour has been induced by radiation. Therefore, suspected radiation-induced tumours should be reported to the radiation oncologist. As late normal tissue reactions are the main dose-limiting factor in modern radiotherapy, detailed follow-up of patients with analysis of outcome is the only option for the radiation oncologists to further refine model-based radiation treatment planning. Therefore, long-term follow-up of patients is established good clinical practice in radiotherapy, and in some countries even mandatory by law. Utilizing radiobiological knowledge: dose per fraction, overall treatment time, volume Fractionation in curative treatment is aimed at broadening the therapeutic window Early in the twentieth century, both radiation treatment with a high-dose single irradiation or few fractions (German school) and treatments with a large number of fractions (French school) were in use in radiotherapy [1, 16]. Such schedules would be categorized as moderately hypofractionated and accelerated radiotherapy. Treatment with single doses or few fractions were reintroduced to curative clinical radiotherapy in the context of modern stereotactic ablative radiotherapy approaches. From a radiobiological point of view, fractionated radiotherapy has the following main advantages compared to single-dose treatments or radiotherapy with few fractions [19, 20]: increasing total dose increased dose per fraction short time intervals between fractions increased volume additional damage. Today the radiation dose applied to the tumour is usually limited by the risk of late normal tissue reactions. Secondary malignancies Ionizing radiation is well recognized as a potential cause of secondary malignancies. Management of radiation-induced normal tissue effects the management of side effects requires a high level of expertise. Early reactions need intense supportive care during radiation treatment to prevent treatment interruption or other unwarranted modifications of treatment. Patients with early normal tissue reactions should always be seen by their radiation oncologists who needs to Early normal tissue damage depends significantly on overall treatment time, that is on dose-intensity (dose per week). Thus, fractionated treatments over longer treatment periods lead to less early normal tissue reactions and are better tolerated by the patients. Moderate hypofractionation has, among techniques, an emerging role in particle therapy. Late normal tissue damage increases with increasing dose per fraction, while this is not the case for many tumours. Thus, application of higher number of low-dose fractions widens the therapeutic window between tumours and late-responding normal tissues, given that the time interval between the fractions is long enough (usually six to eight hours; for some tissues even more). For example, the probability of locally controlling breast cancer and likely prostate cancer at the same total dose increases with dose per fraction; however, there might be significant intertumoral heterogeneity. Radiation first kills the sensitive cells but, dependent on dose and the proportion of hypoxic cells, these will dominate the overall effect. During fractionated radiotherapy, hypoxic tumour cells may reoxygenate, which would enhance the therapeutic effect. Single-dose treatment or hypofractionation Single-dose treatment of hypofractionation doses per fractions of 3 Gy or more is regularly used for palliative treatments where total doses are low. It also is used clinically on a routine basis for high-precision stereotactic radiotherapy to small tumours using high, so-called ablative doses. Furthermore, there are microscopic tumour extensions or microscopic deposits of tumour cells which cannot be depicted by imaging but need to be defined by statistical experience. In earlier times, generous margins were applied to account for all these uncertainties. Thus, high-precision radiotherapy, which conforms the dose to the tumour and spares as much sensitive normal tissue as possible, reduces the risk of normal tissue damage substantially and widens the therapeutic window as long as all tumour tissue is covered. Conformal radiotherapy has also allowed substantial escalation of the doses applied over the past decades, thereby significantly improving local tumour control rates. Over the past decades modified fractionation schedules have been developed based on the following radiobiological principles. The latter may be the consequence of too short time intervals between fractions or very intense normal tissue reactions leading to consequential late effects. Evidence is emerging that for concurrent radiochemotherapy the impact of overall treatment time on local tumour control is less than for radiotherapy given alone. These are applied either using cobalt 60 units or, much more frequently today, linear electron accelerators (linacs). Particle therapy with protons, carbon ions, or other ions is emerging as a new clinical treatment modality, but currently is available at only a few centres worldwide. Electrons have an energy-dependent finite range in tissue and are therefore mainly suitable for treatment of superficial tumours where they can spare underlying deeper normal tissues. Megavoltage X-rays of different energies show an energy-dependent build-up region at the entrance surface before they reach their dose maximum at the depth of a few centimetres. This build-up reflects the energy transfer onto secondary electrons which is of great clinical importance for sparing skin Moderate hypofractionation In tumours with potentially high repair capacity, such as breast cancer, moderate hypofractionation, with, for example, 3 Gy per fraction, can achieve the same local tumour control at lower total dose, that is at a lower number of fraction. Introduction of megavoltage beams into clinical radiotherapy between the 1950s and 1970s because of their depth-dose characteristics has been a major technological breakthrough compared to lower energy X-rays used before. For photon beams there is an energy-dependent decrease of dose behind the dose maximum. At the end of the range, a large portion of their energy is deposited over a very small distance, resulting in the so called Bragg peak. The range of the particles in tissue and thereby the depth of the Bragg peak depends on the beam energy. Thus, compared to photon beams, particle beams show an inverted dose distribution which can be utilized for improved protection of normal tissues. This concentrates the high-dose region to the tumour (crossfire irradiation), but at the cost of smearing lower doses to larger volumes of normal tissues. Arc treatments extend this concept to an extreme by delivering the radiation practically through an infinite number of fields. Stereotactic body or brain radiotherapy also uses this concept, utilizing either arcs or a high number of fields to treat small tumours with very steep fall-off of dose to the periphery. With increasing number of treatment fields the conformality of the high-dose region to the tumour increases, while low doses are smeared to larger volumes. While the biological effects of protons are usually considered similar to those of photons (exceptions are currently under intense radiobiological investigations), heavier ions are biologically more effective, particularly in the Bragg peak, which may potentially gain further advantage of such beam qualities. However, as pointed out later in this chapter, many practical issues still need to be solved and appropriate clinical trials must be performed before the value of particle beams relative to photon beams may soundly be assessed for a wide range of tumour sites [25]. Brachytherapy delivers very high doses in the proximity of the source with a rapid fall-off to the periphery. Particle beams may be conformed to the target volume by passive scattering using scatter foils, collimating-apertures, range shifter and compensators to shape the field and spread out the Bragg peak. Alternatively, the Bragg peak may be actively scanned over the tumour volume allowing for intensity-modulated proton therapy.

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