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Program Director, Pacific Northwest University of Health Sciences

Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines. Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. Adenovirus E1A, simian virus 40 tumor antigen and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Regions of human papillomavirus type 16 E7 oncoprotein required for immortalization of human keratinocytes. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21cip1-mediated inhibition of cdk2. Immortalization and altered differentiation of human keratinocytes in vitro by the E6 and E7 open reading frames of human papillomavirus type 18. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. The bovine papillomavirus E6 oncoprotein interacts with paxillin and disrupts the actin cytoskeleton. The human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Smoking as a risk factor in cancer of the cervix: additional evidence from a case control study. Tumorigenic agents in tobacco products and their uptake by chewers, smokers and nonsmokers. Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events. Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix. C-myc proto-oncogene expression and prognosis in early carcinoma of the uterine cervix. Presence of human papillomavirus type 16 related sequences in verrucous carcinoma of the larynx. Frequency and distribution of papillomavirus structural antigens in verrucae, multiple papillomas, and condylomata of the oral cavity. Characterization of human papillomavirus type 13 from lesions of focal epithelial hyperplasia Heck lesions. A new type of human papillomavirus associated with oral focal epithelial hyperplasia. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Malignant lymphoma in cotton-top marmosets after inoculation with Epstein-Barr virus. Epstein-Barr virus-associated B cell lymphoproliferative disorders following bone marrow transplantation. Tan-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Epstein-Barr virus latency in blood mononculear cells: analysis of viral gene transcription during primary infection and in the carrier state.

It is critical for classical conditioning and for attaching emotional value to learning processes and memory. Animal research has demonstrated that there is increased activation of the amygdala in rat pups that have odor cues paired with electrical shock when their mother is absent. This leads to an aversion to the odor cue that suggests the rats learned to fear the odor cue. Interestingly, when the mother was present, the rats actually showed a preference for the odor cue despite its association with an electrical shock. This suggests a differential effect on the amygdala by the context (the presence or absence of the mother) determined whether the pups learned to fear the odor or to be attracted to it (Moriceau & Sullivan, 2006). Raineki, Cortйs, Belnoue, and Sullivan (2012) demonstrated that, in rats, negative early life experiences could alter the function of the amygdala and result in adolescent patterns of behavior that mimic human mood disorders. In this study, rat pups received either abusive or normal treatment during postnatal days 8­12. The mother rat had insufficient bedding material in her cage to build a proper nest that resulted in her spending more time away from her pups trying to construct a nest and less times nursing her pups. The second form of abusive treatment had an associative learning task that involved pairing odors and an electrical stimulus in the absence of the mother, as described above. The control group was in a cage with sufficient bedding and was left undisturbed with their mothers during the same time period. The rat pups that experienced abuse were much more likely to exhibit depressive-like symptoms during adolescence when compared to controls. These depressive-like behaviors were associated with increased activation of the amygdala. Human research also suggests a relationship between the amygdala and psychological disorders of mood or anxiety. Changes in amygdala structure and function have been demonstrated in adolescents who are either at-risk or have been diagnosed with various mood and/or anxiety disorders (Miguel-Hidalgo, 2013; Qin et al. It has also been suggested that functional differences in the amygdala could serve as a biomarker to differentiate individuals suffering from bipolar disorder from those suffering from major depressive disorder (Fournier, Keener, Almeida, Kronhaus, & Phillips, 2013). Hippocampus As mentioned earlier, the hippocampus is also involved in emotional processing. Like the amygdala, 356 Chapter 10 Emotion and Motivation research has demonstrated that hippocampal structure and function are linked to a variety of mood and anxiety disorders. A cultural display rule is one of a collection of culturally specific standards that govern the types and frequencies of displays of emotions that are acceptable (Malatesta & Haviland, 1982). Therefore, people from varying cultural backgrounds can have very different cultural display rules of emotion. For example, research has shown that individuals from the United States express negative emotions like fear, anger, and disgust both alone and in the presence of others, while Japanese individuals only do so while alone (Matsumoto, 1990). Furthermore, individuals from cultures that tend to emphasize social cohesion are more likely to engage in suppression of emotional reaction so they can evaluate which response is most appropriate in a given context (Matsumoto, Yoo, & Nakagawa, 2008). While research into gender differences in emotional display is equivocal, there is some evidence that men and women may differ in regulation of emotions (McRae, Ochsner, Mauss, Gabrieli, & Gross, 2008). Despite different emotional display rules, our ability to recognize and produce facial expressions of emotion appears to be universal. In fact, even congenitally blind individuals produce the same facial expression of emotions, despite their never having the opportunity to observe these facial displays of emotion in other people. In fact, there is substantial evidence for seven universal emotions that are each associated with distinct facial expressions. These include: happiness, surprise, sadness, fright, disgust, contempt, and anger (Figure 10. The facial feedback hypothesis asserts that facial expressions are capable of influencing our emotions, meaning that smiling can make you feel happier (Buck, 1980; Soussignan, 2001; Strack, Martin, & Stepper, 1988). Recent research explored how Botox, which paralyzes facial muscles and limits facial expression, might affect emotion.

Those of us with an internal locus of control ("internals") tend to believe that most of our outcomes are the direct result of our efforts. Those of us with an external locus of control ("externals") tend to believe that our outcomes are outside of our control. On the other hand, if you possess an external locus of control, you might conclude that the test was too hard and not bother studying for the next test, because you figure you will fail it anyway. Researchers have found that people with an internal locus of control perform better academically, achieve more in their careers, are more independent, are healthier, are better able to cope, and are less depressed than people who have an external locus of control (Benassi, Sweeney, & Durfour, 1988; Lefcourt, 1982; Maltby, Day, & Macaskill, 2007; Whyte, 1977, 1978, 1980). A low score on this questionnaire indicates an internal locus of control, and a high score indicates an external locus of control. Mischel surveyed several decades of empirical psychological literature regarding trait prediction of behavior, and his conclusion shook the foundations of personality psychology. His report triggered a decades-long period of self-examination, known as the person-situation debate, among personality psychologists. Mischel suggested that perhaps we were looking for consistency in the wrong places. And as you will see next regarding his famous "marshmallow test," Mischel also found that behavior is consistent in equivalent situations across time. When we talk about will power, we tend to think of it as the ability to delay gratification. However, Bettina forfeited the pleasure of eating one, because she is training for a 5K race and wants to be fit and do well in the race. Would you be able to resist getting a small reward now in order to get a larger reward later? In the marshmallow study, Mischel and his colleagues placed a preschool child in a room with one marshmallow on the table. The child was told that he could either eat the marshmallow now, or wait until the researcher returned to the room and then he could have two marshmallows (Mischel, Ebbesen & Raskoff, 1972). What Mischel and his team found was that young children differ in their degree of self-control. Mischel and his colleagues continued to follow this group of preschoolers through high school, and what do you think they discovered? The children who had more self-control in preschool (the ones who waited for the bigger reward) were more successful in high school. On the other hand, those children who had poor self-control in preschool (the ones who grabbed the one marshmallow) were not as successful in high school, and they were found to have academic and behavioral problems. Today, the debate is mostly resolved, and most psychologists consider both the situation and personal factors in understanding behavior. The children in the marshmallow test each processed, or interpreted, the rewards structure of that situation in their own way. Instead of behavior being determined by the situation, people use cognitive processes to interpret the situation and then behave in accordance with that interpretation. It does not suggest that psychoanalytic, behaviorist, and other points of view are incorrect but argues that these perspectives do not recognize the depth and meaning of human experience, and fail to recognize the innate capacity for self-directed change and transforming personal experiences. One pioneering humanist, Abraham Maslow, studied people who he considered to be healthy, creative, and productive, including Albert Einstein, Eleanor Roosevelt, Thomas Jefferson, Abraham Lincoln, and others. Maslow (1950, 1970) found that such people share similar characteristics, such as being open, creative, loving, spontaneous, compassionate, concerned for others, and accepting of themselves. The highest need is the need for self-actualization, which is the achievement of our fullest potential. If your response is primarily positive, then you tend to feel good about who you are, and you see the world as a safe and positive place. Rogers further divided the self into two categories: the ideal self and the real self. The ideal self is the person that you would like to be; the real self is the person you actually are.

This can have important clinical ramifications for highly schedule-dependent agents such as methotrexate, which distributes to "third spaces" such as pleural effusions or ascites. The great majority of xenobiotic metabolism takes place in the liver, although cytochrome P-450 enzymes and uridine diphosphate­glucuronosyltransferases are present in the small bowel, 5,15 and both carboxylesterases 16 and deaminases17 are present in plasma and other tissues. Phase I reactions are oxidative, or reductive, reactions and include the P-450 system. These metabolic reactions evolved for the purpose of xenobiotic detoxification, but can also result in drug activation. Selected Drug-Metabolizing Enzymes of Importance in Oncology An area of rapidly increasing importance is genetically determined variability in drug-metabolizing enzymes. Malnutrition, like hepatic dysfunction, may result in decreased synthesis of drug-metabolizing enzymes, decreased clearance, and enhanced toxicity. Cancer patients receive a large number of medications that can affect metabolism (and excretion) of concomitant chemotherapy (Table 19. Given the complexity of most treatment regimens (multiple cytotoxic agents, antiemetics, analgesics, anticonvulsants, corticosteroids), relatively few specific data are available in this regard. Both are complex processes involving a chain of events, any of which can be modulated by disease processes or other medications. Biliary excretion involves a number of transport systems, including P glycoprotein, a known cause of multidrug resistance. However, this is only a marker of impaired excretion, and it is poorly correlated with impaired metabolism. This becomes even more relevant if patients with a low clearance have an increased risk of toxicity. If saturation occurs at clinically relevant concentrations, the clearance generally decreases dramatically at higher doses, and the drug is considered to have nonlinear pharmacokinetics. Optimal administration of such drugs requires a full understanding of the complexities involved, as well as the potential effects of disease and other medications. Only the free (unbound) drug is active, whereas conventional assays quantitate the total (free plus bound) drug. If significant variability in protein binding is found for a highly bound drug, it may be difficult to interpret plasma concentrations without directly measuring the free drug or extent of protein binding. For some agents, however, such as etoposide, it may be possible to estimate protein binding from simple parameters, such as serum albumin, bilirubin, and age. Although half-life and clearance are generally inversely correlated, an increased half-life may also be a consequence of an increased volume of distribution. This finding is becoming increasingly well recognized as an important factor in both toxicity and response. It may also be critical to know the half-life for estimating when plasma cytotoxic activity is negligible in the context of peripheral stem cell reinfusion or colony-stimulating factor administration. These include drugs that are true prodrugs, having no intrinsic cytotoxic activity, and drugs that have metabolites with comparable or greater cytotoxicity to the parent. There may be theoretical advantages to enhancing or inhibiting formation of the active metabolites, which may have a different "therapeutic index" (ratio of beneficial to harmful effects) than the parent drug. This alteration of active metabolite formation can potentially be accomplished by the use of inhibitors. The only generalization that can be made is that variability increases as end-organ dysfunction develops. Proper conduct of such studies requires a great deal of planning, as well as technical and logistical expertise. These generally include evaluations of in vitro cytotoxicity, preclinical pharmacokinetics, in vitro metabolism, in vitro toxicology (myelosuppression), and whole-animal toxicology. Pharmacokinetic data can be collected using either intensive or sparse sampling strategies. Data from all patients can be combined in two basic ways: either with a simple descriptive summary (mean ± standard deviation) of the fundamental parameters, or by pooling all data into a single analysis. The latter approach requires a high level of statistical and computational sophistication, but may generate insights not available by other means. These subsequent studies are often primarily concerned with pharmacodynamic issues, relating toxicity or response to pharmacokinetic variables. Such studies benefit greatly from the use of optimal sampling strategies, in which only a few samples are collected on each patient.

Responses by Th2 cells promote humoral immunity, allergic reactions, and immediate hypersensitivity reactions, which provide defenses against extracellular pathogens. Th1 and Th2 cells appear to represent a later stage of differentiation from Th0 cells, which display an intermediate cytokine profile. As with humoral and cellular immunity, the responses of the two classes of helper T cells often are regulated in a reciprocal fashion, and here the influence of cytokines is critical. Cytokine patterns themselves have been identified as type 1 or type 2, analogous to those typically produced by Th1 or Th2 mouse cells, to refer to their functions rather than their cellular source. Possible mechanisms include an effect of cytokines that nonspecifically interfere with proliferation or differentiation of immune cells. Alternatively, bystander T cells, activated against other antigens, may consume the cytokines essential for T-cell responses against the antigen of interest. States of increased nonspecific suppression have been observed in several pathologic conditions, including some tumor-bearing hosts. Veto cells destroy T cells that recognize antigens on the surface of the veto cell. The absence of a strong immune response does not necessarily reflect the absence of antigen recognition by the immune system but rather may reflect suppression. A common feature among them, however, is that cytotoxicity is a regulated process. They are generally activated as a result of cell surface ligands on the target cells binding and triggering selected cell surface receptor molecules on the effector cells. They may appear as small, resting, agranular lymphocytes or as large, blastic, granular cells or as gradations in between. The distinction between T cells with cytotoxic activity and those with helper activity is not absolute. The granules contain two types of proteins that contribute to the destruction of target cells: perforin (cytolysin), which is related to the terminal component of complement and forms pores in the outer membrane of the target cells, and granzymes, a subfamily of serine proteases that are found in lymphocytes and appear to be necessary for apoptosis of the target cells. The serine proteases may enter the target cells through the perforin-generated pores. However, not all Fas-expressing lymphocytes are susceptible to apoptosis through this pathway; prolonged stimulation for at least a period of days may be needed. Understanding which cells are susceptible to this mode of down-regulation is at an early stage. They contribute to the balance between activation and inhibition of T-cell cytotoxic function. The cytotoxic activity of the released mediators, however, is not target cell­specific. After cell contact, both types of effector cells can be triggered to kill sensitive target cells by antibody-independent interactions between surface molecules on effector and target cells. Thus, apart from their independent roles in host defense, these cells are also important accessories to cytotoxic immunity. In addition, their production of cytokines and chemokines as part of the early, innate host defense response can strongly influence subsequent adaptive immune responses. Another family, designated killer inhibitory receptors, is controlled by genes clustered on human chromosome 19 that encode particular glycoproteins in the Ig superfamily. When cross-linked, the receptors can deliver a dominant signal that inhibits triggering of cytotoxic activity and cytokine expression. The greater cytotoxic activity of these cells appears to result, in part, from their activation-enhanced expression of surface molecules that contribute to target cell binding and to triggering cytotoxic activity. Macrophages can be activated by many additional factors, including tumor cell contact. Several mechanisms limit bystander effects, including short half-lives of the cytotoxic factors. Correlations have been established in several animal models between progressive tumor growth in vivo and resistance of tumor cells to macrophage cytotoxicity in vitro. However, macrophages can also promote growth of some tumors by effects on the tissue stroma, the blood supply, or the tumor cells themselves.