Social Cognitive Effects and Mediators of a Pilot Telephone Counseling Intervention to Increase Aerobic Exercise in Hematologic Cancer Survivors.

BACKGROUND: Theory-based telephone counseling exercise (TCE) interventions can increase aerobic exercise behavior in cancer survivors. Few studies, however, assess intervention effects on social cognitive variables. Here, the authors examined changes in social cognitive variables from a TCE intervention based on the multi-process action control framework in hematologic cancer survivors. METHODS: A total of 51 hematologic cancer survivors were randomized to weekly TCE (n = 26) or self-directed exercise (n = 25) for 12 weeks. Participants self-reported on demographic and cancer variables, as well as motivational, regulatory, and reflexive ratings pertaining to aerobic exercise at baseline and post-intervention. RESULTS: Small-to-large between-group differences in all variables favored the TCE group. The most prominent effects were noted for differences in coping planning (adjusted mean between-group difference [MBGDadj] = 1.4, 95% confidence interval [CI], 0.7 to 2.2, d = 1.04), instrumental attitude (MBGDadj = 0.5, 95% CI, 0.1 to 1.0, d = 1.11), affective attitude (MBGDadj = 0.6, 95% CI, 0.1 to 1.2, d = 0.71), and perceived opportunity (MBGDadj = 0.4, 95% CI, -0.3 to 1.2, d = 0.50). Changes in coping planning (b = 24.98, ß = 0.18, 95% CI, -0.03 to 0.56), perceived opportunity (b = 17.95, ß = 0.13, 95% CI, 0.01 to 0.36), exercise identity (b = 17.43, ß = 0.12, 95% CI, -0.05 to 0.41), and habit (b = 14.64, ß = 0.10, 95% CI, -0.01 to 0.42) accounted for the largest mediating effects on aerobic exercise behavior. CONCLUSIONS: Multi-process action control framework-based TCE interventions may strengthen motivational, regulatory, and reflexive profiles that translate into increased aerobic exercise behavior in hematologic cancer survivors.

Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.

Inappropriate kinase expression and subsequent promiscuous activity defines the transformation of many solid tumors including renal cell carcinoma (RCC). Thus, the expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Further, identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. Here, we report the identification of the RTK-like orphan receptor 2 (Ror2), a new tumor-associated kinase in RCC cell lines and primary tumors. Ror2 is an orphan receptor tyrosine kinase with physiological expression normally seen in the embryonic kidney. However, in RCC, Ror2 expression correlated with expression of genes involved at the extracellular matrix, including Twist and matrix metalloprotease-2 (MMP2). Expression of MMP2 in RCC cells was suppressed by Ror2 knockdown, placing Ror2 as a mediator of MMP2 regulation in RCC and a potential regulator of extracellular matrix remodeling. The suppression of Ror2 not only inhibited cell migration, but also inhibited anchorage-independent growth in soft agar and growth in an orthotopic xenograft model. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within a subset of renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.

Universal tumor antigens as targets for immunotherapy.

BACKGROUND: Clinically successful Ag-specific cancer immunotherapy depends on the identification of tumor-rejection Ags. Historically, tumor Ags have been identified by analyzing cancer patients' own T-cell or Ab responses. METHODS: The unveiling of the human genome and optimized immunological analytical tools, particularly 'reverse immunology', have made it possible to screen any given protein for immunogenic epitopes. These advances enable the immunological characterization of universal tumor-associated gene products that mediate critical functions for tumor growth and development. RESULTS: Four examples of candidate universal tumor Ags reviewed here include the telomerase reverse transcriptase (hTERT), the inhibitor of apoptosis survivin, the p53-interacting protein MDM2, and the cytochrome P450 isoform 1B1--each at various levels of preclinical and clinical development. DISCUSSION: The cardinal feature of universal TAA is that they are expressed in (nearly) all tumors and in no normal tissues. They are directly involved in the malignant phenotype of the tumor. Certain peptides derived from such Ags are expressed on the tumor-cell surface, as evidenced by Ag-specific, MHC-restricted T-cell anti-tumor reactivity in vitro. It is hoped that these features imply a pre-existing, high-affinity T-cell pool that can be activated in vivo in patients, without immunoselection of variant tumor cells no longer expressing the Ag of choice.

Antigens recognized by autologous antibody in patients with renal-cell carcinoma.

The screening of cDNA expression libraries derived from human tumors with autologous antibody (SEREX) is a powerful method for defining the structure of tumor antigens recognized by the humoral immune system. Sixty-five distinct antigens (NY-REN-1 to NY-REN-65) reactive with autologous IgG were identified by SEREX analysis of 4 renal cancer patients and were characterized in terms of cDNA sequence, mRNA expression pattern, and reactivity with allogeneic sera. REN-9, -10, -19, and -26 have a known association with human cancer. REN-9 (LUCA-15) and REN-10 (gene 21) map to the small cell lung cancer tumor suppressor gene locus on chromosome 3p21.3. REN-19 is equivalent to LKB1/STK11, a gene that is defective in Peutz-Jeghers syndrome and cancer. REN-26 is encoded by the bcr gene involved in the [t(9:22)] bcr/abl translocation. Genes encoding 3 of the antigens in the series showed differential mRNA expression; REN-3 displays a pattern of tissue-specific isoforms, and REN-21 and REN-43 are expressed at a high level in testis in comparison to 15 other normal tissues. The other 62 antigens were broadly expressed in normal tissues. With regard to immunogenicity, 20 of the 65 antigens reacted only with autologous sera. Thirty-three antigens reacted with sera from normal donors, indicating that their immunogenicity is not restricted to cancer. The remaining 12 antigens reacted with sera from 5-25% of the cancer patients but not with sera from normal donors. Seventy percent of the renal cancer patients had antibodies directed against one or more of these 12 antigens. Our results demonstrate the potential of the SEREX approach for the analysis of the humoral immune response against human cancer.

Isoforms of the human PDZ-73 protein exhibit differential tissue expression.

Patients with renal and colon cancer frequently develop IgG autoantibodies toward the NY-CO-38/PDZ-73 antigen, a protein of 652 amino acids (73 kDa) which contains three copies of the PDZ protein-protein interaction domain. The gene encoding PDZ-73 mapped to chromosome 11p15.4-p15.1. Additional tissue-specific isoforms were identified: PDZ-45, which lacks the third PDZ domain and the putative PEST protein degradation motif, is expressed in kidney, colon, small intestine, brain and testis; PDZ-54 and PDZ-59, which also lack the third PDZ domains, have unique carboxyl terminal amino acids and are expressed in brain, kidney, bladder, colon cancer and renal cancer; and a putative PDZ-37 isoform, containing only the third PDZ domain, that is expressed in the central nervous system. Immunohistochemical staining with anti-PDZ 73 monoclonal antibodies showed strong cytoplasmic reactivity in epithelial cells of the small intestine, colon and kidney tubules, with a prominent apical staining pattern in cells of the small intestine. The reactivity pattern of the antibodies with various tissues correlated with the mRNA expression pattern of the PDZ-45 isoform. The existence of multiple PDZ-73 isoforms with variations in tissue distribution, PDZ domains, protein degradation sequences and carboxyl terminal structure indicate that these isoforms have distinct tissue-specific functions.

Aspects of GnRH neurobiology conserved across vertebrate forms.

The decapeptide gonadotropin-releasing hormone (GnRH) came into prominence because of its roles in releasing luteinizing hormone and follicle-stimulating hormone and promoting reproductive behavior. At least three aspects of GnRH neurobiology have features which may be universal among vertebrates. First, the GnRH neuronal migration from the olfactory placode into the basal forebrain appears to hold true for forms ranging from fish to humans. Second, for proper agonist activity in the anterior pituitary, GnRH must be released in a pulsatile fashion. Since GT-1 neuronal cell cultures can demonstrate pulsatile release, it must be concluded that GnRH neuronal networks themselves can manage this type of pulsatility. Using a neuronal mathematical model with "minimalist" assumptions, we demonstrated that a network of identical neurons can achieve this self-organizing property without the use of, or spontaneous appearance of, "pacemaker cells." Indeed, since many parameter combinations worked, and since no information about species identity or chemical cell type is provided to the model, this conclusion could apply across many vertebrate forms and, perhaps, even for other neuroendocrine cell types. Third, Fernald and colleagues (this issue of General and Comparative Endocrinology) have demonstrated remarkable effects of social context on GnRH expression in fish. Reviewed here are some data in musk shrews suggesting that behavioral and social stimuli can also modify GnRH neurons in mammals. Therefore, although GnRH neuronal mechanisms are adapted to meet species-typical variations in environment and physiology, some of the important features of this system appear to be widely conserved.

Characterization of human colon cancer antigens recognized by autologous antibodies.

The screening of cDNA expression libraries derived from human tumors with autologous antibody (SEREX) has proven to be a powerful method for defining the structure of tumor antigens recognized by the humoral immune system. In the present study, 48 distinct antigens (NY-CO-1-NY-CO-48) reactive with autologous IgG were identified by SEREX analysis in 4 patients with colon cancer. Sequencing analysis showed that 17 of the cDNA clones were previously uncharacterized molecules and 31 represented known gene products. The individual cDNA clones were analyzed in the following manner: a search for mutations or other structural changes; an analysis of mRNA expression in a panel of normal tissues; and a frequency analysis of the antibody response to the expressed product in the sera of colon cancer patients and normal individuals. The initial analysis showed NY-CO-13 to be a mutated version of the p53 tumor suppressor gene. Three of the 48 antigens showed a differential pattern of mRNA expression, with NY-CO-27 (galectin-4) expressed primarily in gastrointestinal tract, and NY-CO-37 and -38 showing a pattern of tissue-specific isoforms. With regard to immunogenicity, 20 of the 48 antigens were detected by allogeneic sera; 14 of these were reactive with sera from both normal donors and cancer patients, and 6 other clones (NY-CO-8, -9, -13, -16, -20 and -38) reacted exclusively with sera from colon cancer patients (ranging from 14% to 27%). Our results on colon cancer illustrate both the complexity and the potential of the SEREX approach for analysis of the humoral immune response against human cancer.

Mathematical exploration of pulsatility in cultured gonadotropin-releasing hormone neurons.

Pulsatile gonadotropin-releasing hormone (GnRH) release has been demonstrated in cultures of an immortalized line of GnRH expressing neurons (GT1 cells) in experiments by four different research groups. Pulsatile release is known to play a crucial role in GnRH-mediated signaling in vivo, and thus deserves theoretical and quantitative consideration, especially as GT1 cells are presumably genetically homogeneous. Here we have modeled idealized GT1 cells with a differential equation/logic based modeling program, Stella II. We have created a network of 'neurons', with randomized (within the same preset limits for each neuron) thresholds, number and weight of connections to other neurons, and build-up of signal; as well as continuous decay of stored signal. Surprisingly, we found that with this minimal set of assumptions, without any sort of predefined pacemaking cells, it is possible to create pulsatility similar to that observed in the laboratory. A variety of different parameter sets was found to produce these pulses. Network behaviors similar to those of GT1 cells depended on the degree of interconnection between neurons and their functioning within a critical range of network excitability. These findings allow for a clearer consideration of the critical elements of such networks as well as experimental predictions regarding the production of pulsatile behavior.

Reproductive functions illustrating direct and indirect effects of genes on behavior.

Effects of gene products on reproductive behavior which are relatively direct include those of the estrogen receptor and progesterone receptor. For example, work with estrogen receptor-deficient (ERKO) female mice has extended previous evidence contributing to the neurochemical analysis of lordosis behavior. On the other hand, sex differences in behavior present a classic example of indirect effects of genes on behavior. Work with ERKO male mice shows the necessity of ER gene expression for normal masculinization of the brain. In particular, behavioral assay results distinguish apparent motivational performance of ERKO males from male mating reflexes: the former is similar to that of wild-type males in important respects, while the latter are deficient in ERKO males. The present paper first reviews a small number of clear genetic contributions to reproductive behaviors, and then reports one experiment pertinent to the interpretation of the behavioral status of ERKO male mice.