A T-cell receptor associated with naturally occurring human tumor immunity.

The onconeural antigens appear to serve as tumor rejection antigens in the paraneoplastic neurologic disorders. Here, we used an unbiased peptide binding screen, followed by studies in HLA-A2.1 transgenic mice to identify naturally processed HLA-A2.1 restricted epitopes of the paraneoplastic cerebellar degeneration breast/ovarian cancer antigen cdr2. These mice were used to clone high-avidity cdr2-specific CD8(+) T cells that recognize human tumor cells presenting endogenously loaded MHC class I-cdr2 peptide. T cells with this specificity were detected in the peripheral blood of two HLA-A2.1(+) paraneoplastic cerebellar degeneration patients. We cloned T cell receptor (TCR) alpha and beta genes from cdr2-specific T cells; electroporation of RNA encoding this TCR turned nonreactive donor T cells into efficient killers of human cdr2-expressing tumor cells. Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers.

The Strong African American Families Program: a cluster-randomized prevention trial of long-term effects and a mediational model.

The Strong African American Families Program, a universal preventive intervention to deter alcohol use among rural African American adolescents, was evaluated in a cluster-randomized prevention trial. This 7-week family skills training program is based on a contextual model in which intervention effects on youth protective factors lead to changes in alcohol use. African American 11-year-olds and their primary caregivers from 9 rural communities (N = 332 families) were randomly selected for study participation. Communities were randomized to prevention and control conditions. Intent-to-treat analyses indicated that fewer prevention than control adolescents initiated alcohol use; those who did evinced slower increases in use over time. Intervention-induced changes in youth protective factors mediated the effect of group assignment on long-term changes in use.

Performing forward-viewing endoscopy at time of pancreaticobiliary EUS and ERCP may detect additional upper gastrointestinal lesions.

BACKGROUND AND STUDY AIMS: It is unknown whether significant incidental upper gastrointestinal lesions are missed when using non-forward-viewing endoscopes without completing a forward-viewing exam in linear endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) exams. We evaluated whether significant upper GI lesions are missed during EUS and ERCP when upper endoscopy is not performed routinely with a gastroscope. PATIENTS AND METHODS: A retrospective analysis was performed in which an EGD with a forward-viewing gastroscope was performed after using a non-forward-viewing endoscope (linear echoendoscope, duodenoscope, or both) during a single procedure. Upper gastrointestinal tract findings were recorded separately for each procedure. Significant lesions found with a forward-viewing gastroscope were defined as findings that led to a change in the patient's medication regimen, additional endoscopic surveillance/interventions, or the need for other imaging studies. RESULTS: A total of 168 patients were evaluated. In 83 patients, a linear echoendoscope was used, in 52 patients a duodenoscope was used, and in 33 patients both devices were used. Clinically significant additional lesions diagnosed with a gastroscope but missed by a non-forward-viewing endoscope were found in 30 /168 patients (18 %). EGD after linear EUS resulted in additional lesion findings in 17 /83 patients (20.5 %, χ(2) = 13.385, P = 0.00025). EGD after use of a duodenoscope resulted in additional lesions findings in 10 /52 patients (19.2 %, χ(2) = 9.987, P = 0.00157). EGD after the use of both a linear echoendoscope and a duodenoscope resulted in additional lesions findings in 3/33 patients (9 %, χ(2) = 3.219, P = 0.07). CONCLUSION: Non forward-viewing endoscopes miss a significant amount of incidental upper gastrointestinal lesions during pancreaticobiliary endoscopy. Performing an EGD with a gastroscope at the time of linear EUS or ERCP can lead to increased yield of upper gastrointestinal lesions.

Hepatic manifestations of non-steroidal inflammatory bowel disease therapy.

Inflammatory bowel disease (IBD) is composed of Crohn's disease and ulcerative colitis and is manifested by both bowel-related and extraintestinal manifestations. Recently the number of therapeutic options available to treat IBD has dramatically increased, with each new medication having its own mechanism of action and side effect profile. A complete understanding of the hepatotoxicity of these medications is important in order to distinguish these complications from the hepatic manifestations of IBD. This review seeks to evaluate the hepatobiliary complications of non-steroid based IBD medications and aide providers in the recognition and management of these side-effects.

Smoking onset in adolescence: a person-centered analysis with time-varying predictors.

Predictions from smoking-specific versus contextual models of smoking onset were tested with data from a 4-wave sample with 1,364 adolescents. Predictor variables were derived from stress-coping theory, social influence theory, and problem-behavior theory. In addition to groups of abstainers and experimenters, cluster analysis of smoking data indicated 3 groups who showed onset either in 7th grade (early onset), 9th grade (intermediate onset), or 10th grade (late onset). Almost all study variables discriminated the smoking groups from the abstainers. The onset groups were discriminated by Group X Time interactions showing differential changes in predictors (increases in risk factors and declines in protective factors), which occurred just prior to onset. The results generally support a contextual model of the onset process.

The role of self-control in early escalation of substance use: a time-varying analysis.

This research tested predictions about the role of temperament and self-control in early substance use (tobacco, alcohol, and marijuana). A sample of 1,526 participants was assessed in 6th grade (mean age = 11.5 years) and followed with yearly assessments through 9th grade. Latent growth models showed temperament dimensions were related to early substance use, and their effects were mediated through generalized self-control ability. Time-varying effects indicated rate of growth in substance use was higher among participants who showed increases in poor self-control and lower among participants who showed increases in good self-control. Results in self-report data were corroborated by independent teacher ratings. Findings are discussed with reference to epigenetic models of protection and vulnerability.

Moderators of the relation between substance use level and problems: test of a self-regulation model in middle adolescence.

The authors tested predictions, derived from a self-regulation model, about variables moderating the relationship between level of substance use (tobacco, alcohol, and marijuana) and problems associated with use. Data were from two independent studies of adolescents, with mean ages of 15.4 and 15.5 years (Ns = 1,699 and 1,225). Factor analysis indicated correlated dimensions of control problems and conduct problems. Protective moderation was found for variables indexing good self-control; risk-enhancing moderation was found for variables indexing poor self-control. These effects were generally independent of deviance-prone attitudes and externalizing symptomatology. Multiple-group structural modeling indicated moderation occurred for paths from life stress and coping motives and for paths from level to control and conduct problems. Moderation effects were also found for parental variables, peer variables, and academic competence.

Buffering effect of religiosity for adolescent substance use.

This research examined the hypothesis that religiosity buffers the impact of life stress on adolescent substance use. Data were from a sample of 1,182 participants surveyed on 4 occasions between 7th grade (mean age = 12.4 years) and 10th grade. Religiosity was indexed by Jessor's Value on Religion Scale (R. Jessor & S. L. Jessor, 1977). Zero-order correlations showed religiosity inversely related to alcohol, tobacco, and marijuana use. Significant Life Events x Religiosity buffer interactions were found in cross-sectional analyses for tobacco, alcohol, and marijuana use. A latent growth analysis showed that religiosity reduced the impact of life stress on initial level of substance use and on rate of growth in substance use over time. Implications for further research on religiosity and substance use are discussed.

Role of parent support and peer support in adolescent substance use: a test of mediated effects.

This research tested comparative effects of parent and peer support on adolescent substance use (tobacco, alcohol, and marijuana) with data from 2 assessments of a multiethnic sample of 1,826 adolescents, mean age 12.3 years. Multiple regression analyses indicated that parental support was inversely related to substance use and that peer support was positively related to substance use, as a suppression effect. Structural modeling analyses indicated that effects of support were mediated through pathways involving good self-control, poor self-control, and risk-taking tendency; parent and peer support had different patterns of relations to these mediators. The mediators had pathways to substance use through positive and negative recent events and through peer affiliations. Effects for gender and ethnicity were also noted. Mechanisms of operation for parent and peer support are discussed.

Family communication and religiosity related to substance use and sexual behavior in early adolescence: a test for pathways through self-control and prototype perceptions.

This research tested predictions about pathways to substance use and sexual behavior with a community sample of 297 African American adolescents (M age: 13.0 years). Structural modeling indicated that parent-adolescent communication had a path to unfavorable prototypes of substance users; quality of parent-adolescent relationship had paths to good self-control, higher resistance efficacy, and unfavorable prototypes of sexually active teens; and religiosity had inverse direct effects to both substance use and sexual behavior. Self-control constructs had paths to prototypes of abstainers, whereas risk taking had paths to prototypes of drug and sex engagers and direct effects to outcomes. Prototypes had paths to outcomes primarily through resistance efficacy and peer affiliations. Effects were also found for gender, parental education, and temperament characteristics. Implications for self-control theory and prevention research are discussed.

Context and cognitions: environmental risk, social influence, and adolescent substance use.

This study examined the cognitions thought to mediate the impact of context on adolescent substance use and also the extent to which context moderates the relations between these cognitions and use. Risk cognitions and behaviors were assessed in a panel of 746 African American adolescents (M age 10.5 at Wave 1, 12.2 at Wave 2). Results indicated that adolescents living in high-risk neighborhoods were more inclined toward substance use and more likely to be using at Wave 2. These context effects were mediated by the adolescents' risk cognitions: their risk images, willingness to use, and intentions to use. Also, context moderated the relation between willingness and use (the relation was stronger in high-risk neighborhoods) but it did not moderate the intentions to use relation.

Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells.

Paraneoplastic neurologic disorders (PNDs) offer an uncommon opportunity to study human tumor immunity and autoimmunity. In small cell lung cancer (SCLC), expression of the HuD neuronal antigen is thought to lead to immune recognition, suppression of tumor growth, and, in a subset of patients, triggering of the Hu paraneoplastic neurologic syndrome. Antigen-specific CTLs believed to contribute to disease pathophysiology were described 10 years ago in paraneoplastic cerebellar degeneration. Despite parallel efforts, similar cells have not been defined in Hu patients. Here, we have identified HuD-specific T cells in Hu patients and provided an explanation for why their detection has been elusive. Different Hu patients harbored 1 of 2 kinds of HuD-specific CD8+ T cells: classical IFN-gamma-producing CTLs or unusual T cells that produced type 2 cytokines, most prominently IL-13 and IL-5, and lacked cytolytic activity. Further, we found evidence that SCLC tumor cells produced type 2 cytokines and that these cytokines trigger naive CD8+ T cells to adopt the atypical type 2 phenotype. These observations demonstrate the presence of an unusual noncytotoxic CD8+ T cell in patients with the Hu paraneoplastic syndrome and suggest that SCLC may evade tumor immune surveillance by skewing tumor antigen-specific T cells to this unusual noncytolytic phenotype.

Localization and distribution of cartilage oligomeric matrix protein in the rat intervertebral disc.

STUDY DESIGN: Whole rat intervertebral disc (IVD), as well as the anulus fibrosus (AF) and the nucleus pulposus (NP) were studied using immunoblot, immunohistochemistry, and reverse-transcription followed by polymerase chain reaction (RT-PCR) methods to investigate the expression and distribution of cartilage oligomeric matrix protein (COMP). OBJECTIVES: To investigate the expression and distribution patterns of COMP in normal IVD. SUMMARY OF BACKGROUND DATA: COMP is an extracellular matrix protein abundantly expressed in articular and growth plate cartilage, as well as bone, ligament, tendon, and synovium. The potential importance of COMP to the spine has been underscored by its mutations that lead to skeletal dysplasia with characteristic platyspondyly. However, the expression and distribution of COMP in spine and IVD has not been illustrated before. METHODS: The presence of COMP protein was investigated by immunoblotting using a COMP antibody F8 on protein extractions from whole IVD and AF or NP. To compare the expression levels of COMP between lumbar and tail IVDs, and between AF and NP of the IVD, wet weight of the tissues were used for normalization. To show that COMP can be made by IVD cells in situ, RT-PCR was used to investigate the COMP mRNA message. The distribution patterns of COMP in IVD were investigated using immunohistochemistry studies with COMP antibody F8. RESULTS: COMP is expressed at both the protein and mRNA levels in both the AF and NP of both the lumbar spine and tail IVD. Immunohistochemistry studies show that COMP is found in the extracellular matrix of the IVD, exhibiting lamellar distribution pattern in the AF region. When normalized to wet weight, COMP is found to be expressed at higher levels in the lumbar than the tail IVD, and within the IVD, greater in the AF than the NP region. CONCLUSIONS: Our results demonstrate the expression of COMP in both the AF and NP of the IVD. COMP is a component of the extracellular matrix of AF and NP, with a lamellar distribution pattern in the AF. Our data suggest that COMP may play a role in the normal structure of IVD.

Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins.

Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system. Although COMP/TSP5 abnormalities are associated with several pathological conditions, its normal function remains unclear. This study was undertaken to delineate the function(s) of COMP/TSP5 in cartilage, especially regarding its interaction with chondrocytes. We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. Chondrocyte attachment to COMP/TSP5 in the calcium-replete conformation was inhibited by function-blocking integrin alpha5 and beta1 antibodies, suggesting the involvement of the alpha5beta1 integrin. Under this condition, a function-blocking antibody against alphaVbeta3 did not have any effect on cell attachment. On the other hand, chondrocyte attachment to reduced COMP/TSP5 was instead sensitive to alphaVbeta3 function-blocking antibodies, suggesting that COMP/TSP5 mediates attachment through chondrocyte alphaVbeta3 integrin under this condition. Cell attachment to reduced COMP/TSP5 was not inhibited by beta1 antibodies. These data indicate that COMP/TSP5 in different conformations can utilize different integrin receptors. These results are the first to demonstrate that COMP/TSP5 can mediate chondrocyte attachment through interactions with integrins. Through these interactions, COMP/TSP5 may be able to regulate cellular activities and respond to environment in the surrounding cartilage matrix.

Temperament and adolescent substance use: a transactional analysis of emerging self-control.

Presented is a conceptual framework linking the construct of temperament with environmental factors that covary with the onset and escalation of substance use. We propose that transactions between temperament characteristics of the child in family and peer contexts influence the development of self-control ability, a mediating factor for onset and possible transition to abuse in later adolescence. Risk-promoting dimensions may influence the emergence of self-control by amplifying relationship processes that detract from competence development. Emergence of good self-control can serve as a resilience factor and is linked with health-promoting cognitions. We also suggest that temperament and self-control moderate links between parenting, peer associations, and substance use. Implications of the transactional model for clinical intervention and research are discussed.