Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules.

Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT. On TCR stimulation of T cells from these mice, proximal signaling and cytokine production was elevated in 2KR versus wild-type (WT) LAT mice. Enhanced cytolytic activity as well as T-helper responses were observed on LAT expression, which were further elevated by 2KR LAT expression. Despite greater T-effector function, WT or 2KR LAT expression did not have any effect on clearance of certain pathogens or tumors. Our data support the model that lack of tumor clearance is due to increased differentiation and acquisition of effector phenotype that is associated with suboptimal immunity in an immunotherapy model. Thus, our data further reinforce the role of LAT ubiquitination in TCR signaling and uncovers a novel role for LAT in driving T-cell differentiation.

Inhibition of TGF-ß signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy.

Transforming growth factor ß (TGF-ß) is a cytokine with complex biological functions that may involve tumor promotion or tumor suppression. It has been reported that multiple types of tumors secrete TGF-ß, which can inhibit tumor-specific cellular immunity and may represent a major obstacle to the success of tumor immunotherapy. In this study, we sought to enhance tumor immunotherapy using genetically modified antigen-specific T cells by interfering with TGF-ß signaling. We constructed three γ-retroviral vectors, one that expressed TGF-ß-dominant-negative receptor II (DNRII) or two that secreted soluble TGF-ß receptors: soluble TGF-ß receptor II (sRII) and the sRII fused with mouse IgG Fc domain (sRIIFc). We demonstrated that T cells genetically modified with these viral vectors were resistant to exogenous TGF-ß-induced smad-2 phosphorylation in vitro. The functionality of antigen-specific T cells engineered to resist TGF-ß signaling was further evaluated in vivo using the B16 melanoma tumor model. Antigen-specific CD8+ T cells (pmel-1) or CD4+ T cells (tyrosinase-related protein-1) expressing DNRII dramatically improved tumor treatment efficacy. There was no enhancement in the B16 tumor treatment using cells secreting soluble receptors. Our data support the potential application of the blockade of TGF-ß signaling in tumor-specific T cells for cancer immunotherapy.

The speaker as listener: The interpretation of structural regularities in verbal behavior.

Regularities in word order not specifically addressed by Skinner require behavioral interpretation if our field is to become more influential among students of language. Three such phenomena are briefly described in traditional structural terms and are offered as test cases: subtle differences in dative verbs, transformational traces, and the formation of compound nouns. It is argued that the variables that control such regularities derive from the speaker's repertoire as listener. Intraverbal frames are established as verbal responses in the listener through reinforcement by parity. Transitions from element to element in such frames are controlled, moment to moment in time, partly by the speaker's responses as a listener to his or her own verbal behavior. Although this account offers only a tentative interpretation of grammar and syntax in a limited domain, it suggests that the conceptual tools of behavior analysis are adequate to the task of explaining even the most subtle of grammatical rules.

The S-R issue: its status in behavior analysis and in Donahoe and Palmer's learning and complex behavior.

The central focus of this essay is whether the effect of reinforcement is best viewed as the strengthenng of responding or the strengthening of the environmental control of responding. We make the argument that adherence to Skinner's goal of achieving a moment-to-moment analysis of behavior compels acceptance of the latter view. Moreover, a thoroughgoing commitment to a moment-to-moment analysis undermines the fundamental distinction between the conditioning process instantiated by operant and respondent contingencies while buttressing the crucially important differences in their cumulative outcomes. Computer simulations informed by experimental analyses of behavior and neuroscience are used to illustrate these points.

A selectionist approach to reinforcement.

We describe a principle of reinforcement that draws upon experimental analyses of both behavior and the neurosciences. Some of the implications of this principle for the interpretation of behavior are explored using computer simulations of adaptive neural networks. The simulations indicate that a single reinforcement principle, implemented in a biologically plausible neural network, is competent to produce as its cumulative product networks that can mediate a substantial number of the phenomena generated by respondent and operant contingencies. These include acquisition, extinction, reacquisition, conditioned reinforcement, and stimulus-control phenomena such as blocking and stimulus discrimination. The characteristics of the environment-behavior relations selected by the action of reinforcement on the connectivity of the network are consistent with behavior-analytic formulations: Operants are not elicited but, instead, the network permits them to be guided by the environment. Moreover, the guidance of behavior is context dependent, with the pathways activated by a stimulus determined in part by what other stimuli are acting on the network at that moment. In keeping with a selectionist approach to complexity, the cumulative effects of relatively simple reinforcement processes give promise of simulating the complex behavior of living organisms when acting upon adaptive neural networks.

Essentialism and selectionism in cognitive science and behavior analysis.

Contingencies of selection, be they phylogenetic or ontogenetic, merely set boundaries on units; they do not provide blueprints. Thus, variability is fundamental to all products of selection. Skinner, by characterizing the units of analysis in behavior as generic in nature, established his science squarely within the selectionist paradigm, thereby avoiding the tendency, common throughout psychology, to slip into essentialist analyses. The distinction between essentialism and selectionism is refined in this article, and prominent examples of essentialism in linguistics, theories of memory, theories of representation, associationism, and even in behavior analysis are identified. Recent trends in cognitive science--specifically, research on adaptive networks--is amenable to a selectionist interpretation, suggesting the possibility of future fruitful interactions with behavior analysis.

Small cell undifferentiated carcinoma of the pancreas. Report of a patient with tumor marker studies.

BACKGROUND: Small cell undifferentiated carcinoma of the pancreas is a rare type of pancreatic neoplasm. METHODS: The authors report the clinical and pathologic aspects of a patient with this malignant lesion and an extensive serologic and immunohistochemical survey of potential ectopically produced hormones or tumor markers. RESULTS: Neuron-specific enolase (NSE) emerged as a tumor marker. CONCLUSIONS: NSE could be valuable in the diagnosis and management of other patients with this rare disease.

Testicular seminoma in a long-term survivor of the prune belly syndrome.

Patients with the prune belly syndrome have cryptorchidism as a constant feature of the constellation of anomalies. Testes that do not spontaneously descend represent a well-known risk factor for the development of testicular cancer. In this paper, we present the second case of a primary testicular germ cell tumor in a long-term survivor with prune belly syndrome.

Response to exogenous cholecystokinin of six human gastrointestinal cancers xenografted in nude mice.

Gastrointestinal hormones regulate growth of cancers as well as normal tissues. We investigated whether long-term cholecystokinin (CCK) administration might affect growth or metabolism of human tumors xenografted in nude mice. In each experiment, approximately 20 nude mice bearing subcutaneous xenografts of the particular cancer line being studied were used. Half received CCK and half received saline solution intraperitoneally twice daily for 14 days. Tumor volume and body weight were measured every 3 days. If the tumors produced marker substances, these were measured in nude mouse serum and also in the xenografts. Tumor growth was significantly retarded by CCK in two of the six cancers studied. In each case, DNA, RNA, and protein reflected tumor volumes. In one of these tumors (SLU 077), serum carcinoembryonic antigen (CEA) levels paralleled the tumor volumes. In another tumor (SLU 132), serum CEA levels and tumor immunolabeling for CEA and pancreatic oncofetal antigen increased in response to CCK administration, whereas tumor volumes did not. These findings suggest that exogenous highdose CCK altered the growth and metabolism in two of six human cancers studied.

The prognostic importance of steroid receptors in endometrial carcinoma.

Three hundred forty-nine cases of primary endometrial carcinoma (endometrioid, adenosquamous, and clear-cell) were studied to investigate the relative prognostic importance of age, menopausal status, stage, histology, myometrial invasion, and estrogen and progesterone receptor content. Excluding menopausal status, all of these variables had a significant relationship to overall survival in a univariate analysis. Using a Cox multivariate regression analysis, stage, age, and an estrogen receptor value of more than 70 fmol/mg protein, combined with a progesterone receptor value of more than 30 fmol/mg protein, were independently associated with survival. The results demonstrate that for maximum prognostic information, both estrogen and progesterone content of tumors should be measured. Maximum prognostic information is obtained by using cutoff levels that are much higher than those traditionally accepted. This has particular relevance for patient stratification in clinical trials investigating receptor information and response to adjuvant or therapeutic treatment.

Clinical temporary ventricular assist. Pathologic findings and their implications in a multi-institutional study of 41 patients.

Forty-one patients, distributed among four centers, had left (33 patients), right (five), or bilateral (three) temporary ventricular assistance with textured (24) or smooth (17) surfaced diaphragm pumps, during an evaluation supported by the National Institutes of Health. Cardiac failure had occurred in 39 postoperative patients (after aorta-coronary bypass [23], valve replacement [four], both [nine], or other [three]), with total cardiopulmonary bypass time mean 306 minutes (range 69 to 600). Two patients had cardiomyopathy. Death of 35 nonsurvivors was due to myocardial necrosis (14), hemorrhage (nine), cerebrovascular accidents (three), infection (three), and other (six). Mean duration of support in all patients was 62 hours. In 16 patients (40%) whose condition improved, cardiac assist duration was mean 127 hours (range 48 to 264), compared with mean 19 hours (range 1 to 120) in 25 who did not. Of 17 patients in whom duration of support exceeded 72 hours, 15 (88%) improved, 11 were weaned, and six survived long term. Tissue examination (in 33 patients) by biopsy at pump implantation or autopsy revealed coagulation or contraction band myocyte necrosis, with or without hemorrhage, in 26 patients; of these, 10 improved and six were long-term survivors. Pump-related complications (two) included pulmonary embolism, most likely related to a cannulation site thrombus, and an aortic cannulation site infection in one patient each. This study suggests that mechanical cardiac assist may be accomplished with a low complication rate; should not necessarily be denied to patients with existing necrosis, because myocardial necrosis does not preclude improvement or survival; and frequently leads to functional myocardial recovery if patients survive early noncardiac complications, often the result of long duration of cardiopulmonary bypass.