Enhanced cytotoxicity against colon carcinoma by combinations of noncompeting monoclonal antibodies to the 17-1A antigen.

The purpose of this report was to investigate the binding specificities and ability to generate antibody dependent cell mediated cytotoxicity (ADCC) or antibody dependent complement mediated cytotoxicity of three novel monoclonal antibodies (mAbs), designated M74, M77, and M79, raised against the colorectal carcinoma antigen 17-1A. As determined by indirect radioimmunoassay, all three mAbs, as well as mAb 17-1A, bound to a similar extent to adherent cultures of the human colon carcinoma cell line, HT-29. Scatchard analysis of direct binding data for mAbs 17-1A, M74, M77, and M79 to HT-29 cells demonstrated equivalent association constants (7.54-9.77 X 10(7) liters/mol) and molecules bound per cell (2.15-2.69 X 10(5)). In contrast to mAbs M77 and M79, mAb M74 inhibited the binding of 125I-labeled mAb 17-1A to HT-29 cells. Similar to mAb 17-1A, incubation of human lymphocytes and blood monocytes with mAbs M74, M77, or M79 generated ADCC activity against HT-29 colon carcinoma cells. Various combinations of noncompeting mAbs to the 17-1A antigen (17-1A and M74; M77 and M79; M74 and either M77 or M79) but not competing mAbs (17-1A and M74; M77 and M79) resulted in a heightened level of ADCC activity. Under optimum conditions (saturation of antigenic sites with mAb), ADCC generated by the combination of noncompeting mAbs to the 17-1A antigen was additive to the activity seen with the respective mAbs alone. Under suboptimum conditions, the combination of noncompeting mAbs to the 17-1A antigen resulted in tumor cell cytotoxicity which was synergistic to the lysis obtained with the respective mAbs alone. No mAb used alone was able to generate antibody dependent complement mediated cytotoxicity against a panel of 17-1A positive colon carcinoma cells. Similarly, no antibody dependent complement mediated cytotoxicity activity was obtained with the combination of competing mAbs to the 17-1A antigen. However, HT-29 cells treated with noncompeting mAbs to the 17-1A antigen antigen were rendered susceptible to lysis by human complement. We conclude that the combination of mAbs recognizing different epitopes on the same tumor antigen could have important implications for the passive immunotherapy of cancer.

Activation by marginally perceptible ("subliminal") stimuli: dissociation of unconscious from conscious cognition.

Introduces a linear regression method for investigating unconscious cognition. For words that were obscured by simultaneous dichoptic masking, indirect effects (semantic priming) and direct effects (perceptual identification) were assessed in 20 experiments (total N = 2,026). When measures of both indirect and direct effects have rational zero points, a statistically significant intercept in the indirect-on-direct-measure regression shows that (a) the indirect effect occurred in the absence of the direct effect, and (b) unconscious cognition is involved. For a position discrimination task, but not for an evaluative decision task, indirect-on-direct regression showed the significant intercept effect. Although small in magnitude, this intercept effect provides the statistically most secure finding yet obtained of a much-sought and controversial data pattern--indirect effect with no direct effect. With one added assumption (which appears plausible for the present data), this pattern indicates that unconscious cognition is dissociated from (i.e., occurs separately from) conscious cognition.

Is the unconscious smart or dumb?

How sophisticated is unconscious cognition? This is one of the most fundamental questions about the unconscious that has been posed by research psychologists over the past century. Anthony Greenwald takes a contemporary look at this classical problem and concludes that unconscious cognition is severely limited in its analytic capability. In response, other leading scholars agree that the reality of unconscious processes is no longer questionable. Although there is some disagreement about just how sophisticated these processes are, the consensus is that exciting times are ahead for both research and theory concerning the mental processes involved in unconscious cognition.

Implicit and explicit memory in autism: is autism an amnesic disorder?

Medial temporal lobe amnesic disorder is characterized by an impairment in explicit memory (e.g., remembering a shopping list) and intact implicit memory (e.g., a woman seems familiar although you cannot remember having met her before). This study examined whether children with high-functioning autism have this same dissociation between explicit and implicit memory abilities. Children with autism and normal development participated in three memory tasks: one implicit task (perceptual identification) and two explicit tasks (recognition and recall). Children with autism showed intact implicit and explicit memory abilities. However, they did not show the typical pattern of recalling more items from both the beginning and end of a list and instead only recalled items from the end of the list. These results do not support the theory that high-functioning autism is a type of medial temporal lobe amnesia. However, these findings suggest that persons with autism use different organizational strategies during encoding or retrieval of items from memory.

Unconscious priming of association judgments.

Participants judged whether pairs of target words were associated or not-associated in meaning (association judgment task). Target pairs were preceded by a brief (200 ms) related or unrelated (prime) word presented to the nondominant eye. Each participant performed 2 blocks of association judgment task trials: 1 with primes that were legible, and 1 with primes that were masked by a pattern simultaneously presented to the dominant eye. Across 2 experiments, significantly larger masked priming effects were observed for participants who could not detect priming words (low-d' participants) than for participants who could partially see priming words (high-d' participants). This result suggests that undetectable masked primes can activate word meaning and that conscious attempts to process masked primes may inhibit unconscious activation. Additionally, evidence is presented that supports claims that spreading activation is the crucial mechanism responsible for unconscious priming.

Mechanisms of unconscious priming: I. Response competition, not spreading activation.

Four experiments were conducted to replicate and expand upon A. G. Greenwald, S. C. Draine, and R. L. Abrams's (1996) demonstration that unconsciously perceived priming words can influence judgments of other words. The present experiments manipulated 2 types of relationships between priming and target stimuli: (a) whether priming and target stimuli possess a preexisting semantic relationship (an affective relationship in Experiments 1, 2, and 4; an associative relationship in Experiment 3; and an animacy relationship in Experiment 4) and (b) whether the primes and targets produce the same response. Large priming effects were found only when the primes and targets possessed response compatibility. No residual effects for affective, animacy, or semantic relatedness were observed. Although these results strongly support the conclusion that word meaning can be unconsciously activated, they do not support the claim that the unconscious perception effects obtained in Greenwald et al.'s (1996) paradigm are caused by automatic spreading activation of word meaning. Instead, the results reported here are consistent with a claim that unconsciously perceived words automatically trigger response tendencies that facilitate or interfere with target responding.

The roles of attention and awareness in the false recognition effect.

Jacoby and Whitehouse (1989) reported that masked words can unconsciously bias memory judgments. Others suggest that these results cannot be taken as evidence that words are perceived without awareness, as Jacoby and Whitehouse claimed. In the present experiments, participants' ability to attend to briefly presented context words was manipulated by masking the context words and by an instructional manipulation. In Experiment 1, masked context words increased false recognitions. Different from Jacoby and Whitehouse's results, nonmasked context words showed a similar pattern. In Experiment 2, these effects were replicated and an attended condition was added in which participants read the context words aloud and tried to remember them. False recognition was increased in both masked and unmasked conditions and decreased in the attended condition. These results suggest that the condition for increase or decrease in false recognition is not whether a stimulus is seen or not but whether a stimulus is attended. They suggest that the qualitative difference criterion proposed by Jacoby and Whitehouse is insufficient for determining whether participants are aware of masked presentations.

Visual masking and unconscious processing: differences between backward and simultaneous masking?

Visual masking procedures are considered to have great potential for studying information processing that occurs outside of consciousness. Unfortunately, effects that indicate processing of masked word stimuli have been both difficult to obtain and, once obtained, difficult to replicate. The present seven experiments failed to obtain an effect of lexicality (word vs. nonword targets) on detection that was recently reported by Doyle and Leach (1988). Whereas Doyle and Leach had used backward binocular masking, most of the present experiments used simultaneous dichoptic masking. Doyle (1990) recently suggested that the effect of lexicality on detection (coupled with an effect of knowledge of results, which was also not obtained in the present research) could explain why Greenwald, Klinger, and Liu (1989) found no evidence for detectability of masked words that were nevertheless analyzed semantically. The differences of the present findings from those of Doyle and Leach (1988) not only confirm the uncertainty of generalizing across masking procedures, but also indicate that Greenwald et al.'s "detectionless processing" interpretation remains viable.

Unconscious processing of dichoptically masked words.

In three experiments, the subjects' task was to decide whether each of a series of words connoted something good (e.g., fame, comedy, rescue) or bad (stress, detest, malaria). One-half second before the presentation of each such target word, an evaluatively polarized priming word was presented briefly to the nondominant eye and was masked dichoptically by either the rapidly following (Experiment 1) or simultaneous (Experiments 2 and 3) presentation of a random letter-fragment pattern to the dominant eye. (The effectiveness of the masking procedure was demonstrated by the subjects' inability to discriminate the left vs. right position of a test series of words.) In all experiments, significant masked priming effects were obtained; evaluative decisions to congruent masked prime-target combinations (such as a positive masked prime followed by a positive target) were significantly faster than those to incongruent (e.g., negative prime/positive target) or noncongruent (e.g., neutral prime/positive target) combinations. Also, in two of the three experiments, when subjects were at chance accuracy in discriminating word position, their position judgments were nevertheless significantly influenced by the irrelevant semantic content (LEFT vs. RIGHT) of the masked position-varying words. The series of experiments demonstrated that two very different tasks--speeded judgment of evaluative meaning and nonspeeded judgment of word position--yielded statistically significant and replicable influences of the semantic content of apparently undetectable words. Coupled with previous research by others using the lexical decision task, these findings converge in establishing the reliability of the empirical phenomenon of semantic processing of words that are rendered undetectable by dichoptic pattern masking.

The effect of pain on memory for affective words.

Memory is a key cognitive variable in pain management, but lacks extensive research. This study is a replication and extension of Seltzer and Yarczower's investigation of pain's influence on memory for affective words, which found fewer positive words and more negative words recalled if subjects were in acute pain (versus no pain). In the present study, two experiments were conducted: one with a recall memory test and one with a recognition memory test. One hundred sixty undergraduate subjects were randomly placed in one of four groups: two groups had the same condition (pain or no pain) for both the encoding task and memory test, and two groups had mixed conditions (pain at encoding-no pain at memory test or no pain at encoding-pain at memory test). Pain was induced by 0 degrees-2 degrees C water immersion. At encoding, subjects categorized words by judging them as either positive or negative. Results of both experiments show that pain impairs memory. In neither experiment were differences found on memory for positive and negative words. These results do not support Seltzer and Yarczower's discriminative effects of pain on word category, but they are consistent with other research using acute pain manipulations and chronic pain populations, suggesting that pain interferes with memory. It is hypothesized that pain depletes scarce attentional resources, thereby interfering with concurrent cognitive tasks such as thinking, reasoning, and remembering.

Biological characterization of a chimeric mouse-human IgM antibody directed against the 17-1A antigen.

A chimeric antibody was constructed in which the murine H- and L-chain variable regions of mAb 17-1A, raised against human colorectal cancer cells, were joined with the human constant mu and kappa regions. Transfection of these constructs into the murine myeloma Sp2/0 resulted in the expression and secretion of a pentameric Ig, designated chimeric 17-1A IgM. The chimeric 17-1A IgM was subsequently compared to a previously described chimeric 17-1A IgG1 for biological activities. Both chimeric mAbs were equally effective (weight basis) in competing against the binding of murine 125I-17-1A to cultures of HT-29 colon carcinoma cells. The calculated association constants for the chimeric 17-1A IgM and IgG1 were 1.63 x 10(8) l/mol and 3.41 x 10(7) l/mol, respectively. Unlike chimeric 17-1A IgG1, the chimeric 17-1A IgM was able to render colon carcinoma target cells susceptible to lysis by both xenogeneic (rabbit) and human complement. The extent of complement-mediated lysis dependent upon chimeric 17-1A IgM was correlated to 17-1A antigen expression on target cells. HT-29 colon carcinoma cells treated with chimeric 17-1A IgM did not directly result in antibody-dependent cellular cytotoxicity by human peripheral blood monocytes. However, chimeric 17-1A IgM greatly enhanced the deposition of C3 on complement-treated HT-29 cells, and concomitant incubation with monocytes resulted in heightened lysis of the tumor cells. The feasibility of enhancing host defense against gastrointestinal malignancies by the administration of this chimeric 17-1A IgM may have certain clinical advantages.