Abstract

Convincing evidence indicates that malignant transformation of melanocytes is frequently associated wit h abnormalities in HLA class I antigen expression and/or function. These abnormalities appear to play a role in the clinical course of the disease, since they are associated with histopathological characteristics of malignant lesions and with disease-free interval and survival. Defects in the HLA class I antigen processing machinery are caused by mutations in the genes encoding their components including HLA class Isubunits and/or by defects in the mechanisms regulating their expression and/or function. It is likely that the presence, in malignant lesions, of tumor cell populations with HLA class Iantigen abnormalities reflects T cell selective pressure which results in the isolation of cells which have escaped immune recognition and destruction. A high percentage of cell lines and malignant lesions has been found to possess multiple defects in the HLA class Iantigen processing machinery. This finding suggests that when the main tumor cell population in a patient acquires resistance to an ongoing tumor associated antigen (TAA) specific CTL response, a patient's immune response changes its specificity. The selective pressure imposed by the use of a new target of the immune response results in the outgrowth of a tumor cell population with additional defects which provide resistance to the new immune attack. If our hypothesis is correct, the data we have presented in conjunction with the frequent detection in patients with malignancies of anti- TAA antibodies utilizing the SEREX methodology argue against the possibility that immunological ignorance and/or tolerance underlie tumor growth. Immune escape mechanisms appear to be a more likely possibility. (Presented at the 1254th Meeting, May 22, 2002.)

Deregulation of cell growth can be described in its broadest sense as deregulated signal transduction. The classical pathway leads from the cell membrane receptor to effector molecules of first and second generation. With respect to analysis of oncogenic mutations, there is emerging evidence that certain signalling molecules are involved more frequently than others. These molecules belong to the so called tyrosine kinases which are master enzymes dominating entire signalling cascades. An example is the tyrosine kinase receptor for the human stem cell factor (SCF), which is also called ckit. This receptor harbours various mutations in human leukemia or solid tumors as GIST-tumors. In-vitro, it has been shown that inhibition of c-kit signalling using the tyrosine kinase inhibitor STI-571 (Imatinib mesylate, GleevecTM) results in inhibition of proliferation and induction of apoptosis. Recently, two clinical trials in GIST-tumors provided proof of the concept, that inhibition of the c-kit tyrosine kinase is associated with clinical benefit. In CML, the translocation t(9;22) results in constitutive activation of the Bcr-Abl kinase. Recently, STI-571 has been shown to specifically inhibit the Abl kinase activity. Phase Iand phase IIclinical trials in BCR-ABL positive CML and ALL showed a high level of clinical activity and low toxicity. These examples show that deregulated tyrosine kinases are attractive and clinically relevant targets. It will be very interesting to investigate whether malignancies featuring complex molecular pathology (as c-kit positive SCLC or c-kit positive AML) will also respond to inhibition of tyrosine kinase activity using imatinib mesylate. (Presented at the 1256th Meeting, May 31, 2002.)

The objective of this project is to study how bipolar cell signals segregated in various strata in the inner plexiform layer (IPL) of the retina are integrated and computed by amacrine cells (ACs) and ganglion cells (GCs). A previous study suggests that various attributes of visual signals are segregated by stratification of bipolar cell axon terminals in the IPL. Confocal microscopic analysis reveals that axon terminals of bipolar cells are either monostratified, multiistratified, or pyramidally branching in the IPL. About 30% of ACs have narrowly monostratified dendrites in one of the ten strata of the IPL, and they receive segregated bipolar cell inputs: the light-evoked excitatory cation current, ?IC, in strata 1, 2 and 4 are OFF, in strata 3, 7, 8, 9 and 10 are ON, and in strata 5 and 6 are ON-OFF. The remaining 70% of ACs have either broadly monostratified, multistratified or diffuse dendrites, and they integrate bipolar cell signals through layer-by-layer summation: ACs with dendrites ramified in multiple strata exhibit ?IC that are sums of ?ICs of individual strata. The lightevoked inhibitory chloride current, ?ICl, in strata 1, 2, 4, 5 and 6 are ON-OFF, and ?ICl in strata 3, 7, 8, 9 and 10 are ON. There are very few narrowly monostratified GCc and thus most GCs integrate bipolar cell and AC signals by summing up inputs from multiple strata in the IPL. (Presented at the 1260th Meeting, June 3, 2002.)

Idiopathic dilated cardiomyopathy (DCM) is one of the leading causes for the severe heart failure and the most common cause for heart transplantation due to its ventricular dilatations and contractile dysfuntions. Twenty percent of DCM is in familiar form and the rest is sporadic. The clinical impact of DCM is far greater than its position in epidemiological terms. Despite recent improvements in therapy, both incidence and mortality are still very high. The main problem is its heterogeneous etiology. So far, three factors have been identified to be potentially important: enteroviral infection, immune mechanism and genetic factors. During the last 10 years there have been many investigations showing distinct autoantibodies or other immune factors in heterogeneous subsets of DCM which have contributed supportive and confounding evidence to hypothesis that multiple autoimmune mechanisms are involved in DCM. Accumulated evidence hitherto demonstrated a variety of circulating autoantibodies in the sera of patients with DCM including antireceptor autoantibodies, myosin and ADP/ATP translocator protein etc. Data available from both in-vitro and invivo studies of antireceptor autoantibodies as well as from other autoantibodies and autoreactive lymphocytes demonstrated evidently that a subgroup of DCM is autoimmunity-mediated. This is understandable because DCM is heterogeneous, implying that different subgroups of DCM may have different pathogeneses. It may be practical in the future to separate "autoimmune cardiomyopathy" from other "idiopathic" DCM. (Presented at the 1264th Meeting, July 3, 2002.)

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