Vascular density in melanoma xenografts correlates with vascular permeability factor expression but not with metastatic potential

Previous studies have shown that human airway epithelial cells (AEC) can stimulate allogeneic peripheral blood T-lymphocyte (PBT) proliferation. We now sought to determine which AEC surface molecule/T-cell coreceptors are involved in this process. AEC-induced PBT proliferation was inhibited by 25 microM genestein or herbamycin A (0.9 and 1.8 microM), both tyrosine kinase inhibitors. Anti-phosphotyrosine immunoblots performed on PBT lysates after coculture with AEC demonstrated phosphorylation of 56kD and 60kD bands. To determine whether CD3 associated p59fyn, or CD4 and CD8 associated p56lck phosphotyrosine kinases (PTK) were involved, we assayed kinase activity in lymphocyte lysates immunoprecipitated with anti-p56lck and p59fyn mAbs. PBT cells or murine T-cell line transfectants expressing human CD4 (3G4) or human CD8alpha (3G8) were cocultured with AEC or A549, an alveolar-like cell line lacking class II Ag expression. After A549 or AEC coculture, p56lck activity in PB T-cells peaked at 2 min whereas p59fyn kinase activity continued to rise at 8 min. AEC (expressing class II Ags) stimulate PTK activity in both 3G8 and 3G4 cells. A549 stimulated p56lck in 3G8, but not in 3G4 cells. This activation of p56lck was not blocked by preincubation of A549 with anti-class I or anti-CD1d mAbs. An antibody generated in our laboratory, which recognizes an epithelial specific surface molecule (mAb L12) and which blocks AEC driven PBT proliferation, was shown to block PTK activity of peripheral blood T-cell lysates, though not of 3G8 lysates. These studies suggest that AEC are capable of stimulating CD4 and CD8 associated lck and CD3 associated fyn kinases through class II dependent and independent pathways.     

CMAP: a novel cystatin-like gene involved in liver metastasis

The distribution and ultrastructure of class II major histocompatibility complex (MHC)-positive cells were investigated in human dental pulp, employing immunohistochemistry using an anti-human leukocyte antigen (HLA)-DR-monoclonal antibody. HLA-DR-immunopositive cells, appearing spindle-like or dendritic in profile, were densely distributed throughout the dental pulp. Under the electron microscope, these cells exhibited various sizes of vesicles containing clear or opaque contents, multivesicular bodies and characteristic fine tubulovesicular structures in their cytoplasm. Some reactive cells possessed coated pits and vesicles including electron-dense materials, indicating an active endocytosis. At the periphery of the pulp tissue, the HLA-DR-immunopositive cells were predominantly situated in the subodontoblastic layer, with some located in the odontoblast layer and/or predentin and extending their cytoplasmic processes into the dentinal tubules. Cell processes of these cells occasionally made contact with several odontoblast processes in the same way as the nerve fibers in the predentin. These cells never contained the typical phagosomes frequently observed in the HLA-DR-immunoreactive macrophages in the subodontoblastic layer and the pulp core. The results suggest that the HLA-DR-immunopositive cells in the odontoblast layer and/or predentin have some regulatory function on the odontoblasts under physiological conditions, in addition to their involvement in the initial defense reaction after tooth injury.     

Identification of molecules associated with the development of metastasis in human malignant melanoma

Differential antibody reactivity has been used to identify molecules which change in expression or which are modified during tumor progression in human malignant melanoma. Such molecules may play a role in the development of the metastatic capacity of this tumor. Two of these molecules (ICAM-1 and MUC18) have been identified as cell adhesion molecules which are potentially involved in tumor-leukocyte-endothelial interactions.     

Loss of expression of the p16INK4/CDKN2 gene in cutaneous malignant melanoma correlates with tumor cell proliferation and invasive stage

The profile of leprosy in children currently seen in a referral hospital is compared with that of children with leprosy admitted in the 1970s. Children with leprosy under the age of 15 years in 1974 and 1979 comprised one group (Group I) while those during 1989 and 1994 constituted the second group (Group II) The variables studied included age, sex, type of leprosy, deformity and contact status. Multidrug therapy (MDT) was introduced in the treatment of leprosy in 1982. The probable change it has made in the presentation of leprosy in children is discussed.     

Anti-cell death activity promotes pulmonary metastasis of melanoma cells

Bcl-2 inhibits apoptosis from a variety of stimuli, and a Bcl-2-binding protein BAG-1 also functions in protection from apoptosis in concert with Bcl-2. Here, we provide evidence that prolonged cell survival introduced by overexpression of Bcl-2 or BAG-1 proteins strongly promotes experimental pulmonary metastasis of melanoma B16-BL6 cells. In murine melanoma cell line B16-BL6, gene transfer-mediated expression of the Bcl-2 or BAG-1 led to prolonged cell survival against serum-starved apoptosis in vitro. The Bcl-2-expressing B16 cells, B16-Bcl-2 and the BAG-1-expressing B16 cells, B16-BAG-1 strongly enhanced pulmonary metastasis in allogenic BALB/c nude mice and whole lung weights were increased by 2.4-fold and 1.4-fold, respectively, compared with control transfectants, suggesting that Bcl-2 is a stronger positive modulator of metastasis. When the viable B16-Bcl-2 and control transfectants were injected subcutaneously into BALB/c nude mice, the colony numbers of pulmonary metastasis of the B16-Bcl-2 transfectant increased by 5.6-fold compared with the control transfectants. These enhanced metastatic potentials in the B16-Bcl-2 and the B16-BAG-1 transfectants were well correlated with anti-cell death activity against serum-starvation and enhanced cell viability on limiting dilution. Analysis of the transfectants however revealed that their growth rates, invasive ability and cell motility were not significantly altered by overexpression of either Bcl-2 or BAG-1 proteins. Taken together, these studies demonstrate that prolonged cell survival is a crucial factor to promote metastasis of melanoma, thereby contributing to tumor progression.     

Cognitive event-related potential correlates of schizophrenia.

Reviews findings relating schizophrenia to 4 event-related brain voltage potential components: contingent negative variation (CNV), N100, P300, and slow wave. Research indicates that schizophrenics manifest several cognitive event-related potential (ERP) abnormalities relative to control Ss, including a diminished CNV in warned reaction time (RT) paradigms during the warning stimulus–imperative stimulus interval. This CNV continues beyond presentation of the imperative stimulus as the postimperative negative variation (PINV). CNV attenuation may reflect a state marker of psychosis in acute schizophrenics, but it may serve as a trait marker regardless of current symptoms in more chronic patients. In contrast, the PINV may be more of a state marker for both acute and chronic patients. There is a pattern of P100–N100 reducing in acute schizophrenics that is not seen in chronic and paranoid patients, as well as evidence of an attenuated enhancement of N100 to stimuli presented in an attended channel, especially at slower event rates. A diminished late positive complex apparently due more to a diminished P300 than a diminished slow wave has been observed in schizophrenics, which may to a degree reflect a trait marker of high risk for schizophrenia as well as a residual deficit state that often remains following the remission of positive symptoms. With the possible exception of the PINV elicited in standard CNV paradigms, these ERP abnormalities do not appear to be specific to schizophrenia, as they are also found in association with a variety of other disorders. (5 p ref) (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Brain potential correlates of number errors in the Turkish language

Event-related potentials (ERPs) were recorded from 16 native speakers of Turkish while they watched Turkish sentences flashed upon the screen of a videomonitor. The sentences were three words long and contained a verb at the terminal position that was manipulated (1) to have either the correct or the incorrect number with regard to the subject of the sentence, and (2) to be semantically appropriate, inappropriate or to be a pseudoverb. The ERPs from 19 scalp channels revealed a more positive waveform at the left-fronto-temporal site with an onset latency of about 200 ms for the verbs having the wrong number regardless of the semantic appropriateness of the word, while at right fronto-temporal sites a more negative waveform was observed for plural words only. This number incongruency ERP-effect in Turkish is clearly at odds with findings from other languages.     

Simultaneous enucleation of a pulmonary melanoma metastasis and myocardial revascularization

BACKGROUND: The incidence of late, recurrence of malignant melanoma, is a well known, but very rare clinical experience. CASE REPORT: We report a case of simultaneous myocardial revascularisation and resection of pulmonary melanoma metastasis. In 1963 an enucleation of the right eye was necessary due to an ocular melanoma. In 1993 the patient suffered acute left heart failure and a 3-vessel disease with severe reduced left ventricular function was diagnosed. Chest X-ray examination revealed a singular pulmonary lesion in the right lower lobe with a diameter of 5.5 cm. Myocardial revascularisation and resection of the pulmonary focus was performed simultaneously without complication. The histological examination documented a pulmonary late recurrence of malignant melanoma. Up to this time (3 years later) the patient is free of cardiac symptoms and there is no evidence of further late recurrence of malignant melanoma. CONCLUSION: The appreciable number of patients who, after a disease-free interval of 10 to 20 years, develop a late recurrence of a malignant melanoma, and in particular-as in the present case-a choroidal melanoma, is powerful evidence for a need to keep these patients under lifelong surveillance.     

Tumor-associated antigen TA-90 immune complex assay predicts subclinical metastasis and survival for patients with early stage melanoma

BACKGROUND: TA-90 is a tumor-associated antigen first identified in the urine and sera of patients with metastatic melanoma. In the early stages of disease, TA-90 is present in circulating immune complexes (ICs) that may be detected with an antigen specific enzyme-linked immunosorbent assay (ELISA). In this study, the authors evaluated the efficacy of the TA-90 IC assay in detecting subclinical metastasis of early stage melanoma and predicting the survival of patients with this disease. METHODS: Archival sera were collected preoperatively from 114 patients who underwent wide excision with or without regional lymphadenectomy in the treatment of clinical Stage I melanoma. Sera were analyzed for TA-90 IC in a blinded fashion, and results were correlated with the patient's clinical course as determined by database and chart review. Subclinical metastases were considered present at the time of surgery if the lymphadenectomy specimen was pathologically positive and/or the patient subsequently developed recurrence. RESULTS: The TA-90 IC assay predicted subclinical metastasis in 43 of 56 patients (P < 0.0001), with 14 false-positive and 13 false-negative results. Sensitivity and specificity for the detection of occult metastasis were 77% and 76%, respectively. Positive and negative predictive values were 75% and 77%, respectively. Fifteen of 18 tumor positive regional lymph node basins (83%) and 34 of 46 recurrences (74%) were accurately predicted when considered independently (P < 0.004). Preoperative TA-90 IC status was also highly correlated with survival: 5-year overall and disease free survival rates were 63% and 46%, respectively, for the TA-90 IC positive group, compared with 88% and 82%, respectively, for the TA-90 IC negative group (P=0.0001). A multivariate analysis with standard prognostic variables identified preoperative TA-90 IC status as a strong, independent prognostic factor for both overall and disease free survival. CONCLUSIONS: To the authors' knowledge, TA-90 is the first tumor marker that accurately predicts subclinical metastatic disease and survival for patients with early stage melanoma. For this reason, the TA-90 IC assay has the potential to improve dramatically the prognostic evaluation of patients with this disease. Its role in postoperative risk stratification and early detection of recurrence is being evaluated in a prospective study.     

Immunotherapy, including gene therapy, for metastatic melanoma

Current standard therapy for distant metastatic melanoma is ineffective and often compromises the quality of a patient's life. Immunotherapy is briefly reviewed in relation to its many forms: from local non-specific to the more recent specific vaccines, including those using specific melanoma peptides (e.g. from the proteins encoded by melanoma-associated gene (MAGE)) and those involving genetically transduced autologous melanoma cells using retroviral vectors in vitro. The mode of action of genetically transduced melanoma cells incorporating the granulocyte macrophage colony stimulating factor (GM-CSF) gene (GVAX) is presented as a paradigm for cytokine-mediated strategies. Trials of GVAX and other cytokine gene strategies are under way in Brisbane, Boston and Amsterdam, and some interim perspectives on the clinical outcomes and immunological mechanisms involved are sketched. Some of the compounding problems in immunotherapeutic strategies for cancer are identified, and possible adjunct manoeuvres for overcoming them are discussed.