Cell biology and possible therapeutic applications of anti-CD3-activated killer-T cells (review)

Polyclonal T lymphocyte populations can be stimulated with anti-CD3 antibody to proliferate, secrete cytokines, and mediate MHC-unrestricted cytotoxic activity against a wide range of tumor target cells. Because anti-CD3-activated killer-T (AK-T) cells may be useful in the immunotherapy of human cancers, it is important to understand the signaling pathways and cell-surface structures involved in the induction and tumoricidal effector function of AK-T cells. Studies in the mouse model system have characterized the cytokines, signal transduction pathways, and costimulatory molecules involved in AK-T cell development. The recognition/adhesion and subsequent signaling events which lead to tumoricidal activity by mouse AK-T cells have also been defined. These findings, providing they translate accurately to the human system, may allow for the design of effective strategies to use AK-T cells for the treatment of human cancers. However, to date, the encouraging results obtained with anti-CD3 antibody/AK-T cell-based immunotherapies in mouse models of cancer have not been duplicated in clinical trials. The most likely explanation for this dis-appointing result is that tumor-reactive T lymphocytes in long term tumor-bearers fail to function correctly in the tumor microenvironment due to tumor-induced immune suppression and defects in key signal transduction molecules. It is clear that a detailed understanding of the inhibitory effect of established tumors on host T cells and the means to overcome tumor-induced immunosuppression are needed before anti-CD3 antibody/AK-T cell-based immunotherapies can be expected to succeed in the clinical setting.     

Confirmation that Thiobacillus halophilus and Thiobacillus hydrothermalis are distinct species within the gamma-subclass of the Proteobacteria

BACKGROUND: There is controversy regarding the most appropriate investigation for suspected colorectal carcinoma. We offered these patients same-day flexible sigmoidoscopy (FS) and double-contrast barium enema (DCBE). METHODS: We reviewed the results of 117 consecutive adult patients. All patients underwent FS followed by DCBE on the same day. The radiographs were reviewed by two of the authors who were blinded to the clinical information, flexible sigmoidoscopy reports, and the original DCBE report. RESULTS: One hundred seventeen patients made up the study population. Thirty-four of the 117 patients had polyps and/or carcinoma. Three malignant tumours were detected by DCBE; one of these was also seen on FS, and the other two cancers were out of FS range. Fifty-three polyps were found by FS; nine were removed by biopsy prior to the enema examination. Of the 44 remaining polyps, DCBE failed to detect 87% of the 0-9-mm group and 67% of the >9-mm group. Ten polyps were seen only on DCBE; seven of these 10 were beyond the range of the sigmoidoscope, and the three remaining polyps were less than 5 mm. CONCLUSION: DCBE is insensitive in the detection of rectosigmoid polyps. FS should continue to be used as a complementary examination to DCBE in the investigation of suspected colorectal carcinoma.     

Biological impact of small air ions

The thrust of the experimental data presented here is that small air ions are biologically active. There is convincing evidence that both negative and positive ions (i) inhibit growth of bacteria and fungi on solid media; (ii) exert a lethal effect on vegetative forms of bacteria suspended in water when opportunity is provided for contact of cells and ions; and (iii) reduce the viable count of bacterial aerosols. Through physical action, ions of either charge upset the stability of aerolosized bacterial suspensions and, in addition, have a direct lethal effect which is more prominent with negative ions than with positive ions. With regard to the serotonin hypothesis of air ions action, the situation is more complex. The essential fact is that mice and rats display a charge-related metabolic response to air ions and this phenomenon also occurs in humans. Because serotonin is such a potent hormone, the ultimate functional changes incident to air ion action are impressive and account for the signs of symptoms of the sharav syndrome. Alterations in the cumulative mortality rate with three experimental respiratory disease in the mouse also are charge-dependent, positive ions routinely exercising a detrimental effect. Further, in the case of mice infected with influenza virus, ion-deprivation increases the cumulative mortality rate. Since ion depletion is a constant concomitant of modern urban life, one reasonably may speculate about comparable inimical effects on humans.     

Molecular genetic investigations of autism

Genetic factors are likely to play a major role in the etiology of autism. The genetics of the disorder is however complex, probably involving the action of several genes. In an attempt to identify autism susceptibility loci we are currently undertaking a systematic screening of the whole human genome using multiplex families. We describe the resources and the methods needed to achieve such a task, including extensive collection of family data, semiautomated genotyping technology, and specialized statistical approaches for linkage analysis of complex traits.     

A consensus model for molecular packing of type I collagen

In this review, recent results from X-ray diffraction studies of tendon are used to develop an understanding of the molecular packing of type I collagen in tendon fibrils. These cover the definition of the unit cell as triclinic, the lateral architecture of molecular packing in a fibril and the molecular packing topology of a structure that gives good agreement with X-ray diffraction data. The proposed model is a 1D staggered left handed microfibril; the molecular orientation of the telopeptides indicates that there are interconnections between microfibrils that may explain the difficulty in isolating individual microfibrillar structures. This is the first structure that defines the absolute molecular packing of molecular segments based on X-ray diffraction data. These results are discussed in the light of direct and indirect evidence relating to molecular packing such as mineralization, natural crosslink position, and biomechanical evidence. The ability of the proposed structure to fulfill many of the structural and biochemical criteria point towards the structure providing a basis for a consensus model of collagen packing.     

In vitro repression of Brca1-associated RING domain gene, Bard1, induces phenotypic changes in mammary epithelial cells

BRCA1-associated RING domain (BARD1) was identified as a protein interacting with the breast cancer gene product BRCA1. The identification of tumorigenic missense mutations within BRCA1 that impair the formation of BARD1-BRCA1 complexes, and of BARD1 mutations in breast carcinomas, sustain the view that BARD1 is involved in BRCA1-mediated tumor suppression. We have cloned the murine Bard1 gene and determined that its expression in different tissues correlates with the expression profile of Brca1. To investigate the function of Bard1, we have reduced Bard1 gene expression in TAC-2 cells, a murine mammary epithelial cell line that retains morphogenetic properties characteristic of normal breast epithelium. Partial repression of Bard1, achieved by the transfection of TAC-2 cells with plasmids constitutively expressing ribozymes or antisense RNAs, resulted in marked phenotypic changes, consisting of altered cell shape, increased cell size, high frequency of multinucleated cells, and aberrant cell cycle progression. Furthermore, Bard1-repressed cell clones overcame contact inhibition of cell proliferation when grown in monolayer cultures and lost the capacity to form luminal structures in three-dimensional collagen gels. These results demonstrate that Bard1 repression induces complex changes in mammary epithelial cell properties which are suggestive of a premalignant phenotype.     

Seizure induced C-Fos mRNA in the rat brain: comparison between young and aging animals

Although there are many publications on the usefulness of magneto-therapy, discrepancies exist about the utility of electromagnetic fields in skin wound healing. The objective of this work was to study the effect of electromagnetic fields on wound healing in rats. Thirty six male Wistar rats were used; a rectangular lesion was made in the back of each animal (4.2 cm x 2.3 cm). They were divided into 3 groups: group C (control) with sham treatment; group C50, treated with continuous electromagnetic fields of 5 mT (50 Gauss) and group P200, treated with pulsed electromagnetic fields of 20 mT (200 G). The treatments were of 30 minutes a day during 21 days. The corporal weights (Table 1) and the wound longitudinal and transversal maximal axis (Figures 1, 2) were weekly recorded and the data was evaluated by analysis of variance. On day 14, the P200 group showed the maximal longitudinal axis which was smaller than that of group C (p < 0.01). On day 21 in both treated groups the maximal longitudinal axis was smaller than that of group C (p < 0.01); besides the axis was smaller in the P200 group than in the C50 group (p < 0.05). No statistical differences were observed in the remaining data. The results showed a facilitating effect of electromagnetic fields on wound healing in rats. Pulsed electromagnetic fields seem to have a precocious and larger healing effect than continuous electromagnetic fields.