Immunity to murine sarcoma virus induced tumours. IV. Direct cellular cytolysis of 51Cr labelled target cells in vitro and analysis of blocking factors which modulate cytotoxicity.

The antigen specific cell mediated cytotoxicity of MSV immune spleen lymphocytes to 51Cr labelled murine lymphoma cells was wholly abolished by pretreatment of the spleen cells with anti-theta antibody and complement. Early during the immune response to MSV the cytotoxic acitivity was inhibited by incubation of immune lymphocytes with "late progressor" or "early regressor" serum. Immune lymphocytes at later times were more refractory to such inhibition by serum blocking factors. Although unfractionated cytotoxic lymphocytes, irrespective of the time after MSV infection at which they were tested, were inhibited by soluble tumour associated antigen (TAA), a subpopulation of cytotoxic T cells was identified which was inhibited neither by antigen nor serum

Inhibition of cell proliferation rather than of cell lysis as a measure of immune reactivity in embryo-antigen-challenged mice.

An assay system is described in which effector cells added along with suitable target cells inhibit, in a quantitative fashion, the subsequent uptake of 3H-thymidine by those target cells. Effector cells active in this assay, using embryonic fibroblast cells as targets, develop spontaneously in cultures of mouse lymphoid cells, but are apparently different from those described earlier by investigators of activity in cytotoxic assays. Further evidence is presented to show the development of spleen-derived effector cells with cytostatic activity (for embryonic fibroblast target cells) in mice during the course of normal pregnancy, or growth of spontaneously appearing mammary adenocarcinomas. Indeed, such effector cells can also be found within the growing solid mass itself. Different populations of tumour cells isolated from a solid tumour apparently differ in their susceptibility to growth inhibition by tumour-bearer-derived cytostatic effector cells, a phenomenon which may be related to metastatic spread of tumour cells

Tumour-cell susceptibility to cytotoxic or cytostatic effector cells in vitro and the regulation of tumour-cell growth in vivo.

Tumour-cell growth in lung nodules after i.v. transfer to sublethally irradiated mice has been followed after adoptive transfer of different populations of lymphoid cells. Spleen cells deliberately immunized in vitro and in vivo against stimulator cells bearing embryo-associated antigens and which are cytostatic in vitro for targets bearing such antigens, can diminish the number of lung nodules found after i.v. transfer. In contrast, cytotoxic (in vitro) spleen cells, while capable of diminishing local (s.c.) growth of tumour cells, cannot control systemic tumour growth. Within a given solid tumour mass, the subpopulations resistant to cytostatic effector cells in vitro are the ones most likely to produce lung colonies after adoptive transfer in vivo, though they show no more local (s.c.) growth than to cytostatic-sensitive cells in vivo

Immunity to Murine Sarcoma Virus Induced Tumors. III. Analysis of the Cell Populations Involved in Protection from Lethal Tumour Progression of Sublethally Irradiated, MSV Inoculated, Mice

A comparison was made between the cells responsible for demonstrable activity against MSV antigens, using both in vivo and in vitro assays. Similar cells (in terms of size and sensitivity to anti-theta serum) were detected in both assays. However, while lymphoid cells from animals at all stages post-MSV infection were active in protecting irradiated mice from the lethal effect of induction of MSV sarcomata, cells from animals at early stages post-MSV infection (when the tumour was in a progressive phase of growth) were not active in the in vitro assay. By manipulation of the in vivo assay conditions a situation was observed in which cells from “progressor animals” were able to suppress both the in vitro and in vivo activity of regressor lymphoid cells. The potential physiological role of this cell type is disussed

Culturally Adapted Interventions in Mental Health: Global Position Statement

The preponderance of western psychological concepts are often relied upon to conceptualise health-related phenomena. It is hardly surprising therefore that despite the availability of a number of interventions, studies have concluded that outcomes for minority cultural groups are not as good as for Caucasian people (western Europe and North America) in many high and middle income countries (HMIC). The evidence base of most psychosocial interventions is yet to be established in Low and Middle Income Countries (LMICs). There has been a propensity in some quarters to view low and middle income countries as passive beneficiaries of mental health knowledge, rather than as contributors or partners in knowledge production and development. A move towards a more equal bilateral relationship is called for, which should lead to better service provision. This Position Statement aims to highlight the current position and need for culturally adapted interventions. It is a global call for action to achieve a standardised mechanism to achieve parity of access and outcomes across all cultural groups regardless of country of residence

Parameters of Reserpine Analogs That Induce MSH2/MSH6-Dependent Cytotoxic Response

Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule that are required to interact with MSH2/MSH6 to induce MSH2/MSH6-dependent cytotoxic response. A multidisciplinary approach involving structural modeling, chemical synthesis, and cell biology analyzed reserpine analogs and modifications. We demonstrate that the parameters controlling the induction of MSH2/MSH6-dependent cytotoxicity for reserpine-analogous molecules reside in the specific requirements for methoxy groups, the size of the molecule, and the orientation of molecules within the protein-binding pocket. Reserpine analog rescinnamine showed improved MSH2-dependent cytotoxicity. These results have important implications for the identification of compounds that require functional MMR proteins to exhibit their full cytotoxicity, which will avoid resistance in MMR-deficient cells