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PubMed1999

Fibroblast-secreted macrophage colony-stimulating factor is responsible for generation of biphenotypic B/macrophage cells from a subset of mouse B lymphocytes.

Normal and malignant CD5+ B lymphocytes can develop macrophage-like characteristics. One stimulus of this phenotypic shift is culture of normal mouse splenic B lymphocytes with splenic fibroblasts or their conditioned media. These biphenotypic B/macrophage (B/M phi) cells simultaneously display macrophage characteristics, such as phagocytosis and F4/80 expression, while retaining B cell features, including expression of surface Ig, CD5, B220, and rearranged Ig genes. The present study investigated the fibroblast-secreted factor that promotes this phenotypic change from B cell to B/M phi cell. RT-PCR analysis demonstrated that mRNA for M-CSF is produced by splenic fibroblasts. Recombinant M-CSF (CSF-1) could replace fibroblast-conditioned medium to elicit the development and survival of B/M phi cells from splenic B lymphocytes. In addition, neutralization of fibroblast-secreted M-CSF with specific mAbs abrogated the ability of conditioned supernatants to promote outgrowth of B/M phi cells. The transition from B lymphocyte to B/M phi cell was marked by the kinetic appearance of mRNA for the M-CSF receptor, c-fms, at day 3 following culture initiation. These results demonstrate that M-CSF is important in the development and physiology of mouse B/M phi cells and potentially in the growth of human biphenotypic hematological malignancies. Interestingly, the presence of IFN-gamma in splenic B lymphocyte cultures abrogated the effect of fibroblast-conditioned medium or M-CSF on outgrowth of B/M phi cells. Furthermore, these findings suggest that a Th1 microenvironment favored by typical macrophages is detrimental to the outgrowth of B/M phi cells.

Animals↗
PubMed1984

Lineage switch in acute leukemia.

Conversions of leukemic cell lineage (lymphoid or myeloid) have been reported only rarely. Our review of the cytochemical and immunophenotypic features of 89 cases of childhood leukemia in marrow relapse indicated lineage switch (lymphoid to myeloid or the reverse) in six patients (6.7%). Five patients with acute lymphoblastic leukemia (ALL) at diagnosis had converted to acute nonlymphoblastic leukemia (ANLL), and one had converted from ANLL to ALL. Each child received lineage-specific multiagent chemotherapy when initially diagnosed, and all achieved a complete remission. After conversion, four patients readily achieved second remissions with treatment for the phenotype evident at lineage switch. Two patients with ANLL at conversion failed ALL-directed reinduction, while one of the two responded to high-dose cytarabine but died during bone marrow hypoplasia, emphasizing the importance of prompt recognition of lineage switch and selection of an appropriate plan of retreatment. Cytogenetic studies disclosed evidence of clonal selection in one patient and clonal stability in two. These findings indicate an unexpectedly high frequency of lineage switch in patients who relapse in the bone marrow after intensive chemotherapy. Although specific causative factors could not be identified, our observations suggest at least two general mechanisms for lineage switch in acute leukemia. In one, chemotherapy appears to eradicate the dominant clone present at diagnosis, permitting expansion of a secondary clone with a different phenotype. In the second, drug-induced changes in the original clone may either amplify or suppress differentiation programs so that phenotypic shift is possible.

Acute Disease↗
PubMed1995

Experimental induction of epithelial-mesenchymal interconversions.

Under some in vitro conditions, such as exposure to collagen, growth factors and related molecules, and agents affecting DNA methylation, a cell phenotype shift can be observed from an epithelial to a mesenchymal state of differentiation. The reverse process, a mesenchymal-to-epithelial conversion can likewise be obtained by certain experimental manipulations. In some instances the change is fully reversible by removing the inducer substances, but in others the conversion appears to be stable and irreversible. Only a partial modulation of the cell phenotype is often seen, but sometimes a complete switch to a new phenotype occurs, and morphological, biochemical and functional characteristics of the parent cells can be abrogated. In some in vivo models development of sarcomatous tumours can be seen in animals transplanted with several types of carcinoma, and it is possible that in some of these experiments an epithelial-to-mesenchymal conversion has occurred too. In normal embryonic development as well as in pathological lesions including tissue repair, tumour invasion, and some malignant biphasic tumours, changes similar to the ones observed in experimental epithelial-mesenchymal interconversion seem to take place. Therefore, it is conceivable that experimentally-induced phenotype conversions reflect an inherent potential of cells, and that under some experimental circumstances normally silent genetic programs for epithelial or mesenchymal differentiation are activated, thus recapitulating a phenomenon that occurs in physiopathological circumstances in vivo.

Animals↗
PubMed1987

Trichomonas vaginalis NYH286 phenotypic variation may be coordinated for a repertoire of trichomonad surface immunogens.

Trichomonas vaginalis isolate NYH286 was fractionated with immunoglobulin G of sera from patients with trichomoniasis. Subpopulations of trichomonads with phenotypes of either patient serum-immunoglobulin G reactive (PS+) or nonreactive (PS-) were obtained. Flow cytofluorometry of PS+ and PS- subpopulations with a monoclonal antibody called C20A3 which reacts with a high-molecular-weight immunogen of T. vaginalis gave corresponding fluorescent (positive) and nonfluorescent (negative) phenotypes. No relationship was seen between PS+ and PS- phenotypes and binding of soybean agglutinin, wheat germ agglutinin, and concanavalin A, showing that PS- organisms still possessed carbohydrate moieties on their surfaces based on lectin binding. Phenotypic variation among the PS+ and PS- trichomonads was observed during in vitro growth. A positive-to-negative phenotype shift was also recorded for parasites obtained from lesions of mice subcutaneously infected with PS+ trichomonads. The involvement of surface proteins in the differential PS+ and PS- reactions was supported by soluble antigen and whole cell radioimmunoprecipitation assays. Finally, enhanced parasitism and killing of HeLa cells in monolayer cultures were observed for PS- subpopulations as compared with PS+ counterparts. The data support the idea that phenotypic variation for T. vaginalis may be coordinated for a repertoire of trichomonad immunogens and that such membrane dynamics influence expression of virulence determinants for these sexually transmitted disease agents.

Antibodies, Monoclonal↗
PubMed1989

Reversion of tumorigenicity in an EBV-converted Burkitt's lymphoma line.

One of five Epstein-Barr virus (EBV)-converted sublines of an EBV-negative Burkitt's lymphoma line (BL-41) was identified as a non-tumorigenic phenotypic revertant with low clonability, comparable to that of an EBV-transformed lymphoblastoid cell line (IARC-171) derived from the same patient. This revertant subline (BL-41/95) also showed the most LCL-like phenotype of the five convertants tested. It is suggested that reversion was due to the phenotypic shift of the cell from a 'window' of cell ontogeny that contains virgin B cells and memory B cells to the stage of the activated immunoblast. Constitutive activation of the c-myc gene by translocation to an immunoglobulin locus continues to drive proliferation of B cells in vivo even after they have undergone a programmed switch to a basically resting (virgin or memory cell) phenotype. An activated immunoblast invariably expresses c-myc. It is also suggested that proliferation of the activated immunoblast is regulated by negative host controls that prevent clonal overexpansion and keep the B cell pool constant. The sensitivity of the immunoblast to this control overrides the 'forward-driving' force of both EBV and the activated myc gene.

Biomarkers, Tumor↗
PubMed1995

Spleen cells from antigen-minimized mice are superior to spleen cells from germ-free and conventional mice in the stimulation of primary in vitro proliferative responses to nominal antigens.

T lymphocytes from mice reared under conditions of differential exposure to food, environmental and microbial antigens were compared for phenotypic shifts that may be associated with prior exposure to antigens as well as functional variations in the ability to respond to antigens de novo. While the intra-epithelial CD8 T cell compartment was found to differ significantly in the type of T cell receptor predominantly expressed, CD4 T cells from various lymphoid organs of conventionally reared specific pathogen-free (CL-SPF) mice showed only subtle phenotypic differences from cells obtained from antigen-minimized germ-free (AF) and germ-free (GF) mice. Cells derived from mice exposed to a reduced antigen load exhibited primary in vitro proliferative responses to antigens such as dinitrophenyl-keyhole limpet hemocyanin which were significantly enhanced when compared with similar responses of cells from conventional mice. In cell mixing experiments, differences in the reactivity of T cells from the spleens of AF, GF and CL-SPF mice were dependent on the source of the spleen cells employed as antigen-presenting cells (APC). Experiments in which the T cell population was held constant revealed that, as APC, spleen cells from AF mice were most often superior to spleen cells from GF mice which were in turn considerably better than a similar population from SPF mice. We conclude that the enhanced primary reactivity of spleen cells from AF mice to nominal antigen in vitro is likely to be the result of a difference in the function and/or regulatory activities of the cell population employed as APC in this investigation.

Animals↗
PubMed1997

Functional properties of conditioned skeletal muscle: implications for muscle-powered cardiac assist.

Latissimus dorsi (LD) muscles of six canines were studied to assess changes induced by electrical conditioning and to quantify the capacity of these muscles to perform hemodynamic work. Muscles were conditioned using burst stimuli delivered over an 8-wk period. Contralateral LD were used as control. Muscles were tested in situ to simulate anticipated linear-pull cardiac assist conditions. This training process reduced muscle mass and cross-sectional area by 16 and 17%, respectively. Muscle phenotype shifted to a predominantly "slow" form by coordinate reduction of myosin heavy chain (MHC) 2A expression and increased expression of the MHC beta/slow form. Force generation was reduced by 54%, and contractile duration increased 13%. Fatigue resistance was markedly enhanced, and chronic stroke work increased from 0.19 to 0.72 mJ/g. The highest steady-state power output (2.06 mW/g) was obtained from one muscle fully converted to a slow phenotype. These data suggest that single LD trained via conventional techniques can provide energy sufficient for partial cardiac assistance but cannot sustain work levels needed to achieve total circulatory support.

Animals↗
PubMed2005

Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR.

Minimal (i.e. submicroscopic) residual disease (MRD) predicts outcome in childhood acute lymphoblastic leukaemia (ALL). To be used clinically, MRD assays must be reliable and accurate. Two well-established techniques, flow cytometry (FC) and polymerase chain reaction (PCR), can detect leukaemic cells with a sensitivity of 0.01% (10(-4)). We analysed diagnostic samples of 45 ALL-patients (37 B-lineage ALL, eight T-lineage ALL) by four-colour FC and real-time PCR. Leukaemia-associated immunophenotypes, at a sensitivity of MRD detection by FC at the 0.01% level, were identified in 41 cases (91%); antigen-receptor gene rearrangements suitable for MRD detection with a sensitivity of 0.01% or better by PCR were identified in 38 cases (84%). The combined use of FC and PCR allowed MRD monitoring in all 45 patients. In 105 follow-up samples, MRD estimates by both methods were highly concordant, with a deviation factor of <5 by Bland-Altman analysis. Importantly, the concordance between FC and PCR was also observed in regenerating bone marrow samples containing high proportions of CD19(+) cells, and in samples studied 24 h after collection. We conclude that both MRD assays yield generally concordant results. Their combined use should enable MRD monitoring in virtually all patients and prevent false-negative results due to clonal evolution or phenotypic shifts.

Adolescent↗
PubMed1997

Intestinalization of gastric signet ring cell carcinomas with progression.

Recent developments in mucin histochemistry and immunohistochemistry have made reliable determination of the gastric and intestinal phenotypes of gastric carcinoma cells possible. Phenotypic expression changes from gastric epithelial cell type to intestinal epithelial cell type with the growth of gastric tumours in experimental animals. We studied cell differentiation in gastric signet ring cell carcinomas with progression in 203 surgically obtained specimens. The results showed that the proportion of gastric phenotype carcinomas, in which over 90% of the tissue consists of gastric epithelial cell type cells, decreases with the depth of invasion. The proportion of mixed phenotype carcinomas (between 10% and 90% of the tissue made up of gastric and/or intestinal epithelial cell type cells) increases. The intestinal phenotype (over 90% intestinal epithelial cell type carcinoma cells) was found in four carcinomas (about 2%) involving the serosa. No clear relationship was evident between phenotypic expression of carcinoma cells and the degree of intestinal metaplasia of the surrounding mucosa. Progression of gastric signet ring cell carcinomas is associated with a phenotypic shift from gastric to intestinal type expression.

Carcinoma, Signet Ring Cell↗
PubMed1996

Reversion of UVC-induced tumorigenic human hybrid cells to the non-tumorigenic phenotype.

Non-tumorigenic HeLa x skin fibroblast human hybrid cells were UVC-irradiated (10 J/m2) and induced to neoplastic transformation with accompanying morphological change and expression of the HeLa tumour-associated antigen, intestinal alkaline phosphatase (IAP). A single-cell-derived cell line was cloned out of a neoplastically transformed focus and designated as UV-12. In low density culture, this cell line demonstrated the ability to undergo reversion to a morphology similar to that of the non-tumorigenic parent with accompanying, much reduced levels of IAP expression. The frequency of this reversion to low IAP expression increased with passage of low density cultures reaching 10(-2) at 26 passages. A revertant colony was selected and expanded into a cell line which was designated UV-12-RM-1. This cell line had a 67-fold reduction in IAP expression compared to UV-12 and demonstrated a much reduced tumorigenic phenotype. A cell line reconstituted from a tumour derived from this cell line demonstrated a high IAP expression level (3-fold less than UV-12) and was highly tumorigenic. Six single-cell-derived lines were cloned from UV-12-RM-1 and all had low IAP expression. Of these, one demonstrated an aggressive tumorigenicity, four showed the reduced tumorigenic phenotype characteristic of UV-12-RM-1, and one (UV-12-RM-105) was non-tumorigenic. However, with passage in culture, this latter cell line reverted to a weakly tumorigenic phenotype and a much elevated IAP level. It is hypothesised that the phenotypic shifts demonstrated by these UV-induced tumorigenic cells are under epigenetic control, and that they are most likely a consequence of an underlying genetic instability in the survivors of UVC-irradiation.

Alkaline Phosphatase↗
PubMed2005

Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes.

OBJECTIVE: To determine the influence of osteoarthritic (OA) phenotype of subchondral osteoblasts on the phenotype of human chondrocytes. METHODS: Human chondrocytes were isolated from OA cartilage and cultured in alginate beads for 4 or 10 days in the absence or in the presence of osteoblasts in monolayer. The osteoblasts were either isolated from non-sclerotic (N) or sclerotic (SC) zones of human subchondral bone. Before co-culture, osteoblasts were incubated for 72 h with or without 1.7 ng/ml interleukin (IL)-1beta, 100 ng/ml IL-6 with its soluble receptor (50 ng/ml) or 10 ng/ml oncostatin M. SOX9, type I, II and X collagen (COL1, COL2, COL10), osteoblasts-stimulating factor (OSF)-1, bone alkaline phosphatase (ALP), parathyroid hormone related peptide (PTHrP) and its receptor (PTH-R) messenger RNA (mRNA) levels in chondrocytes were quantified by real-time polymerase chain reaction. RESULTS: In comparison with chondrocytes cultured alone in alginate beads, chondrocytes after 4 days in co-culture with N or SC osteoblasts expressed significantly less SOX9 and COL2 mRNA. The decrease of SOX9 and COL2 gene expression was significantly more pronounced in the presence of SC than in the presence of N osteoblasts (P<0.001). OSF-1 mRNA level in chondrocyte was increased by both N and SC osteoblasts, but to a larger extent by SC osteoblasts (P<0.001). PTHrP expression in chondrocytes was 21-fold increased by N osteoblasts but four-fold inhibited by SC osteoblasts. PTHrP secretion was also increased by N but reduced by SC osteoblasts. SC, but not N osteoblasts, induced a significant decrease of PTH-R gene expression in chondrocyte. In our experimental conditions, chondrocytes did not express COL1, COL10 or ALP, even after 10 days of co-culture with osteoblasts. CONCLUSIONS: In co-culture, SC subchondral osteoblasts decrease SOX9, COL2, PTHrP and PTH-R gene expression by chondrocytes but increase that of OSF-1. These findings suggest that SC osteoblasts could initiate chondrocyte phenotype shift towards hypertrophic differentiation and subsequently further matrix mineralization.

Aged↗
PubMed1992

A multidrug-resistant ovarian carcinoma cell line with a malignant suppressed phenotype is a CD44 gene expression defective mutant.

A multidrug-resistant cell subline (OV1/VCR) derived from an ovarian adenocarcinoma cell line (OV1/P) was characterized by a typical suppressed malignant phenotype and by a unique karyotypic change: del(11)(p13). In an attempt to discern some genetic alteration of 11p genes that may be relevant to the phenotypic shift, cells were analyzed with DNA probes mapped in the deleted region and with monoclonal antibodies (MoAbs) against 11p-encoded membrane molecules. Southern blot did not detect abnormal restriction patterns of the probed sequences. OV1/VCR cells did not express the CD44 epitope (11p13 MIC4 locus) recognized by the F10-44 MoAb and did not accumulate RNAs of the CD44 (Hermes) core peptide. This defect was not detected in another OV1/P-derived drug-resistant subline that retained the malignant behavior and did not have the del(11p) marker. It may have contributed to phenotypic reversion because evidence shows that CD44 membrane molecule is involved in cell-cell interaction and growth regulation of cancer cells.

Blotting, Northern↗
PubMed1983

Lyt-phenotype conversion of cytotoxic T lymphocytes specific for the A and E class II major histocompatibility complex molecules.

The Lyt-1+ (high) Lyt-2+/- (low) primary cytotoxic T lymphocytes (CTL) specific for A(A alpha A beta) molecules and the Lyt-1+Lyt-2+ primary E(E alpha E beta)-specific CTL are both shown to become Lyt-1 Lyt-2+ effector cells after secondary in vitro stimulation. Thus CTL specific for class II major histocompatibility complex molecules exhibit the same Lyt-phenotype shift as class-I-specific CTL do. The data suggest that either both class-I-specific and class-II-specific CTL follow the same differentiation pathway or regulatory cellular interactions allow only Lyt-1-Lyt-2+ cells to differentiate to secondary CTL.

Animals↗
PubMed1985

Monosomy 7 and multipotential stem cell transformation.

Monosomy 7 was the sole karyotypic abnormality seen in a case of biphenotypic leukaemia involving both the myeloid and lymphoid lineages and in a case of de novo ALL undergoing a phenotypic shift to acute myeloid leukaemia at relapse. These observations suggest that monosomy 7 can be associated with transformation of a common lymphoid-myeloid progenitor cell.

Aged↗
PubMedDate not supplied

Ultrastructural phenotype of "intestinal-type" cells in columnar-lined esophagus.

An intestinal-type epithelium is often present at columnar-lined esophagus, gastroesophageal junction or within the so-called short segment Barrett's esophagus, but ultrastructural study failed to detect enterocytes in columnar-lined esophagus. The authors have analyzed the intestinal aspects present in areas of columnar-lined esophagus in a population of patients with reflux esophagitis to better understand the morphology and histogenesis of the proliferating elements. Columnar-lined mucosa was studied in 35 patients. Columnarsurface cells displayed a wide spectrum of ultrastructural features. Well-differentiated columnar secretory cells, secretory-absorptive cells, poorly differentiated columnar cells, atypical columnar cells, and goblet cells were detected. Well-differentiated absorptive cells were never found, These results demonstrate that the areas of intestinal metaplasia show a wide spectrum of ultrastructural phenotypes, ranging from poorly to well-differentiated cells. However, true enterocytes were not found and the most represented phenotype is that of secretory-absorptive cells, whose principal characteristic is the presence of secretory and absorptive aspects together. They can be described as secretory enterocytes or cells with double specialization. To the authors' knowledge, similar cells were not previously described in normal intestinal mucosa, and ultrastructural studies are consistent in describing a broad spectrum of ultrastructural features, suggesting that Barrett's specialized metaplasia is derived from cells with the capacity for a wide range of differentiation. Therefore, despite the wide use of term intestinal metaplasia in the medical literature, experimental data clearly failed to detect enterocytes in the columnar-lined esophagus, and ultrastructural data do not support the concept of intestinal metaplasia. The cellular heterogeneity seems to be the result of a "phenotypic shift" of undifferentiated elements, which show a different pattern of evolution. The result of this process is the formation of new cell types dissimilar from those normally present in esophageal, gastric, or duodenal mucosa.

Adolescent↗
PubMed1992

Phenotypic and functional analysis of peripheral blood lymphocytes in oral lichen planus.

To assess cellular immunity in oral lichen planus (OLP), peripheral blood mononuclear cells (PBMC) were obtained from 19 OLP patients and 30 control subjects. The proportions of circulating CD45RA+ and CD29+ lymphocyte subsets were determined. The proliferative activity of PBMC to the non-specific plant mitogens phytohemagglutinin (PHA) and concanavalin A (Con A) was examined together with the spontaneous proliferative response and the response in the autologous mixed lymphocyte reaction (AMLR). In the OLP group, the proportion of CD4+ CD45RA+ T lymphocytes was significantly less than control subjects and the proportion of CD4+ CD29+ T lymphocytes was increased significantly. The proliferative response to PHA was similar in OLP and controls subjects. Con A-stimulated PBMC proliferation was decreased significantly in the OLP group. Spontaneous PBMC proliferation in patients with non-reticular lesions was significantly less than control subjects. Despite a mildly depressed response in the AMLR in OLP patients, this result was not statistically significant. Results of the phenotypic analysis of peripheral blood lymphocytes indicate a decreased proportion of naive T cells and an increased proportion of primed memory T cells, although the antigen specificity of these memory cells remains to be determined. Results of the functional assays would seem to reflect this phenotypic shift, and as T cells responding to Con A stimulation and in the AMLR possess suppressor-inducer activity, these results may also suggest an association between OLP and defective innate T cell-mediated suppressor circuits.

Adult↗
PubMed2001

Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats.

UNLABELLED: OBJECTIVES; We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix. BACKGROUND: Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF. METHODS: Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group). RESULTS: High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group. CONCLUSIONS: Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.

Amlodipine↗
PubMed1995

Contribution of apoptosis to the phenotypic changes of adrenocortical cells in primary culture.

The aim of this study was to evaluate the occurrence and physiological consequences of apoptosis in primary cultures of bovine adrenocortical cells (of fasciculata-reticularis origin). Under ACTH-free culture conditions, we observed apoptotic cells in the cell layer and the accumulation of apoptotic bodies in the culture medium. These were hardly detectable in ACTH-supplemented cultures. Under ACTH-free conditions, the DNA content of apoptotic bodies collected over 48 h represented up to 10-15% of that of the cell layer at the onset of the culture (as compared to 3% in ACTH-supplemented cultures). Past the fourth day of culture in the absence of ACTh, most cells lacked several markers of their originating fasciculata-reticularis phenotype and progressively evolved to an undifferentiated phenotype. The vast majority of the apoptotic bodies released during the first 4 days of culture were immunoreactive for P450 17 alpha. Inversely, during the same period of time, the proliferating cells (PCNA-positive) did not appear to express P450 17 alpha. Therefore, apoptosis could contribute, together with dedifferentiation, to the phenotype shift observed in ACTH-depleted cultures of adrenal fasciculata-reticularis cells. These observations also characterize this endocrine cell system as an in vitro model for the study of hormone-repressed apoptosis.

Adrenal Cortex↗