Proliferation of human malignant hematopoietic cells in immunodeficient mice: suppression by antibody to pluripotent K-562 leukemia cells involves direct cytolysis and effector cells

Six human hematopoetic cell lines were successfully heterotransplanted into athymic (nude) and asplenic-athymic (lasat) neonatal mice. The tumors arising from leukemia and lymphoma cells could then be serially transplanted into adult nude mice. Seven days after the fourth serial mouse passage, each mouse was treated with goat immune gamma globulin against K-562 cells. One control group was treated similarly, but with nonimmune (normal) gamma globulin, while another control group was not treated. The goat gamma globulin was not toxic for nude and lasat mice, and the immune, but not the normal, gamma globulin suppressed local subcutaneous growth of myelosarcomas, lymphosarcomas, and Burkitt lymphoma cells. On the other hand, the growth of lung, breast, and prostatic carcinomas and a melanoma of human origin were not altered by the immune gamma globulin. Since suppression of cell growth occurred equally well in decomplemented mice, a complement-mediated cytotoxicity apparently cannot be considered as responsible for the abrogation. The Fab fragment of the immunoglobulin did not suppress the growth of the myelosarcomas. We conclude that antibody suppression of the in vivo proliferation was specific for malignant hematopoietic cells and that the Fc portion of IgG is necessary for in vivo cytolysis of leukemia cells. The most probable mechanisms are direct antibody cytolysis and antibody-dependent macrophage-mediated cytotoxicity.     

Expression of bcl-xL can confer a multidrug resistance phenotype

It has been suggested that genes that regulate apoptotic cell death may play an important role in determining the sensitivity of tumor cells to chemotherapy. We have recently cloned a member of the bcl-2 family, bcl- x. To test whether bcl-XL expression affects the sensitivity of tumor cells to chemotherapy, we have created stable cell lines overexpressing bcl-XL and have tested these cells for resistance to cell death induced by metabolic inhibitors and chemotherapeutic agents. Bcl-XL expression dramatically reduces the cytotoxicity of bleomycin, cisplatin, etoposide, vincristine, hygromycin B, and mycophenolic acid for up to 4 days in culture. Bcl-XL does not prevent cells from undergoing cell cycle arrest in response to these drugs, but rather prevents treated cells from undergoing apoptosis. Cell-cycle analysis on cells treated with the chemotherapeutic agents bleomycin, cisplatin, etoposide, and vincristine, show that the drugs cause growth arrest in different positions within the cell cycle. Bcl-XL expressing cells treated with chemotherapeutic drugs retain their proliferative ability after the drugs are removed. Interestingly, vincristine-treated cells expressing bcl-XL become polyploid after drug removal. These data show that bcl-XL protects cells from a wide variety of apoptotic stimuli, acts in multiple positions within the cell cycle, and confers a multidrug resistance phenotype. The ability of bcl-XL to prevent apoptotic cell death in response to chemotherapy-induced DNA damage and cell-cycle arrest may contribute to the accumulation of chromosomal aberrations within tumors. The expression of bcl-XL in tumor cells is likely to be an important indicator of chemotherapeutic efficacy.     

Bcl-x rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center

Both rapid B-cell proliferation and programmed cell death (PCD) occur during the differentiation and selection of B cells within the germinal center. To help elucidate the role of Bcl-x in B-cell antigen selection and PCD within the germinal center, we examined its expression in defined B-cell populations and by immunochemistry of tonsil tissue. Purified B-cell fractions enriched for centrocytes express high amounts of Bcl-x and relatively low amounts of Bcl-2, whereas fractions enriched for centroblasts lack significant levels of both proteins. Consistent with this observation, immunocytochemistry localized Bcl-x within cells scattered throughout the germinal center. Stimulation of tonsil B cells with either CD40 or Staphylococcus aureus Cowan increase bcl-x mRNA and protein levels. Treatment of a cell line with a germinal center phenotype (RAMOS) or the tonsillar B-cell centroblast fraction with CD40 rapidly increased Bcl-x levels and partially rescued B cells from PCD. These data suggest that Bcl-x rather than Bcl-2 may rescue centrocytes during selection in the germinal center.     

Cholesterol efflux capacity of high‐density lipoprotein was not associated with cognitive decline and brain structures in older people with diabetes mellitus

Aims/IntroductionTo examine the association between cholesterol efflux capacity (CEC) of serum high‐density lipoprotein (HDL) and cognitive function and brain structures in older people with diabetes mellitus.Materials and MethodsParticipants of a randomized placebo‐controlled trial of 27‐month vitamin B₁₂ supplementation in older people with diabetes mellitus, which showed no effect on cognition, were further followed up at month 72. Cognitive tests included the Clinical Dementia Rating scale, Neuropsychological Test Battery in memory, executive function and psychomotor speed. Brain magnetic resonance imaging scans were carried out in a subset at baseline, month 27 and month 45. Fasting serum at baseline, month 9, month 27 and month 72 were analyzed for adenosine triphosphate‐binding cassette transporter A1‐mediated CEC of HDL and apolipoprotein A1 (ApoA1).ResultsSerum HDL cholesterol at baseline was associated with better executive and memory function at follow up. Serum ApoA1 was associated with a better memory Z‐score at month 18. Serum CEC and ApoA1 were not associated with Clinical Dementia Rating scale, Neuropsychological Test Battery, hippocampal volume and white matter disease on magnetic resonance imaging at baseline and whole brain atrophy rates. They were also not associated with cognitive function at month 27 and 72 on multilevel modeling. CEC and ApoA1 decreased significantly from baseline to month 27. Faster decliners in CEC had a greater increase in brain peak width of skeletonized mean diffusivity.ConclusionsHigher serum HDL cholesterol was associated with more favorable changes in memory and executive function in older people with diabetes mellitus. However, this was not due to CEC or ApoA1. A decline in CEC was associated with small vessel disease in the brain.     

Vesicoureteric reflux and renal injury

Renal injury associated with the intrarenal reflux (IRR) of urine that is either infected, under high pressure, or both, is a major cause of severe hypertension during childhood and adolescence and of chronic renal insufficiency in patients less than 30 years of age. Many, but not all, adolescent and adult patients with reflux nephropathy (RN) give a history of urinary tract infection (UTI) or unexplained fevers in infancy or early childhood, when the kidney is thought to be at greatest risk of injury. Although vesicoureteric reflux (VUR) is observed more commonly in infants than children with UTI, it is rare in uninfected patients at any age and should never be considered a normal finding during human development. Renal scarring may not be obvious in radiographic or radionuclear studies to medical management alone, no definite benefit of one over the other was observed, regardless of the grade of VUR. Moreover, progressive renal injury in scarred kidneys has been noted even after VUR had been corrected, when infection had been prevented, and while hypertension had been controlled satisfactorily. Focal glomerular sclerosis, a lesion found in patients with proteinuria and RN, has been identified not only in scarred kidneys, but also may be seen in contralateral, unscarred kidneys without VUR, which might suggest a humoral factor or, perhaps, a hyperfiltration phenomenon. RN is one of the most frequent causes of end-stage renal disease (ESRD) in children, adolescents, and young adults, which is potentially preventable. However, prevention will depend on early identification of patients at risk--infants and young children after the first UTI and siblings of patients with VUR--aggressive and effective treatment of UTI, minimizing intravesical pressure, and education of patients, parents, and physicians.