Citations

Abstract The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples. (Cancer Epidemiol Biomarkers Prev 2006;15(5):935–8)

Abstract Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF), a recently cloned member of the tumor necrosis factor superfamily, and macrophage colony–stimulating factor. OPG-L/ODF is produced by osteoblast lineage cells and exerts its biological effects through binding to its receptor, osteoclast differentiation and activation receptor (ODAR)/receptor activator of NF-κB (RANK), on osteoclast lineage cells, in either a soluble or a membrane-bound form, the latter of which requires cell-to-cell contact. Binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts and, at higher concentrations, in increased functional activity and reduced apoptosis of mature osteoclasts. The biological activity of OPG-L/ODF is neutralized by binding to osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor superfamily that also is secreted by osteoblast lineage cells. The biological importance of this system is underscored by the induction in mice of severe osteoporosis by targeted ablation of OPG/OCIF and by the induction of osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF. Thus, osteoclast formation may be determined principally by the relative ratio of OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in this ratio may be a major cause of bone loss in many metabolic disorders, including estrogen deficiency and glucocorticoid excess. That changes in but two downstream cytokines mediate the effects of large numbers of upstream hormones and cytokines suggests a regulatory mechanism for osteoclastogenesis of great efficiency and elegance.

Abstract Most estimates of osteoporosis in older U.S. adults have been based on its occurrence in white women, even though it is known to affect men and minority women. In the present study, we used dual-energy X-ray absorptiometry measurements of femoral bone mineral density (BMD) from the third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) to estimate the overall scope of the disease in the older U.S. population. Specifically, we estimate prevalences of low femoral BMD in women 50 years and older and explore different approaches for defining low BMD in older men in that age range. Low BMD levels were defined in accordance with an approach proposed by an expert panel of the World Health Organization and used BMD data from 382 non-Hispanic white (NHW) men or 409 NHW women ages 20–29 years from the NHANES III dataset. For women, estimates indicate 13–18%, or 4–6 million, have osteoporosis (i.e., BMD >2.5 standard deviations [SD] below the mean of young NHW women) and 37–50%, or 13–17 million, have osteopenia (BMD between 1 and 2.5 SD below the mean of young NHW women). For men, these numbers depend on the gender of the reference group used to define cutoff values. When based on male cutoffs, 3–6% (1–2 million) of men have osteoporosis and 28–47% (8–13 million) have osteopenia; when based on female cutoffs, 1–4% (280,000–1 million) have osteoporosis and 15–33% (4–9 million) have osteopenia. Most of the older U.S. adults with low femur BMD are women, but, regardless of which cutoffs are used, the number of men is substantial.

AbstractWe present results of 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 × 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment effects in these patients included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2V617F mutation burden (1 patient). Grade 3 or 4 adverse events included neutropenia (31%) and thrombocytopenia (19%). We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.