-Aviv University, Ramat Aviv Tel Aviv, Israel BRCA1/BRCA2 mutations account for a substantial proportion of familial breast cancer, but clearly mutations in additional genes exist, one candidate being the p53 gene. To evaluate its putative involvement in inherited predisposition to breast/ovarian cancer in Jewish high-risk women, mutational analysis of the p53 gene (exons 4 -9) was carried out using exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. Overall, 132 Jewish breast cancer patient non-BRCA1/2 mutation carriers and 167 average risk controls (Ashkenazi (n ¼ 60), non-Ashkenazi (n ¼ 107)) were genotyped, and no inactivating p53 germline mutations were detected. Consistent migration abnormalities were noted in 167 fragments, 134 of which were shown to be the Arg72Pro polymorphism, whereas migration abnormalities in fragments containing exons 4 (n ¼ 2) and 6 (n ¼ 23) and introns 3 (n ¼ 4) and 9 (n ¼ 4) corresponded to five previously described polymorphisms. Allele distribution of the R72P missense mutation between ethnically diverse Jewish breast cancer cases and average risk controls showed significant differences: among non-Ashkenazi breast cancer cases, 62.5%, 33.3% and 4.2% were homozygous, heterozygous and homozygous for the Arg72, Arg72Pro and the Pro72 polymorphism, respectively, whereas for controls, the distribution was 22.4%, 65.4% and 12.2%, respectively (P ¼ 0.00052), and among Ashkenazi breast cancer cases, allele distribution was 68.5%, 29.6% and 1.9%, whereas for controls, the distribution was 50%, 40% and 10%, respectively (P ¼ 0.0125). We conclude that arginine homozygosity at codon 72 of the p53 gene is associated with a significant increased breast cancer risk in Jewish high-risk population.

Dear Sir,Fewer than 1% of all breast cancers occur in males. 1 Known risk factors for male breast cancer primarily include Klinefelter syndrome and other clinical conditions associated with aberrant hormonal status (e.g., benign breast disease and gynecomastia, liver cirrhosis, estrogen therapy, testicular pathologies), exposure ionizing radiation and either personal or family history of breast cancer. 2,3 Incidence of male breast cancer varies between populations, with higher rates observed among men of African and Jewish ancestry. 3,4 In Israel, male breast cancer rates are higher for Ashkenazi (East European ancestry) than non-Ashkenazi Jews. 5 These observations may be attributable in part to the relatively high carrier frequency (Ͼ2%) of the founder BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) mutations in the general Ashkenazi population. 6 Combined, these 3 founder mutations account for Ն17% of all incident Israeli male breast cancer cases, with higher prevalence of mutations detected among Ashkenzi individuals with family history of breast and ovarian cancer. 7,8 In other ethnic populations, BRCA2 mutations account for 4 -14% of male breast cancer cases, 9,10 and as many as 40% in the Icelandic population, where a single founder mutation (BRCA2: 999del5) occurs at a rate of 0.6% in the general population. 11 The proportion of male breast cancer cases attributable to BRCA1 appears to be lower, with no mutations identified in some population-based patient series, 10,12 whereas other studies find as many as 4 -10% of cases to carry deleterious BRCA1 mutations. 7,13 These differences in observed mutation frequencies may reflect enrichment for BRCA1 mutation carriers in the latter studies due to populationspecific founder effects or ascertainment bias. Thus, both BRCA1 and BRCA2 germline mutations have been reported to confer elevated risk of male breast cancer. Cumulative risk estimates for BRCA2 are 2.8% (95% CI ϭ 0.6 -13%) by age 70 years, and 6.9% (95% CI ϭ 1.2-38.6%) by age 80 years, 14 whereas that estimated for BRCA1 in a smaller cohort is reported to be 5.8% by age 110 years (95% CI ϭ 1.3-10.4). 15 To date, few genes other than BRCA1 and BRCA2 have been implicated in conferring male breast cancer susceptibility. Germline mutations of androgen receptor appear to contribute to a small proportion of cases. 16 -19 Similarly, germline mutations of the PTEN 20 and hMLH1 21,22 genes in male breast cancer patients suggest elevated risks in the context of Cowden and hereditary non-polyposis colorectal cancer (HNPCC) familial cancer syndromes, respectively. A modest risk is associated with a promoter polymorphism in the CYP17 gene (OR ϭ 2.10; 95% CI ϭ 1.04 -4.27). 23 Similarly, there is some suggestion, although not statistically significant, that long alleles (Ն30 repeats) of the androgen receptor exon 1 polymorphic CAG repeat may be associated with disease. 18,24 More recently, an approximately 10-fold increased risk of male breast cancer associated with the CHEK2*1100delC variant was reported in high ris...

SummarySevere neutropenia and protracted thrombocytopenia remain serious clinical problems following cord blood transplantation (CBT) due to the paucity of stem and progenitor cells in the grafts. Administration of ex-vivo expanded megakaryocyte progenitor cells may facilitate platelet production. We propose a novel strategy to expand these rare cells ex-vivo, from a small portion of the cord blood (CB) unit, using fibronectin (FN), a major component of hematopoietic niches, combined with cytokines, including thrombopoietin and the hematopoietic stress-associated acetylcholinesterase readthrough peptide (ARP). Application of multiple gates and high definition flow cytometry enabled clear resolution of expanded hematopoietic stem/ precursor cells (HSPC) and megakaryocyte progenitors (Mk-p) and their early subsets while eliminating positively stained non-relevant cells. FN increased viability, expansion of all CD34 + HSPC populations and Mk-p. The combination of FN + thrombopoietin + ARP maintained and expanded very early myeloid and thrombopoietic precursors, increased the proliferation of megakaryocyte, granulocyte-macrophage and multilineage colony-forming progenitors and supported Mk maturation as measured by ploidy and glycoprotein IIb/IIIa expression by quantiative reverse transcription polymerase chain reaction. This approach, which involves expanding HSPC and Mk precursors from a small portion of the CB unit, without sacrificing the coveted stem cells, may lead to improved cell therapy modalities to facilitate earlier myelopoiesis and platelet production post-CBT.

We discuss the problem of counting distinct elements in a stream. A stream is usually considered as a sequence of elements that come one at a time. An exact solution to the problem requires memory space of the size of the stream. For many applications this solution is infeasible due to very large streams. The solution in that case, is to use a probabilistic data structure (also called sketch), from which we can estimate with high accuracy the cardinality of the stream. We present a new algorithm, ExtendedHyperLogLog (EHLL), which is based on the state-of-the-art algorithm, HyperLogLog (HLL). In order to achieve the same accuracy as HLL, EHLL uses 16% less memory. In recent years, a martingale approach has bean developed. In the martingale setting we receive better accuracy at the price of not being able to merge sketches. EHLL also works in the martingale setting. Martingale EHLL achieves the same accuracy as Martingale HLL using 12% less memory.