A specific deletion in the breakpoint cluster region of the ALL-1 gene is associated with acute lymphoblastic T-cell leukemias.

A variety of chromosomal translocations to the ALL-1 gene are regularly observed in acute leukemias and are thought to play a key role in the leukemogenic process. Chimeric proteins are encoded by the breakpoint regions of the derivative chromosomes have been proposed to be the relevant oncogenic agents. In addition, internal duplications of the ALL-1 gene have been observed in patients with specific acute myeloid leukemias. Thus, it has been hypothesized that oncogenic variants of the ALL-1 protein may be generated by both chimerization and self-fusion, but the critical structural features endowing the altered proteins with their oncogenic potential are still unknown. Here a novel structural alteration of the ALL-1 gene was observed in three patients presenting with acute T-cell leukemia (ALL) without chromosomal translocations or self-fusions of the ALL-1 gene. These unrelated patients carried an internal deletion in one of the two alleles of the ALL-1 gene that eliminated parts of introns 7 and 8, together with exon 8. The deletion was found in 3 of 74 ALL patients, but not in acute myeloid leukemias, follicular lymphomas, or peripheral blood leukocytes from healthy donors. One ALL patient showed the deletion at diagnosis but no longer at remission or at 9 months after remission. These findings support the hypothesis that the ALL-1 protein may be converted to an oncogenic variant, not only by chimerization or self-fusion, but also by deletion of sequences coded by exon 8. They further suggest that these three different types of structural alterations of the ALL-1 protein may each cause a distinct disease phenotype. Alternatively spliced mRNA species omitting exon 8 were observed in 14 of 24 ALL patients without detectable macroscopic alterations of the ALL-1 gene and also in peripheral blood leukocytes from healthy donors.

Isolation of two interleukin-6 response element binding proteins from acute phase rat livers.

Proteins binding at the IL-6 response element of the rat alpha 2 macroglobulin gene were purified by a combination of conventional chromatographic procedures and binding-site specific DNA affinity chromatography. The proteins were purified from the nuclei of rat livers, excised at the peak of an experimentally induced acute phase response. By this procedure three polypeptides of 92, 91 and 86 kD were enriched more than 6,000-fold. Partial proteolysis with lysyl endopeptidase and aminoacid sequence analysis of proteolytic peptides identified the 86 and 91 kD species as the transcription factor Stat3 and the 92 kD species as a Stat factor distinct from Stats 1 and 3. cDNA clones for Stats 1, 3 and this 92 kD factor were isolated from a cDNA library prepared with mRNA from acute phase rat livers. Parts of their DNA sequences were determined and the sequences of the purified peptides were found in these cDNA sequences. Thus, the identity of the factors as Stat3 and a Stat factor different from Stats 1 and 3 was confirmed. These results suggest, that APRF/Stat3 and p91/Stat1 are not the only factors mediating the effects of IL-6 on class 2 acute phase genes. The 92 kD Stat factor binding at the IL-6 RE probably also functions as a transcription factor in the cytokine-induced activation of the alpha 2M gene.

The structure of the human ALL-1/MLL/HRX gene.

The human ALL-1/MLL/HRX gene on chromosome 11q23 is the site of many locally clustered chromosomal alterations associated with several types of acute leukemias, including deletions. partial duplications and reciprocal translocations. Structurally variant proteins derived from an altered ALL-1 gene presumably make essential contributions to the malignant transformation of hematopoietic progenitor cells. The ALL-1 gene is spread over approximately 92 kb and consists of at least 37 exons. An exon/intron map including the position of the 3'-end of the gene and a detailed restriction map were produced and an updated map is presented. Data from other laboratories were incorporated where compatible. Exon/intron boundaries were sequenced and an intron-phase analysis was performed. The results are expected to contribute to a better understanding of those structural alterations of the gene that conserve the open reading frame and produce presumably oncogenic variants of the ALL-1 protein. They will also facilitate the rapid molecular diagnosis of structural alterations of this gene and the choice of therapeutic options. Mechanisms that may potentially account for the striking clustering of the translocation breakpoints in the breakpoint cluster region of the gene are discussed.

Social capital, income inequality, and firearm violent crime.

Studies have shown that poverty and income are powerful predictors of homicide and violent crime. We hypothesized that the effect of the growing gap between the rich and poor is mediated through an undermining of social cohesion, or social capital, and that decreased social capital is in turn associated with increased firearm homicide and violent crime. Social capital was measured by the weighted responses to two items from the U.S. General Social Survey: the per capita density of membership in voluntary groups in each state; and the level of social trust, as gauged by the proportion of residents in each state who believed that "most people would take advantage of you if they got the chance". Age-standardized firearm homicide rates for the years 1987-1991 and firearm robbery and assault incidence rates for years 1991-1994 were obtained for each of the 50 U.S. states. Income inequality was strongly correlated with firearm violent crime (firearm homicide, r = 0.76) as well as the measures of social capital: per capita group membership (r = -0.40) and lack of social trust (r = 0.73). In turn, both social trust (firearm homicide, r = 0.83) and group membership (firearm homicide, r = -0.49) were associated with firearm violent crime. These relationships held when controlling for poverty and a proxy variable for access to firearms. The profound effects of income inequality and social capital, when controlling for other factors such as poverty and firearm availability, on firearm violent crime indicate that policies that address these broader, macro-social forces warrant serious consideration.

Phylloquinone, what can we learn from plants?

The plant plasma membrane contains redox proteins able to mediate a trans-membrane electron flow. This electron flow might be responsible for the generation of the active oxygen species observed as a reaction to pathogen attack or stress. Vitamin K1 could be identified as a possible lipid soluble electron carrier in plant plasma membrane preparations. Such a function would be analogous to coenzyme Q in animal plasma membranes. What we are going to outline in this contribution is a concept of how the electron transport system of the plant plasma membrane could interact with quinones, thus contributing to the metabolism of free radicals in plants.

(Dis)respect and black mortality.

OBJECTIVES: A growing number of studies have documented the deleterious health consequences of the experience of racial discrimination in African Americans. The present study examined the association of racial prejudice--measured at a collective level--to black and white mortality across the United States. METHODS: Cross-sectional ecologic study, based on data from 39 states. Collective disrespect was measured by weighted responses to a question on a national survey, which asked: "On the average blacks have worse jobs, income, and housing than white people. Do you think the differences are: (A) Mainly due to discrimination? (yes/no); (b) Because most blacks have less in-born ability to learn? (yes/no); (c) Because most blacks don't have the chance for education that it takes to rise out of poverty? (yes/no); and (d) Because most blacks just don't have the motivation or will power to pull themselves up out of poverty? (yes/no)." For each state, we calculated the percentage of respondents who answered in the affirmative to the above statements. Age-standardized total and cause-specific mortality rates in 1990 were obtained for each state. RESULTS: Both measures of collective disrespect were strongly correlated with black mortality (r = 0.53 to 0.56), as well as with white mortality (r = 0.48 to 0.54). A 1 percent increase in the prevalence of those who believed that blacks lacked innate ability was associated with an increase in age-adjusted black mortality rate of 359.8 per 100,000 (95% confidence interval: 187.5 to 532.1 deaths per 100,000). CONCLUSIONS: These data suggest that racism, measured as an ecologic characteristic, is associated with higher mortality in both blacks and whites.

Social capital: a guide to its measurement.

The primary aims of this paper are to review the concept of social capital and related constructs and to provide a brief guide to their operationalization and measurement. We focus on four existing constructs: collective efficacy, psychological sense of community, neighborhood cohesion and community competence. Each of these constructs taps into slightly different, yet overlapping, aspects of social capital. The existence of several instruments to measure each of these constructs calls for further study into their use as measures of social capital. Despite differences in the approach to measurement, there is general agreement that community characteristics, such as social capital, should be distinguished from individual characteristics and measured at the community level.

Social capital, income inequality, and mortality.

OBJECTIVES: Recent studies have demonstrated that income inequality is related to mortality rates. It was hypothesized, in this study, that income inequality is related to reduction in social cohesion and that disinvestment in social capital is in turn associated with increased mortality. METHODS: In this cross-sectional ecologic study based on data from 39 states, social capital was measured by weighted responses to two items from the General Social Survey: per capita density of membership in voluntary groups in each state and level of social trust, as gauged by the proportion of residents in each state who believed that people could be trusted. Age-standardized total and cause-specific mortality rates in 1990 were obtained for each state. RESULTS: Income inequality was strongly correlated with both per capita group membership (r = -.46) and lack of social trust (r = .76). In turn, both social trust and group membership were associated with total mortality, as well as rates of death from coronary heart disease, malignant neoplasms, and infant mortality. CONCLUSIONS: These data support the notion that income inequality leads to increased mortality via disinvestment in social capital.

State-level income inequality and individual mortality risk: a prospective, multilevel study.

OBJECTIVES: Previous studies have linked state-level income inequality to mortality rates. However, it has been questioned whether the relationship is independent of individual-level income. The present study tests whether state-level income inequality is related to individual mortality risk, after adjustment for individual-level characteristics. METHODS: In this prospective, multilevel study design, the vital status of National Health Interview Survey (NHIS) respondents was ascertained by linkage to the National Death Index, with additional linkage of state-level data to individuals in the NHIS. The analysis included data for 546,888 persons, with 19,379 deaths over the 8-year follow-up period. The Gini coefficient was used as the measure of income inequality. RESULTS: Individuals living in high-income-inequality states were at increased risk of mortality (relative risk = 1.12; 95% confidence interval = 1.04, 1.19) compared with individuals living in low-income-inequality states. In stratified analyses, significant effects of state income inequality on mortality risk were found, primarily for near-poor Whites. CONCLUSIONS: State-level income inequality appears to exert a contextual effect on mortality risk, after income is adjusted for, providing further evidence that the distribution of income is important for health.

Molecular analysis of the chromosomal breakpoint and fusion transcripts in the acute lymphoblastic SEM cell line with chromosomal translocation t(4;11).

The chromosomal breakpoint and fusion transcripts of the pre-B-leukaemia-derived SEM cell line carrying a reciprocal t(4;11)(q21;q23) translocation were analysed. The breakpoint from derivative chromosome der4 was cloned and sequenced. The crossover site was localized in intron 7 of the ALL-1 gene on chromosome 11q23 and in a large intron of the AF-4 (FEL) gene. RNA transcripts from both wild-type genes and both hybrid genes were detected by reverse transcriptase polymerase chain reaction (RT-PCR) assays. In addition, alternatively spliced mRNA species derived from the der4 chromosome were found. They were generated by using the exon 5' of the breakpoint on der4 as a common splice donor site and the 5' boundaries of exons 8 or 9 of the ALL-1 gene as alternative splice acceptor sites. The hypothesis is proposed that selective pressure operators to maintain the presence of both derivative chromosomes as important elements in the leukaemogenic process.

Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias.

The acute lymphoblastic leukaemia (ALL)-1 gene on human chromosome 11q23 is the site of many locally clustered chromosomal alterations associated with several types of acute leukaemias, including deletions, partial duplications and translocations. Structurally variant proteins derived from the altered gene presumably cause the malignant transformation of early haemopoietic progenitor cells. According to previously published reports, the gene consisted of at least 21 exons spread over approximately 100 kb. In this report a set of genomic fragments was isolated that represent a total of 35 exons (exons 3-37) encompassing > 95% of the protein-coding region (except exons 1 and 2) and the 3'-non-translated region of the gene. The distances between these exons were determined and a detailed restriction map was produced. The majority of the exon/intron boundaries were sequenced and an intron-phase analysis was performed. The results form the basis for a greater understanding of the translocations and other structural alterations of the gene that conserve the open reading frame and thus produce presumably oncogenic variants of the ALL-1 protein.

A novel set of hepatic mRNAs preferentially expressed during an acute inflammation in rat represents mostly intracellular proteins.

A cloning of hepatic cDNAs associated with the early phase of an acute, systemic inflammation was carried out by differential screening of arrayed cDNA clones from rat livers obtained at 4-8 h postchallenge with Freund's complete adjuvant. End sequencing of 174 selected clones provided three cDNA groups that coded for: (i) 23 known acute-phase proteins, (ii) 31 known proteins whose change in hepatic synthesis during an acute phase was so far unsuspected, and (iii) 36 novel proteins whose cDNAs were completely sequenced. For 16 proteins in the third group the hepatic mRNA could be detected and quantitated by Northern blot hybridization in Freund's adjuvant-challenged animals, and an extrahepatic expression in healthy animals was further investigated. Matching the open reading frames of the 36 novel proteins with general and specialized data libraries indicated the potential relationships of 16 of these proteins with known protein families/superfamilies and/or the presence of functional domains previously described in other proteins. Overall, our search for novel inflammation-associated proteins selected mostly known or as yet undescribed proteins with an intracellular or membrane location, which extends our knowledge of the proteins involved in the intracellular metabolism of hepatic cells during a systemic, acute-phase response. Finally, some of the cDNAs above allowed us to successfully identify hepatic mRNAs that are differentially expressed in acute vs chronic (polyarthritis) inflammatory conditions in rat.