NPM1 Deletion Is Associated with Gross Chromosomal Rearrangements in Leukemia

BACKGROUND: NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated. METHODOLOGY AND PRINCIPAL FINDINGS: Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the "5q- syndrome" but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p=0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion. CONCLUSIONS AND SIGNIFICANCE: NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML

The landscape effects on water quality parameters: understanding relationships to improve water resources management planning

Although it is well known that the water quality is dependent on many factors, among them the catchment's landscape characteristics, there are not enough research in tropical climate regions that could support aquatic environment quality management through the catchment's land-use management, most studies being leaded in temperate regions. This research attempted to investigate the relations between the land-use and the stream water in the Juquery River Basin, part of the more important public water supply system in the São Paulo Metropolitan Region. Remote sensing images were analyzed within a GIS environment and used to calculate land-use class area and runoff estimation, in order to relate to water quality parameters sampled in the field. The land-use map is an official data obtained from visual interpretation of IKONOS images. The runoff estimation was obtained from TOPODATA image analyzed in GIS environment. The water quality parameters considered are ammonia, pH, and faecal coliforms sampled at the effluents connection with the Juquery channel. Statistical analysis was performed to examine the water quality parameters. Ammonia discharge was significantly related to regenerating forest, human disperse occupation, forest, bare ground and urban area; pH was related to all this land-uses and also anthropic fields and silviculture; and faecal coliform was influenced by disperse human occupation, forest, bare ground, and urban area. The digital elevation model used showed an important rule in those analyses.Pages: 1161-116

Benthic macroinvertebrates as bioindicators of water quality in Billings Reservoir fishing sites (SP, Brazil)

Abastract: Aim The Billings Reservoir is the largest reservoir in the metropolitan region of São Paulo and has multiple uses, including artisanal fishing. Its surroundings present intense occupation, resulting in various environmental impacts. Although the water is degraded, affecting the composition and quality of the fish, this reservoir supports artisanal fishermen who survive through this activity. This study aimed to analyze the water quality in the main sites of artisanal fishing activity, with an emphasis on the benthic community as a bioindicator. Methods Three sampling sites were selected, in which water and zoobenthos samples were collected monthly from April 2012 to March 2013. Water analyses consisted of the determination of pH, temperature, conductivity, turbidity, total dissolved solids, dissolved oxygen, total nitrogen, total phosphorus, and trophic state as well as a principal components analysis. The zoobenthos analysis consisted of determining the relative abundance and total density of taxa, the Shannon-Weaver diversity index, taxa richness, uniformity, Simpson’s dominance index, and the benthic community index and conducting a canonical correspondence analysis. The non-parametric Kruskal-Wallis test followed by the Student-Newman-Keuls test were used to investigate the existence of significant differences in the abiotic and biotic variables among the sites. Results The studied sites showed a high degree of eutrophication, with nitrogen and phosphorus totals levels above the limits defined by current Brazilian legislation. Taquacetuba (P1) showed the best environmental conditions for the development of fishing activity, with the presence of sensitive organisms (Polymitarcyidae) and higher levels of dissolved oxygen. Alvarenga (P2) had the worst water quality, with a predominance of tolerant organisms (Oligochaeta) and lower levels of dissolved oxygen. Conclusion In conclusion, the benthic community in association with abiotic metrics proved to be a useful tool as a bioindicator of environmental conditions, indicating that fishing activity at Alvarenga is not recommended due to the degradation of water quality

Rescue of genomic information in adult acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics: a GIMEMA centralized biological study

P>Metaphase (M-) and array (A-) Comparative Genomic Hybridization (CGH) were used to investigate 40 cases of T- and 32 of B-cell acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics. M-CGH was performed in all cases and A-CGH in 10/12 T-ALL cases with uncertain/normal M-CGH results. M-CGH was abnormal in 38/72 cases, with a total of 110 imbalances (60 gains, 50 losses). 25/40 patients with T-ALL (62 center dot 5%) showed 77 imbalances, with at least 1 genomic imbalance and a mean of 3 aberrations/patient (range 1-12). 13/32 patients with B-ALL (40 center dot 6%) presented 34 imbalances, with a mean of 2 center dot 6 imbalances (range 1-8). A-CGH detected 4 more T-ALL cases with genomic imbalances. A-CGH identified NF1/17q11 center dot 2 deletion and interphase fluorescence in situ hybridization provided a 10 center dot 8% estimated overall incidence of NF1/17q11 center dot 2 deletion in T-ALL. In all but one case (6/7) with NF1 deletion, denaturing high-performance liquid chromatography and direct sequencing detected NOTCH1 gene mutations. Three or more imbalances in CGH-positive cases were significantly associated with resistance to treatment and death during or after induction therapy. We suggest that the work-up for ALL at diagnosis should include CGH investigations, particularly when cytogenetics is uninformative, because they may provide potentially valuable information with prognostic and therapeutic implications

Combined interphase fluorescence in situ hybridization elucidates the genetic heterogeneity of T-cell acute lymphoblastic leukemia in adults

Background Molecular lesions in T-cell acute lymphoblastic leukemias affect regulators of cell cycle, proliferation, differentiation, survival and apoptosis in multi-step pathogenic pathways. Full genetic characterization is needed to identify events concurring in the development of these leukemias. Design and Methods We designed a combined interphase fluorescence in situ hybridization strategy to study 25 oncogenes/tumor suppressor genes in T-cell acute lymphoblastic leukemias and applied it in 23 adult patients for whom immunophenotyping, karyotyping, molecular studies, and gene expression profiling data were available. The results were confirmed and integrated with those of multiplex-polyrnerase chain reaction analysis and gene expression profiling in another 129 adults with T-cell acute lymphoblastic leukemias. Results The combined hybridization was abnormal in 21/23 patients (91%), and revealed multiple genomic changes in 13 (56%). It found abnormalities known to be associated with T-cell acute lymphoblastic leukemias, i.e. CDKN2A-B/9p21 and GRIK2/6q16 deletions, TCR and TLX3 rearrangements, SIL-TAL1, CALM-AF10, MLL-translocations, del(17)(q12)/NF1 and other cryptic genomic imbalances, i.e. 9q34, 11p, 12p, and 17q11 duplication, del(5)(q35), del(7)(q34), del(9)(q34), del(12)(p13), and del(14)(q11). It revealed new cytogenetic mechanisms for TCRB-driven oncogene activation and C-MYB duplication. In two cases with cryptic del(9)(q34), fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction detected the TAF_INUP214 fusion and gene expression profiling identified a signature characterized by HOXA and NUP214 upregulation and TAF_I, FNBP1, C9orf78, and USP20 down-regulation. Multiplex-polymerase chain reaction analysis and gene expression profiling of 129 further cases found five additional cases of TAF_INUP214-positive T-cell acute lymphoblastic leukemia. Conclusions Our combined interphase fluorescence in situ hybridization strategy greatly improved the detection of genetic abnormalities in adult T-cell acute lymphoblastic leukemias. It identified new tumor suppressor genes/oncogenes involved in leukemogenesis and highlighted concurrent involvement of genes. The estimated incidence of TAF_I-NUP214, a new recurrent fusion in adult T-cell acute lymphoblastic leukemias, was 4.6% (7/152)

Prognostic performance of the 'DICA' endoscopic classification and the 'CODA' score in predicting clinical outcomes of diverticular disease: an international, multicentre, prospective cohort study

To investigate the predictive value of the Diverticular Inflammation and Complication Assessment (DICA) classification and to develop and validate a combined endoscopic-clinical score predicting clinical outcomes of diverticulosis, named Combined Overview on Diverticular Assessment (CODA)

Bloating is associated with worse quality of life, treatment satisfaction, and treatment responsiveness among patients with constipation-predominant irritable bowel syndrome and functional constipation

Background: The management of bloating is unclear and its relationship with patients' well-being and treatment satisfaction independent of other abdominal symptoms is uncharacterized. We evaluated the association of bloating with patient-reported outcomes. Methods: Thirty-nine centers for functional gastrointestinal disorders joined the laxative inadequate relief survey. We enrolled 2203 consecutive outpatients with functional constipation (FC) or constipation-predominant irritable bowel syndrome (IBS-C) in two cross-sectional waves. Both wave 1 and 2 included the SF-12, the patient assessment of constipation-symptoms (PAC-SYM), and the treatment satisfaction questionnaire for medication (TSQM-2). Wave 2 only included a global rating of change (GRC) scale to assess patients' assessment of efficacy concerning treatment switches occurred in the 3 months prior to the interview. Bloating in the abdomen was defined on the basis of PAC-SYM item 3. Key Results: The average age was 50.1 years (SD, 16.7) and 82.1% of patients were women. The prevalence of bloating was 91.6% (n = 1970). Bloating was associated with SF-12 Physical Composite Score (p &lt; 0.01), SF-12 Mental Composite Score (p &lt; 0.01), GRC (p &lt; 0.01), Satisfaction with treatment effectiveness (p &lt; 0.01), convenience of administration (p &lt; 0.01), and side effects (p &lt; 0.01) after adjustment for possible confounders. Conclusions &amp; Inferences: Our data suggest that patients regard bloating as a key element in assessing clinical changes and treatments' efficacy as this symptom exerts a strong influence on patient-reported outcomes independent of possible confounders and other symptoms of constipation. Our data provide the rationale to investigate the efficacy and tolerability of new treatments specifically addressing this important, yet disregarded, patients' complain