OBJECTIVE—Safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 70/30, prebreakfast and presupper) were compared with once-daily insulin glargine in type 2 diabetic subjects inadequately controlled on oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS—This 28-week parallel-group study randomized 233 insulin-naive patients with HbA1c values ≥8.0% on >1,000 mg/day metformin alone or in combination with other OADs. Metformin was adjusted up to 2,550 mg/day before insulin therapy was initiated with 5–6 units BIAsp 70/30 twice daily or 10–12 units glargine at bedtime and titrated to target blood glucose (80–110 mg/dl) by algorithm-directed titration. RESULTS—A total of 209 subjects completed the study. At study end, the mean HbA1c value was lower in the BIAsp 70/30 group than in the glargine group (6.91 ± 1.17 vs. 7.41 ± 1.24%, P < 0.01). The HbA1c reduction was greater in the BIAsp 70/30 group than in the glargine group (−2.79 ± 0.11 vs. −2.36 ± 0.11%, respectively; P < 0.01), especially for subjects with baseline HbA1c >8.5% (−3.13 ± 1.63 vs. −2.60 ± 1.50%, respectively; P < 0.05). More BIAsp 70/30–treated subjects reached target HbA1c values than glargine-treated subjects (HbA1c ≤6.5%: 42 vs. 28%, P < 0.05; HbA1c <7.0%: 66 vs. 40%, P < 0.001). Minor hypoglycemia (episodes/year) was greater in the BIAsp 70/30 group than in the glargine group (3.4 ± 6.6 and 0.7 ± 2.0, respectively; P < 0.05). Weight gain and daily insulin dose at study end were greater for BIAsp 70/30–treated subjects than for glargine-treated subjects (weight gain: 5.4 ± 4.8 vs. 3.5 ± 4.5 kg, P < 0.01; insulin dose: 78.5 ± 39.5 and 51.3 ± 26.7 units/day, respectively). CONCLUSIONS—In subjects with type 2 diabetes poorly controlled on OADs, initiating insulin therapy with twice-daily BIAsp 70/30 was more effective in achieving HbA1c targets than once-daily glargine, especially in subjects with HbA1c >8.5%.

OBJECTIVE -Multiple daily injection (MDI) therapy of bolus insulin aspart and basal insulin glargine was compared with continuous subcutaneous insulin infusion (CSII) with aspart in type 1 diabetic patients previously treated with CSII.RESEARCH DESIGN AND METHODS -One hundred patients were enrolled in a randomized, multicenter, open-label, crossover study. After a 1-week run-in period with aspart by CSII, 50 subjects were randomly assigned to MDI therapy (aspart immediately before each meal and glargine at bedtime) and 50 subjects continued CSII. After 5 weeks of the first treatment, subjects crossed over to the alternate treatment for 5 weeks. During the last week of each treatment period, subjects wore a continuous glucose monitoring system for 48 -72 h.RESULTS -Mean serum fructosamine levels were significantly lower after CSII therapy than after MDI therapy (343 Ϯ 47 vs. 355 Ϯ 50 mol/l, respectively; P ϭ 0.0001). Continuous glucose monitoring profiles over a 24-h time period showed that glucose exposure was 24 and 40% lower for CSII than MDI as measured by area under the curve (AUC) glucose Ն80 mg/dl (1,270 Ϯ 742 vs. 1,664 Ϯ 1,039 mg ⅐ h ⅐ dl Ϫ1 ; P Ͻ 0.001) and AUC glucose Ն140 mg/dl (464 Ϯ 452 vs. 777 Ϯ 746 mg ⅐ h ⅐ dl Ϫ1 , CSII vs. MDI, respectively; P Ͻ 0.001). Similar percentages of subjects reported hypoglycemic episodes (CSII: 92%, MDI: 94%) and nocturnal (12:00 A.M. to 8:00 A.M.) hypoglycemic episodes (CSII: 73%, MDI: 72%). Major hypoglycemia was infrequent (CSII: two episodes, MDI: five episodes).CONCLUSIONS -In a trial of short duration, CSII therapy with insulin aspart resulted in lower glycemic exposure without increased risk of hypoglycemia, as compared with MDI with insulin aspart and glargine. Diabetes Care 28:533-538, 2005

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.

The classification of a gene as an oncogene or a tumor suppressor has been a staple of cancer biology for decades. However, as we delve deeper into the biology of these genes, this simple classification has become increasingly difficult for some. In the case of heterogeneous nuclear ribonuclear protein K (hnRNP K), its role as a tumor suppressor has recently been described in acute myeloid leukemia and demonstrated in a haploinsufficient mouse model. In contrast, data from other clinical correlation studies suggest that hnRNP K may be more fittingly described as an oncogene, due to its increased levels in a variety of malignancies. hnRNP K is a multifunctional protein that can regulate both oncogenic and tumor suppressive pathways through a bevy of chromatin-, DNA-, RNA-, and protein-mediated activates, suggesting its aberrant expression may have broad-reaching cellular impacts. In this review, we highlight our current understanding of hnRNP K, with particular emphasis on its apparently dichotomous roles in tumorigenesis.

Mycobacterium lepromatosis is a newly discovered leprosy-causing organism. Preliminary phylogenetic analysis of its 16S rRNA gene and a few other gene segments revealed significant divergence from Mycobacterium leprae, a well-known cause of leprosy, that justifies the status of M. lepromatosis as a new species. In this study we analyzed the sequences of 20 genes and pseudogenes (22,814 nucleotides). Overall, the level of matching of these sequences with M. leprae sequences was 90.9%, which substantiated the species-level difference; the levels of matching for the 16S rRNA genes and 14 protein-encoding genes were 98.0% and 93.1%, respectively, but the level of matching for five pseudogenes was only 79.1%. Five conserved protein-encoding genes were selected to construct phylogenetic trees and to calculate the numbers of synonymous substitutions (dS values) and nonsynonymous substitutions (dN values) in the two species. Robust phylogenetic trees constructed using concatenated alignment of these genes placed M. lepromatosis and M. leprae in a tight cluster with long terminal branches, implying that the divergence occurred long ago. The dS and dN values were also much higher than those for other closest pairs of mycobacteria. The dS values were 14 to 28% of the dS values for M. leprae and Mycobacterium tuberculosis, a more divergent pair of species. These results thus indicate that M. lepromatosis and M. leprae diverged ϳ10 million years ago. The M. lepromatosis pseudogenes analyzed that were also pseudogenes in M. leprae showed nearly neutral evolution, and their relative ages were similar to those of M. leprae pseudogenes, suggesting that they were pseudogenes before divergence. Taken together, the results described above indicate that M. lepromatosis and M. leprae diverged from a common ancestor after the massive gene inactivation event described previously for M. leprae.Leprosy, one of the oldest human diseases, remains a significant public health problem in many developing countries (8). Mycobacterium leprae was the only known cause of leprosy until recently, when a new mycobacterium, Mycobacterium lepromatosis, was found to be the cause of diffuse lepromatous leprosy (DLL), a unique form of leprosy endemic in Mexico and the Caribbean (17). The discovery of this new species may provide an explanation for the clinical and geographic variability of leprosy.The initial phylogenetic analysis of M. lepromatosis was carried out using the sequences of the 16S rRNA gene and segments of groEL, rpoB, and other genes (total, 4.99 kb) (17). This study revealed significant sequence differences between M. lepromatosis and all known Mycobacterium species and placed M. lepromatosis closest to M. leprae. However, the sequence variation justified assigning a new species for the new organism instead of classifying it as a variant of M. leprae. All M. leprae strains collected worldwide have been found to be clonal and to differ by only single-nucleotide polymorphism or variable numbers of tandem repeats (24). Also, the genomes of t...