Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1.

Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.

A novel stroke locus identified in a northern Sweden pedigree: linkage to chromosome 9q31-33.

OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke. Haplotype analysis suggests that a shared genetic factor is of particular importance for intracerebral hemorrhage.

A prospective radiological analysis of fragment displacement in fractures of the mandibular condyle: evaluation of 96 consecutive cases.

A prospective radiological study of 96 patients with mandibular condylar neck fractures was undertaken to assess frequency and nature of mandibular condylar displacement. Data collected included age, gender, aetiology, and anatomical site of fracture and direction of displacement. Men aged 20-29 years sustained the majority of condylar fractures. Assault was the major cause of condylar fracture, followed by motor vehicle accidents and sport accidents. No anterior or posterior displacement of the condyle was noted. Medial displacement of the superior fragment was most frequently observed.

Does the lead apron and collar always reduce radiation dose?

The possibility that personal lead shielding devices can increase absorption of radiation has not been entertained. The purpose of the present investigation specifically was to determine whether pituitary dose might be increased when a leaded apron and thyroid collar are used. Thermoluminescent dosimeters (TLDs) were used to measure absorbed dose. They were calibrated at the kVp used in the clinical situation and a calibration curve relating light output to dose was generated. Lithium fluoride TLD discs were placed in the pituitary gland region of a Rando-Alderson female human phantom. The equivalent of 100 transpharyngeal exposures were delivered. The resultant light output from recovered dosimeters was converted to a uGy value using the calibration curve. The experiment was repeated using a 0.25 mm lead equivalent collar and apron fitted to the phantom in the customary manner. The entire process was repeated in order to have 30 dosimeters for the unshielded and 30 dosimeters for the shielded conditions. A further 30 dosimeters were sham irradiated and served as controls. A statistical comparison between unshielded and shielded conditions was performed. When the leaded apron and thyroid collar were used the absorbed dose to the pituitary gland was increased significantly (P < 0.05). Following this a second group, using a different dosimetry system and a male phantom repeated the experiment. In both cases, the shielded phantom received significantly higher dose to the pituitary region than the unshielded.

Tooth root colour as a measure of chronological age.

The purpose of this study was to assess a possible colour shift in the root surfaces of adult human teeth and if so, whether this colour change is related to chronological age. Teeth extracted from persons of known age and gender were obtained from Ontario dental practitioners and grouped into five-year age ranges. Three experiments were undertaken: (1) to identify a possible difference in yellow colouration between the four surfaces of tooth roots (mesial, distal, lingual, and buccal), (2) to investigate the difference in yellow colouration of tooth roots between non-molar teeth and molar teeth and (3) to assess the correlation between the age of teeth and root colour saturation for yellow, magenta, cyan and black. The teeth in all investigations were scanned by a flat-bed digital colour scanner with a Kodak colour scale control and viewed on a colour computer monitor. In the first two experiments the yellow colour saturation of the root surfaces was measured at six points on each root using Photoshop 5.0 software. A significant difference was observed in the percentage yellow colour saturation between the mesial and the other three anatomical surfaces (p < 0.01), and between the root surfaces of non-molar and molar teeth (p < 0.01) (ANOVA with Bonferroni post-test). The authors then randomly assigned tooth surfaces to select an equivalent number of posterior and anterior teeth in the study, assessing the relationship between age and root colouration. Four points of colour measurement on 40 teeth (sample size permitting, see Table 1) for each known age and gender were assessed for colour saturation (cyan, magenta, yellow and black). The correlation of chronological age to colour saturation was linear for all colours, with correlation coefficients ranging from r = 0.81 to r = 0.94. The high correlation values strongly support the conclusion that chronological age is related to increased root colouration.