Thrombosis is associated with inferior survival in multiple myeloma.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Patients with multiple myeloma are at an increased risk of venous thromboembolism and arterial thrombosis. We assessed the impact of venous and arterial thrombosis on survival in a population-based study of 9,399 multiple myeloma patients diagnosed in Sweden from 1987 to 2005. We found multiple myeloma patients with venous thromboembolism to have a higher mortality at 1-, 5-, and 10-years of follow up compared with those without, with hazard ratios of 2.9 (95% confidence interval (CI) 2.4-3.5), 1.6 (95% CI: 1.5-1.8), and 1.6 (95% CI: 1.4-1.7), respectively. There was an increase in risk of death among multiple myeloma patients with arterial thrombosis, with hazard ratios of 3.4 (95% CI: 3.0-3.8), 2.2 (95% CI: 2.0-2.3), and 2.1 (95% CI: 1.9-2.1), respectively. In landmark analyses at six months, early arterial but not venous thromboembolism was associated with a higher risk of death. Thus, in contrast to prior smaller studies, we found the development of thrombosis to be associated with significantly poorer survival. The prevention of thrombosis in multiple myeloma is an important goal in the management of these patients.regional agreement on medical training and clinical research (ALF) between Stockholm County Council regional agreement on medical training and clinical research (ALF) between Karolinska Institutet Cancer Society in Stockholm Intramural Research Program of the NIH, NC

Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.No comprehensive evaluation has been made to assess the risk of viral and bacterial infections among patients with monoclonal gammopathy of undetermined significance. Using population-based data from Sweden, we estimated risk of infections among 5,326 monoclonal gammopathy of undetermined significance patients compared to 20,161 matched controls. Patients with monoclonal gammopathy of undetermined significance had a 2-fold increased risk (P<0.05) of developing any infection at 5- and 10-year follow up. More specifically, patients with monoclonal gammopathy of undetermined significance had an increased risk (P<0.05) of bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis), and viral (influenza and herpes zoster) infections. Patients with monoclonal gammopathy of undetermined significance with M-protein concentrations over 2.5 g/dL at diagnosis had highest risks of infections. However, the risk was also increased (P<0.05) among those with concentrations below 0.5 g/dL. Patients with monoclonal gammopathy of undetermined significance who developed infections had no excess risk of developing multiple myeloma, Waldenström macroglobulinemia or related malignancy. Our findings provide novel insights into the mechanisms behind infections in patients with plasma cell dyscrasias, and may have clinical implications.Stockholm County Council Karolinska Institutet Cancer Society in Stockholm NIH, NC

Effect of polygenic scores of telomere length alleles on telomere length in newborns and parents

In adults, polygenic scores (PGSs) of telomere length (TL) alleles explain about 4.5% of the variance in TL, as measured by quantitative polymerase chain reaction (qPCR). Yet, these PGSs strongly infer a causal role of telomeres in aging-related diseases. To better understand the determinants of TL through the lifespan, it is essential to examine to what extent these PGSs explain TL in newborns. This study investigates the effect of PGSs on TL in both newborns and their parents, with TL measured by Southern blotting and expressed in base-pairs (bp). Additionally, the study explores the impact of PGSs related to transmitted or non-transmitted alleles on TL in newborns. For parents and newborns, the PGS effects on TL were 172 bp (p =  2.03 × 10−15) and 161 bp (p =  3.06 × 10−8), explaining 6.6% and 5.2% of the TL variance, respectively. The strongest PGS effect was shown for maternally transmitted alleles in newborn girls, amounting to 214 bp (p =  3.77 × 10−6) and explaining 7.8% of the TL variance. The PGS effect of non-transmitted alleles was 56 bp (p = 0.0593) and explained 0.6% of the TL variance. Our findings highlight the importance of TL genetics in understanding early-life determinants of TL. They point to the potential utility of PGSs composed of TL alleles in identifying susceptibility to aging-related diseases from birth and reveal the presence of sexual dimorphism in the effect of TL alleles on TL in newborns. Finally, we attribute the higher TL variance explained by PGSs in our study to TL measurement by Southern blotting.publishedVersio

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Throug

Towards quantifying the glacial runoff signal in the freshwater input to Tyrolerfjord–Young Sound, NE Greenland

Terrestrial freshwater runoff strongly influences physical and biogeochemical processes at the fjord scale and can have global impacts when considered at the Greenland scale. We investigate the performance of the HIRHAM5 regional climate model over the catchments delivering freshwater to Tyrolerfjord and Young Sound by comparing to the unique Greenland Ecological Monitoring database of in situ observations from this region. Based on these findings, we estimate and discuss the fraction of runoff originating from glacierized and non-glacierized land delivered at the daily scale between 1996 and 2008. We find that glaciers contributed on average 50–80% of annual terrestrial runoff when considering different sections of Tyrolerfjord–Young Sound, but snowpack depletion on land and consequently runoff happens about one month earlier in the model than observed in the field. The temporal shift in the model is a likely explanation why summer surface salinity in the inner fjord did not correlate to modelled runoff. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13280-016-0876-4) contains supplementary material, which is available to authorized users

A computed tomographic study of the molar teeth of Babyrousa spp.

A photographic and computed tomography (CT) scanning study was carried out on the molar teeth of 18 adult male Babyrousa babyrussa skulls and 8 skulls of Babyrousa celebensis including 7 adult males, 1 adult female and 1 subadult male. The occlusal morphology of the adult maxillary and mandibular molar teeth of B. babyrussa was very similar to that of B. celebensis. Most B. babyrussa maxillary molar teeth had 6 roots, with small numbers of teeth having 4, 5 or 7 roots. A similar pattern was suggested in B. celebensis. Mandibular molar teeth had between 4 and 8 roots. Tooth roots of first and second maxillary and mandibular molar teeth were largely tapering, rod-like structures.The roots of the 111/211 teeth had a more complex arrangement; some inserted almost vertically into the maxilla; others orientated in a more distal direction. The mesial and distal roots were splayed in appearance. The 311/411 tooth roots retained elements of the open ‘C’ shape and were generally orientated distally. The pulp chambers were arched to fit under the main cusps in all molar teeth. Pulp canals were variable in number

A Computed Tomographic Study of the Premolar Teeth of Babyrousa spp.

A photographic and computed tomography (CT) scanning study was carried out on the premolar teeth of 18 adult male Babyrousa babyrussa skulls, 10 skulls of Babyrousa celebensis, including 6 adult males, 1 adult female, 1 subadult male, 1 subadult female, and 1 juvenile male. The occlusal morphology of the permanent maxillary premolar teeth of B. babyrussa was very similar to that of B. celebensis. Almost all the maxillary third premolar teeth (107/207) had 2 roots, whereas maxillary fourth premolar teeth (108/208) had 3 or 4 roots. All of the mesial tooth roots of 107/207 and 108/208 were tapering rod-like structures; each contained a single pulp canal. Almost all distal roots of 107/207 were “C” shaped and contained 2 pulp canals. The 108/208 palatal roots were “C” shaped and contained 2 pulp canals. The mesial and distal roots of the mandibular third premolar teeth (307/407) teeth were uniformly rod-like, as were the mesial roots of the mandibular fourth premolar teeth (308/408) teeth. The distal roots of the 308/408 teeth were “C” shaped. All B. babyrussa 307/407 teeth have a single pulp canal located in each of the mesial and distal roots. The 308/408 mesial tooth root contained 1 pulp canal. In all but 3 of the 36 distal 308/408 roots of B. babyrussa teeth and in 7 of the 14 distal roots of B. celebensis teeth there was a single pulp canal; in the other 7 teeth there were 2 pulp canals. Each of the 3 medial roots contained 1 pulp canal

A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.This research was funded by Agnes og Poul Friis Fond (81008-003), Købmand Sven Hansen og Hustru Ina Hansens Fond, Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) y Fondo Europeo de Desarrollo Regional (FEDER; RTI2018-101818-B-I00, UE), and by Gobierno Vasco, Universidad del País Vasco (GV, IT 992-16; UPV)