Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide ...drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.
We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.
In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants 41% vs. 0 of 27 0%, P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants 51% vs. 0 of 37 0%), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.
Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
A multi-criteria analysis (MCA) approach to describe the effective utilization of geospatial techniques for disaster risk reduction at village level in Kopili River Basin (KRB) of Assam State, India ...is presented. The KRB is chronically flood affected due to seasonal monsoon and rise in water levels of Kopili River. Based on the MCA approach using flood hazard layer derived from the spatio-multi-temporal historic satellite data-sets (comprising of sensors from RISAT-1 SAR, Radarsat SAR and IRS AWiFS), socio-economic data (based on five census variables), infrastructure (road network) and land use vulnerabilities (cropped and uncropped areas), flood risk zones are derived. Our study elucidates that 24,837 ha of crop area spread across 95 villages in the KRB falls in high risk zone, about 39,209 ha distributed in 150 villages falls under moderate-high risk zones and remaining area spread over 162 villages is more or less unaffected. The proposed approach can be applied elsewhere in other river basins to estimate the flood risk so as to mitigate the disaster risk posed by the floods.
Electricity grids are critical infrastructures. They are credible targets of active (e.g., terrorist) attacks since their disruption may lead to sizable losses economically and in human lives. It is ...thus crucial to develop decision support that can guide administrators in deploying defense resources for system security and reliability. Prior work on the defense of critical infrastructures has typically used static or Stackelberg games. These approaches view network interdictions as one-time events. However, infrastructure protection is also a continual process in which the defender and attacker interact to produce dynamic states affecting their best actions, as witnessed in the continual attack and defense of transmission networks in Colombia and Yemen. In this paper, we use zero-sum Markov games to model these interactions subject to underlying uncertainties of real-world events and actions. We solve equilibrium mixed strategies of the players that maximize their respective minimum payoffs with a time-decayed metric. We also show how the defender can use deception as a defense mechanism. Using results for a 5-bus system, a WECC 9-bus system, and an IEEE standard 14-bus system, we illustrate that our game model can provide useful insights. We also contrast our results with those of static games, and quantify the gain in defender payoff due to misinformation of the attacker.
The stiffness and mass matrices of a rotating twisted and tapered beam element are derived. The angle of twist, breadth and depth are assumed to vary linearly along the length of beam. The effects of ...shear deformation and rotary inertia are also considered in deriving the elemental matrices. The first four natural frequencies and mode shapes in bending–bending mode are calculated for cantilever beams. The effects of twist, offset, speed of rotation and variation of depth and breadth taper ratios are studied.
We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell ...growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM-BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.
Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We ...report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy.
Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces.
Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.
MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis ...protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms that determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3'UTR of the XIAP messenger RNA (mRNA) to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array comparative genomic hybridization and spectral karyotype analysis reveal that genomic copy number loss at the miR-24 locus is concordant with the loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3'UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. Interference with miR-24's binding of the critical seed region, resulting from site-directed mutagenesis of the 3'UTR, significantly abrogated miR-24's effects on XIAP expression. Moreover, miR-24 overexpression can overcome apoptosis resistance in cancer cells via downregulation of XIAP expression, and the resulting cancer cell death induced by tumor necrosis factor-related apoptosis-inducing ligand is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells.
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