Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine.

Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted

Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.

BackgroundNovel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.MethodsLevels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes.ResultsBoth primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib.ConclusionsNeuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma

Organisational downsizing, sickness absence, and mortality: 10-town prospective cohort study

Objective To examine whether downsizing, the reduction of personnel in organisations, is a predictor of increased sickness absence and mortality among employees.Design Prospective cohort study over 7.5 years of employees grouped into categories on the basis of reductions of personnel in their occupation and workplace: no downsizing ( 18%).Setting Four towns in Finland.Participants 5909 male and 16 521 female municipal employees, aged 19-62 years, who kept their jobs.Main outcome measures Annual sickness absence rate based on employers' records before and after downsizing by employment contract; all cause and cause specific mortality obtained from the national mortality register.Results Major downsizing was associated with an increase in sickness absence (P for trend < 0.001) in permanent employees but not in temporary employees. The extent of downsizing was also associated with cardiovascular deaths (P for trend < 0.01) but not with deaths from other causes. Cardiovascular mortality was 2.0 (95% confidence interval 1.0 to 3.9) times higher after major downsizing than after no downsizing. Splitting the follow up period into two halves showed a 5.1 (1.4 to 19.3) times increase in cardiovascular mortality for major downsizing during the first four years after downsizing. The corresponding hazard ratio was 1.4 (0.6 to 3.1) during the second half of follow up.Conclusion Organisational downsizing may increase sickness absence and the risk of death from cardiovascular disease in employees who keep their jobs

Perencanaan dan Simulasi Jaringan LTE ( Long Term Evolution ) di Kota Pekanbaru

The development of information and communication technologies growing more rapidly, as well as wireless communications technology. At the same time, theneed for information is also greater with the higher mobility. Technology Long Term Evolution (LTE) is believed to be able to answer that question.LTE is a technology developed by 3GPP as the development of mobile communication technology before. In theory LTE in this thesis is to make an LTE network simulation based methods duplex Frequency Division Duplex (FDD) with a frequency of 1800 MHz in the city of Pekanbaru using software Atoll. In this paper used the method of planning coverage to support the model propagated COST-231 hata are in use by means of simulation.The simulation results show Pekanbaru require at least 99 LTE site that is covered Ratio Signal (RS) and Carrier to Interference Noise Ratio (CINR) of at least 97%. The results of the simulation throughput, customers who successfully connected to the network at abandwidth of 5 MHz amounted to 82.7% and to a frequency of 10 MHz by 86.4%, while for a frequency of 15 MHz at 86.4%, and to a frequency of 20 MHz by 66%

Analisa Penerapan Kinerja Frame Relay pada Pemodelan Jaringan

The development of the internet today has given us so many benefits for the user as well as for industries that use it as a communication medium that is cheap, effective, and efficient. With the development of Internet and various technologies that go with it then it is also directly proportional to the need for the use of the internet is more reliable and reasonable. In the use ofthe internet there are several technologies that can be used, one of which is Frame Relay. Frame Relay network is a network share (shared services) by utilizing the Permanent Virtual Circuit(PVC) so as to ensure minimum access level CIR (Committed Information Rate) specific. Frame Relay is designed to reduce the processing on each node by reducing the format and proceduresused. In this research, frame relay network modeling and analysis of network performance using software GNS3, frame relay network performance will be determined by the parameters of delay,throughput and packet loss. With this study will be obtained performance of some frame relay network model that can be used as a reference in designing the new network

Optimasi Perencanaan Jaringan LTE FDD 1800 MHz di Kota Pekanbaru

LTE is a cellular technology developed by 3GPP which has improved from the previous mobile technologies. The implementation of LTE in Indonesia is still not evenly distributed and only for big cities. Hence, it takes some planning and a deeper study for the area that will be implemented by LTE network. Planning and network optimization is necessary in order to meet consumer needs of the LTE network. There are different ways of optimization methods can be used, in previous studies used a joint base station technique, optimization in other research done by changing basic parameters such as replacing the feeder cable and the addition site. In this study optimization techniques used by changing the type of modulation thus affecting the utilization values of SNR. The simulation results based on two scenarios i.e the number of sites for scenario 1in the total of 479 sites, while for scenario 2 indicates number of sites . in the mean time for a signal level coverage for scenario 1 and scenario 2 show -90 dBm and -95 dBm, respectively

Perancangan Topologi Ring dengan Spanning Tree Protocol pada Jaringan Internet Area Perkantoran Bangko PT. Chevron Pacific Indonesia

Bangko Offices Area in PT. Chevron Pacific Indonesia require a network with reliability, stability, and efficiency to support the company. Currently, there are many problems that occur in today\u27s network such as the link that was frequently interrupted, no backup paths in the network, and the speed of the link is still not uniform. Therefore, it is important to design a new network to solve that problem. In the new network design, used a ring topology plus additional backup lines, 1 Gbps bandwidth allocation, and the use of the spanning tree protocol. The design of the new network is done by using software OPNET Modeler with the parameters are delays and throughput. The needs of planning for next 5 years will be fulfilled with 1 Gpbs bandwidth alocation and the implementation of the spanning tree protocol will avoid loops and maintain network connectivity. With the new network design will be obtained a good Quality of Service with the network delays value corresponding to the category of delay and regularly use the service based on the priority determined

Perancangan Jaringan Voice Over Internet Protocol (VOIP) Fakultas Teknik Universitas Riau

This research discuss the designing of Voice over Internet Protocol (VoIP) in Engineering Faculty of Riau University. LAN of Engineering Faculty is connected through fast ethernet 100baseT cable and the backbone is connected through fiber optic. The project is designed using OPNET Modeler 14.5 Educational Version which consist of two skenario, VoIP network without router and with router. In the VoIP network with router, the network performance is measured by First-In-First-Out Queuing (FQ), Priority Queuing (PQ) and Weighted Fair Queuing (WFQ). The results showed that the value of MOS network with router (4.1 ) is more steadier than the network without router. The best performance of voice application is found in the routerand PQ network, where packet delay, jitter and Mean Opinion Score (MOS) are 330 ms, 0.9 ms, 4.1 respectively. Furthermore the best performance of video conference application is found in the same network where packet delay and jitter are 0.6 secondsand 0.2 seconds