Although glioblastoma (GBM) has always been recognized as a heterogeneous tumor, the advent of largescale molecular analysis has enabled robust categorization of this malignancy into several specific ...subgroups. Among the subtypes designated by expression profiling, mesenchymal tumors have been associated with an inflammatory microenvironment, increased angiogenesis, and resistance to therapy. Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that plays a prominent role in mediating many of the central features associated with mesenchymal differentiation. This review summarizes the mechanisms by which NF-κB proteins and their co-regulating partners induce the transcriptional network that underlies the mesenchymal phenotype. Moreover, both the intrinsic changes within mesenchymal GBM cells and the microenvironmental factors that modify the overall NF-κB response are detailed.
The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the ...incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In ad-dition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of the literature and clinical trials provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is pos-sible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies.
The clinical application of intracranial compliance (ICC), ∆V/∆P, as one of the most critical indexes for hydrocephalus evaluation was demonstrated previously. We suggest a new definition for the ...concept of ICC (long-term ICC) where there is a longer amount of elapsed time (up to 18 months after shunting) between the measurement of two values (V
1
and V
2
or P
1
and P
2
). The head images of 15 adult patients with communicating hydrocephalus were provided with nine sets of imaging in nine stages: prior to shunting, and 1, 2, 3, 6, 9, 12, 15, and 18 months after shunting. In addition to measuring CSF volume (CSFV) in each stage, intracranial pressure (ICP) was also calculated using fluid–structure interaction simulation for the noninvasive calculation of ICC. Despite small increases in the brain volume (16.9%), there were considerable decreases in the ICP (70.4%) and CSFV (80.0%) of hydrocephalus patients after 18 months of shunting. The changes in CSFV, brain volume, and ICP values reached a stable condition 12, 15, and 6 months after shunting, respectively. The results showed that the brain tissue needs approximately two months to adapt itself to the fast and significant ICP reduction due to shunting. This may be related to the effect of the “viscous” component of brain tissue. The ICC trend between pre-shunting and the first month of shunting was descending for all patients with a “mean value” of 14.75 ± 0.6 ml/cm H
2
O. ICC changes in the other stages were oscillatory (nonuniform). Our noninvasive long-term ICC calculations showed a nonmonotonic trend in the CSFV–ICP graph, the lack of a
linear
relationship between ICC and ICP, and an oscillatory increase in ICC values during shunt treatment. The oscillatory changes in long-term ICC may reflect the clinical variations in hydrocephalus patients after shunting.
The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes ...G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphorylation is a well-described consequence of TMZ treatment, we find that TMZ also robustly induces CDK1 expression. Analysis of this pathway demonstrates that CDK1 is regulated by NF-κB via a putative κB-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor κB protein, BCL-3. Treatment with TMZ induced binding of NF-κB to the κB-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the κB-site and underlined the requirement of p50 and BCL-3 for activation. Targeted knockdown of CDK1 or chemical inhibition with the selective CDK1 inhibitor, RO-3306, potentiated the cytotoxic effect of TMZ. These results identify CDK1 as an NF-κB target gene regulated by p50 and BCL-3 and suggest that targeting CDK1 may be a strategy to improve the efficacy of TMZ against GBM.
The unpredictable complexities in hydrocephalus shunt outcomes may be related to the recovery behavior of brain tissue after shunting. The simulated cerebrospinal fluid (CSF) velocity and ...intracranial pressure (ICP) over 15 months after shunting were validated by experimental data. The mean strain and creep of the brain had notable changes after shunting and their trends were monotonic. The highest stiffness of the hydrocephalic brain was in the first consolidation phase (between pre-shunting to 1 month after shunting). The viscous component overcame and damped the input load in the third consolidation phase (after the fifteenth month) and changes in brain volume were stopped. The long-intracranial elastance (long-IE) changed oscillatory after shunting and there was not a linear relationship between long-IE and ICP. We showed the long-term effect of the viscous component on brain recovery behavior of hydrocephalic brain. The results shed light on the brain recovery mechanism after shunting and the mechanisms for shunt failure.
Abstract
p50, the mature product of
NFKB1
, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT ...domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.
The present study aims to use enhanced ionic polymer-metal composites (IPMC) as an artificial muscle (a soft-active actuator) to restore eyelid movement of patients with ptosis. The previous eyelid ...movement mechanisms contained drawbacks, specifically in the lower eyelid. We used finite element analysis (FEA) to find the optimal mechanism among two different models (A and B). In addition to common electrodes of IPMC (gold and platinum), the bovine serum albumin (BSA) and microcrystalline cellulose (MCC) polymers, with optimal weight percentages of carbon nanotube (CNT) nanofiller, were also utilized as non-metallic electrodes to improve the efficiency of the IPMC actuator. In both models, IPMC with nanocomposite electrodes had higher efficiency as compared to the metallic electrodes. In model A, which moved eyelids indirectly, IPMC with MCC-CNT electrode generated a higher force (25.4%) and less stress (5.9 times) as compared to IPMC with BSA-CNT electrode. However, the use of model A (even with IPMCs) with nanocomposite electrodes can have limitations such as possible malposition issues in the eyelids (especially lower). IPMC with MCC-CNT nanocomposite electrode under model B, which moved eyelids directly, was the most efficient option to restore eyelid movement. It led to higher displacements and lower mechanical stress damage as compared to the BSA-CNT. This finding may provide surgeons with valuable data to open a window in the treatment of patients with ptosis.
Nuclear factor-κB (NF-κB) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-κB response as a prerequisite to ...identifying novel factors that affect sensitivity to DNA damaging chemotherapy.
Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with κB DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-κB activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-β. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis.
These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.
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