97 results on '"Bakhtiar Yamini"'
Search Results
2. p52 signaling promotes cellular senescence
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Giovanna M. Bernal, Longtao Wu, David J. Voce, Ralph R. Weichselbaum, and Bakhtiar Yamini
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p52 ,Senescence ,STAT3 ,S100A4 ,CYPA ,NF-κB ,Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Nuclear factor-κB is a multi-subunit transcription factor that plays a central role in cellular senescence. We previously reported that an increase in the p52 subunit is seen in senescent cells and aged tissue. In the current work, we examined the mechanism by which p52 is activated and whether the increase in p52 promotes senescence. Results Using both primary mouse embryonic fibroblasts (MEFs) and WI-38 human lung fibroblasts, we examined cells after serial passage and following prolonged culture. An increase in p52 was found in the nucleus relative to pre-senescent cells. The increase in p52 protein was not reflected by an increase in NFKB2 mRNA or by an increase in the abundance of upstream activating kinases, IKKα and NIK. To examine whether p52 promotes senescence, we over-expressed mature p52 in primary MEFs. Significantly more senescence was seen compared to control, a finding not seen with p52 mutated at critical DNA binding residues. In addition, blocking p52 nuclear translocation with the peptide inhibitor, SN52, decreased β-galactosidase (β-gal) formation. Subsequent filtration studies demonstrated that proteins in conditioned media (CM) were necessary for the increase in p52 and mass spectrometry identified S100A4 and cyclophilin A (CYPA) as potential factors in CM necessary for induction of p52. The requirement of these proteins in CM for induction of p52 was confirmed using depletion and supplementation studies. In addition, we found that activation of STAT3 signaling was required for the increase in p52. Finally, genome wide ChIP-sequencing analysis confirmed that there is an increase in p52 chromatin enrichment with senescence and identified several downstream factors whose expression is regulated by increased p52 binding. Conclusions These results demonstrate that p52 nuclear translocation is increased in senescent cells by factors in conditioned media and that mature p52 induces cellular senescence. The data are consistent with the prior observation that p52 is elevated in aged tissue and support the hypothesis that p52 contributes to organismal aging.
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- 2022
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3. A New Definition for Intracranial Compliance to Evaluate Adult Hydrocephalus After Shunting
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Seifollah Gholampour, Bakhtiar Yamini, Julie Droessler, and David Frim
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brain material ,hydrocephalus ,shunt ,intracranial compliance ,intracranial pressure ,fluid–structure interaction ,Biotechnology ,TP248.13-248.65 - Abstract
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 (V1 and V2 or P1 and P2). 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 H2O. 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.
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- 2022
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4. CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma
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David J. Voce, Giovanna M. Bernal, Kirk E. Cahill, Longtao Wu, Nassir Mansour, Clayton D. Crawley, Paige-Ashley S. Campbell, Ainhoa Arina, Ralph R. Weichselbaum, and Bakhtiar Yamini
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Medicine ,Science - Abstract
Abstract 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.
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- 2021
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5. p50 mono-ubiquitination and interaction with BARD1 regulates cell cycle progression and maintains genome stability
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Longtao Wu, Clayton D. Crawley, Andrea Garofalo, Jackie W. Nichols, Paige-Ashley Campbell, Galina F. Khramtsova, Olufunmilayo I. Olopade, Ralph R. Weichselbaum, and Bakhtiar Yamini
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Science - Abstract
p50 is a constitutively produced NF-κB subunit that modulates the response to DNA damage. Here, the authors show that activation of ATR during S phase induces p50 interaction with BARD1 resulting in p50 mono-ubiquitination, facilitating cell cycle progression and promoting chromosome integrity.
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- 2020
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6. DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy
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Szymon J. Szymura, Giovanna M. Bernal, Longtao Wu, Zhongqin Zhang, Clayton D. Crawley, David J. Voce, Paige-Ashley Campbell, Diana E. Ranoa, Ralph R. Weichselbaum, and Bakhtiar Yamini
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DDX39B ,Extracellular matrix ,LGP2 ,NF-κB ,PIASx ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background 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. Results 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. Conclusions 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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- 2020
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7. Enhanced Ionic Polymer–Metal Composites with Nanocomposite Electrodes for Restoring Eyelid Movement of Patients with Ptosis
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Sara Sadat Hosseini, Bakhtiar Yamini, Levan Ichkitidze, Majid Asadi, Julie Fernandez, and Seifollah Gholampour
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ptosis ,artificial muscle ,ionic polymer–metal composites (IPMC) ,carbon nanotube (CNT) ,bovine serum albumin (BSA) ,microcrystalline cellulose (MCC) ,Chemistry ,QD1-999 - Abstract
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.
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- 2023
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8. NF-κB, Mesenchymal Differentiation and Glioblastoma
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Bakhtiar Yamini
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NF-κB ,GBM ,glioma ,mesenchymal ,proneural ,EMT ,microenvironment ,Cytology ,QH573-671 - Abstract
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.
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- 2018
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9. Data from Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma
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Bakhtiar Yamini, Ralph R. Weichselbaum, Nikolai N. Khodarev, Gustavo Larsen, Luis Nunez, Ruben Spretz, David R. Raleigh, Abhineet Uppal, Szymon J. Szymura, Kirk E. Cahill, Nassir M. Mansour, Wei Zhang, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and David J. Voce
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Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-κB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-κB–dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel κB- and p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both κB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticle-encapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA.Significance:These findings identify NF-κB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.
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- 2023
10. Supplementary Table 1 from Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma
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Bakhtiar Yamini, Ralph R. Weichselbaum, Nikolai N. Khodarev, Gustavo Larsen, Luis Nunez, Ruben Spretz, David R. Raleigh, Abhineet Uppal, Szymon J. Szymura, Kirk E. Cahill, Nassir M. Mansour, Wei Zhang, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and David J. Voce
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Clinical characteristics of patients included in TMA
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- 2023
11. Supplemental Figures 1-8 from Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma
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Bakhtiar Yamini, Ralph R. Weichselbaum, Nikolai N. Khodarev, Gustavo Larsen, Luis Nunez, Ruben Spretz, David R. Raleigh, Abhineet Uppal, Szymon J. Szymura, Kirk E. Cahill, Nassir M. Mansour, Wei Zhang, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and David J. Voce
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Figure S1 shows the results of the p50 dependent gene expression analysis, Figure S2 shows MALAT1 expression in different GBM cell lines, Figure S3 demonstrates a schematic of putative binding sites on MALAT1, Figure S4 shows killing and survival studies in multiple GBM cell lines targeting MALAT1 with two distinct si-RNA sequences, Figure S5 demonstrates hindlimb xenograft growth following treatment with nanoparticles targeting MALAT1 and TMZ, Figure S6 shows in-situ hybridization of MALAT1, Figure S7 shows survival curves of GBM patients with differential MALAT1 expression, Figure S8 shows differential MALAT1 expression among GBM subtypes.
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- 2023
12. Supplementary Table 3 from Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma
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Bakhtiar Yamini, Ralph R. Weichselbaum, Nikolai N. Khodarev, Gustavo Larsen, Luis Nunez, Ruben Spretz, David R. Raleigh, Abhineet Uppal, Szymon J. Szymura, Kirk E. Cahill, Nassir M. Mansour, Wei Zhang, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and David J. Voce
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Genome-wide expression analysis of sh-p105 vs. sh-p105 with TMZ
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- 2023
13. Supplementary Table 4 from Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma
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Bakhtiar Yamini, Ralph R. Weichselbaum, Nikolai N. Khodarev, Gustavo Larsen, Luis Nunez, Ruben Spretz, David R. Raleigh, Abhineet Uppal, Szymon J. Szymura, Kirk E. Cahill, Nassir M. Mansour, Wei Zhang, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and David J. Voce
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Table of significantly altered genes from sh-control cells with a FDR < 0.01
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- 2023
14. Supplementary Table 2 from Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma
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Bakhtiar Yamini, Ralph R. Weichselbaum, Nikolai N. Khodarev, Gustavo Larsen, Luis Nunez, Ruben Spretz, David R. Raleigh, Abhineet Uppal, Szymon J. Szymura, Kirk E. Cahill, Nassir M. Mansour, Wei Zhang, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and David J. Voce
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Genome-wide expression analysis of sh-control vs. sh-control with TMZ
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- 2023
15. Supplementary Figures 1-10 from Inhibition of Nuclear Factor-κB Activity by Temozolomide Involves O6-Methylguanine–Induced Inhibition of p65 DNA Binding
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Ralph R. Weichselbaum, Donald W. Kufe, Michael H. Wu, M. Eileen Dolan, Xiaohong Yu, and Bakhtiar Yamini
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Supplementary Figures 1-10 from Inhibition of Nuclear Factor-κB Activity by Temozolomide Involves O6-Methylguanine–Induced Inhibition of p65 DNA Binding
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- 2023
16. Supplementary Figure Legends 1-10 from Inhibition of Nuclear Factor-κB Activity by Temozolomide Involves O6-Methylguanine–Induced Inhibition of p65 DNA Binding
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Ralph R. Weichselbaum, Donald W. Kufe, Michael H. Wu, M. Eileen Dolan, Xiaohong Yu, and Bakhtiar Yamini
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Supplementary Figure Legends 1-10 from Inhibition of Nuclear Factor-κB Activity by Temozolomide Involves O6-Methylguanine–Induced Inhibition of p65 DNA Binding
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- 2023
17. Data from Inhibition of Nuclear Factor-κB Activity by Temozolomide Involves O6-Methylguanine–Induced Inhibition of p65 DNA Binding
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Ralph R. Weichselbaum, Donald W. Kufe, Michael H. Wu, M. Eileen Dolan, Xiaohong Yu, and Bakhtiar Yamini
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The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O6-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-κB (NF-κB). Temozolomide inhibits basal and tumor necrosis factor α (TNFα)–induced NF-κB transcriptional activity without altering phosphorylation or degradation of inhibitor of κB-α. Inhibition of NF-κB is secondary to attenuation of p65 DNA binding, not nuclear translocation. Inhibition of DNA binding is shown both in vitro, with gel shift studies and DNA binding assays, and in vivo at κB sites. Consistent with inhibition of NF-κB activity, temozolomide reduces basal and TNFα-induced κB-dependent gene expression. Temozolomide also inhibits NF-κB activated by inducers other than TNFα, including lipopolysaccharide, doxorubicin, and phorbol 12-myristate 13-acetate. The inhibitory action of temozolomide on NF-κB is observed to be maximal following pretreatment of cells with temozolomide for 16 h and is also seen with the SN1-type methylating agent methylnitrosourea. The ability of temozolomide to form O6-methylguanine adducts is important for inhibition of NF-κB as is the presence of a functioning mismatch repair system. Activation of NF-κB with TNFα before administration of temozolomide reduces the cytotoxicity of temozolomide, whereas 16-h pretreatment with temozolomide resensitizes cells to killing. This work shows a mechanism whereby O6-methylguanine adducts formed by temozolomide lead to inhibition of NF-κB activity and illustrates a link between mismatch repair processing of alkylator-induced DNA damage and cell death. [Cancer Res 2007;67(14):6889–98]
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- 2023
18. Supplementary figure 2 from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
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Bakhtiar Yamini, Ralph R. Weichselbaum, Gustavo F. Larsen, Luis Nunez, Ruben Spretz, Wei Zhang, Irina V. Balyasnikova, David J. Voce, Kirk E. Cahill, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and Nassir M. Mansour
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Supplementary figure 2. A, ChIP using DCR1 promoter specific primers. Quantitative data show chromatin enrichment of Bcl3 relative to input after controlling for non-specific binding using anti-histone H1 (positive control) and anti-IgG, normalized to vehicle treatment, {plus minus} SD of 3 triplicate samples repeated. Semi-quantitative blot of the PCR product from the p50 and Bcl3 ChIP experiments are shown (right). B, immunoblot with anti-DcR1 or anti-Bcl3 in U87 cells transfected with empty vector (EV) or Bcl3 and treated with 100 μM TMZ for the indicated time. C, qPCR analysis of DCR1 mRNA expression in U87 clones expressing the indicated sh-DcR1 or sh-control construct. Data show mean DCR1 transcript expression relative to GAPDH, {plus minus}SD of triplicate samples. D, trypan blue dye exclusion in sh-cntl and sh-DcR1-3 cells following treatment with vehicle or 100 μM TMZ for the indicated times. Data show mean % cell death, {plus minus} SD of triplicate samples. *, P < 0.05. **, P < 0.01.
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- 2023
19. Supplementary figure 4 from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
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Bakhtiar Yamini, Ralph R. Weichselbaum, Gustavo F. Larsen, Luis Nunez, Ruben Spretz, Wei Zhang, Irina V. Balyasnikova, David J. Voce, Kirk E. Cahill, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and Nassir M. Mansour
- Abstract
Supplementary figure 4. A, clonogenic assay in U87 cells treated with Fas ligand (30 ng/ml) and/or FNAb (1 μg/ml). B, clonogenic assay in U87 cells transfected with the indicated siRNA following treatment with vehicle or Fas ligand (30 ng/ml). Data is normalized to vehicle for each si-RNA condition. C, clonogenic assay in U87 cells expressing empty vector (EV) or HA-DcR1 following treatment with Fas ligand (30 ng/ml). *, P < 0.05. D, tumor growth curves of U87 hindlimb xenografts (n = 5 mice per group) treated with the indicated combinations of TMZ and/or NPs carrying the indicated siRNA. Treatments were given as shown. *, P < 0.05, TMZ + NP-si-DcR1 vs. TMZ + NP-si-cntl.
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- 2023
20. Supplementary figure 1Figure S1 from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
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Bakhtiar Yamini, Ralph R. Weichselbaum, Gustavo F. Larsen, Luis Nunez, Ruben Spretz, Wei Zhang, Irina V. Balyasnikova, David J. Voce, Kirk E. Cahill, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and Nassir M. Mansour
- Abstract
Supplementary figure 1. A, Venn diagram showing overview of genes significantly (FDR < 0.05) altered in response to TMZ in U87 cells stably expressing control or p105 shRNA. DCR1 (TNFRSF10C) was identified as a gene specific to control cells. B, flow cytometric analysis of DcR1 surface expression in U87 cells following treatment with 100 μM TMZ for the indicated time. C, flow cytometric analysis of DcR1 expression in U87-sh-cntl and U87-sh-p105 cells following treatment with TMZ at the indicated concentration. D, immunoblot with anti-p53 and anti-p21 antibodies in U87 cells at indicated time following treatment with 100 μM TMZ.
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- 2023
21. Supplementary figure 3 from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
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Bakhtiar Yamini, Ralph R. Weichselbaum, Gustavo F. Larsen, Luis Nunez, Ruben Spretz, Wei Zhang, Irina V. Balyasnikova, David J. Voce, Kirk E. Cahill, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and Nassir M. Mansour
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Supplementary figure 3. A, annexin V binding in U251 cells treated with vehicle or temozolomide (TMZ, 100 μM) following transfection with the indicated siRNA. B, clonogenic assay in A172 cells transfected with the indicated siRNA following treatment with the indicated concentration of TMZ. C, clonogenic assay in U251 cells transfected with si-RNA and treated with TMZ. *, P < 0.05.
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- 2023
22. Supplementary figure 5 from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
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Bakhtiar Yamini, Ralph R. Weichselbaum, Gustavo F. Larsen, Luis Nunez, Ruben Spretz, Wei Zhang, Irina V. Balyasnikova, David J. Voce, Kirk E. Cahill, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and Nassir M. Mansour
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Supplementary figure 5. Kaplan-Meier survival curves from the REMBRANDT database stratified based on DCR1 mRNA expression level.
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- 2023
23. Supplementary Data Legends from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
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Bakhtiar Yamini, Ralph R. Weichselbaum, Gustavo F. Larsen, Luis Nunez, Ruben Spretz, Wei Zhang, Irina V. Balyasnikova, David J. Voce, Kirk E. Cahill, Clayton D. Crawley, Longtao Wu, Giovanna M. Bernal, and Nassir M. Mansour
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Supplementary Data Legends. Legends for supplementary data presented for publication.
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- 2023
24. Characterizing Racial and Socioeconomic Disparities in Access to Surgery for Pituitary Adenomas at High-Volume Hospitals in the United States: A Retrospective Cohort Analysis from the National Cancer Database
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Miguel A. Jimenez, Julian L. Gendreau, Andrew Palmer, Jackson Nagamoto, Bakhtiar Yamini, Nicholas Rowan, and Debraj Mukherjee
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- 2023
25. Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma
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Lakshmi R. Bollu, Prashant V. Bommi, Paige J. Monsen, Lijie Zhai, Kristen L. Lauing, April Bell, Miri Kim, Erik Ladomersky, Xinyu Yang, Leonidas C. Platanias, Daniela E. Matei, Marcelo G. Bonini, Hidayatullah G. Munshi, Rintaro Hashizume, Jennifer D. Wu, Bin Zhang, Charles David James, Peiwen Chen, Masha Kocherginsky, Craig Horbinski, Michael D. Cameron, Arabela A. Grigorescu, Bakhtiar Yamini, Rimas V. Lukas, Gary E. Schiltz, and Derek A. Wainwright
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Mice ,Brain Neoplasms ,Drug Discovery ,Tryptophan ,Molecular Medicine ,Humans ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Proteolysis Targeting Chimera - Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.
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- 2022
26. Practice patterns and provider satisfaction in a virtual rhinology and skull base surgery clinic
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Emily Papazian, DaraR. Adams, Matthew Du, Esther Wang, Nadieska Caballero, Paramita Das, Peleg Horowitz, Jay Pinto, Louis Portugal, Bakhtiar Yamini, and Christopher R. Roxbury
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Otorhinolaryngology ,Immunology and Allergy - Published
- 2022
27. Computer simulations and in vivo convection-enhanced delivery of fluorescent nanoparticles demonstrate variable distribution geometry.
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Eric Lueshen, Michael LaRiviere, Bakhtiar Yamini, and Andreas A. Linninger
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- 2014
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28. Cerebrospinal fluid hydrocephalus shunting: cisterna magna, ventricular frontal, ventricular occipital
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Seifollah Gholampour, Jay Patel, Bakhtiar Yamini, and David Frim
- Subjects
Cisterna Magna ,Humans ,Surgery ,Equipment Failure ,Neurology (clinical) ,General Medicine ,Child ,Cerebrospinal Fluid Shunts ,Neurosurgical Procedures ,Hydrocephalus - Abstract
Despite advances in cerebrospinal fluid shunting technology, complications remain a significant concern. There are some contradictions about the effectiveness of proximal catheter entry sites that decrease shunt failures. We aim to compare efficiency of shunts with ventricular frontal, ventricular occipital, and cisterna magna entry sites. The systemic search was conducted in the database from conception to February 16, 2022 following guidelines of PRISMA. Between 2860 identified articles, 24 articles including 6094 patients were used for data synthesis. The aggregated results of all patients showed that "overall shunt failure rate per year" in mixed hydrocephalus with ventricular frontal and occipital shunts, and cisterna magna shunt (CMS) were 9.0%, 12.6%, and 30.7%, respectively. The corresponding values for "shunt failure rate" due to obstruction were 15.3%, 31.5%, and 10.2%, respectively. The similar results for "shunt failure rate" due to infection were 11.3%, 9.1%, and 27.2%, respectively. The related values for "shunt failure rate" due to overdrainage were 2.9%, 3.9%, and 13.6%, respectively. CMS was successful in the immediate resolution of clinical symptoms. Shunting through an occipital entry site had a greater likelihood of inaccurate catheter placement and location. Contrary to possible shunt failure due to overdrainage, the failure likelihood due to obstruction and infection in pediatric patients was higher than that of mixed hydrocephalus patients. In both mixed and pediatric hydrocephalus, obstruction and overdrainage were the most and least common complications of ventricular frontal and occipital shunts, respectively. The most and least common complications of mixed CMS were infection and obstruction, respectively.
- Published
- 2022
29. Identification and Characterization of a Novel Brain-Penetrant Indoleamine 2,3 Dioxygenase 1 Protein Degrader for Glioblastoma
- Author
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Lakshmi Bollu, Prashant V. Bommi, Paige J. Monsen, Lijie Zhai, Kristen L. Lauing, April Bell, Miri Kim, Erik Ladomersky, Leonidas C. Platanias, Daniela E. Matei, Marcelo G. Bonini, Hidayatullah G. Munshi, Rintaro Hashizume, Jennifer D. Wu, Bin Zhang, C. David James, Peiwen Chen, Masha Kocherginsky, Craig Horbinski, Michael D. Cameron, Arabela A. Grigorescu, Bakhtiar Yamini, Rimas V. Lukas, Gary E. Schiltz, and Derek Alan Wainwright
- Published
- 2022
30. Primary Sellar Paraganglioma: Case Report with Literature Review and Immunohistochemistry Resource
- Author
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Shiraz Fidai, Peter Pytel, Bakhtiar Yamini, Sean P. Polster, and Seán B. Lyne
- Subjects
Adenoma ,medicine.medical_specialty ,Optic chiasm ,Diagnosis, Differential ,Paraganglioma ,Meningioma ,03 medical and health sciences ,0302 clinical medicine ,Pituitary adenoma ,medicine ,Humans ,Pituitary Neoplasms ,Sella Turcica ,Aged ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,medicine.disease ,Craniopharyngioma ,medicine.anatomical_structure ,Optic Chiasm ,030220 oncology & carcinogenesis ,Female ,Surgery ,Neurology (clinical) ,Radiology ,Differential diagnosis ,business ,030217 neurology & neurosurgery - Abstract
Background Differential diagnosis of sellar masses includes adenoma, meningioma, craniopharyngioma, and metastasis. Primary paraganglioma is seldom considered. We present a case of this unique pathology, review the relevant literature, and compile a compendium of immunohistochemical characteristics for use as a resource. Case Description A 73-year-old woman presented to the hospital with visual changes in her left hemifield. Noncontrast head computed tomography demonstrated a large sellar mass with suprasellar extension and displacement of the optic chiasm (diameter of 3.1 cm). Magnetic resonance imaging was unobtainable owing to an incompatible pacemaker. Computed tomography characterization was most consistent with a macroadenoma. Given the acute visual decline, surgical decompression via an endonasal transsphenoidal route was performed without complication. A diagnosis of paraganglioma was made based on histopathology. Following resection, the patient's visual field deficit improved. Computed tomography body imaging was negative for a metastatic origin. Conclusions Paraganglioma is a rare but potential differential diagnosis to consider when evaluating sellar masses.
- Published
- 2019
31. An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma
- Author
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Seán B. Lyne and Bakhtiar Yamini
- Subjects
0301 basic medicine ,Drug ,Cancer Research ,medicine.medical_specialty ,media_common.quotation_subject ,repurposing ,Review ,GBM ,03 medical and health sciences ,0302 clinical medicine ,therapeutics ,Medicine ,In patient ,Intensive care medicine ,RC254-282 ,Repurposing ,media_common ,repositioning ,business.industry ,glioblastoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,chemosensitization ,Clinical trial ,Patient population ,Drug repositioning ,030104 developmental biology ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,radiosensitization ,business ,Glioblastoma - Abstract
Simple Summary Glioblastoma is a devastating malignancy that has continued to prove resistant to a variety of therapeutics. No new systemic therapy has been approved for use against glioblastoma in almost two decades. This observation is particularly disturbing given the amount of money invested in identifying novel therapies for this disease. A relatively rapid and economical pipeline for identification of novel agents is drug repurposing. Here, a comprehensive review detailing the state of drug repurposing in glioblastoma is provided. We reveal details on studies that have examined agents in vitro, in animal models and in patients. While most agents have not progressed beyond the initial stages, several drugs, from a variety of classes, have demonstrated promising results in early phase clinical trials. Abstract 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.
- Published
- 2021
32. Telemedicine in a Tertiary Rhinology and Endoscopic Skull Base Surgery Practice: Utility, Impact, and Patient Satisfaction in the Post–COVID-19 Era
- Author
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Bakhtiar Yamini, Matthew Du, Peleg M. Horowitz, Christopher R. Roxbury, Jayant M. Pinto, Dara R. Adams, Paramita Das, Nadieska Caballero, and Louis G. Portugal
- Subjects
Rhinology ,medicine.medical_specialty ,Univariate analysis ,Telemedicine ,Patient satisfaction ,Coronavirus disease 2019 (COVID-19) ,Otorhinolaryngology ,business.industry ,General surgery ,medicine ,Specialty ,Neurosurgery ,business - Abstract
Introduction: Telemedicine may be a strategy to provide timely care to patients in the rhinology and endoscopic skull basesurgery (ESBS) practice due to the coronavirus disease-19 (COVID-19) pandemic. Few studies have investigated its utilityin otolaryngology, and none have assessed its application to the ESBS practice. This study aims to assess the utility oftelemedicine to increase patient access and determine patient satisfaction in this setting. Methods: This project was considered as a quality improvement initiative and was therefore exempt from institutionalreview board review. A retrospective chart review between July 1 and August 31, 2020, extracted demographic and clinicalinformation from new patient telemedicine and in-person visits in our ESBS practice (rhinology and neurosurgery). Aseparate phone survey was conducted in a subset of patients after their visits answering questions related to satisfactionscored on a 5-point Likert scale ([ Fig. 1 ]). Univariate analysis with Mann-Whitney and Fisher's exact tests were performed for continuous and categorical variables. Results: Overall, there were 137 patients who were seen in-person or via telemedicine. Mean age was 52.7 ± 16.2 years, 59(43.1%) were white, and 85 (62.0%) were female. The majority, 115, (84.0%) were seen by an otolaryngologist and 22(16.1%) by a neurosurgeon. One-hundred thirteen (82.5%), 18 (13.1%), and 6 (4.4%) patients underwent in-office, video,and telephone visits, respectively. The median distance from patient residence to the clinic was 12.3 miles (range: 0.6-184.0). The median round-trip drive time was 52 minutes (range: 6.0-420.0;[ Fig. 2 ]). Median expected round-trip drivetime did not significantly differ between telemedicine and in-person visits (58 and 52 minutes, respectively). For those whoreceived phone surveys ( N = 30), the mean age was 50.0 ± 14.7 years, 15 (50.0%) were African American, and 17 (56.7%)were female. Twenty-five (83.3%) and 5 (16.7%) patients had an otolaryngology and neurosurgery appointment,respectively. Seventeen (56.7%), 11 (36.7%), and 2 (6.7%) patients had an in-office, video, and telephone visit,respectively. Half were new and half were return visits. The majority (27/30, 90%) reported overall satisfaction with theirvisit as defined by a score of 4 or 5 on the Likert scale, and 20/30 (66.7%) believed telemedicine to be more convenientthan in person. Nevertheless, the majority (20/30, 66.7%) expressed a preference for a future visit to occur in person.Patient satisfaction was not associated with age, race, mode of visit (telemedicine vs. in person), visit specialty, or visitstatus (new vs. return;p > 0.05, all). Conclusion: Patients with rhinology and skull base pathology would gain better access to care with less travel time usingtelemedicine. Although the majority were satisfied with telemedicine and its convenience, most patients still prefer in-person consultation. Telemedicine could prove useful in screening patients in the tertiary ESBS setting in the post-COVID-19 era prior to in person evaluation.
- Published
- 2021
33. Glioblastoma as an age-related neurological disorder in adults
- Author
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Lijie Zhai, Bin Zhang, Charles David James, Craig Horbinski, Derek A. Wainwright, Priya Kumthekar, Kaitlyn O'Shea, Maciej M. Mrugala, Zachary Z. Reinstein, Lifang Hou, Karan Dixit, Andreas Mozny, Masha Kocherginsky, Kristen L. Lauing, Maya Hrachova, April Bell, Bakhtiar Yamini, Rimas V. Lukas, David A. Reardon, Erik Rabin, Erik Ladomersky, Margaret Johnson, Lakshmi Reddy Bollu, Yinan Zheng, Vikram C. Prabhu, Quinn T. Ostrom, Leonidas C. Platanias, Miri Kim, Jennifer D. Wu, and Sarah A. Merrill
- Subjects
Oncology ,medicine.medical_specialty ,senescence ,business.industry ,aging ,Hazard ratio ,Reviews ,Cancer ,Neurological disorder ,medicine.disease ,CD4 ,IDO ,Clinical trial ,glioma ,Internal medicine ,Survivorship curve ,Glioma ,Epidemiology ,AcademicSubjects/MED00300 ,Medicine ,AcademicSubjects/MED00310 ,immunotherapy ,Risk factor ,business - Abstract
Background Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. Methods The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Results Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Conclusions Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.
- Published
- 2021
34. p50 mono-ubiquitination and interaction with BARD1 regulates cell cycle progression and maintains genome stability
- Author
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Bakhtiar Yamini, Clayton D. Crawley, Longtao Wu, Andrea Garofalo, Olufunmilayo I. Olopade, Jackie W. Nichols, Galina Khramtsova, Ralph R. Weichselbaum, and Paige-Ashley Campbell
- Subjects
0301 basic medicine ,Genome instability ,Molecular biology ,General Physics and Astronomy ,Biochemistry ,Mice ,Neuroblastoma ,0302 clinical medicine ,Ubiquitin ,Serine ,lcsh:Science ,Cancer ,Multidisciplinary ,biology ,Chemistry ,Cell Cycle ,Cell cycle ,Chromatin ,Cell biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,Science ,Ubiquitin-Protein Ligases ,Protein domain ,Breast Neoplasms ,General Biochemistry, Genetics and Molecular Biology ,Article ,Genomic Instability ,03 medical and health sciences ,Protein Domains ,BARD1 ,Cell Line, Tumor ,Animals ,Humans ,Binding site ,Binding Sites ,Lysine ,Tumor Suppressor Proteins ,Ubiquitination ,NF-kappa B p50 Subunit ,General Chemistry ,Fibroblasts ,NFKB1 ,030104 developmental biology ,biology.protein ,lcsh:Q ,Protein Processing, Post-Translational - 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., p50 is a constitutively produced NF-κB subunit that modulates the response to DNA damage. Here, the authors show that activation of ATR during S phase induces p50 interaction with BARD1 resulting in p50 mono-ubiquitination, facilitating cell cycle progression and promoting chromosome integrity.
- Published
- 2020
35. CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA
- Author
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Longtao Wu, Vinai Gondi, Seán B. Lyne, John Collins, Ryan Merrell, Deric M. Park, Roger Stupp, Peter Pytel, Bakhtiar Yamini, Rimas V. Lukas, Giovanna M. Bernal, S.J. Chmura, Sean Grimm, Riley Driscoll, Theodore Karrison, and Martin K. Nicholas
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Temozolomide ,business.industry ,Phases of clinical research ,Astrocytoma ,O-6-methylguanine-DNA methyltransferase ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,Chemotherapy regimen ,Internal medicine ,Glioma ,Medicine ,Neurology (clinical) ,Progression-free survival ,business ,Acetazolamide ,medicine.drug - Abstract
Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.
- Published
- 2021
36. Post-Trial Enhanced Deployment and Technical Performance with the MISTIE Procedure per Lessons Learned
- Author
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Ali Mansour, Christopher M. Kramer, Peter C. Warnke, Sean P. Polster, Matthew F. Sharrock, Fernando D. Goldenberg, Faten El Ammar, Issam A. Awad, Meghan Hildreth, Christos Lazaridis, W. Andrew Mould, Agnieszka Stadnik, Daniel F. Hanley, Paramita Das, Ronald Alvarado-Dyer, Bakhtiar Yamini, and Andrea Loggini
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Databases, Factual ,medicine.medical_treatment ,Protocol Deviation ,Neurosurgical Procedures ,Article ,Artificial Intelligence ,Predictive Value of Tests ,Single site ,Humans ,Medicine ,Thrombolytic Therapy ,Aged ,Cerebral Hemorrhage ,Retrospective Studies ,Aged, 80 and over ,Intracerebral hemorrhage ,business.industry ,Rehabilitation ,Thrombolysis ,Middle Aged ,medicine.disease ,Technical performance ,Treatment Outcome ,Clinical Trials, Phase III as Topic ,Software deployment ,Cohort ,Emergency medicine ,Radiographic Image Interpretation, Computer-Assisted ,Female ,Surgery ,Neurology (clinical) ,Tomography, X-Ray Computed ,Cardiology and Cardiovascular Medicine ,Catheter placement ,business - Abstract
Objective We hypothesize that procedure deployment rates and technical performance with minimally invasive surgery and thrombolysis for intracerebral hemorrhage (ICH) evacuation (MISTIE) can be enhanced in post-trial clinical practice, per Phase III trial results and lessons learned. Materials and Methods We identified ICH patients and those who underwent MISTIE procedure between 2017–2021 at a single site, after completed enrollments in the Phase III trial. Deployment rates, complications and technical outcomes were compared to those observed in the trial. Initial and final hematoma volume were compared between site measurements using ABC/2, MISTIE trial reading center utilizing manual segmentation, and a novel Artificial Intelligence (AI) based volume assessment. Results Nineteen of 286 patients were eligible for MISTIE. All 19 received the procedure (6.6% enrollment to screening rate 6.6% compared to 1.6% at our center in the trial; p=0.0018). Sixteen patients (84%) achieved evaculation target 70% removal, compared to 59.7% in the trial surgical cohort (p=0.034). No poor catheter placement occurred and no surgical protocol deviations. Limitations of ICH volume assessments using the ABC/2 method were shown, while AI based methodology of ICH volume assessments had excellent correlation with manual segmentation by experienced reading centers. Conclusions Greater procedure deployment and higher technical success rates can be achieved in post-trial clinical practice than in the MISTIE III trial. AI based measurements can be deployed to enhance clinician estimated ICH volume. Clinical outcome implications of this enhanced technical performance cannot be surmised, and will need assessment in future trials.
- Published
- 2021
37. Management of glioblastoma in elderly patients
- Author
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Katherine B. Peters, Bakhtiar Yamini, Rimas V. Lukas, Steven J. Chmura, Jacob S. Young, and Derek A. Wainwright
- Subjects
Oncology ,Treatment response ,medicine.medical_specialty ,medicine.medical_treatment ,Malignant brain tumor ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Chemotherapy ,Brain Neoplasms ,urogenital system ,business.industry ,Incidence (epidemiology) ,Optimal treatment ,Disease Management ,medicine.disease ,nervous system diseases ,Surgery ,Radiation therapy ,Clinical trial ,Neurology ,030220 oncology & carcinogenesis ,Neurology (clinical) ,Glioblastoma ,business ,030217 neurology & neurosurgery - Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults over 55 years of age. The median age of diagnosis for patients with GBM is 64 years old, with the incidence of patients between 75 and 85 increasing. The optimal treatment paradigm for elderly GBM patients continues to evolve due to the higher frequency of age-related and/or medical co-morbidities. Geriatric GBM patients have historically been excluded from larger, controlled clinical trials due to their presumed decreased likelihood of a sustained treatment response and/or a prolonged good outcome. Here, we highlight current treatment considerations of elderly GBM patients with respect to surgical, radiotherapeutic and systemic modalities, with considerations for improving future clinical outcomes for this patient population.
- Published
- 2017
38. Temozolomide treatment induces lncRNA MALAT1 in an NF-кB and p53 co-dependent manner in glioblastoma
- Author
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Wei Zhang, Nassir M. Mansour, Kirk E. Cahill, Ruben Spretz, Ralph R. Weichselbaum, David R. Raleigh, Nikolai N. Khodarev, Clayton D. Crawley, Abhineet Uppal, Bakhtiar Yamini, Luis Nunez, David J. Voce, Longtao Wu, Giovanna M. Bernal, Szymon J. Szymura, and Gustavo Larsen
- Subjects
Male ,Cancer Research ,Nude ,chemistry.chemical_compound ,Transactivation ,Mice ,Cytotoxicity ,Cancer ,MALAT1 ,Tumor ,Chemistry ,Brain Neoplasms ,NF-kappa B ,Prognosis ,Alkylating ,Oncology ,5.1 Pharmaceuticals ,Gene Knockdown Techniques ,Long Noncoding ,RNA, Long Noncoding ,Development of treatments and therapeutic interventions ,Biotechnology ,medicine.drug ,P50 ,Oncology and Carcinogenesis ,Mice, Nude ,Antineoplastic Agents ,In situ hybridization ,Article ,Cell Line ,Rare Diseases ,Downregulation and upregulation ,Cell Line, Tumor ,Genetics ,medicine ,Temozolomide ,Animals ,Humans ,Oncology & Carcinogenesis ,Antineoplastic Agents, Alkylating ,Human Genome ,Neurosciences ,NF-κB ,Xenograft Model Antitumor Assays ,Brain Disorders ,Brain Cancer ,Cancer research ,RNA ,Tumor Suppressor Protein p53 ,Glioblastoma ,DNA Damage - Abstract
Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-κB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-κB–dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel κB- and p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both κB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticle-encapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA. Significance: These findings identify NF-κB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.
- Published
- 2019
39. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial
- Author
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Laurence J.N. Cooper, Arnold Gelb, Francois Lebel, Hiroshi Nakashima, John A. Barrett, Isaac H. Solomon, Jill Buck, Jethro Hu, Patrick Y. Wen, Jeremy Rudnick, Priya Kumthekar, Rimas V. Lukas, John Zhou, Bakhtiar Yamini, Daniel Triggs, David A. Reardon, Brittany M. Stopa, Nathan Demars, Ajay Naik, Keith L. Ligon, John S. Yu, and E. Antonio Chiocca
- Subjects
Adult ,Male ,medicine.medical_specialty ,endocrine system ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Gastroenterology ,Heterocyclic Compounds, 4 or More Rings ,Dexamethasone ,Article ,Interferon-gamma ,Adrenal Cortex Hormones ,Internal medicine ,Glioma ,medicine ,Humans ,Adverse effect ,Pseudoprogression ,Aged ,business.industry ,General Medicine ,Genetic Therapy ,Middle Aged ,medicine.disease ,Interleukin-12 ,Discontinuation ,Cytokine release syndrome ,Cytokine ,Tolerability ,Gene Expression Regulation ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-γ (IFN-γ) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus ≤20 mg of dexamethasone (days 0 to 14), mOS was 6.4 and 16.7 months, respectively, in all patients and 6.4 and 17.8 months, respectively, in the 20-mg VDX cohort. Re-resection in five of five patients with suspected recurrence after Ad-RTS-hIL-12 revealed mostly pseudoprogression with increased tumor-infiltrating lymphocytes producing IFN-γ and programmed cell death protein 1 (PD-1). These inflammatory infiltrates support an immunological antitumor effect of hIL-12. This phase 1 trial showed acceptable tolerability of regulated hIL-12 with encouraging preliminary results.
- Published
- 2019
40. Long-Term Outcome of Vagus Nerve Stimulation Therapy in Young Children with Intractable Epilepsy
- Author
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Lubov Romantseva, Bakhtiar Yamini, Michael Kohrman, David M. Frim, and James H. Tonsgard
- Subjects
Seizure frequency ,business.industry ,medicine.medical_treatment ,Medical record ,Intractable epilepsy ,medicine.disease ,Epilepsy ,Alertness ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Cohort ,medicine ,Etiology ,Neurology (clinical) ,business ,Vagus nerve stimulation - Abstract
Vagus nerve stimulation (VNS) is approved by FDA for treatment of intractable epilepsy in children over 12 years of age. We assessed the efficacy of VNS therapy in younger children. The study was a retrospective review of the medical records of medically refractory epilepsy patients under 12 years old at VNS implantation. Out of 42 patients studied, 28 had at least 50% decrease in seizure frequency, one-half of patients had 75% decrease in seizures, and 7% became seizure-free. A total 69% of patients reported improved mood and alertness. Complication rate was 7%. Age at VNS implantation, prior duration of epilepsy, electroencelphographic focality, and etiology of epilepsy did not influence the outcome ( p > 0.05). Our cohort demonstrated a lasting benefit of VNS therapy over 5 years, including seizure reduction and improved mood and alertness. VNS is a safe and effective adjunctive therapy for young children with medically intractable epilepsy.
- Published
- 2015
41. Final results of controlled IL-12 monotherapy in adults with grade III or IV gliomas
- Author
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John Loewy, Christina Amidei, Jill Buck, E. Antonio Chiocca, John S. Yu, Yunxia Wang, Nira Hadar, Arnold Gelb, Nathan Demars, Bakhtiar Yamini, Nancy Ann Oberheim Bush, Rimas V. Lukas, Taylor Estupinan, Laurence J.N. Cooper, and John Miao
- Subjects
Cancer Research ,Immune system ,Oncology ,business.industry ,Immunology ,Interleukin 12 ,Master regulator ,Medicine ,business - Abstract
3040 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas. Methods: Multicenter, phase 1, open-label, 3 + 3 dose escalation study of Ad (a single intratumoral injection, 2 × 1011 viral particles, Day 0) with oral V dosing (Days 0 to 14) of 10, 20, 30, and 40 mg in subjects with rGBM. Results: 38 subjects were treated (resection group: V 10 mg (n = 6); 20 mg (n = 15); 30 mg (n = 4); 40 mg (n = 6); and, stereotactic group: V 20 mg, n = 7). The adverse event profile of Ad+ V, was predictable and controllable, with the main adverse reactions (ARs) being mild to moderate. All ARs were manageable and reversible upon withholding V. We observed increased peak (mean ± SEM) serum recombinant IL-12 and downstream endogenous IFN-g: V 10mg 21.4 ± 11.7 pg/mL and 14.6 ± 7.1 pg/mL; V 20 mg 25.8 ± 7.1 pg/mL and 57.0 ± 26.5 pg/mL; V 30 mg 65.7 ± 45.5 pg/mL and 60.7 ± 50.0 pg/mL; V 40mg 108.8 ± 41.0 pg/mL and 167.5 ± 70.9 pg/mL, V 20mg (stereotactic) 25.1 ± 7.2 pg/mL and 69.8 ± 48.5 pg/mL, respectively. In the V 20 mg cohort , there was an increase in tumor-associated T cells (CD3+CD8+%) from pre-Ad (mean ± SEM) 0.6 ± 0.4 to biopsy (~5 mons) 6.3 ± 5.0 and production of IFN-g 97.2 ± 85.3 pg/g (n = 2). Median overall survival (mOS) in the V 20 mg cohort (resection, n = 15) was 12.7 mons (mean follow-up, 13.1 mons). Subjects with unifocal disease (n = 6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons. Tumor response data will be presented. Conclusions: Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-g resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n = 36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM. Clinical trial information: NCT02026271 .
- Published
- 2020
42. Response to BRAF/MEK Inhibition After Progression With BRAF Inhibition in a Patient With Anaplastic Pleomorphic Xanthoastrocytoma
- Author
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Steven J. Chmura, Rimas V. Lukas, Craig Horbinski, Bakhtiar Yamini, and Faiz Hussain
- Subjects
Adult ,Male ,Proto-Oncogene Proteins B-raf ,endocrine system diseases ,BRAF inhibitor ,Astrocytoma ,Aggressive course ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Enzyme Inhibitors ,Vemurafenib ,neoplasms ,Pleomorphic xanthoastrocytoma ,Trametinib ,Mitogen-Activated Protein Kinase Kinases ,business.industry ,Brain Neoplasms ,MEK inhibitor ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,digestive system diseases ,Regimen ,030220 oncology & carcinogenesis ,Cancer research ,Disease Progression ,Neurology (clinical) ,Anaplastic pleomorphic xanthoastrocytoma ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Pleomorphic xanthoastrocytoma (PXA) is a rare primary central nervous system tumor which frequently harbors mutations in BRAF. Anaplastic PXA follow a more aggressive course than their nonanaplastic counterparts. We present the case of an anaplastic PXA initially treated with the BRAF inhibitor vemurafenib. After progression of disease the MEK inhibitor trametinib was added to the regimen leading to radiographic improvement. The rationale for combined BRAF and MEK inhibition in PXA is reviewed.
- Published
- 2018
43. Convection-Enhanced Delivery of Polymeric Nanoparticles Encapsulating Chemotherapy in Canines with Spontaneous Supratentorial Tumors
- Author
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Luis Nunez, Bakhtiar Yamini, Sean P. Polster, Michael Podell, Nassir Mansour, Jacob S. Young, Gustavo Larsen, and Giovanna M. Bernal
- Subjects
Male ,medicine.medical_specialty ,Polymers ,medicine.medical_treatment ,Antineoplastic Agents ,Pilot Projects ,Convection ,Article ,03 medical and health sciences ,0302 clinical medicine ,Dogs ,Drug Delivery Systems ,Glioma ,medicine ,Temozolomide ,Distribution (pharmacology) ,Animals ,Dog Diseases ,Magnetite Nanoparticles ,Supratentorial Tumors ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Brain ,Supratentorial Neoplasms ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Tumor Burden ,Clinical trial ,Dacarbazine ,Treatment Outcome ,030220 oncology & carcinogenesis ,Nanoparticles ,Surgery ,Female ,Neurology (clinical) ,Radiology ,business ,Convection-Enhanced Delivery ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Despite aggressive multimodal treatment, survival for patients with glioblastoma remains dismal. One obstacle to improving patient outcomes is the difficulty in delivering adequate therapeutic to the central nervous system due to the presence of the blood–brain barrier. Although direct drug infusion by convection-enhanced delivery (CED) can bypass the blood–brain barrier and facilitate delivery to intracranial tumors, determining the distribution of delivered therapeutic remains problematic. Image guidance is a strategy that can optimize the accuracy of therapeutic delivery. Methods Here we performed an open-label clinical trial in 10 pet dogs with spontaneous intracranial tumors to examine the target coverage accuracy of delivering polymeric magnetite nanoparticles (PMNPs) encapsulating temozolomide (TMZ). A modified small animal frame was applied to the head of each subject, and PMNPs were delivered stereotactically to the center of the tumor. Magnetic resonance imaging (MRI) was performed immediately postoperatively to examine PMNP distribution, and the animals were followed until death. Results Nine of the 10 dogs underwent PMNP infusion without complications. No infusate backflow was observed during any procedure. In 70% of the cases, the infusion accurately targeted the tumor mass, as determined by the presence of PMNP signal in the tumor on immediate postoperative MRI. Conclusions These data suggest that CED of PMNPs carrying TMZ is safe in dogs with intracranial tumors and can lead to nanoparticle distribution in the region of the target. Image guidance is an important adjunct to CED, because distribution is unpredictable, with the potential for missed target delivery.
- Published
- 2018
44. Intracranial hemorrhage as initial manifestation of plasma cell myeloma: A case report
- Author
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Jonathan G. Hobbs, Charles Van Slambrouck, Bakhtiar Yamini, and Jonathan L. Miller
- Subjects
Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Hematoma ,Physiology (medical) ,Plasma Cell Myeloma ,Biopsy ,medicine ,Humans ,Multiple myeloma ,Vascular imaging ,medicine.diagnostic_test ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Right frontal lobe ,medicine.anatomical_structure ,Neurology ,Surgery ,Neurology (clinical) ,Radiology ,Bone marrow ,business ,Multiple Myeloma ,Intracranial Hemorrhages ,030217 neurology & neurosurgery ,Computed tomography of the head - Abstract
This is the case of a previously healthy 48 year-old male whom presented with mild confusion, low-grade headache, and left sided weakness. Computed tomography of the head revealed a large acute right frontal lobe intracranial hemorrhage (ICH) and intraventricular extension, with normal vascular imaging. Initial laboratory testing was inconsequential. The patient required emergent evacuation, with pathology revealing only elements of a hematoma. Further laboratory testing and bone marrow biopsy results confirmed the diagnosis of plasma cell myeloma. Other systemic signs/symptoms of this disease were notably absent. This report provides the first description of an ICH as the presenting manifestation of plasma cell myeloma (PCM; multiple myeloma).
- Published
- 2017
45. Computer simulations and in vivo convection-enhanced delivery of fluorescent nanoparticles demonstrate variable distribution geometry
- Author
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Andreas A. Linninger, Bakhtiar Yamini, Eric Lueshen, and Michael J. LaRiviere
- Subjects
Volume of distribution ,Variable (computer science) ,Fluorescent nanoparticles ,Materials science ,In vivo ,General Chemical Engineering ,Drug delivery ,Distribution (pharmacology) ,Geometry ,Computer Science Applications ,Biomedical engineering ,Diffusion MRI ,Sphericity - Abstract
Objective Convection-enhanced delivery (CED) has emerged as a promising technique for bypassing the blood–brain barrier to deliver therapeutic agents. However, animal studies and clinical trials that utilize the technique suggest that it may require further optimization before it can be safely used in humans. In particular, while volume of distribution in the target tissue can be controlled, the geometrical spread into a desired target region is highly variable from experiment to experiment. In the present paper we have sought to characterize the non-uniform distribution geometry using fluorescent nanoparticles in both a rat model and computer simulations. Methods Using diffusion tensor imaging MRI data of the rat brain, we performed computer simulations of a 0.5 μL/min CED infusion. A step design catheter targeting the striatum was simulated to infuse 20 μL of infusate. Using the same infusion parameters, we then performed in vivo CED experiments where we infused fluorescently labeled polyethylene glycol-polylactide-polycaprolactone nanoparticles (FPNPs) into the rat striatum. Fluorescence microscopy was used to examine the distribution geometry histologically. Results The computer simulations demonstrated large variations in distribution patterns when catheter placement was shifted by only 1 mm. Animal infusions also exhibited highly irregular and variable distribution geometries despite the use of relatively small flow rates. Conclusion Computer simulations and repeated in vivo infusions demonstrate the difficulty of achieving desired drug distribution in target tissue. We have proposed a calculation for sphericity which, along with the ubiquitous volume of distribution measure, may prove helpful in describing distribution geometry. Taken together, our results suggest that CED's limitations must be considered and further optimization may be required before the technique sees widespread use in humans.
- Published
- 2014
46. Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor
- Author
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Xiaohong Yu, Abhineet Uppal, Ralph R. Weichselbaum, Megan E. McNerney, Bakhtiar Yamini, Ashley M. Nassiri, Giovanna M. Bernal, Joshua S. Wahlstrom, Kirk E. Cahill, Adam M. Schmitt, Kenan Onel, David J. Voce, Clayton D. Crawley, and Kevin P. White
- Subjects
Male ,Cancer Research ,Programmed cell death ,Heterozygote ,Myeloid ,Alkylation ,DNA damage ,Down-Regulation ,lymphoma ,Haploinsufficiency ,Biology ,Article ,NF-κB ,law.invention ,Mice ,Downregulation and upregulation ,law ,Radiation, Ionizing ,Genetics ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Cell Death ,Tumor Suppressor Proteins ,NF-kappa B p50 Subunit ,Heterozygote advantage ,Mice, Inbred C57BL ,DNA Alkylation ,medicine.anatomical_structure ,Hypoxanthine-guanine phosphoribosyltransferase ,Immunology ,Cancer research ,Suppressor ,Female ,tumor suppression - Abstract
NF-κB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-κB1 as being necessary for cytotoxicity in response to DNA alkylation damage. Given the importance of damage-induced cell death for the maintenance of genomic stability, we examined whether Nfkb1 acts as a tumor suppressor in the setting of alkylation damage. Hprt mutation analysis demonstrates that Nfkb1(-/-) cells accumulate more alkylator-induced, but not ionizing radiation (IR)-induced, mutations than similarly treated wild-type cells. Subsequent in vivo tumor induction studies reveal that following alkylator treatment, but not IR, Nfkb1(-/-) mice develop more lymphomas than similarly treated Nfkb1(+/+) animals. Heterozygous mice develop lymphomas at an intermediate rate and retain functional p50 in their tumors, indicating that Nfkb1 acts in a haploinsufficient manner. Analysis of human cancers, including therapy-related myeloid neoplasms, demonstrates that NFKB1 mRNA expression is downregulated compared with control samples in multiple hematological malignancies. These data indicate that Nfkb1 is a haploinsufficient, pathway-specific tumor suppressor that prevents the development of hematologic malignancy in the setting of alkylation damage.
- Published
- 2014
47. Convection-enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma
- Author
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Peter Pytel, Giovanna M. Bernal, Nassir Mansour, Shijun Kang, Gustavo Larsen, Michael J. LaRiviere, Bakhtiar Yamini, Ulrich Welp, Sandra Noriega, Luis Nunez, David J. Voce, Kirk E. Cahill, Ruben Spretz, and Ralph R. Weichselbaum
- Subjects
Pathology ,medicine.medical_specialty ,Materials science ,Polymers ,Dacarbazine ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Nanoparticle ,Bioengineering ,Convection ,Ferric Compounds ,Article ,Mice ,Drug Delivery Systems ,In vivo ,Cell Line, Tumor ,Glioma ,Temozolomide ,medicine ,Animals ,Humans ,Distribution (pharmacology) ,General Materials Science ,Brain Neoplasms ,fungi ,Cancer ,medicine.disease ,Magnetic Resonance Imaging ,Xenograft Model Antitumor Assays ,Rats ,Radiography ,Cancer research ,Nanoparticles ,Molecular Medicine ,Preclinical imaging ,medicine.drug - Abstract
A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells was demonstrated. Convection-enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ-bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma. From the Clinical Editor GBM remains one of the most notoriously treatment-unresponsive cancer types. In this study, a multifunctional nanoparticle-based temozolomide delivery system was demonstrated to possess enhanced treatment efficacy in a rodent xenograft GBM model, with the added benefit of MRI-based tracking via the incorporation of iron oxide as a T2* contrast material in the nanoparticles.
- Published
- 2014
48. DNA damage-induced cytotoxicity is mediated by the cooperative interaction of phospho-NF-κB p50 and a single nucleotide in the κB-site
- Author
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David R. Raleigh, Shijun Kang, Ralph R. Weichselbaum, Bakhtiar Yamini, David J. Voce, Clayton D. Crawley, and Adam M. Schmitt
- Subjects
Transcription, Genetic ,DNA damage ,Gene Regulation, Chromatin and Epigenetics ,Biology ,Cell Line ,Promoter Regions ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetic ,Information and Computing Sciences ,Serine ,Genetics ,Animals ,Phosphorylation ,Binding site ,Promoter Regions, Genetic ,Gene ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Binding Sites ,Nucleotides ,NF-kappa B ,NF-kappa B p50 Subunit ,DNA ,Biological Sciences ,Molecular biology ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,DNA methylation ,Transcription ,Environmental Sciences ,Cytosine ,DNA Damage ,Protein Binding ,Developmental Biology - Abstract
Phosphorylation of the NF-κB subunit, p50, is necessary for cytotoxicity in response to DNA methylation damage. Here, we demonstrate that serine 329 phosphorylation regulates the interaction of p50 with specific NF-κB binding elements based on the identity of a single κB-site nucleotide. Specifically, S329 phosphorylation reduces the affinity of p50 for κB-sites that have a cytosine (C) at the −1 position without affecting binding to sequences with a −1 adenine. The differential interaction between phospho-p50 and the −1 base regulates the downstream transcriptional response and underlies the inhibition of anti-apoptotic gene expression following DNA damage. In genes with multiple κB-sites, the presence of a single −1C κB-site enables inhibition of NF-κB-dependent activity. The data suggest that interaction between phospho-p50 and the −1 κB nucleotide facilitates cytotoxicity in response to DNA damage. Moreover, although conservation of the entire κB-site sequence is not seen across species, the identity of the −1 nt in critical anti-apoptotic genes is conserved such that the overall response to DNA damage is maintained.
- Published
- 2012
49. Evaluating the Cavus Foot
- Author
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Ananth S. Eleswarapu, Bakhtiar Yamini, and Robert J. Bielski
- Subjects
Pes cavus ,medicine.medical_specialty ,Adolescent ,Physical examination ,Primary care ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Deformity ,Humans ,Unstable gait ,030222 orthopedics ,medicine.diagnostic_test ,business.industry ,Foot ,Cavus foot ,030229 sport sciences ,medicine.disease ,Magnetic Resonance Imaging ,body regions ,medicine.anatomical_structure ,Talipes Cavus ,Pediatrics, Perinatology and Child Health ,Female ,medicine.symptom ,Ankle ,business ,Foot (unit) - Abstract
The cavus foot is a deformity characterized by abnormal elevation of the medial arch of the foot. Unique among foot deformities, cavus typically occurs secondary to a spinal cord or neuromuscular pathology, with two-thirds of patients having an underlying neurologic diagnosis. Thus, recognition of cavus foot and appropriate evaluation are essential in the primary care setting. Patients may present with unstable gait, frequent ankle sprains, or pain along the metatarsal heads or the lateral border of the foot. The diagnosis can be confirmed with a lateral weight-bearing radiograph, with several key measurements defining a pes cavus alignment. A thorough history and physical examination should be performed to look for possible secondary causes. The first step in the treatment of cavus deformity is to address the underlying cause. After that, a variety of treatment options are available to alleviate the pain and dysfunction caused by this deformity. [ Pediatr Ann . 2016;45(6):e218–e222.]
- Published
- 2016
50. Nuclear factor-κB in glioblastoma: insights into regulators and targeted therapy
- Author
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Kirk E. Cahill, Bakhtiar Yamini, and Ramin A. Morshed
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Central nervous system ,Review ,Bioinformatics ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Glioma ,medicine ,Animals ,Humans ,Transcription factor ,Cell Proliferation ,business.industry ,Brain Neoplasms ,NF-kappa B ,Cancer ,NF-κB ,medicine.disease ,Phenotype ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Neurology (clinical) ,Signal transduction ,business ,Glioblastoma - Abstract
Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that regulates multiple aspects of cancer formation, growth, and treatment response. Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system, is characterized by molecular heterogeneity, resistance to therapy, and high NF-κB activity. In this review, we examine the mechanisms by which oncogenic pathways active in GBM impinge on the NF-κB system, discuss the role of NF-κB signaling in regulating the phenotypic properties that promote GBM and, finally, review the components of the NF-κB pathway that have been targeted for treatment in both preclinical studies and clinical trials. While a direct role for NF-κB in gliomagenesis has not been reported, the importance of this transcription factor in the overall malignant phenotype suggests that more rational and specific targeting of NF-κB-dependent pathways can make a significant contribution to the management of GBM.
- Published
- 2015
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