Publications by authors named "Aleksandra Gruslova"

11 Publications

  • Page 1 of 1

Differentiation of Brain Tumor Microvasculature From Normal Vessels Using Optical Coherence Angiography.

Lasers Surg Med 2021 Jun 15. Epub 2021 Jun 15.

Department of Biomedical Engineering, The University of Texas Austin, Austin, Texas, 78712, USA.

Background And Objectives: Despite rapid advances and discoveries in medical imaging, monitoring therapeutic efficacy for malignant gliomas and monitoring tumor vasculature remains problematic. The purpose of this study is to utilize optical coherence angiography for vasculature characterization inside and surrounding brain tumors in a murine xenograft brain tumor model. Features included in our analysis include fractional blood volume, vessel tortuosity, diameter, orientation, and directionality.

Study Design/materials And Methods: In this study, five tumorous mice models at 4 weeks of age were imaged. Human glioblastoma cells were injected into the brain and allowed to grow for 4 weeks and then imaged using optical coherence tomography.

Results: Results suggest that blood vessels outside the tumor contain a greater fractional blood volume as compared with vessels inside the tumor. Vessels inside the tumor are more tortuous as compared with those outside the tumor. Results indicate that vessels near the tumor margin are directed inward towards the tumor while normal vessels show a more random orientation.

Conclusion: Quantification of vascular microenvironments in brain gliomas can provide functional vascular parameters to aid various diagnostic and therapeutic studies. © 2021 Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/lsm.23446DOI Listing
June 2021

FASN inhibition as a potential treatment for endocrine-resistant breast cancer.

Breast Cancer Res Treat 2021 Jun 24;187(2):375-386. Epub 2021 Apr 24.

UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX, USA.

Purpose: The majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and its expression is commensurate with tumor grade and resistance to numerous therapies.

Methods: The effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen-resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by Western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA.

Results: TVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine-resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress.

Conclusion: Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for the treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine-resistant breast cancer should be considered.
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http://dx.doi.org/10.1007/s10549-021-06231-6DOI Listing
June 2021

Implantable Cardiac Kirigami-Inspired Lead-Based Energy Harvester Fabricated by Enhanced Piezoelectric Composite Film.

Adv Healthc Mater 2021 04 12;10(8):e2002100. Epub 2021 Jan 12.

Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.

Harvesting biomechanical energy to power implantable electronics such as pacemakers has been attracting great attention in recent years because it replaces conventional batteries and provides a sustainable energy solution. However, current energy harvesting technologies that directly interact with internal organs often lack flexibility and conformability, and they usually require additional implantation surgeries that impose extra burden to patients. To address this issue, here a Kirigami inspired energy harvester, seamlessly incorporated into the pacemaker lead using piezoelectric composite films is reported, which not only possesses great flexibility but also requires no additional implantation surgeries. This lead-based device allows for harvesting energy from the complex motion of the lead caused by the expansion-contraction of the heart. The device's Kirigami pattern has been designed and optimized to attain greatly improved flexibility which is validated via finite element method (FEM) simulations, mechanical tensile tests, and energy output tests where the device shows a power output of 2.4 µW. Finally, an in vivo test using a porcine model reveals that the device can be implanted into the heart straightforwardly and generates voltages up to ≈0.7 V. This work offers a new strategy for designing flexible energy harvesters that power implantable electronics.
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http://dx.doi.org/10.1002/adhm.202002100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062299PMC
April 2021

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation.

Genome Biol 2020 08 6;21(1):195. Epub 2020 Aug 6.

Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA.

Background: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy.

Results: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites.

Conclusions: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.
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http://dx.doi.org/10.1186/s13059-020-02115-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412812PMC
August 2020

Stable Isotope Dilution LC-HRMS Assay To Determine Free SN-38, Total SN-38, and SN-38G in a Tumor Xenograft Model after Intravenous Administration of Antibody-Drug Conjugate (Sacituzumab Govitecan).

Anal Chem 2020 01 9;92(1):1260-1267. Epub 2019 Dec 9.

Antibody-drug conjugates (ADCs) have gained significant interest over the past few years due to their targeted delivery, higher efficacy, decreased toxicity and improved therapeutic index over conventional anticancer therapies. Sacituzumab govitecan (SG) is an ADC composed of a Trop-2-targeted antibody conjugated to the cytotoxic payload SN-38. SG is currently being evaluated in clinical trials of several solid cancers. In this nonclinical study, we have developed a highly sensitive and selective approach to measure free and total SN-38 and its glucuronidation metabolite (SN-38G) using stable isotope dilution (SID) ultrahigh-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). An efficient and fast hydrolysis procedure (2 h at 100 °C) was established to release SN-38, conjugated to the antibody by carbonate linkage. The assay involves the extraction of free SN-38, SN-38G by protein precipitation, and subsequent acid hydrolysis of the protein layer to release antibody-bound SN-38. The developed UHPLC-HRMS method resulted in good linearity ( ≥ 0.997), accuracy (RE ≤ ± 9.1%), precision (CVs ≤ 7.7%), and extraction recoveries (85.6-109.3%). The validated method was applied in the plasma and tumor of mice bearing human brain (U251) and breast (MDA-MB-468) tumor xenografts treated with a single dose (0.5 mg) of SG for 6 h. Results revealed the presence of trace level of SN-38G and free SN-38 in plasma, which suggests an improved therapeutic index of SG. The established method makes a significant contribution to the assessment of SG in different cancers.
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http://dx.doi.org/10.1021/acs.analchem.9b04419DOI Listing
January 2020

Laser brain cancer surgery in a xenograft model guided by optical coherence tomography.

Theranostics 2019 26;9(12):3555-3564. Epub 2019 May 26.

University of Texas at Austin.

Higher precision surgical devices are needed for tumor resections near critical brain structures. The goal of this study is to demonstrate feasibility of a system capable of precise and bloodless tumor ablation. An image-guided laser surgical system is presented for excision of brain tumors in a murine xenograft model. The system combines optical coherence tomography (OCT) guidance with surgical lasers for high-precision tumor ablation (Er:YAG) and microcirculation coagulation (Thulium (Tm) fiber laser). A fluorescent human glioblastoma cell line was injected into mice and allowed to grow four weeks. Craniotomies were performed and tumors were imaged with confocal fluorescence microscopy. The mice were subsequently OCT imaged prior, during and after laser coagulation and/or ablation. The prior OCT images were used to compute three-dimensional tumor margin and angiography images, which guided the coagulation and ablation steps. Histology of the treated regions was then compared to post-treatment OCT images. Tumor sizing based on OCT margin detection matched histology to within experimental error. Although fluorescence microscopy imaging showed the tumors were collocated with OCT imaging, margin assessment using confocal microscopy failed to see the extent of the tumor beyond ~ 250 µm in depth, as verified by OCT and histology. The two-laser approach to surgery utilizing Tm wavelength for coagulation and Er:YAG for ablation yielded bloodless resection of tumor regions with minimal residual damage as seen in histology. Precise and bloodless tumor resection under OCT image guidance is demonstrated in the murine xenograft brain cancer model. Tumor margins and vasculature are accurately made visible without need for exogenous contrast agents.
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http://dx.doi.org/10.7150/thno.31811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587169PMC
June 2020

Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study.

Neuro Oncol 2018 08;20(9):1231-1239

University of Texas, Austin, Texas.

Background: Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM.

Methods: Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival.

Results: Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement.

Conclusions: Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.
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http://dx.doi.org/10.1093/neuonc/noy015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071657PMC
August 2018

Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma.

Sci Rep 2016 04 29;6:24185. Epub 2016 Apr 29.

The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.

Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERβ, a second receptor for estrogen, targeting ERβ with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERβ agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERβ agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM.
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http://dx.doi.org/10.1038/srep24185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850367PMC
April 2016

VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme.

J Neurooncol 2015 Sep 25;124(3):365-72. Epub 2015 Jun 25.

Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.

Glioblastoma multiforme (GBM) is among the most highly vascularized of solid tumors, contributing to the infiltrative nature of the disease, and conferring poor outcome. Due to the critical dependency of GBM on growth of new endothelial vasculature, we evaluated the preclinical activity of a novel adenoviral gene therapy that targets the endothelium within newly formed blood vessels for apoptosis. VB-111, currently in phase II clinical trials, consists of a non-replicating Adenovirus 5 (El deleted) carrying a proapoptotic human Fas-chimera (transgene) under the control of a modified murine promoter (PPE-1-3×) which specifically targets endothelial cells within the tumor vasculature. Here we report that a single intravenous dose of 2.5 × 10(11) or 1 × 10(11) VPs was sufficient to extend survival in nude rats bearing U87MG-luc2 or nude mice bearing U251-luc, respectively. Bioluminescence imaging of nude rats showed that VB-111 effectively inhibited tumor growth within four weeks of treatment. This was confirmed in a select group of animals by MRI. In our mouse model we observed that 3 of 10 nude mice treated with VB-111 completely lost U251 luciferase signal and were considered long term survivors. To assess the antiangiogenic effects of VB-111, we evaluated the tumor-associated microvaculature by CD31, a common marker of neovascularization, and found a significant decrease in the microvessel density by IHC. We further assessed the neovasculature by confocal microscopy and found that VB-111 inhibits vascular density in two separate mouse models bearing U251-RFP xenografts. Collectively, this study supports the clinical development of VB-111 as a treatment for GBM.
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http://dx.doi.org/10.1007/s11060-015-1853-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584173PMC
September 2015

Combined single-channel and macroscopic recording techniques to analyze gating mechanisms of the large conductance Ca2+ and voltage activated (BK) potassium channel.

Methods Mol Biol 2013 ;998:133-47

Department of Radiology, University of Miami School of Medicine, Miami, FL, USA.

Ion channels are integral membrane proteins that regulate membrane potentials and signaling of cells in response to various stimuli. The patch-clamp technique enables the study of single channels or a population of channels. The macroscopic recording approaches are powerful in revealing population-averaged behaviors of channels both under basal conditions and in response to various stimuli, modulators and drugs. On their own, however, these approaches can be insufficient for determinations of channel gating mechanisms as they do not accurately report channel open probabilities below 10(-2) to 10(-3). This obstacle can be overcome with the use of single-channel recording techniques. Single-channel recording techniques can be applied to one or a few channels to estimate P o over a larger range than macroscopic recordings. The combination of heterologous overexpression of ion channels with macroscopic and single-channel recordings can be applied to hundreds of channels to estimate P o between 1 and 10(-8). Here, we describe practical approaches of single-channel recordings that our laboratory utilizes. We also provide examples where the combined macroscopic and single channel approach can be employed to study gating mechanisms of the BK type, large conductance, Ca(2+) and voltage activated potassium channel in a mammalian expression system. The techniques presented should be generally applicable to the studies of ion channels in heterologous expression systems.
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http://dx.doi.org/10.1007/978-1-62703-351-0_10DOI Listing
September 2013

An extracellular domain of the accessory β1 subunit is required for modulating BK channel voltage sensor and gate.

J Gen Physiol 2012 Jan 12;139(1):57-67. Epub 2011 Dec 12.

Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

A family of tissue-specific auxiliary β subunits modulates large conductance voltage- and calcium-activated potassium (BK) channel gating properties to suit their diverse functions. Paradoxically, β subunits both promote BK channel activation through a stabilization of voltage sensor activation and reduce BK channel openings through an increased energetic barrier of the closed-to-open transition. The molecular determinants underlying β subunit function, including the dual gating effects, remain unknown. In this study, we report the first identification of a β1 functional domain consisting of Y74, S104, Y105, and I106 residues located in the extracellular loop of β1. These amino acids reside within two regions of highest conservation among related β1, β2, and β4 subunits. Analysis in the context of the Horrigan-Aldrich gating model revealed that this domain functions to both promote voltage sensor activation and also reduce intrinsic gating. Free energy calculations suggest that the dual effects of the β1 Y74 and S104-I106 domains can be largely accounted for by a relative destabilization of channels in open states that have few voltage sensors activated. These results suggest a unique and novel mechanism for β subunit modulation of voltage-gated potassium channels wherein interactions between extracellular β subunit residues with the external portions of the gate and voltage sensor regulate channel opening.
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http://dx.doi.org/10.1085/jgp.201110698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250105PMC
January 2012
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