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1.  Real time optical Biopsy: Time-resolved Fluorescence Spectroscopy instrumentation and validation 
Scientific Reports  2016;6:38190.
The Time-resolved fluorescence spectroscopy (TR-FS) has the potential to differentiate tumor and normal tissue in real time during surgical excision. In this manuscript, we describe the design of a novel TR-FS device, along with preliminary data on detection accuracy for fluorophores in a mixture. The instrument is capable of near real-time fluorescence lifetime acquisition in multiple spectral bands and analysis. It is also able to recover fluorescence lifetime with sub-20ps accuracy as validated with individual organic fluorescence dyes and dye mixtures yielding lifetime values for standard fluorescence dyes that closely match with published data. We also show that TR-FS is able to quantify the relative concentration of fluorescence dyes in a mixture by the unmixing of lifetime decays. We show that the TR-FS prototype is able to identify in near-real time the concentrations of dyes in a complex mixture based on previously trained data. As a result, we demonstrate that in complex mixtures of fluorophores, the relative concentration information is encoded in the fluorescence lifetime across multiple spectral bands. We show for the first time the temporal and spectral measurements of a mixture of fluorochromes and the ability to differentiate relative concentrations of each fluorochrome mixture in real time.
doi:10.1038/srep38190
PMCID: PMC5144092  PMID: 27929039
2.  Ocular indicators of Alzheimer’s: exploring disease in the retina 
Acta Neuropathologica  2016;132(6):767-787.
Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer’s disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, Aβ deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated Aβ42/40 peptides, morphologically diverse Aβ plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal Aβ deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.
doi:10.1007/s00401-016-1613-6
PMCID: PMC5106496  PMID: 27645291
Alzheimer’s disease; Amyloid-beta; Tauopathy; Retinal biomarkers; Ocular abnormalities; Neurodegenerative disease
3.  Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer’s disease 
Brain  2015;138(8):2399-2422.
Infiltrating monocyte-derived macrophages contribute to the clearance of amyloid-beta in the brain. Koronyo et al. show that monthly injection of a subset of bone marrow monocytes into the peripheral blood of symptomatic Alzheimer’s disease mouse models, and/or weekly immunization with glatiramer acetate, substantially reduces cognitive decline. The improved cognition is associated with synaptic preservation.
Infiltrating monocyte-derived macrophages contribute to the clearance of amyloid-beta in the brain. Koronyo et al. show that monthly injection of a subset of bone marrow monocytes into the peripheral blood of symptomatic Alzheimer’s disease mouse models, and/or weekly immunization with glatiramer acetate, substantially reduces cognitive decline. The improved cognition is associated with synaptic preservation.
Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer’s disease resulted in retained cognition (Morris water maze test), decreased amyloid-β plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115+ monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer’s disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6–8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001–0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-β protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-β; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-β plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-β, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-β1–42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-β phagocytosis, and the amyloid-β-degrading enzyme MMP9 (P < 0.0001–0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer’s models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-β as well as regulation of brain inflammation.
Infiltrating monocyte-derived macrophages contribute to the clearance of amyloid-beta in the brain. Koronyo et al. show that monthly injection of a subset of bone marrow monocytes into the peripheral blood of symptomatic Alzheimer’s disease mouse models, and/or weekly immunization with glatiramer acetate, substantially reduces cognitive decline. The improved cognition is associated with synaptic preservation.
doi:10.1093/brain/awv150
PMCID: PMC4840949  PMID: 26049087
Alzheimer’s disease; neuroprotection; neuroinflammation; dementia; behavioural neurology
4.  ACE Over Expression in Myelomonocytic Cells: Effect on a Mouse Model of Alzheimer's Disease 
While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice over express ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-β protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD.
doi:10.1007/s11906-014-0444-x
PMCID: PMC4051235  PMID: 24792094
ACE 10/10; Alzheimer's disease; macrophages; monocytes; neuroinflammation; blood pressure
5.  Curcumin Targeted, Polymalic Acid-Based MRI Contrast Agent for the Detection of Aβ Plaques in Alzheimer’s Diseasea 
Macromolecular bioscience  2015;15(9):1212-1217.
Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer’s disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium–DOTA(Gd–DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.
Graphical abstract
doi:10.1002/mabi.201500062
PMCID: PMC4794283  PMID: 26036700
Alzheimer disease; curcumin; MRI; nanoimaging agent; polymalic acid
6.  MRI Virtual Biopsy and Treatment of Brain Metastatic Tumors with Targeted Nanobioconjugates: Nanoclinic in the Brain 
ACS nano  2015;9(5):5594-5608.
Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections, or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise noninvasive MRI diagnostic method, we have engineered a new class of poly(β-L-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood–brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative “MRI virtual biopsy” method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in a significant increase in animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.
Graphical abstract
doi:10.1021/acsnano.5b01872
PMCID: PMC4768903  PMID: 25906400
nanoconjugate; brain metastasis; MRI; nanomedicine; blood; brain barrier; tumor treatment; tumor targeting
7.  Quality of surgical care and readmission in elderly glioblastoma patients 
Neuro-Oncology Practice  2014;1(2):33-39.
Background
Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studies have shown that complex interactions of multiple factors are responsible for these hospitalizations.
Methods
A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Medicare database of newly diagnosed elderly glioblastoma multiforme (GBM) patients who underwent surgical resection between 1991 and 2007. Hospitals were classified into high- or low-readmission rate cohorts using a risk-adjusted methodology. Bivariate comparisons of outcomes were conducted. Multivariate analysis evaluated differences in quality of care according to hospital readmission rates.
Results
A total of 1,273 patients underwent surgery in 338 hospitals; 523 patients were treated in 228 high-readmission hospitals and 750 in 110 low-readmission hospitals. Patient characteristics for high-versus low-readmission hospitals were compared. In a confounder-adjusted model, patients treated in high- versus low-readmission hospitals had similar outcomes. The hazard of mortality for patients treated at high- compared to low-readmission hospitals was 1.06 (95% CI, 0.095%–1.19%). While overall complications were comparable between high- and low-readmission hospitals (16.3% vs 14.3%; P = .33), more postoperative pulmonary embolism/deep vein thrombosis complications were documented in patients treated at high-readmission hospitals (7.5% vs 4.1%; P = .01). Adverse events and levels of resection achieved during surgery were comparable at high- and low-readmission hospitals.
Conclusions
For patients undergoing GBM resection, quality of care provided by hospitals with the highest adjusted readmission rates was similar to the care delivered by hospitals with the lowest rates. These findings provide evidence against the preconceived notion that 30-day readmissions can be used as a metric for quality of surgical and postsurgical care.
doi:10.1093/nop/npu008
PMCID: PMC4371163  PMID: 26034614
glioblastoma multiforme, high- and low-readmission hospitals; overall survival; quality of care; risk-adjusted readmission
8.  Quantitative Analysis of PMLA Nanoconjugate Components after Backbone Cleavage 
Multifunctional polymer nanoconjugates containing multiple components show great promise in cancer therapy, but in most cases complete analysis of each component is difficult. Polymalic acid (PMLA) based nanoconjugates have demonstrated successful brain and breast cancer treatment. They consist of multiple components including targeting antibodies, Morpholino antisense oligonucleotides (AONs), and endosome escape moieties. The component analysis of PMLA nanoconjugates is extremely difficult using conventional spectrometry and HPLC method. Taking advantage of the nature of polyester of PMLA, which can be cleaved by ammonium hydroxide, we describe a method to analyze the content of antibody and AON within nanoconjugates simultaneously using SEC-HPLC by selectively cleaving the PMLA backbone. The selected cleavage conditions only degrade PMLA without affecting the integrity and biological activity of the antibody. Although the amount of antibody could also be determined using the bicinchoninic acid (BCA) method, our selective cleavage method gives more reliable results and is more powerful. Our approach provides a new direction for the component analysis of polymer nanoconjugates and nanoparticles.
doi:10.3390/ijms16048607
PMCID: PMC4425099  PMID: 25894227
polymalic acid; selective cleavage; PMLA nanoconjugate; quantitative analysis
9.  Glioma Stem Cell Research for the development of Immunotherapy 
Glioma, especially high-grade glioblastoma multiforme (GBM), is the most common and aggressive type of brain tumor, accounting for about half of all the primary brain tumors. Despite continued advances in surgery, chemotherapy and radiotherapy, the clinical outcomes remain dismal. The two-year survival rate of GBM is <30%. Better understanding of GBM biology is desirable to develop novel therapies. Recent studies have demonstrated the existence of a small subpopulation of cells with stem like features cancer stem cells otherwise known as (CSC). These GBM CSCs are self-renewable and highly tumorigenic. They are not only chemo-radio- resistant, but also often multi-drug resistance genes and drug transporter genes. These characteristic enable GBM CSCs to survive standard cytotoxic therapies. Among GBM CSCs, CD133+ cells are a well-defined population and are prospectively isolated by their cell-surface marker. There are increasing data that CD133+ CSC presence highly correlates with patient survival. This makes it an ideal immunotherapy target population. In this article, we will review recent studies related with GBM CSCs, particularly CD133+ CSCs as well as the novel therapeutic strategies targeting these cells.
doi:10.1016/j.nec.2009.08.006
PMCID: PMC2786895  PMID: 19944974
cancer stem cell; glioma; CD133+; immunotherapy
10.  PDE5 Inhibitors Enhance Tumor Permeability and Efficacy of Chemotherapy in a Rat Brain Tumor Model 
Brain research  2008;1230:290-302.
The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (KCa) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB “opener”, bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhance anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors.
doi:10.1016/j.brainres.2008.06.122
PMCID: PMC2632551  PMID: 18674521
brain tumor; PDE5 inhibitor; drug transport; drug delivery; blood-brain barrier; blood-brain tumor barrier
11.  Different Effects of KCa and KATP Agonists on Brain Tumor Permeability between Syngeneic and Allogeneic Rat Models 
Brain research  2008;1227:198-206.
The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (KATP agonist), minoxidil sulfate (KATP agonist) or NS1619 (KCa agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both KATP and KCa channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of KATP in surgical specimens. KATP mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of KATP were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.
doi:10.1016/j.brainres.2008.06.046
PMCID: PMC2605468  PMID: 18602898
Blood-brain barrier; Potassium channel; chemotherapy; Brain tumor model
12.  The Somatic Genomic Landscape of Glioblastoma 
Cell  2013;155(2):462-477.
We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.
doi:10.1016/j.cell.2013.09.034
PMCID: PMC3910500  PMID: 24120142
13.  Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine? 
Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.
doi:10.3791/50668
PMCID: PMC4118553  PMID: 24962356
Chemistry; Issue 88; Cancer treatment; personalized medicine; polymalic acid; nanodrug; biopolymer; targeting; host compatibility; biodegradability
14.  The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery 
Biomaterials  2011;32(22):5269-5278.
Membranolytic macromolecules are promising vehicles forcytoplasmic drug delivery, but their efficiency and safety remains primary concerns. To address those concerns, membranolytic properties of various poly(β-l-malic acid) (PMLA) copolymers were extensively investigated as a function of concentration and pH. PMLA, a naturally occurring biodegradable polymer, acquires membranolytic activities after substitution of pendant carboxylates with hydrophobic amino acid derivatives. Ruled by hydrophobization and charge neutralization, membranolysis of PMLA copolymers increased as a function of polymer molecular weight and demonstrated a maximum with 50% substitution of carboxylates. Charge neutralization was achieved either conditionally by pH-dependent protonation or permanently by masking carboxylates. Membranolysis of PMLA copolymers containing tripeptide ofleucine, tryptophan and phenylalanine were pH-dependent in contrast to pH-independent copolymers of Leucineethylester and Leu-Leu-Leu-NH2 with permanent charge neutralization. PMLA and tripeptides seemed a unique combination for pH-dependent membranolysis. In contrast to nontoxic pH-dependent PMLA copolymers, pH-independent copolymers were found toxic at high concentration, which is ascribed to their nonspecific disruption of plasma membrane at physiological pH.pH-dependent copolymers were membranolytically active only at acidic pH typical of maturating endosomes, and are thus devoid of cytotoxicity. The PMLA tripeptide copolymers are useful for safe and efficient cytoplasmic delivery routed through endosome.
doi:10.1016/j.biomaterials.2011.03.073
PMCID: PMC4110056  PMID: 21514661
15.  Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine? 
Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.
doi:10.3791/50668
PMCID: PMC4118553  PMID: 24962356
Chemistry; Issue 88; Cancer treatment; personalized medicine; polymalic acid; nanodrug; biopolymer; targeting; host compatibility; biodegradability
16.  Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment 
Journal of drug targeting  2013;21(10):956-967.
Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconju-gate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.
doi:10.3109/1061186X.2013.837470
PMCID: PMC4043297  PMID: 24032759
Hematologic; immunogenicity; in vivo treatment; nanoconjugate drugs; polymalic acid; toxicity; triple-negative breast cancer
17.  Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline 
The Journal of Clinical Investigation  2014;124(3):1000-1012.
Cognitive decline in patients with Alzheimer’s disease (AD) is associated with elevated brain levels of amyloid β protein (Aβ), particularly neurotoxic Aβ1–42. Angiotensin-converting enzyme (ACE) can degrade Aβ1–42, and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE10/10 mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APPSWE/PS1ΔE9 mouse model of AD (AD+). Evaluation of brain tissue from these AD+ACE10/10 mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Aβ1–42 were reduced compared with those in AD+ mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aβ levels in AD+ACE10/10 mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD+ACE10/10 mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aβ plaques. At 11 and 12 months of age, the AD+ACE10/WT and AD+ACE10/10 mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.
doi:10.1172/JCI66541
PMCID: PMC3934162  PMID: 24487585
18.  Distinct mechanisms of membrane permeation induced by two polymalic acid copolymers 
Biomaterials  2012;34(1):217-225.
Anionic polymers are valuable components used in cosmetics and health sciences, especially in drug delivery, because of their chemical versatility and low toxicity. However, because of their highly negative charge they pose problems for penetration through hydrophobic barriers such as membranes. We have engineered anionic polymalic acid (PMLA) to penetrate biological membranes. PMLA copolymers of leucine ethyl ester (P/LOEt) or trileucine (P/LLL) show either pH-independent or pH-dependent activity for membrane penetration. We report here for the first time on the mechanisms which are different for those two copolymers. Formation of hydrophobic patches in either copolymer is detected by fluorescence techniques. The copolymers display distinctly different properties in solution and during membranolysis. P/LOEt copolymer binds to membrane as single molecules with high affinity, and induces leakage cooperatively through a mechanism known as “carpet” model, in which the polymer aligns at the surface throughout the entire process of membrane permeation. In contrast, P/LLL self-assembles to form an oligomer of 105 nm in a pH-dependent manner (pKa 5.5) and induces membrane leakage through a two-phase process: the concentration dependent first-phase of insertion of the oligomer into membrane followed by a concentration independent second-phase of rearrangement of the membrane-oligomer complex. The insertion of P/LLL is facilitated by hydrophobic interactions between trileucine side chains and lipids in the membrane core, resulting in transmembrane pores, through mechanism known as “barrel-stave” model. The understanding of the mechanism paves the way for future engineering of polymeric delivery systems with optimal cytoplasmic delivery efficiency and reduced systemic toxicity.
doi:10.1016/j.biomaterials.2012.08.016
PMCID: PMC3487713  PMID: 23063368
19.  High levels of phosphorylated MAP kinase are associated with poor survival among patients with glioblastoma during the temozolomide era 
Neuro-Oncology  2012;15(1):104-111.
We investigated whether high levels of activated mitogen-activated protein kinase (p-MAPK) were associated with poor survival among patients with newly diagnosed glioblastoma during the temozolomide era. Nuclear p-MAPK expression of 108 patients with GBM was quantified and categorized in the following levels: low (0%–10%), medium (11%–40%), and high (41%–100%). Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model. Our study included 108 patients with newly diagnosed GBM. Median age was 65 years, and 74% had high Karnofsky performance status (KPS ≥ 80). Median overall survival among all patients was 19.5 months. Activated MAPK expression levels of <10%, 11%–40%, and ≥41% were observed in 33 (30.6%), 37 (34.3%), and 38 (35.2%) patients, respectively. Median survival for low, medium, and high p-MAPK expression was 32.4, 18.2, and 12.5 months, respectively. Multivariate analysis showed 2.4-times hazard of death among patients with intermediate p-MAPK than low p-MAPK expression (hazard ratio [HR], 2.4; P = .02); high-expression patients were 3.9 times more likely to die, compared with patients with low p-MAPK (HR, 3.9; P = .007). Patients aged ≥65 years (HR, 2.8; P = .002) with KPS < 80 (HR, 3.1; P = .0003) and biopsy or partial resection (HR, 1.9; P = .02) had higher hazard of death. MGMT and PTEN expression were not associated with survival differences. This study provides quantitative means of evaluating p-MAPK in patients with GBM. It confirms the significant and independent prognostic relevance of p-MAPK in predicting survival of patients with GBM treated in the temozolomide era and highlights the need for therapies targeting the p-MAPK oncogenic pathway.
doi:10.1093/neuonc/nos272
PMCID: PMC3534422  PMID: 23115159
EGFR; glioblastoma multiforme (GBM); IDH1; MGMT; overall survival; PTEN; p-MAPK
20.  Exploitation of adaptive evolution in glioma treatment 
CNS oncology  2013;2(2):171-179.
SUMMARY
Glioblastoma multiforme (GBM) is a malignant neoplasm of the CNS with almost uniform lethality. Even with standard-of-care treatments, the prognosis for patients remains dismal. GBM, as with other malignancies, often acquires treatment resistance after an initial response to therapy. Treatment resistance may come about through the adaptive evolution of tumors in response to selection pressures from treatment interventions and the microenvironment. This review discusses how adaptive evolution might potentially be exploited as a new paradigm in GBM treatment.
doi:10.2217/cns.12.46
PMCID: PMC3746825  PMID: 23977426
21.  Seizures and Hemiparesis in a Young Woman 24 Years After Treatment of Astrocytoma 
Western Journal of Medicine  1989;150(2):180-186.
An edited transcript of Neurology Grand Rounds held at the University of California, Los Angeles, Medical Center on January 27, 1988. John Mazziotta, MD, PhD, Professor of Neurology and Radiology, is the coordinator of these conferences. This conference was edited by Harry V. Vinters, MD.
Images
PMCID: PMC1026331  PMID: 2728438
22.  Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: What should be the policy? 
NeuroImage  2010;54(Suppl 1):S106-S124.
Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1–100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law–healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines.
doi:10.1016/j.neuroimage.2010.01.105
PMCID: PMC3524337  PMID: 20149882
Nanoplatforms; Nanotechnology; Image-guided therapy; Nanomedicine; Nanoneurosurgery; Nanostructures; Contrast agents; Nanoparticles; Nanotechnology policy; Nano-radiology; Nano-neuroscience; Nano-neurology
23.  CHANGES IN LAMININ ISOFORMS ASSOCIATED WITH BRAIN TUMOR INVASION AND ANGIOGENESIS 
Laminins are the major constituents of blood vessel basement membranes (BMs). Each laminin is a trimer consisting of three assembled polypeptide chains, α, β and γ. More than 15 laminin isoforms are known to date and the expression of specific isoforms may change in certain pathological conditions. Here we show that during progression of glial tumors laminin-9 (α4β2γ1) is switched to laminin-8 (α4β1γ1), which is dramatically increased in glial brain tumors. Laminin-8 overproduction by glial tumor cells facilitates spread of glioma. Brain tumors with laminin-8 overexpression recur faster after standard treatment and patients have shorter survival time. Laminin-8 may be thus used as a predictor of tumor recurrence, patient survival and as a potential molecular target for glioma therapy.
PMCID: PMC3506377  PMID: 16146715
Laminin-8; Laminin-9; Basement Membrane; Extracellular Matrix; Angiogenesis; Human; Cancer; Tumor; Neoplasm; Glioma; Glioblastoma Multiforme; Recurrence; Survival; Invasion; Morpholino antisense; Review
24.  Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis 
Angiogenesis  2006;9(4):183-191.
We have previously shown that laminin-8, a vascular basement membrane component, was over-expressed in human glioblastomas multiforme and their adjacent tissues compared to normal brain. Increased laminin-8 correlated with shorter glioblastoma recurrence time and poor patient survival making it a potential marker for glioblastoma diagnostics and prediction of disease outcome. However, laminin-8 therapeutic potential was unknown because the technology of blocking the expression of multi-chain complex proteins was not yet developed. To inhibit the expression of laminin-8 constituents in glioblastoma in vitro and in vivo, we used Polycefin, a bioconjugate drug delivery system based on slime-mold Physarum polycephalum-derived poly(malic acid). It carries an attached transferrin receptor antibody to target tumor cells and to deliver two conjugated morpholino antisense oligonucleotides against laminin-8 α4 and β1 chains. Polycefin efficiently inhibited the expression of both laminin-8 chains by cultured glioblastoma cells. Intracranial Polycefin treatment of human U87MG glioblastoma-bearing nude rats reduced incorporation of both tumor-derived laminin-8 chains into vascular basement membranes. Polycefin was thus able to simultaneously inhibit the expression of two different chains of a complex protein. The treatment also significantly reduced tumor microvessel density (p < 0.001) and area (p < 0.001) and increased animal survival (p < 0.0004). These data suggest that laminin-8 may be important for glioblastoma angiogenesis. Polycefin, a versatile nanoscale drug delivery system, was suitable for in vivo delivery of two antisense oligonucleotides to brain tumor cells causing a reduction of glioblastoma angiogenesis and an increase of animal survival. This system may hold promise for future clinical applications.
doi:10.1007/s10456-006-9046-9
PMCID: PMC3487708  PMID: 17109197
Tumor angiogenesis; Glioma; Laminin-8; Multiple drug targeting; Poly(malic acid)
25.  Polycefin, a New Prototype of a Multifunctional Nanoconjugate Based on Poly(β-l-malic acid) for Drug Delivery 
Bioconjugate chemistry  2006;17(2):317-326.
A new prototype of nanoconjugate, Polycefin, was synthesized for targeted delivery of antisense oligonucleotides and monoclonal antibodies to brain tumors. The macromolecular carrier contains: 1. biodegradable, nonimmunogenic, nontoxic β-poly(l-malic acid) of microbial origin; 2. Morpholino antisense oligonucleotides targeting laminin α4 and β1 chains of laminin-8, which is specifically overexpressed in glial brain tumors; 3. monoclonal anti-transferrin receptor antibody for specific tissue targeting; 4. oligonucleotide releasing disulfide units; 5. l-valine containing, pH-sensitive membrane disrupting unit(s), 6. protective poly(ethylene glycol); 7. a fluorescent dye (optional). Highly purified modules were conjugated directly with N-hydroxysuccinimidyl ester-activated β-poly-(l-malic acid) at pendant carboxyl groups or at thiol containing spacers via thioether and disulfide bonds. Products were chemically validated by physical, chemical, and functional tests. In vitro experiments using two human glioma cell lines U87MG and T98G demonstrated that Polycefin was delivered into the tumor cells by a receptor-mediated endocytosis mechanism and was able to inhibit the synthesis of laminin-8 α4 and β1 chains at the same time. Inhibition of laminin-8 expression was in agreement with the designed endosomal membrane disruption and drug releasing activity. In vivo imaging showed the accumulation of intravenously injected Polycefin in brain tumor tissue via the antibody-targeted transferrin receptor-mediated endosomal pathway in addition to a less efficient mechanism known for high molecular mass biopolymers as enhanced permeability and retention effect. Polycefin was nontoxic to normal and tumor astrocytes in a wide range of concentrations, accumulated in brain tumor, and could be used for specific targeting of several biomarkers simultaneously.
doi:10.1021/bc0502457
PMCID: PMC3487710  PMID: 16536461

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