Search PubMed⌕ Search

Biomedical subjects

Michael D Taylor

Publications and source records attributed to Michael D Taylor.

At least 19 recordsLinked to original sources
PubMed2025

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiotherapy.

UNLABELLED: Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy extended overall survival and induced the clonal selection of radioresistant subpopulations of tumor cells that drove medulloblastoma recurrence. Comparison of recurrent tumors with treatment-naïve newly diagnosed tumors revealed a gene expression signature that was found to be a biomarker of radioresistance and poor prognosis. This prognostic gene signature was shown to be subgroup specific in a large patient cohort. Recurrent tumors had elevated expression of carbonic anhydrase 4, and genetic and pharmacologic modulation of carbonic anhydrase 4 could promote or reduce resistance to radiotherapy. These data suggest that the FDA-approved carbonic anhydrase inhibitor acetazolamide may be a useful radiosensitizer to improve the efficacy of the treatment of newly diagnosed G3 medulloblastoma that could reduce the risk of tumor recurrence and improve survival in pediatric patients. SIGNIFICANCE: G3 medulloblastoma features a prognostic subgroup-specific gene expression signature and can be targeted with a carbonic anhydrase inhibitor to enhance radiosensitivity, reducing the risk of recurrence and improving survival.

Medulloblastoma↗
PubMed2023

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Child↗
PubMed2007

Phylogenetic preservation of alpha3 Na+,K+-ATPase distribution in vertebrate peripheral nervous systems.

The alpha(3) isoform of Na(+),K(+)-ATPase is uniquely expressed in afferent and efferent neurons innervating muscle spindles in the peripheral nervous system (PNS) of adult rats, but the distribution pattern of this isoform in other species has not been investigated. We compared expression of alpha(3) Na(+),K(+)-ATPase in lumbar dorsal root ganglia (DRG), spinal roots, and skeletal muscle samples of amphibian (frog), reptilian (turtle), avian (pigeon and chicken), and mammalian (mouse and human) species. In all species studied, the alpha(3) Na(+),K(+)-ATPase isoform was nonuniformly expressed in peripheral ganglia and nerves. In spinal ganglia, only 5-20% of neurons expressed this isoform, and, in avian and mammalian species, these alpha(3) Na(+),K(+)-ATPase-expressing neurons belonged to a subpopulation of large DRG neurons. In ventral root fibers of pigeons, mice, and humans, the alpha(3) Na(+),K(+)-ATPase was abundantly expressed predominantly in small myelinated axons. In skeletal muscle samples from turtles, pigeons, mice, and humans, alpha(3) Na(+),K(+)-ATPase was detected in intramuscular myelinated axons and in profiles of nerve terminals associated with the equatorial and polar regions of muscle spindle intrafusal fibers. These results show that the expression profiles for alpha(3) Na(+),K(+)-ATPase in the peripheral nervous system of a wide variety of vertebrate species are similar to the profile of rats and suggest that stretch receptor-associated expression of alpha(3) Na(+),K(+)-ATPase is preserved through vertebrate evolution.

Animals↗
PubMed2007

A stretch reflex in extraocular muscles of species purportedly lacking muscle spindles.

It is generally assumed that proprioceptive feedback plays a crucial role in limb posture and movement. However, the role of afferent signals from extraocular muscles (EOM) in the control of eye movement has been a matter of continuous debate. These muscles have atypical sensory receptors in several species and it has been proposed that they are not supported by stretch reflexes. We recorded electromyographic activity of EOM during passive rotations of the eye in sedated rats and squirrel monkeys and observed typical stretch reflexes in these muscles. Results suggest that there is a similarity in the reflexive control of limb and eye movement, despite substantial differences in their biomechanics and sensory receptors. Like in some limb skeletal muscles, the stretch reflex in EOM in the investigated species might be mediated by other length-sensitive receptors, rather than muscle spindles.

Animals↗
PubMed2006

Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive degeneration of the right ventricular myocardium, ventricular arrhythmias, fibrous-fatty replacement, and increased risk of sudden death. Mutations in 6 genes, including 4 encoding desmosomal proteins (Junctional plakoglobin (JUP), Desmoplakin (DSP), Plakophilin 2, and Desmoglein 2), have been identified in patients with ARVD/C. Mutation analysis of 66 probands identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between those DSP missense mutations and ARVD/C, we performed in vitro and in vivo analyses of the mutated proteins. Unlike wild-type (WT) DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in desomosome-forming cell line and failed to bind to and coimmunoprecipitate JUP. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes have failed: analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. We were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or WT DSP. Whereas mice overexpressing WT DSP had no detectable histologic, morphological, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs (IDs) and marked ultra-structural changes of IDs. These data suggest DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and DSP abnormalities result in ARVD/C by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development.

Animals↗
PubMed2006

Effects of inhaled manganese on biomarkers of oxidative stress in the rat brain.

Manganese (Mn) is a ubiquitous and essential element that can be toxic at high doses. In individuals exposed to high levels of this metal, Mn can accumulate in various brain regions, leading to neurotoxicity. In particular, Mn accumulation in the mid-brain structures, such as the globus pallidus and striatum, can lead to a Parkinson's-like movement disorder known as manganism. While the mechanism of this toxicity is currently unknown, it has been postulated that Mn may be involved in the generation of reactive oxygen species (ROS) through interaction with intracellular molecules, such as superoxide and hydrogen peroxide, produced within mitochondria. Conversely, Mn is a required component of an important antioxidant enzyme, Mn superoxide dismutase (MnSOD), while glutamine synthetase (GS), a Mn-containing astrocyte-specific enzyme, is exquisitely sensitive to oxidative stress. To investigate the possible role of oxidative stress in Mn-induced neurotoxicity, a series of inhalation studies was performed in neonatal and adult male and female rats as well as senescent male rats exposed to various levels of airborne-Mn for periods of time ranging from 14 to 90 days. Oxidative stress was then indirectly assessed by measuring glutathione (GSH), metallothionein (MT), and GS levels in several brain regions. MT and GS mRNA levels and regional brain Mn concentrations were also determined. The collective results of these studies argue against extensive involvement of ROS in Mn neurotoxicity in rats of differing genders and ages. There are, however, instances of changes in individual endpoints consistent with oxidative stress in certain brain tissues.

Age Factors↗
PubMed2006

VEGF protein associates to neurons in remote regions following cortical infarct.

Vascular endothelial growth factor (VEGF) is thought to contribute to both neuroprotection and angiogenesis after stroke. While increased expression of VEGF has been demonstrated in animal models after experimental ischemia, these studies have focused almost exclusively on the infarct and peri-infarct regions. The present study investigated the association of VEGF to neurons in remote cortical areas at three days after an infarct in primary motor cortex (M1). Although these remote areas are outside of the direct influence of the ischemic injury, remote plasticity has been implicated in recovery of function. For this study, intracortical microstimulation techniques identified primary and premotor cortical areas in a non-human primate. A focal ischemic infarct was induced in the M1 hand representation, and neurons and VEGF protein were identified using immunohistochemical procedures. Stereological techniques quantitatively assessed neuronal-VEGF association in the infarct and peri-infarct regions, M1 hindlimb, M1 orofacial, and ventral premotor hand representations, as well as non-motor control regions. The results indicate that VEGF protein significantly increased association to neurons in specific remote cortical areas outside of the infarct and peri-infarct regions. The increased association of VEGF to neurons was restricted to cortical areas that are functionally and/or behaviorally related to the area of infarct. There was no significant increase in M1 orofacial region or in non-motor control regions. We hypothesize that enhancement of neuronal VEGF in these functionally related remote cortical areas may be involved in recovery of function after stroke, through either neuroprotection or the induction of remote angiogenesis.

Animals↗
PubMed2006

Depressive symptoms in coronary artery disease patients after hypertension treatment.

BACKGROUND: Depression is highly prevalent and frequently recurs in patients with coronary artery disease (CAD) and hypertension. Certain medications used to treat hypertension are alleged to be associated with higher risk of depression. OBJECTIVE: To compare depressive symptoms before and during treatment with 2 equivalent hypertension treatment strategies in patients with CAD stratified according to a self-reported history of physician-diagnosed depression. METHODS: Patients enrolled in a randomized hypertension treatment study were mailed baseline and one year follow-up surveys and stratified according to a self-reported history of depression. Patients (N = 1152) were 50 years old or older with hypertension and clinically stable CAD. Depressive symptoms were measured using the Center for Epidemiologic Studies-Depression (CES-D). High risk of depression was defined as a history of physician-diagnosed depression reported by patients on the baseline survey. Depressive symptoms were compared for verapamil sustained-release (SR)- and atenolol-based hypertension treatment. RESULTS: Among patients with a previous history of depression, depressive symptoms improved over the one year follow-up period for patients assigned to both treatment regimens. Depressive symptoms improved for patients with no depression history in the verapamil SR group (p < 0.001) and were unchanged in the atenolol group (p = 0.52). Patients assigned to the atenolol-based strategy without prior history of depression were more likely to worsen 5 or more points on the CES-D. CONCLUSIONS: When antihypertensive treatment options are clinically equivalent, prescribers may first consider using a verapamil SR-based strategy, especially in patients with CAD who have no history of depression.

Aged↗
PubMed2006

Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations.

PURPOSE: Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities. MATERIALS AND METHODS: Gene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing. RESULTS: Unsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgroups predicted the presence of key molecular alterations that we subsequently confirmed by gene sequence analysis and FISH. Subgroup-specific abnormalities included mutations in the Wingless (WNT) pathway and deletion of chromosome 6 (subgroup B) and mutations in the Sonic Hedgehog (SHH) pathway (subgroup D). Real-time RT-PCR analysis of gene expression profiles was then used to predict accurately the presence of mutations in the WNT and SHH pathways in a separate group of 31 medulloblastomas. CONCLUSION: Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.

Adolescent↗
PubMed2006

Genetics of choroid plexus tumors.

Choroid plexus tumors consist of papillomas and carcinomas. A variety of germline and somatic genetic changes have been demonstrated for each of these subtypes. In this paper, the authors summarize the current knowledge of the genetic bases of these tumors.

Cerebral Ventricle Neoplasms↗
PubMed2006

Welding fume exposure and associated inflammatory and hyperplastic changes in the lungs of tumor susceptible a/j mice.

It has been suggested that welding fume (WF) exposure increases lung cancer risk in welders. Epidemiology studies have failed to conclude that WF alone causes lung cancer and animal studies are lacking. We examined the course of inflammation, damage, and repair in the lungs of A/J mice, a lung tumor susceptible strain, caused by stainless steel WF. Mice were exposed by pharyngeal aspiration to 40 mg/kg of WF, silica, or saline. Bronchoalveolar lavage (BAL) was performed 24 hours, 1 and 16 weeks to assess lung injury and inflammation and histopathology was done 1, 8, 16, 24, and 48 weeks postexposure. Both exposures increased inflammatory cells, lactate dehydrogenase and albumin at 24 hr and 1 week. At 16 weeks, these parameters remained elevated in silica-exposed but not WF-exposed mice. Histopathologic evaluation at 1 week indicated that WF induced bronchiolar epithelial hyperplasia with associated cellular atypia, alveolar bronchiolo-alveolar hyperplasia (BAH) in peribronchiolar alveoli, and peribronchiolar lymphogranulomatous inflammation. Persistent changes included foci of histiocytic inflammation, fibrosis, atypical bronchiolar epithelial cells, and bronchiolar BAH. The principle changes in silica-exposed mice were histiocytic and suppurative inflammation, fibrosis, and alveolar BAH. Our findings that WF causes persistent bronchiolar and peribronchiolar epithelial changes, suggest a need for studies of bronchiolar changes after WF exposure.

Animals↗
PubMed2005

Retrospective family study of childhood medulloblastoma.

Medulloblastoma is the most common malignant central nervous system tumor of childhood and can occur sporadically or in association with inherited cancer susceptibility syndromes such as the nevoid basal cell carcinoma syndrome (NBCCS). To determine whether an association existed between the risk of developing medulloblastoma and undiagnosed syndromes, we retrospectively reviewed clinical data on 33 patients with medulloblastoma from a single institution and compared them with their unaffected relatives (n = 46). Six patients had tumors showing desmoplastic histology. Two of the six met diagnostic criteria for NBCCS. One NBCCS patient had a missense mutation of patched-1 (PTCH1); the other had no identifiable PTCH1 mutation. Two patients with isolated desmoplastic medulloblastoma had an insertion and splice site mutation, respectively, in suppressor of fused (SUFU). All patients with nondesmoplastic medulloblastoma histology received molecular testing for SUFU. None of these patients had an identifiable mutation in PTCH1 or SUFU. We performed a clinical evaluation for Greig cephalopolysyndactyly syndrome (GCPS) in four medulloblastoma families, who exhibited macrocephaly as the only finding consistent with the diagnosis of GCPS. Molecular analysis of GLI3 in these four families was negative. There was a paucity of clinical findings among the majority of medulloblastoma patients in this study group to suggest a definable cancer genetic syndrome. We conclude that clinically recognizable syndromes are uncommon among patients with medulloblastoma, however, PTCH1 and SUFU mutations are present at a low but significant frequency.

Adolescent↗
PubMed2005

Effect of stainless steel manual metal arc welding fume on free radical production, DNA damage, and apoptosis induction.

Questions exist concerning the potential carcinogenic effects after welding fume exposure. Welding processes that use stainless steel (SS) materials can produce fumes that may contain metals (e.g., Cr, Ni) known to be carcinogenic to humans. The objective was to determine the effect of in vitro and in vivo welding fume treatment on free radical generation, DNA damage, cytotoxicity and apoptosis induction, all factors possibly involved with the pathogenesis of lung cancer. SS welding fume was collected during manual metal arc welding (MMA). Elemental analysis indicated that the MMA-SS sample was highly soluble in water, and a majority (87%) of the soluble metal was Cr. Using electron spin resonance (ESR), the SS welding fume had the ability to produce the biologically reactive hydroxyl radical (*OH), likely as a result of the reduction of Cr(VI) to Cr(V). In vitro treatment with the MMA-SS sample caused a concentration-dependent increase in DNA damage and lung macrophage death. In addition, a time-dependent increase in the number of apoptotic cells in lung tissue was observed after in vivo treatment with the welding fume. In summary, a soluble MMA-SS welding fume was found to generate reactive oxygen species and cause DNA damage, lung macrophage cytotoxicity and in vivo lung cell apoptosis. These responses have been shown to be involved in various toxicological and carcinogenic processes. The effects observed appear to be related to the soluble component of the MMA-SS sample that is predominately Cr. A more comprehensive in vivo animal study is ongoing in the laboratory that is continuing these experiments to try to elucidate the potential mechanisms that may be involved with welding fume-induced lung disease.

Air Pollutants, Occupational↗
PubMed2005

Radial glia cells are candidate stem cells of ependymoma.

Tumors of the same histologic type often comprise clinically and molecularly distinct subgroups; however, the etiology of these subgroups is unknown. Here, we report that histologically identical, but genetically distinct, ependymomas exhibit patterns of gene expression that recapitulate those of radial glia cells in the corresponding region of the central nervous system. Cancer stem cells isolated from ependymomas displayed a radial glia phenotype and formed tumors when orthotopically transplanted in mice. These findings identify restricted populations of radial glia cells as candidate stem cells of the different subgroups of ependymoma, and they support a general hypothesis that subgroups of the same histologic tumor type are generated by different populations of progenitor cells in the tissues of origin.

Animals↗
PubMed2005

Modulation of muscle spindle innervation by neurotrophin-3 following nerve injury.

Muscle spindles monitor changes in muscle length and are innervated by groups Ia and II sensory axons as well as gamma motor axons. Ia sensory axons respond to neurotrophin-3 (NT-3), which plays an important role in sculpting proprioceptive development. Previously, transgenic mice were generated that overexpress NT-3 in muscle (mlc/NT-3 mice). These mice have alterations in proprioceptive elements due to the developmental actions of NT-3 and neuroprotective effects on Ia axons following nerve injury (Taylor, M.D., Vancura, R., Williams, J.M., Riekhof, J.T., Taylor, B.K., Wright, D.E., 2001. Overexpression of neurotrophin-3 in skeletal muscle alters normal and injury-induced limb control. Somatosens. Motor Res. 18 (4), 286-294.) Here, we investigated the actions of NT-3 on each class of injured axons innervating spindles and explored the mechanisms by which NT-3 acts. Immunohistochemical assessment of muscle spindle innervation following crush revealed that the degeneration of Ia axons innervating spindles in mlc/NT-3 mice was substantially reduced, and overall spindle innervation by group II and gamma fibers was greatly improved at later stages. Mlc/NT-3 mice also displayed a significant reduction in the expression of the injury-induced transcription factor ATF3 by retrogradely labeled muscle afferent neurons. The effects of transgenic NT-3 overexpression on spindle innervation could be mimicked if wild-type mice were treated intramuscularly with recombinant NT-3 prior to but not following injury, suggesting that NT-3's actions were due to preexposure to NT-3. This view was supported by in vitro experiments in which large DRG neurons from mlc/NT-3 mice grew significantly longer neurites than wild-type neurons. The results reveal that improved Ia-spindle interactions after injury may enhance spindle innervation by group II and gamma fibers. Finally, exposure of muscle afferent fibers to NT-3 prior to injury alters axonal responses both in vitro and in vivo.

Animals↗