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1.
Indian J Otolaryngol Head Neck Surg ; 76(1): 953-965, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38440488

ABSTRACT

Introduction- Endoscopic minimally invasive pituitary surgery (MIPS) is advantageous over microscopic technique, as it provides superior close up, wide angle view of surgical target area. Image guided navigation system (IGNS) guides the surgeon to localize the lesion. In the present study we analyzed the Image Guided Surgical procedure and outcome of Endoscopic minimally invasive pituitary surgery and shared our experiences regarding disease clearance. MATERIALS AND METHODS: During the period of April 2015 to August 2022 a total 104 patients, diagnosed with pituitary adenoma underwent surgery and further followed up in a multidisciplinary team approach in a tertiary care hospital of Kolkata, India. The data obtained were reviewed statistically to satisfy the study objectives. RESULTS: Total 104 operations were done on 98 patients and total cases taken for calculation and analysis was 98, which consist of 11 microadenomas, 81 macroadenomas. Among 35 patients with normal preoperative hormonal assay, one patient developed postoperative hypopituitarism. Among 6 patients with preoperative hypopituitarism 4 patients (66.6%) recovered after surgery. Overall, 85 cases had total disease clearance as detected on post-operative MRI. In functioning pituitary adenoma (FPA) clinical and endocrinological improvement occurred after primary surgery in 85.36% (n = 35) and after revision surgery it was 84.44% (n = 38). Macroadenomas, giant adenomas were found to have statistically significant higher risk of incomplete disease clearance but large adenomas do not have statistically higher risk of incomplete clearance. CONCLUSION: IGNS requires extra time for setup, but with proper registration of tracker instruments it adds precision to the surgery. IGNS supplements endoscopic visualization with localization of target lesion by real time stereotactic feedback using preset preoperative imaging data, thus increasing accuracy, safety and effectiveness of minimally invasive surgery.

2.
J Infect Dis ; 224(12 Suppl 2): S890-S900, 2021 12 20.
Article in English | MEDLINE | ID: mdl-34718638

ABSTRACT

BACKGROUND: In the densely populated slums of Kolkata, informal healthcare providers' (IHP) diarrhea-related knowledge and rationality of practices should be improved to reduce risk of adverse outcome, expenditure, and antimicrobial resistance. METHODS: A multicomponent intervention was conducted among 140 representative IHPs in the slums of 8 wards in Kolkata to assess its impact on their diarrhea-related knowledge and practice. Six intervention modules in local languages were provided (1 per month) with baseline (N = 140) and postintervention (N = 124) evaluation. RESULTS: Mean overall (61.1 to 69.3; P < .0001) and domain-specific knowledge scores for etiology/spread (5.4 to 8.1; P < .0001), management (6.4 to 7.2; P < .0001), and oral rehydration solution ([ORS] 5.7 to 6.5; P < .0001) increased significantly (at α = 0.05) after intervention and were well retained. Impact on knowledge regarding etiology/spread (adjusted odds ratio [aOR] = 5.6; P < .0001), cholera (aOR = 2.0; P = .0041), management (aOR = 3.1; P < .0001), ORS (aOR = 2.3; P = .0008), and overall (aOR = 4.3; P < .0001) were significant. Intervention worked better for IHPs who practiced for ≥10 years (aOR = 3.2; P < .0001), untrained IHPs (aOR = 4.8; P < .0001), and pharmacists (aOR = 8.3; P < .0001). Irrational practices like empirical antibiotic use for every cholera case (aOR = 0.3; P < .0001) and investigation for every diarrhea case (aOR = 0.4; P = .0003) were reduced. Rationality of testing (aOR = 4.2; P < .0001) and antibiotic use (aOR = 1.8; P = .0487) improved. CONCLUSIONS: Multicomponent educational intervention resulted in sustainable improvement in diarrhea-related knowledge and practices among IHPs in slums of Kolkata. Policy implications should be advocated along with implementation and scale-up.


Subject(s)
Cholera , Diarrhea , Health Knowledge, Attitudes, Practice , Poverty Areas , Cholera/diagnosis , Cholera/drug therapy , Cholera/prevention & control , Cost of Illness , Diarrhea/diagnosis , Diarrhea/drug therapy , Diarrhea/prevention & control , Humans , Hygiene , Sanitation , Water Supply
3.
Acta Orthop Belg ; 84(2): 223-228, 2018 Jun.
Article in English | MEDLINE | ID: mdl-30462606

ABSTRACT

Scarf osteotomy is an effective surgical treatment option for hallux valgus. It can manipulate alignment in three planes, allowing accurate anatomical correction. The potential benefit of intra-operative image intensification (II) to gauge deformity correction during surgery however, has not been quantitatively reported. This study aims to compare the correction of hallux valgus by scarf osteotomy with and without intra-operative imaging. Retrospective analysis of a consecutive series of scarf osteotomy in 2 groups. Group A had intra-operative radiographic assessment and group B did not. Patient and surgical data was collected with a mean follow-up of 14 months. Of 99 scarf osteotomies there was no significant difference in age, gender or pre-operative deformity between the groups (p<0.05). No statistical difference was found between the radiographic corrections of the two groups (p<0.05), although operating time was less in group B. This series shows that intra-operative imaging does not improve accuracy of deformity correction, or implant position in scarf osteotomy. We suggest it is not required routinely during scarf osteotomy.


Subject(s)
Hallux Valgus/surgery , Monitoring, Intraoperative/methods , Osteotomy/methods , Adult , Aged , Aged, 80 and over , Female , Hallux Valgus/diagnostic imaging , Health Care Costs , Humans , Male , Middle Aged , Monitoring, Intraoperative/economics , Osteotomy/economics , Radiography , Retrospective Studies , Treatment Outcome
4.
Oncotarget ; 9(78): 34855, 2018 10 05.
Article in English | MEDLINE | ID: mdl-30410682

ABSTRACT

[This corrects the article DOI: 10.18632/oncotarget.190.].

5.
J Neurosurg ; 128(4): 1226-1234, 2018 04.
Article in English | MEDLINE | ID: mdl-28686119

ABSTRACT

OBJECTIVE A surgical series of 201 benign and malignant peripheral nerve sheath tumors (PNSTs) was assessed to characterize the anatomical and clinical presentation of tumors and identify predictors of neurological outcome, recurrence, and extent of resection. METHODS All surgically treated PNSTs from the Division of Neurosurgery at Toronto Western Hospital from 1993 to 2010 were reviewed retrospectively. Data were collected on patient demographics, clinical presentation, surgical technique, extent of resection, postoperative neurological outcomes, and recurrence. RESULTS One hundred seventy-five patients with 201 tumors had adequate follow-up for analysis. There were 182 benign and 19 malignant PNSTs. Of the benign lesions, 133 were schwannomas, 21 of which were associated with a diagnosis of schwannomatosis. There were 49 neurofibromas, and 26 were associated with neurofibromatosis Type 1 (NF1). Patients presenting with schwannomas were significantly older than those with neurofibromas. Schwannomas were more readily resected than neurofibromas, with the extent of resection of the former influenced by tumor location. Patients with benign PNSTs typically presented with a painful mass and less frequently with motor deficits. The likelihood of worsened postoperative motor function was decreased in patients with fully resected tumors or preoperative deficits. Recurrence of schwannomas and neurofibromas were seen more frequently in patients diagnosed with NF3 and NF1, respectively. Subtotal resection was associated with the increased recurrence of all benign lesions. CONCLUSIONS Outcomes following resection of benign PNSTs depend on tumor histopathology, tumor location, and genetic predisposition syndrome. Gross-total resection should be attempted for benign lesions where possible. The management of malignant PNSTs remains challenging, requiring a multimodal approach.


Subject(s)
Nerve Sheath Neoplasms/surgery , Adult , Algorithms , Clinical Decision-Making , Disease Management , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Nerve Sheath Neoplasms/epidemiology , Nerve Sheath Neoplasms/genetics , Nerve Sheath Neoplasms/pathology , Retrospective Studies , Treatment Outcome
6.
Phys Fluids (1994) ; 29(6): 063602, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28713213

ABSTRACT

A major aim of the present work is to understand and thoroughly document the generation, the three-dimensional distribution, and the evolution of the secondary motion as the fluid progresses downstream through a branched network. Six generations (G0-G5) of branches (involving 63 straight portions and 31 bifurcation modules) are computed in one go; such computational challenges are rarely taken in the literature. More than 30 × 106 computational elements are employed for high precision of computed results and fine quality of the flow visualization diagrams. The study of co-planar vis-à-vis non-planar space-filling configurations establishes a quantitative evaluation of the dependence of the fluid dynamics on the three-dimensional arrangement of the same individual branches. As compared to the secondary motion in a simple curved pipe, three distinctive features, viz., the change of shape and size of the flow-cross-section, the division of non-uniform primary flow in a bifurcation module, and repeated switchover from clockwise to anticlockwise curvature and vice versa in the flow path, make the present situation more complex. It is shown that the straight portions in the network, in general, attenuate the secondary motion, while the three-dimensionally complex bifurcation modules generate secondary motion and may alter the number, arrangement, and structure of vortices. A comprehensive picture of the evolution of quantitative flow visualizations of the secondary motion is achieved by constructing contours of secondary velocity [Formula: see text], streamwise vorticity [Formula: see text], and [Formula: see text] iso-surfaces. It is demonstrated, for example, that for in-plane configuration, the vortices on any plane appear in pair (i.e., for each clockwise rotating vortex, there is an otherwise identical anticlockwise vortex), whereas the vortices on a plane for the out-of-plane configuration may be dissimilar, and there may even be an odd number of vortices. We have formulated three new parameters (ES/P , [Formula: see text], and [Formula: see text]) for a quantitative description of the overall features of the secondary flow field. [Formula: see text] represents a non-uniformity index of the secondary flow in an individual branch, ES/P represents the mass-flow-averaged relative kinetic energy of the secondary motion in an individual branch, and [Formula: see text] provides a measure of the non-uniformity of the secondary flow between various branches of the same generation Gn. The repeated enhancement of the secondary kinetic energy in the bifurcation modules is responsible for the occurrence of significant values of ES/P even in generation G5. For both configurations, it is found that for any bifurcation module, the value of ES/P is greater in that daughter branch in which the mass-flow rate is greater. Even though the various contour plots of the complex secondary flow structure appear visually very different from one another, the values of [Formula: see text] are found to lie within a small range ([Formula: see text]) for the six-generation networks studied. It is shown that [Formula: see text] grows as the generation number Gn increases. It is established that the out-of-plane configuration, in general, creates more secondary kinetic energy (higher ES/P ), a similar level of non-uniformity in the secondary flow in an individual branch (similar [Formula: see text]), and a significantly lower level of non-uniformity in the distribution of secondary motion among various branches of the same generation (much lower [Formula: see text]), as compared to the in-plane arrangement of the same branches.

7.
J Orthop Case Rep ; 6(4): 100-102, 2016.
Article in English | MEDLINE | ID: mdl-28164065

ABSTRACT

INTRODUCTION: Tetanus is a severe and potentially fatal infection caused by the bacterium Clostridium tetani. Of all the cases described in literature, generalized tetanus is by far the most common presentation, but it may also present as neonatal tetanus, cephalic tetanus, and localized tetanus, the latter two being much rarer. In this case report, we present the rare form of this disease, i.e., localized tetanus in an adult male with a history of minimal trauma as well as a late, unusual mode of presentation. CASE REPORT: A 35-year-old Caucasian male presented with an acutely painful, swollen right thumb associated with a small superficial collection on the dorsal aspect of the base of the thumb. A formal wound exploration and washout were carried out in theater, however, at the time of tourniquet inflation, the right hand went into a carpopedal spasm and remained in that position until an infusion of a muscle relaxant was given. The findings were consistent with a case of localized tetanus. The patient was treated with human immunoglobulin and tetanus toxoid and safely discharged home 48 h later without any complications. CONCLUSION: This case report emphasizes the importance of the recognition of a rare form of this fatal infectious disease, which may present with prodromal symptoms before the generalized form shows its clinical effects. Moreover, the astute clinician should be aware of the variable presentations of this infectious disease, with early identification greatly reducing the associated risks of morbidity and mortality.

8.
J Biol Chem ; 290(40): 24534-46, 2015 Oct 02.
Article in English | MEDLINE | ID: mdl-26272609

ABSTRACT

Cancer cells emit extracellular vesicles (EVs) containing unique molecular signatures. Here, we report that the oncogenic EGF receptor (EGFR) and its inhibitors reprogram phosphoproteomes and cargo of tumor cell-derived EVs. Thus, phosphorylated EGFR (P-EGFR) and several other receptor tyrosine kinases can be detected in EVs purified from plasma of tumor-bearing mice and from conditioned media of cultured cancer cells. Treatment of EGFR-driven tumor cells with second generation EGFR kinase inhibitors (EKIs), including CI-1033 and PF-00299804 but not with anti-EGFR antibody (Cetuximab) or etoposide, triggers a burst in emission of exosome-like EVs containing EGFR, P-EGFR, and genomic DNA (exo-gDNA). The EV release can be attenuated by treatment with inhibitors of exosome biogenesis (GW4869) and caspase pathways (ZVAD). The content of P-EGFR isoforms (Tyr-845, Tyr-1068, and Tyr-1173), ERK, and AKT varies between cells and their corresponding EVs and as a function of EKI treatment. Immunocapture experiments reveal the presence of EGFR and exo-gDNA within the same EV population following EKI treatment. These findings suggest that targeted agents may induce cancer cells to change the EV emission profiles reflective of drug-related therapeutic stress. We suggest that EV-based assays may serve as companion diagnostics for targeted anticancer agents.


Subject(s)
DNA/chemistry , ErbB Receptors/metabolism , Exosomes/metabolism , Extracellular Vesicles/metabolism , Phosphoproteins/metabolism , Animals , Antineoplastic Agents/chemistry , Biomarkers/metabolism , Brain Neoplasms/metabolism , Cell Line, Tumor , Cetuximab/chemistry , Culture Media, Conditioned/chemistry , Etoposide/chemistry , Glioma/metabolism , Humans , Mice , Mice, SCID , Morpholines/chemistry , Neoplasm Transplantation , Neoplasms/metabolism , Phosphorylation , Proteomics , Quinazolinones/chemistry , Transfection
9.
Clin Cancer Res ; 21(16): 3750-8, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-25957288

ABSTRACT

PURPOSE: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. EXPERIMENTAL DESIGN: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. RESULTS: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. CONCLUSIONS: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.


Subject(s)
DNA Copy Number Variations/genetics , Ependymoma/genetics , Spinal Neoplasms/genetics , Transcriptome/genetics , Adult , Aged , Ependymoma/pathology , Female , Gene Expression Regulation, Neoplastic , Hexokinase/biosynthesis , Hexokinase/genetics , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Male , Middle Aged , Neoplasm Metastasis , Protein Serine-Threonine Kinases/biosynthesis , Protein Serine-Threonine Kinases/genetics , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Spinal Cord/pathology , Spinal Neoplasms/pathology
10.
Neuro Oncol ; 16(7): 914-23, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24470545

ABSTRACT

BACKGROUND: Grades II and III gliomas have unpredictable rates of progression, making management decisions difficult. Currently, several clinical and radiological characteristics are utilized to predict progression and survival but collectively are suboptimal. METHODS: In this study, we analyzed a set of 108 nonenhancing hemispheric grade II-III gliomas. Demographic variables, including patient age, tumor diameter, extent of resection, and performance status, were combined with molecular data (IDH mutation status [mIDH], 1p/19q codeletion, PTEN deletion, and EGFR amplification). A complete dataset for all variables was compiled for 70 of the 108 patients. Both univariable and multivariable analyses were performed to determine whether the molecular data singly or in combination offer advantages over tumor type and grade for prediction of overall survival (OS) and/or progression-free rate (PFR). RESULTS: Patient age, clinical variables (tumor diameter, extent of resection, performance status), and pathology (tumor type and grade) were not predictive of OS or PFR. IDH mutation status alone was predictive of longer OS and PFR for the entire group of tumors; 1p/19q deletion alone was predictive of OS but not PFR. In the multivariable analysis, none of the clinical or demographic factors were predictive of OS or PFR. IDH mutation status, 1p/19q codeletion, and PTEN deletion were predictive of OS (P = .003, P = .005, P = .02, respectively). Both mIDH (P < .001) and the interaction term of 1p/19q and PTEN (P < .001) were found to be predictive of PFR. CONCLUSIONS: We conclude that the combination of mIDH, 1p/19q codeletion, and PTEN deletion may be particularly effective in discriminating good prognosis from poor prognosis hemispheric gliomas. We propose that such a scheme merits testing on larger prospective cohorts. Should our findings be confirmed, routine clinical analysis of hemispheric gliomas for mIDH, 1p/19q codeletion, and PTEN deletion would be justified.


Subject(s)
Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioma/genetics , Glioma/pathology , Adult , Brain Neoplasms/mortality , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 19/genetics , DNA Mutational Analysis , Disease Progression , Disease-Free Survival , Female , Genotype , Glioma/mortality , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Isocitrate Dehydrogenase/genetics , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Neoplasm Grading , PTEN Phosphohydrolase/genetics , Polymerase Chain Reaction , Prognosis , Proportional Hazards Models , Sequence Deletion , Tissue Array Analysis
11.
Foot Ankle Clin ; 18(4): 619-28, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24215828

ABSTRACT

The key to successful management of the cavovarus foot is identifying the pathoanatomy and dysfunction that are driving the deformity and producing the symptoms. There is no substitute for a thorough clinical evaluation of the foot, evaluating the static alignment and dynamic function. Plain films alone are not sufficient to determine the diagnosis, but they are necessary for procedure selection and correction planning. This is especially true for assessing the degree of hindfoot varus. Some issues are difficult to diagnose, and imaging plays an important role.


Subject(s)
Foot Deformities/diagnostic imaging , Foot/diagnostic imaging , Foot/surgery , Foot Deformities/surgery , Foot Deformities, Acquired/diagnostic imaging , Foot Deformities, Acquired/surgery , Humans , Radiography
12.
Cell ; 155(2): 462-77, 2013 Oct 10.
Article in English | MEDLINE | ID: mdl-24120142

ABSTRACT

We describe the landscape of somatic genomic alterations based on multidimensional 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.


Subject(s)
Brain Neoplasms/genetics , Glioblastoma/genetics , Brain Neoplasms/metabolism , Female , Gene Expression Profiling , Gene Regulatory Networks , Glioblastoma/metabolism , Humans , Male , Mutation , Proteome/analysis , Signal Transduction
13.
Glia ; 61(11): 1862-72, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24038521

ABSTRACT

Gliomas are recognized as a heterogeneous group of neoplasms differing in their location and morphological features. These differences, between and within varying grades of gliomas, have not been explained solely on the grounds of an oncogenic stimulus. Interactions with the tumor microenvironment as well as inherent characteristics of the cell of origin are likely a source of this heterogeneity. There is an ongoing debate over the cell of origin of gliomas, where some suggest a progenitor, while others argue for a stem cell origin. Thus, it is presumed that neurogenic regions of the brain such as the subventricular zone (SVZ) containing large numbers of neural stem and progenitor populations are more susceptible to transformation. Our studies demonstrate that K-ras(G12D) cooperates with the loss of p53 to induce gliomas from both the SVZ and cortical region, suggesting that cells in the SVZ are not uniquely gliomagenic. Using combinations of doxycycline-inducible K-ras(G12D) and p53 loss, we show that tumors induced by the cooperative actions of these genes remain dependent on active K-ras expression, as deinduction of K-ras(G12D) leads to complete tumor regression despite absence of p53. These results suggest that the interplay between specific combinations of genetic alterations and susceptible cell types, rather than the site of origin, are important determinates of gliomagenesis. Additionally, this model supports the view that, although several genetic events may be necessary to confer traits associated with oncogenic transformation, inactivation of a single oncogenic partner can undermine tumor maintenance, leading to regression and disease remission.


Subject(s)
Brain Neoplasms/pathology , Cell Transformation, Neoplastic/pathology , Genes, ras/physiology , Glioma/metabolism , Stem Cells/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Brain/metabolism , Brain/pathology , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cell Transformation, Neoplastic/genetics , Disease Models, Animal , Enzyme Activation , Glioma/genetics , Glioma/pathology , Mice , Mice, Transgenic , Mutation/genetics , Stem Cells/pathology , Tumor Suppressor Protein p53/deficiency
14.
Proc Natl Acad Sci U S A ; 110(35): 14378-83, 2013 Aug 27.
Article in English | MEDLINE | ID: mdl-23942126

ABSTRACT

Gliomas represent the most common type of brain tumor, but show considerable variability in histologic appearance and clinical outcome. The phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of differing oncogenic stimuli. Several studies have demonstrated that some phenotypic differences may be attributed to regional differences in the neural stem cells from which tumors arise. We hypothesized that temporal differences may also play a role, with tumor phenotypic variability reflecting intrinsic differences in neural stem cells at distinct developmental stages. To determine how the tumorigenic potential of lineally related stem cells changes over time, we used a conditional transgenic system that integrates Cre-Lox-mediated and Tet-regulated expression to drive K-ras(G12D) expression in neuro-glial progenitor populations at different developmental time points. Using this model, we demonstrate that K-ras(G12D)-induced transformation is dependent on the developmental stage at which it is introduced. Diffuse malignant brain tumors develop during early embryogenesis but not when K-ras(G12D) expression is induced during late embryogenesis or early postnatal life. We show that differential expression of cell-cycle regulators during development may be responsible for this differing susceptibility to malignant transformation and that loss of p53 can overcome the transformation resistance seen at later developmental stages. These results highlight the interplay between genetic alterations and the molecular changes that accompany specific developmental stages; early progenitors may lack the regulatory mechanisms present at later, more lineage-restrictive, developmental time points, making them more susceptible to transformation.


Subject(s)
Cell Differentiation , Cell Transformation, Neoplastic , Neural Stem Cells/cytology , Neuroglia/cytology , Animals , Base Sequence , Brain/metabolism , Brain/pathology , DNA Primers , Embryonic Stem Cells/cytology , Genes, ras , Mice , Mice, Transgenic , Oncogenes , Polymerase Chain Reaction
15.
Mol Cancer ; 12: 74, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23855374

ABSTRACT

BACKGROUND: A major barrier to effective treatment of glioblastoma multiforme (GBM) is the invasion of glioma cells into the brain parenchyma rendering local therapies such as surgery and radiation therapy ineffective. GBM patients with such highly invasive and infiltrative tumors have poor prognosis with a median survival time of only about a year. However, the mechanisms leading to increased cell migration, invasion and diffused behavior of glioma cells are still poorly understood. METHODS: In the current study, we applied quantitative proteomics for the identification of differentially expressed proteins in GBMs as compared to non-malignant brain tissues. RESULTS: Our study led to the identification of 23 proteins showing overexpression in GBM; these include membrane proteins, moesin and CD44. The results were verified using Western blotting and immunohistochemistry in independent set of GBM and non-malignant brain tissues. Both GBM tissues and glioma cell lines (U87 / U373) demonstrated membranous expression of moesin and CD44, as revealed by immunohistochemistry and immunofluorescence, respectively. Notably, glioma cells transfected with moesin siRNA displayed reduced migration and invasion on treatment with hyaluronan (HA), an important component of the extracellular matrix in GBM. CD44, a transmembrane glycoprotein, acts as a major receptor for hyaluronan (HA). Using co-immunoprecipitation assays, we further demonstrated that moesin interacts with CD44 in glioma cells only after treatment with HA; this implicates a novel role of moesin in HA-CD44 signaling in gliomas. CONCLUSIONS: Our results suggest that development of inhibitors which interfere with CD44-moesin interactions may open a new avenue in the future to mitigate cellular migration in gliomas.


Subject(s)
Cell Movement/drug effects , Glioblastoma/metabolism , Hyaluronic Acid/pharmacology , Microfilament Proteins/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/genetics , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Microfilament Proteins/genetics , Protein Binding/drug effects , Proteome , Proteomics
16.
Foot Ankle Clin ; 18(2): 185-94, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23707172

ABSTRACT

This article discusses the role of ankle arthroscopy in the acute management of ankle trauma in athletes. The rate of intra-articular pathology associated with ankle trauma is high and arthroscopic treatment often has an important role to play. Its major role is in the assessment and treatment of joint surface damage, syndesmotic instability, and intra-articular fractures.


Subject(s)
Ankle Injuries/surgery , Ankle Joint/surgery , Arthroscopy/methods , Athletic Injuries/surgery , Athletes , Humans
17.
FEBS Lett ; 587(10): 1466-73, 2013 May 21.
Article in English | MEDLINE | ID: mdl-23583712

ABSTRACT

Neurofibromin (NF1) is encoded by the NF1 tumour suppressor gene. Mutations result in a disorder known as Neurofibromatosis Type 1 (NF-1), and patients are often diagnosed due to the presence of unusual pigmentary patterns that include Café au lait macules (CALMs). Little is known about how loss of NF1 results in pigmentary defects in melanocytes. We sought to identify novel NF1 interacting proteins and elucidate the molecular mechanisms underlying the pigmentary defects. The cytoplasmic Dynein Heavy Chain 1 (DHC) was found to interact with NF1 along microtubules in vesicular structures identified to be melanosomes. Our studies suggest that NF1 is involved in melanosomal localization, and that disruptions in NF1-DHC interactions may contribute to the abnormal pigmentary features commonly associated with this debilitating syndrome.


Subject(s)
Cytoplasmic Dyneins/metabolism , Melanocytes/metabolism , Melanosomes/metabolism , Neurofibromin 1/metabolism , Cells, Cultured , Gene Knockdown Techniques , Humans , Infant, Newborn , Male , Melanocytes/drug effects , Melanocytes/ultrastructure , Melanosomes/drug effects , Microtubules/drug effects , Microtubules/metabolism , Neurofibromin 1/antagonists & inhibitors , Neurofibromin 1/genetics , Protein Binding/drug effects , Protein Binding/genetics , RNA, Small Interfering/pharmacology , Tissue Distribution/drug effects , Tissue Distribution/genetics
18.
Foot Ankle Int ; 34(3): 420-5, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23391624

ABSTRACT

BACKGROUND: There are various methods available to fix a calcaneal osteotomy, ranging from screws to plates and staples. It is not clear if one method is superior to the other. In this series we compare the complications and union rates of 3 different methods of fixation. METHODS: A retrospective review of the records of a consecutive series of patients who had a calcaneal osteotomy was undertaken. All patients had their osteotomy by the same technique, however the subsequent fixation was performed using 3 different methods: a lateral locking plate, a headless, or a headed screw. The screws were placed through a separate stab incision inserted from the infero-posterior heel. Records were kept of subsequent symptoms from the hardware and need for hardware removal as well as any complications. When screws were inserted, the entry point in relation to the weight-bearing surface of the calcaneus was also recorded. Sixty-seven osteotomies were investigated, of which 17 were fixed using a headed screw, 18 using a headless screw, and the remaining 32 were fixed using a lateral plate. RESULTS: There was an overall 97% union rate. The only 2 cases of delayed union were both fixed using a lateral plate. Overall, 47% of the headed screws, 11% of the headless screws, and 6% of the lateral plates were removed to address symptoms that were suspected to arise from the hardware. There was a 10% rate of wound complication in the lateral plate cohort. There were no cases of sural nerve injury or neuroma. No correlation was found between entry position of screw and subsequent hardware symptoms. CONCLUSIONS: Calcaneal osteotomies have high union rates regardless of fixation method. Fixation using a headed screw is associated with a high rate of secondary screw removal. This was unrelated to the position of the screw in relation to the weight-bearing surface of the calcaneus in our series. Hardware problems were less frequent in the headless screw or the lateral plate groups; however, the incidence of local wound complications and radiological delayed union was higher in the group fixed with a lateral plate. This may be related to the greater soft tissue dissection and lesser compression achieved at the osteotomy site. LEVEL OF EVIDENCE: Level III, retrospective case control study.


Subject(s)
Calcaneus/surgery , Osteotomy/methods , Adult , Aged , Aged, 80 and over , Bone Plates , Bone Screws , Female , Humans , Male , Middle Aged , Osteotomy/instrumentation , Postoperative Complications , Retrospective Studies , Treatment Outcome
19.
J Neurosci Res ; 91(4): 494-505, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23361976

ABSTRACT

Loss-of-function mutations and deletions in the neurofibromin tumor suppressor gene (NF1) cause neurofibromatosis type 1 (NF-1), the most common inherited syndrome of the nervous system in humans, with a birth incidence of 1:3,000. The most visible features of NF-1 are the neoplastic manifestations caused by the loss of Ras-GTPase-activating protein (Ras-GAP) activity mediated through the GAP-related domain (GRD) of neurofibromin (NF1), the protein encoded by NF1. However, the syndrome is also characterized by cognitive dysfunction and a number of developmental abnormalities. The molecular etiology of many of these nonneoplastic phenotypes remains unknown. Here we show that the tubulin-binding domain (TBD) of NF1 is a binding partner of the leucine-rich pentatricopeptide repeat motif-containing (LRPPRC) protein. These two proteins complex with Kinesin 5B, hnRNP A2, Staufen1, and Myelin Basic Protein (MBP) mRNA, likely in RNA granules. This interaction is of interest in that it links NF-1 with Leigh's syndrome, French Canadian variant (LSFC), an autosomal recessive neurodegenerative disorder that arises from mutations in the LRPPRC gene. Our findings provide clues to how loss or mutation of NF1 and LRPPRC may contribute to the manifestations of NF-1 and LSFC.


Subject(s)
Cytochrome-c Oxidase Deficiency/metabolism , Leigh Disease/metabolism , Mitochondrial Proteins/metabolism , Neurofibromatosis 1/metabolism , Neurofibromin 1/metabolism , Cell Line, Tumor , Cytochrome-c Oxidase Deficiency/genetics , Humans , Leigh Disease/genetics , Mitochondrial Proteins/genetics , Mutation , Neurofibromatosis 1/genetics , Neurofibromin 1/genetics , Protein Structure, Tertiary , Schwann Cells/metabolism , ras GTPase-Activating Proteins/genetics , ras GTPase-Activating Proteins/metabolism
20.
Genome Res ; 23(3): 431-9, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23222849

ABSTRACT

Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.


Subject(s)
Astrocytoma/diagnosis , Astrocytoma/genetics , Genes, Neurofibromatosis 1 , Neurofibromin 1/genetics , Adolescent , Alleles , Astrocytoma/pathology , Child , DNA Copy Number Variations , DNA Methylation , Female , Genome-Wide Association Study , Humans , Loss of Heterozygosity , Male , Mutation , Neurofibromin 1/metabolism , Phenotype , Reproducibility of Results , Sequence Alignment , Sequence Analysis, DNA , Young Adult
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