Publications by authors named "Giovanni Porta"

41 Publications

Integrating Microstructured Electrospun Scaffolds in an Open Microfluidic System for Studies of Human Patient-Derived Primary Cells.

ACS Biomater Sci Eng 2020 06 4;6(6):3649-3663. Epub 2020 May 4.

Institute of Biomedical Technologies, National Research Council of Italy, via F.lli Cervi 93, 20090 Segrate, Milan, Italy.

Recent studies have suggested that microenvironmental stimuli play a significant role in regulating cellular proliferation and migration, as well as in modulating self-renewal and differentiation processes of mammary cells with stem cell (SCs) properties. Recent advances in micro/nanotechnology and biomaterial synthesis/engineering currently enable the fabrication of innovative tissue culture platforms suitable for maintenance and differentiation of SCs Here, we report the design and fabrication of an open microfluidic device (OMD) integrating removable poly(ε-caprolactone) (PCL) based electrospun scaffolds, and we demonstrate that the OMD allows investigation of the behavior of human cells during culture in real time. Electrospun scaffolds with modified surface topography and chemistry can influence attachment, proliferation, and differentiation of mammary SCs and epigenetic mechanisms that maintain luminal cell identity as a function of specific morphological or biochemical cues imparted by tailor-made fiber post-treatments. Meanwhile, the OMD architecture allows control of cell seeding and culture conditions to collect more accurate and informative assays. In perspective, integrated systems could be tailor-made to mimic specific physiological conditions of the local microenvironment and then analyze the response from screening specific drugs for more effective diagnostics, long-term prognostics, and disease intervention in personalized medicine.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00352DOI Listing
June 2020

The use of chest ultrasonography in suspected cases of COVID-19 in the emergency department.

Future Sci OA 2020 Nov 30;7(1):FSO635. Epub 2020 Nov 30.

Department of Emergency Medicine "Santa Maria delle Grazie" Hospital, 80078 Pozzuoli, Italy.

Aim: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus-specific reverse transcriptase-polymerase chain reaction (RT-PCR) represents the diagnostic gold standard. We explored the value of chest ultrasonography to predict positivity to SARS-CoV-2 on RT-PCR in suspected COVID-19 cases.

Patients & Methods: Consecutive patients with suspect COVID-19 were included if they had fever and/or history of cough and/or dyspnea. Lung ultrasound score (LUSS) was computed according to published methods.

Results: A total of 76 patients were included. A 3-variable model based on aspartate transaminase (AST) > upper limit of normal, LUSS >12 and body temperature >37.5°C yielded an overall accuracy of 91%.

Conclusion: A simple LUSS-based model may represent a powerful tool for initial assessment in suspected cases of COVID-19.
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http://dx.doi.org/10.2144/fsoa-2020-0127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745656PMC
November 2020

Time-weighted lactate as a predictor of adverse outcome in acute heart failure.

ESC Heart Fail 2021 Feb 24;8(1):539-545. Epub 2020 Nov 24.

Emergency Department of San Paolo Hospital, Naples, Italy.

Aims: The role of dynamic changes in lactate concentrations on prognosis in acute heart failure has been poorly investigated. The aim of this study was to explore the predictive value of 24 h time-weighted lactate (LAC ) in patients with acute heart failure.

Methods And Results: Ninety-six consecutive acute heart failure patients presenting to the Emergency Department of San Paolo Hospital, Naples, Italy, were prospectively enrolled. Arterial blood lactate was measured at admission and during the following 24 h at random time intervals. LAC was obtained by the sum of the average lactate values among consecutive time points multiplied by the intervals between consecutive time points and dividing the sum by the total time (24 h). The outcome was a composite of need of admission to the intensive care unit, hospitalization duration >7 days, or intra-hospital death. Admission lactate, maximum measured lactate, and LAC were collected. Univariate and multivariate Cox regression analysis was applied to determine the hazard ratio (HR) of developing the outcome. Forty-three patients experienced the pre-specified outcome. In sex-adjusted and age-adjusted multivariable analysis, LAC predicted the outcome occurrence (HR: 1.51, 95% confidence interval: 1.24, 1.84, P < 0.001). Risk stratification analysis based on LAC tertiles demonstrated a gradual increase in risk of developing the outcome (HR: 17.32, 95% confidence interval: 2.30, 130.23, P = 0.006) for the highest LAC tertile.

Conclusions: In acute heart failure patients, 24 h LAC had a significant independent predictive value for adverse intra-hospital outcome. LAC could be a useful index at identifying high-risk patients who may require a more aggressive treatment during hospitalization.
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http://dx.doi.org/10.1002/ehf2.13112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835560PMC
February 2021

A review of spatial Markov models for predicting pre-asymptotic and anomalous transport in porous and fractured media.

J Contam Hydrol 2021 Jan 27;236:103734. Epub 2020 Oct 27.

Civil and Environmental Engineering and Earth Sciences, University of Notre Dame, South Bend, IN, USA. Electronic address:

Heterogeneity across a broad range of scales in geologic porous media often manifests in observations of non-Fickian or anomalous transport. While traditional anomalous transport models can successfully make predictions in certain geological systems, increasing evidence suggests that assumptions relating to independent and identically distributed increments constrain where and when they can be reliably applied. A relatively novel model, the Spatial Markov model (SMM), relaxes the assumption of independence. The SMM belongs to the family of correlated continuous time random walks and has shown promise across a wide range of transport problems relevant to natural porous media. It has been successfully used to model conservative as well as more recently reactive transport in highly complex flows ranging from pore scales to much larger scales of interest in geology and subsurface hydrology. In this review paper we summarize its original development and provide a comprehensive review of its advances and applications as well as lay out a vision for its future development.
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http://dx.doi.org/10.1016/j.jconhyd.2020.103734DOI Listing
January 2021

Lung ultrasound as diagnostic tool for SARS-CoV-2 infection.

Intern Emerg Med 2021 Mar 3;16(2):471-476. Epub 2020 Oct 3.

Department of Emergency Medicine, COVID Care Unit, Santa Maria Delle Grazie Hospital, Via Domitiana, 5, 80078, Pozzuoli, Naples, Italy.

The aim of this study was to explore the role of lung ultrasound (LUS) in the diagnosis of SARS-CoV-2 infection and to verify its utility in the prediction of lung disease's severity and outcome. Fifty-three consecutive patients presenting to the Emergency Department of Santa Maria delle Grazie Hospital with high suspicion of SARS-CoV-2 infection underwent diagnostic test for SARS-CoV-2 on samples obtained from nasopharyngeal swab as well as complete proper diagnostic work-up that included clinical evaluation, laboratory tests, blood gas analyses, chest CT and LUS. A semiquantitative analysis of B-lines distribution was performed to calculate the LUS score. Patients were divided into two groups according to the results of both SARS-CoV-2 diagnostic test and other exams (Group A = pneumonia due to SARS-CoV2 infection vs Group B = no SARS-CoV2 infection and another definite diagnosis). LUS showed an excellent accuracy in predicting the diagnosis of SARS-CoV-2 infection (area under the ROC curve of 0.92 with a sensibility of 73% and a specificity of 89% a the cut-off of 12.5). LUS score was more impaired in SARS-CoV-2 patients (18.1 ± 6.0 vs 7.6 ± 5.9, p < 0.00001) and it is significantly negatively correlated with PF ratio values (r = - 0.719, p < 0.0001). An intrahospital mortality rate of 46% was found; patients with adverse outcome had significant higher value of LUS, PF, LDH, and APACHE II score. None of these parameters was predictive of mortality. LUS is a useful tool for the early detection of SARS-CoV-2 infection and for the evaluation of the disease severity, but does not predict mortality. Further studies with repeated evaluations of LUS score are needed to further explore the role of LUS in the assessment of severity in SARS-CoV-2 disease and in the monitoring of the response to treatments.
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http://dx.doi.org/10.1007/s11739-020-02512-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532928PMC
March 2021

Homeoprotein OTX1 and OTX2 involvement in rat myenteric neuron adaptation after DNBS-induced colitis.

PeerJ 2020 13;8:e8442. Epub 2020 Feb 13.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Background: Inflammatory bowel diseases are associated with remodeling of neuronal circuitries within the enteric nervous system, occurring also at sites distant from the acute site of inflammation and underlying disturbed intestinal functions. Homeoproteins orthodenticle OTX1 and OTX2 are neuronal transcription factors participating to adaptation during inflammation and underlying tumor growth both in the central nervous system and in the periphery. In this study, we evaluated OTX1 and OTX2 expression in the rat small intestine and distal colon myenteric plexus after intrarectal dinitro-benzene sulfonic (DNBS) acid-induced colitis.

Methods: OTX1 and OTX2 distribution was immunohistochemically investigated in longitudinal muscle myenteric plexus (LMMP)-whole mount preparations. mRNAs and protein levels of both OTX1 and OTX2 were evaluated by qRT-PCR and Western blotting in LMMPs.

Results: DNBS-treatment induced major gross morphology and histological alterations in the distal colon, while the number of myenteric neurons was significantly reduced both in the small intestine and colon. mRNA levels of the inflammatory markers, TNFα, pro-IL1β, IL6, HIF1α and VEGFα and myeloperoxidase activity raised in both regions. In both small intestine and colon, an anti-OTX1 antibody labeled a small percentage of myenteric neurons, and prevalently enteric glial cells, as evidenced by co-staining with the glial marker S100β. OTX2 immunoreactivity was present only in myenteric neurons and was highly co-localized with neuronal nitric oxide synthase. Both in the small intestine and distal colon, the number of OTX1- and OTX2-immunoreactive myenteric neurons significantly increased after DNBS treatment. In these conditions, OTX1 immunostaining was highly superimposable with inducible nitric oxide synthase in both regions. OTX1 and OTX2 mRNA and protein levels significantly enhanced in LMMP preparations of both regions after DNBS treatment.

Conclusions: These data suggest that colitis up-regulates OTX1 and OTX2 in myenteric plexus both on site and distantly from the injury, potentially participating to inflammatory-related myenteric ganglia remodeling processes involving nitrergic transmission.
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http://dx.doi.org/10.7717/peerj.8442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024580PMC
February 2020

Microarray expression studies on bone marrow of patients with Shwachman-Diamond syndrome in relation to deletion of the long arm of chromosome 20, other chromosome anomalies or normal karyotype.

Mol Cytogenet 2020 2;13. Epub 2020 Jan 2.

1Genetica Umana e Medica, Dipartimento di Medicina e Chirurgia, Università dell'Insubria, Via J. H. Dunant, 5, 21100 Varese, Italy.

Background: Clonal chromosome changes are often found in the bone marrow (BM) of patients with Shwachman-Diamond syndrome (SDS). The most frequent ones include an isochromosome of the long arm of chromosome 7, i (7)(q10), and an interstitial deletion of the long arm of chromosome 20, del (20)(q). These two imbalances are mechanisms of somatic genetic rescue. The literature offers few expression studies on SDS.

Results: We report the expression analysis of bone marrow (BM) cells of patients with SDS in relation to normal karyotype or to the presence of clonal chromosome anomalies: del (20)(q) (five cases), i (7)(q10) (one case), and other anomalies (two cases). The study was performed using the microarray technique considering the whole transcriptome (WT) and three gene subsets selected as relevant in BM functions. The expression patterns of nine healthy controls and SDS patients with or without chromosome anomalies in the bone marrow showed clear differences.

Conclusions: There is a significant difference between gene expression in the BM of SDS patients and healthy subjects, both at the WT level and in the selected gene sets. The deletion del (20)(q), with the gene consistently lost, even in patients with the smallest losses of material, changes the transcription pattern: a low proportion of abnormal cells led to a pattern similar to SDS patients without acquired anomalies, whereas a high proportion yields a pattern similar to healthy subjects. Hence, the benign prognostic value of del (20)(q). The case of i (7)(q10) showed a transcription pattern similar to healthy subjects, paralleling the positive prognostic role of this anomaly as well.
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http://dx.doi.org/10.1186/s13039-019-0466-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941278PMC
January 2020

Relevance of lung ultrasound in the diagnostic algorithm of respiratory diseases in a real-life setting: A multicentre prospective study.

Respirology 2020 05 2;25(5):535-542. Epub 2019 Aug 2.

Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Napoli, Italy.

Background And Objective: The aim of this study was to assess the role of lung ultrasound (LUS) in a diagnostic algorithm of respiratory diseases, and to establish the accuracy of LUS compared with chest radiography (CXR).

Methods: Over a period of 2 years, 509 consecutive patients admitted for respiratory-related symptoms to both emergency and general medicine wards were enrolled and evaluated using LUS and CXR. LUS was conducted by expert operators who were blinded to the medical history and laboratory data. Computed tomography (CT) of the chest was performed in case of discordance between the CXR and LUS, suspected lung cancer and an inconclusive diagnosis. Diagnosis made by CT was considered the gold standard.

Results: The difference in sensitivity and specificity between LUS and CXR as demonstrated by ROC curve analyses (LUS-AUROC: 0.853; specificity: 81.6%; sensitivity: 93.9% vs CXR-AUROC: 0.763; specificity: 57.4%; sensitivity: 96.3%) was significant (P = 0.001). Final diagnosis included 240 cases (47.2%) of pneumonia, 44 patients with cancer (8.6%), 20 patients with chronic obstructive pulmonary disease (COPD, 3.9%), 24 patients with heart failure (4.7%) and others (6.1%). In 108 patients (21.2%) with any lung pathology, a CT scan was performed with a positive diagnosis in 96 cases (88.9%); we found that CXR and LUS detected no abnormality in 24 (25%) and 5 (5.2%) cases, respectively. LUS was concordant with the final diagnosis (P < 0.0001), and in healthy patients, there was a low percentage of false positives (5.9%).

Conclusion: The results support the routine use of LUS in the clinical context.
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http://dx.doi.org/10.1111/resp.13659DOI Listing
May 2020

Skin picking disorder in 97 Italian and Spanish Cri du chat patients.

Am J Med Genet A 2019 08 12;179(8):1525-1530. Epub 2019 Jun 12.

Department of Molecular Medicine, IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Skin picking (SP) disorder is characterized by recurrent SP resulting in skin lesions. Several studies estimated its prevalence as approximately 2-4 % of the general population. It is also present in a high percentage of patients with intellectual and developmental disabilities, such as Cri du chat (CdC) syndrome, a rare genetic disorder caused by variable size deletions of the short arm of chromosome 5. The aim of this study was to evaluate, in 97 patients with CdC syndrome, the following data: frequency of SP, patient's age at onset, type, and topographic-anatomic distribution of the lesions presented. The results show that 85% of patients confirm a SP disorder, usually concentrated on the hands, fingers, and the face, with onset between 6 and 10 years of age, regardless of patient's sex. Evidence for early appearance of SP behavior, high prevalence in stressful circumstances, and efficacy of distracting actions immediately suggest the possibility that proper parental information about SP behavior and parental education concerning the methods to deal with this problem may result in its efficient reduction already in childhood.
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http://dx.doi.org/10.1002/ajmg.a.61259DOI Listing
August 2019

Identification of OTX1 and OTX2 As Two Possible Molecular Markers for Sinonasal Carcinomas and Olfactory Neuroblastomas.

J Vis Exp 2019 02 28(144). Epub 2019 Feb 28.

Department of Medicine and Surgery, University of Insubria.

OTX homeobox (HB) genes are expressed during embryonic morphogenesis and during the development of olfactory epithelium in adult organisms. Mutations occurring in these genes are often related to tumorigenesis in human. No data are available today regarding the possible correlation between OTX genes and tumors of the nasal cavity. The aim of this work is to understand if OTX1 and OTX2 can be considered as molecular markers in the development of nasal tumors. We selected nasal and sinonasal adenocarcinomas to investigate the expression of OTX1 and OTX2 genes through immunohistochemical and real-time PCR analyses.Both OTX1 and OTX2 were absent in all the samples of sinonasal Intestinal-Type Adenocarcinomas (ITACs). OTX1 mRNA was identified only in Non-Intestinal Type Adenocarcinomas (NITACs) while OTX2 mRNA was expressed only in Olfactory Neuroblastomas (ONs). We have demonstrated that the differential gene expression for both OTX1 and OTX2 genes might be a useful molecular marker to distinguish the different types of sinonasal tumors.
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http://dx.doi.org/10.3791/56880DOI Listing
February 2019

A Cell-Autonomous Oncosuppressive Role of Human RNASET2 Affecting ECM-Mediated Oncogenic Signaling.

Cancers (Basel) 2019 Feb 22;11(2). Epub 2019 Feb 22.

Unit of Molecular Therapies, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy.

RNASET2 is an extracellular ribonuclease endowed with a marked antitumorigenic role in several carcinomas, independent from its catalytic activity. Besides its antitumorigenic role by the recruitment to the tumor mass of immune cells from the monocyte/macrophage lineage, RNASET2 is induced by cellular stress and involved in actin cytoskeleton remodeling affecting cell interactions with the extracellular matrix (ECM). Here, we aimed to investigate the effects of RNASET2 expression modulation on cell phenotype and behavior in epithelial ovarian cancer (EOC) cellular models. In silico analysis on two publicly available datasets of gene expression from EOC patients ( = 392) indicated that increased RNASET2 transcript levels are associated with longer overall survival. In EOC biopsies ( = 101), analyzed by immunohistochemistry, RNASET2 was found heterogeneously expressed among tumors with different clinical⁻pathological characteristics and, in some cases, its expression localized to tumor-associated ECM. By characterizing in vitro two models of EOC cells in which RNASET2 was silenced or overexpressed, we report that RNASET2 expression negatively affects growth capability by conferring a peculiar cell phenotype upon the interaction of EOC cells with the ECM, resulting in decreased src activation. Altogether, these data suggest that drugs targeting activated src might represent a therapeutic approach for RNASET2-expressing EOCs.
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http://dx.doi.org/10.3390/cancers11020255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406318PMC
February 2019

A spatial Markov model for upscaling transport of adsorbing-desorbing solutes.

J Contam Hydrol 2019 Apr 10;222:31-40. Epub 2019 Feb 10.

Dept. of Civil and Environmental Engineering and Earth Sciences, University of Notre Dame, IN, USA. Electronic address:

The Spatial Markov Model (SMM) is an upscaled model with a strong track record in predicting upscaled behavior of conservative solute transport across hydrologic systems. Here we propose an SMM that can account for reactive linear adsorption and desorption processes and test it on a simple benchmark problem: flow and transport through an idealized periodic wavy channel. The methodology is built using trajectories that are obtained from a single high resolution random walk simulation of conservative transport across one periodic element. Our approach encodes information about where a particle starts at the inlet, where it leaves at the outlet, how long it takes to cross the domain and one additional piece of information, the number of times a particle strikes the boundary, with the objective of predicting large scale transport with arbitrary linear adsorption and desorption rates. Our benchmark problem demonstrates that predictions made with our proposed SMM agree favorably with results from direct numerical simulations, which resolve the full transport problem.
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http://dx.doi.org/10.1016/j.jconhyd.2019.02.003DOI Listing
April 2019

Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.

Br J Haematol 2019 03 26;184(6):974-981. Epub 2018 Dec 26.

Genetica Umana e Medica, Dipartimento di Medicina e Chirurgia, Università dell'Insubria, Varese, Italy.

In Shwachman-Diamond syndrome (SDS), deletion of the long arm of chromosome 20, del(20)(q), often acquired in bone marrow (BM), may imply a lower risk of developing myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), due to the loss of the EIF6 gene. The genes L3MBTL1 and SGK2, also on chromosome 20, are in a cluster of imprinted genes, and their loss implies dysregulation of BM function. We report here the results of array comparative genomic hybridization (a-CGH) performed on BM DNA of six patients which confirmed the consistent loss of EIF6 gene. Interestingly, array single nucleotide polymorphisms (SNPs) showed copy neutral loss of heterozygosity for EIF6 region in cases without del(20)(q). No preferential parental origin of the deleted chromosome 20 was detected by microsatellite analysis in six SDS patients. Our patients showed a very mild haematological condition, and none evolved into BM aplasia or MDS/AML. We extend the benign prognostic significance of del(20)(q) and loss of EIF6 to the haematological features of these patients, consistently characterized by mild hypoplastic BM, no or mild neutropenia, anaemia and thrombocytopenia. Some odd results obtained in microsatellite and SNP-array analysis demonstrate a peculiar genomic instability, in an attempt to improve BM function through the acquisition of the del(20)(q).
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http://dx.doi.org/10.1111/bjh.15729DOI Listing
March 2019

Pressure support ventilation vs Continuous positive airway pressure for treating of acute cardiogenic pulmonary edema: A pilot study.

Respir Physiol Neurobiol 2018 09 24;255:7-10. Epub 2018 Apr 24.

Emergency Department, Cardarelli Hospital, Via Cardarelli 9, Naples, 80131, Italy.

Non-invasive ventilation is usually adopted as a support to medical therapy in patients with acute pulmonary edema, but which modality between Pressure Support Ventilation (PSV) and Continuous Positive Airway Pressure (CPAP) has better favourable effects is not been yet well known. Aim of this observational study was to provide data on these different non-invasive ventilation modalities in the management of acute cardiogenic pulmonary edema. One-hundred-fifty-three patients consecutively admitted to the Emergency Room of two different Center were enrolled and randomly assigned to CPAP or PSV. Data relative to mortality, need of endotracheal intubation, sequential blood gas analysis were compared. Furthermore, there were no significant differences regarding mortality in the two groups, but patients treated with PSV had a significant lower rate of endotracheal intubation and a higher improvement of blood gas analyses parameters. In conclusion, our data support only a slight advantage in favour to PSV versus CPAP.
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http://dx.doi.org/10.1016/j.resp.2018.04.007DOI Listing
September 2018

gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML.

Cell Death Dis 2018 03 2;9(3):349. Epub 2018 Mar 2.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy. Indeed, discontinuation trials (STIM; TWISER; DADI) for those patients who achieved a profound molecular response showed 50% relapsing within 12 months. We performed a comparative analysis on 15 CML patients and one B-ALL patient, between the standard quantitative reverse-transcriptase PCR (qRT-PCR) and our genomic DNA patient-specific quantitative PCR assay (gDNA qPCR). Here we demonstrate that gDNA qPCR is better than standard qRT-PCR in disease monitoring after an average follow-up period of 200 days. Specifically, we statistically demonstrated that DNA negativity is more reliable than RNA negativity in indicating when TKIs therapy can be safely stopped.
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http://dx.doi.org/10.1038/s41419-018-0387-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834620PMC
March 2018

Lactate determination in pleural and abdominal effusions: a quick diagnostic marker of exudate-a pilot study.

Intern Emerg Med 2018 Sep 30;13(6):901-906. Epub 2017 Sep 30.

Emergency Department, "San Paolo" Hospital, Naples, Italy.

Pleural or abdominal effusions are frequent findings in ICU and Internal Medicine patients. Diagnostic gold standard to distinguish between transudate and exudate is represented by "Light's Criteria," but, unfortunately, the chemical-physical examination for their calculation is not a rapid test. Pursuing an acid-base assessment of the fluid by a blood-gas analyzer, an increase of lactate beyond the normal serum range is reported in the exudative effusions. The advantages of this test are that it is a very fast bed-side test, executable directly by the physician. The aim of this study is to evaluate whether the increase in lactate in pleural and abdominal effusions might be used as a criterion for the differential diagnosis of the nature of the fluid. Sixty-nine patients with pleural or abdominal effusions and clinical indication for thoracentesis or paracentesis were enrolled. Acid-base assessment with lactate, total protein, and LDH dosage on the serum, and acid-base assessment with lactate, total protein, and LDH dosage, cytology, and bacterial culture on the fluid were performed to each patient. Fluid-blood lactate difference (ΔLacFB) and fluid-blood lactate ratio (LacFB ratio) were calculated. A statistical analysis was carried out for fluid lactate (LacF), ΔLacFB, and LacFB ratio, performing ROC curves to find the cut-off values with best sensitivity (Sn) and specificity (Sp) predicting an exudate diagnosis: LacF: cut-off value: 2.4 mmol/L; AU-ROC 0.854 95% CI 0.756-0.952; Sn 0.77; Sp 0.84. ΔLacFB: cut-off value: 0.95 mmol/L; Au-ROC 0.876 95% CI 0.785-0.966; Sn 0.80; Sp 0.92. LacFB ratio: cut-off value: 2 mmol/L; Au-ROC 0.730 95% CI 0.609-0.851; Sn 0.74; Sp 0.65. Lactate dosage by blood-gas analyzer on pleural and abdominal effusions seems to be a promising tool to predict a diagnosis of exudate.
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http://dx.doi.org/10.1007/s11739-017-1757-yDOI Listing
September 2018

Space-time mesh adaptation for solute transport in randomly heterogeneous porous media.

J Contam Hydrol 2018 05 5;212:28-40. Epub 2017 Jul 5.

Dipartimento di Ingegneria Civile e Ambientale, Politecnico di Milano, Piazza L. Da Vinci 32, 20133 Milano, Italy; Department of Hydrology and Atmospheric Sciences, University of Arizona, Tucson, AZ 85721, USA.

We assess the impact of an anisotropic space and time grid adaptation technique on our ability to solve numerically solute transport in heterogeneous porous media. Heterogeneity is characterized in terms of the spatial distribution of hydraulic conductivity, whose natural logarithm, Y, is treated as a second-order stationary random process. We consider nonreactive transport of dissolved chemicals to be governed by an Advection Dispersion Equation at the continuum scale. The flow field, which provides the advective component of transport, is obtained through the numerical solution of Darcy's law. A suitable recovery-based error estimator is analyzed to guide the adaptive discretization. We investigate two diverse strategies guiding the (space-time) anisotropic mesh adaptation. These are respectively grounded on the definition of the guiding error estimator through the spatial gradients of: (i) the concentration field only; (ii) both concentration and velocity components. We test the approach for two-dimensional computational scenarios with moderate and high levels of heterogeneity, the latter being expressed in terms of the variance of Y. As quantities of interest, we key our analysis towards the time evolution of section-averaged and point-wise solute breakthrough curves, second centered spatial moment of concentration, and scalar dissipation rate. As a reference against which we test our results, we consider corresponding solutions associated with uniform space-time grids whose level of refinement is established through a detailed convergence study. We find a satisfactory comparison between results for the adaptive methodologies and such reference solutions, our adaptive technique being associated with a markedly reduced computational cost. Comparison of the two adaptive strategies tested suggests that: (i) defining the error estimator relying solely on concentration fields yields some advantages in grasping the key features of solute transport taking place within low velocity regions, where diffusion-dispersion mechanisms are dominant; and (ii) embedding the velocity field in the error estimator guiding strategy yields an improved characterization of the forward fringe of solute fronts which propagate through high velocity regions.
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http://dx.doi.org/10.1016/j.jconhyd.2017.07.001DOI Listing
May 2018

OTX1 and OTX2 as possible molecular markers of sinonasal carcinomas and olfactory neuroblastomas.

Eur J Histochem 2017 Feb 9;61(1):2730. Epub 2017 Feb 9.

University of Insubria, Department of Clinical and Experimental Medicine.

OTX Homeobox genes are involved in embryonic morphogenesis and in the development of olfactory epithelium in adult. Mutations occurring in the OTX genes are reported to be associated to tumorigenisis in human. No reports correlate the expression of OTX genes and neoplasms of the nasal cavity. Thus, through immunohistochemical and Real-time PCR analysis we investigated OTX1 and OTX2 expression in the more frequent types of nasal and sinonasal tumours. Variable expression of both genes were found in normal sinonasal mucosa and in tumours. Interestingly, no expression of both OTX genes were detected in sinonasal intestinal-type adenocarcinomas; only OTX1 was found in non-intestinal-type adenocarcinomas and OTX2 was selectively expressed in olfactory neuroblastomas. In conclusion, OTX1 and OTX2 genes might have a role in the pathogenesis of different types of sinonasal neoplasms.
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http://dx.doi.org/10.4081/ejh.2017.2730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304267PMC
February 2017

Macular hole surgery: the healing process of outer retinal layers to visual acuity recovery.

Eur J Ophthalmol 2017 Mar 22;27(2):235-239. Epub 2017 Feb 22.

Department of Surgical and Morphological Sciences, Section of Ophthalmology, School of Medicine, University of Insubria, Varese - Italy.

Purpose: To evaluate optical coherence tomography (OCT) modifications of outer retinal layers as determinants for functional recovery after surgery for idiopathic macular hole (IMH).

Methods: This prospective study included 23 eyes of 23 consecutive patients who underwent vitreoretinal surgery for IMH. We excluded patients with other retinal diseases. Baseline and follow-up evaluations at months 3 and 6 included complete ophthalmologic and instrumental evaluations. Functional evaluation was performed by Best Corrected Visual Acuity (BCVA) and Amsler test. Morphologic evaluation was performed by spectral-domain 3D-OCT (Topcon, Tokyo, Japan) for a deep analysis of retinal layers as well as central retinal thickness evaluation. A standard 23-G or 25-G vitreoretinal surgery was performed, completed by posterior hyaloid and inner limiting membrane peeling by means of vital dyes and gas tamponade. Statistical analysis was performed on collected data.

Results: The mean BCVA increased significantly from 0.57 ± 0.25 logMAR at baseline to 0.34 ± 0.22 logMAR at month 6. Intraretinal layers modification showed a progressive recomposition of inner segment/outer segment layer in 91% of patients at month 6. Retinal layers recomposition showed a progressive increase in all patients during follow-up from the immediate postoperative control to the last 6-month visit.

Conclusions: Optical coherence tomography examination appears useful to investigate visual recovery after macular hole surgery. To ensure postsurgical functional increase, recomposition of all retinal layers, in particular in the outer retina, is mandatory. This process could be slow and not immediately observable during follow-up examinations.
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http://dx.doi.org/10.5301/ejo.5000905DOI Listing
March 2017

Nitric oxide regulates homeoprotein OTX1 and OTX2 expression in the rat myenteric plexus after intestinal ischemia-reperfusion injury.

Am J Physiol Gastrointest Liver Physiol 2017 Apr 2;312(4):G374-G389. Epub 2017 Feb 2.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Neuronal and inducible nitric oxide synthase (nNOS and iNOS) play a protective and damaging role, respectively, on the intestinal neuromuscular function after ischemia-reperfusion (I/R) injury. To uncover the molecular pathways underlying this dichotomy we investigated their possible correlation with the orthodenticle homeobox proteins OTX1 and OTX2 in the rat small intestine myenteric plexus after in vivo I/R. Homeobox genes are fundamental for the regulation of the gut wall homeostasis both during development and in pathological conditions (inflammation, cancer). I/R injury was induced by temporary clamping the superior mesenteric artery under anesthesia, followed by 24 and 48 h of reperfusion. At 48 h after I/R intestinal transit decreased and was further reduced by -propyl-l-arginine hydrochloride (NPLA), a nNOS-selective inhibitor. By contrast this parameter was restored to control values by 1400W, an iNOS-selective inhibitor. In longitudinal muscle myenteric plexus (LMMP) preparations, iNOS, OTX1, and OTX2 mRNA and protein levels increased at 24 and 48 h after I/R. At both time periods, the number of iNOS- and OTX-immunopositive myenteric neurons increased. nNOS mRNA, protein levels, and neurons were unchanged. In LMMPs, OTX1 and OTX2 mRNA and protein upregulation was reduced by 1400W and NPLA, respectively. In myenteric ganglia, OTX1 and OTX2 staining was superimposed with that of iNOS and nNOS, respectively. Thus in myenteric ganglia iNOS- and nNOS-derived NO may promote OTX1 and OTX2 upregulation, respectively. We hypothesize that the neurodamaging and neuroprotective roles of iNOS and nNOS during I/R injury in the gut may involve corresponding activation of molecular pathways downstream of OTX1 and OTX2. Intestinal ischemia-reperfusion (I/R) injury induces relevant alterations in myenteric neurons leading to dismotility. Nitrergic neurons seem to be selectively involved. In the present study the inference that both neuronal and inducible nitric oxide synthase (nNOS and iNOS) expressing myenteric neurons may undergo important changes sustaining derangements of motor function is reinforced. In addition, we provide data to suggest that NO produced by iNOS and nNOS regulates the expression of the vital transcription factors orthodenticle homeobox protein 1 and 2 during an I/R damage.
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http://dx.doi.org/10.1152/ajpgi.00386.2016DOI Listing
April 2017

OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development.

Aging (Albany NY) 2015 Nov;7(11):928-36

Biochemistry Laboratory, IDI-IRCCS-FLMM, c/o Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133 Rome, Italy.

OTX proteins, homologs of the Drosophila orthodenticle (Otd), are important for the morphogenesis of the neuroectoderm, and for the central nervous system formation. OTX1 and OTX2 are important for the cochlea and macula development, indeed when OTX1 is knocked down, these organs undergo developmental failure. Moreover OTX2 transfection revert this effect in OTX1(-/-) mice. The TA isoform of TP63, involved in Notch regulation pathway, has a critical function in the cochlear neuroepithelium differentiation. TAp63 positively regulates Hes5 and Atoh1 transcription. This pathway has been also demonstrated in p63(-/-) mice, and in patients p63 mutated, affected by Ectodermal Dysplasia (ED, OMIM 129810). These patients are affected by mild sensorineural deafness, most likely related to the mutation in p63 gene impairing the Notch pathway. We demonstrated the role of OTX2 on TAp63 regulation necessary for the correct formation of macular neuroepithelium and we confirmed the impairment of vestibular function caused by p63 mutations. Although the abnormalities found in our patient were still at a subclinical extent, aging could exacerbate this impairment and cause a decrease in quality of life.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694063PMC
http://dx.doi.org/10.18632/aging.100839DOI Listing
November 2015

gDNA Q-PCR for clinical monitoring of CML.

Cell Cycle 2015 ;14(23):3659-60

a Department of Clinical and Experimental Medicine ; University of Insubria ; Varese , Italy.

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http://dx.doi.org/10.1080/15384101.2015.1006053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825716PMC
October 2016

Genomic quantitative real-time PCR proves residual disease positivity in more than 30% samples with negative mRNA-based qRT-PCR in Chronic Myeloid Leukemia.

Oncoscience 2014 23;1(7):510-21. Epub 2014 Jul 23.

Department of Experimental and Clinical Medicine, Insubria University, Varese, Italy.

Imatinib mesylate (IM) is the first line therapy against Chronic Myeloid Leukemia, effectively prolonging overall survival. Because discontinuation of treatment is associated with relapse, IM is required indefinitely to maintain operational cure. To assess minimal residual disease, cytogenetic analysis is insensitive in a high background of normal lymphocytes. The qRT-PCR provides highly sensitive detection of BCR-ABL1 transcripts, but mRNA levels are not directly related to the number of leukemic cells, and undetectable results are difficult to interpret. We developed a sensitive approach to detect the number of leukemic cells by a genomic DNA (gDNA) Q-PCR assay based on the break-point sequence, with a formula to calculate the number of Ph-positive cells. We monitored 8 CML patients treated with IM for more than 8 years. We tested each samples by patient specific gDNA Q-PCR in parallel by the conventional techniques. In all samples positive for chimeric transcripts we showed corresponding chimeric gDNA by Q-PCR, and in 32.8% (42/128) of samples with undetectable levels of mRNA we detected the persistence of leukemic cells. The gDNA Q-PCR assay could be a new diagnostic tool used in parallel to conventional techniques to support the clinician's decision to vary or to STOP IM therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278316PMC
http://dx.doi.org/10.18632/oncoscience.65DOI Listing
January 2015

Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy: results from 8 years follow-up of NID-2 study.

Acta Diabetol 2015 Apr 11;52(2):239-47. Epub 2014 Aug 11.

Department of Internal and Experimental Medicine "Magrassi-Lanzara", Second University of Naples, Via F. Petrarca, 64, 80122, Naples, Italy,

The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics . A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan-Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91-1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy.
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http://dx.doi.org/10.1007/s00592-014-0623-xDOI Listing
April 2015

Vitreous substitutes: the present and the future.

Biomed Res Int 2014 4;2014:351804. Epub 2014 May 4.

Department of Surgical and Morphological Sciences, Section of Ophthalmology, School of Medicine, University of Insubria, Via Guicciardini 9, 21100 Varese, Italy.

Vitreoretinal surgery has advanced in numerous directions during recent years. The removal of the vitreous body is one of the main characteristics of this surgical procedure. Several molecules have been tested in the past to fill the vitreous cavity and to mimic its functions. We here review the currently available vitreous substitutes, focusing on their molecular properties and functions, together with their adverse effects. Afterwards we describe the characteristics of the ideal vitreous substitute. The challenges facing every ophthalmology researcher are to reach a long-term intraocular permanence of vitreous substitute with total inertness of the molecule injected and the control of inflammatory reactions. We report new polymers with gelification characteristics and smart hydrogels representing the future of vitreoretinal surgery. Finally, we describe the current studies on vitreous regeneration and cell cultures to create new intraocular gels with optimal biocompatibility and rheological properties.
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http://dx.doi.org/10.1155/2014/351804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024399PMC
February 2015

Expression of VEGF-A, Otx homeobox and p53 family genes in proliferative vitreoretinopathy.

Mediators Inflamm 2013 21;2013:857380. Epub 2013 Oct 21.

Department of Surgical and Morphological Sciences, Section of Ophthalmology, University of Insubria, Ospedale di Circolo, Via F. Guicciardini 9, 21100 Varese, Italy.

Introduction: Proliferative vitreoretinopathy (PVR) is a severe inflammatory complication of retinal detachment. Pathological epiretinal membranes grow on the retina surface leading to contraction, and surgery fails in 5% to 10% of the cases. We evaluated the expression of VEGF-A, Otx1, Otx2, Otx3, and p53 family members from PVR specimens to correlate their role in inducing or preventing the pathology.

Methods: Twelve retinal samples were taken from patients affected by PVR during therapeutic retinectomies in vitreoretinal surgery. Gene expression was evaluated using quantitative real-time reverse transcriptase PCR analysis and immunohistochemistry, using four healthy human retinae as control.

Result: Controls showed basal expression of all genes. PVR samples showed little or no expression of Otx1 and variable expression of VEGF-A, Otx2, Otx3, p53, and p63 genes. Significant correlation was found among VEGF-A, Otx2, p53, and p63 and between Otx1 and Otx3.

Conclusions: Otx homeobox, p53 family, and VEGF-A genes are expressed in PVR human retina. We individuated two possible pathways (VEGF-A, Otx2, p53, p63 and Otx1 and Otx3) involved in PVR progression that could influence in different manners the course of the pathology. Individuating the genetic pathways of PVR represents a novel approach to PVR therapies.
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http://dx.doi.org/10.1155/2013/857380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818919PMC
June 2014

Rapamycin regulates biochemical metabolites.

Cell Cycle 2013 Aug 28;12(15):2454-67. Epub 2013 Jun 28.

Medical Research Council; Toxicology Unit; Leicester, UK; Department of Pharmacy, Health and Nutritional Sciences; University of Calabria; Rende, Cosenza, Italy.

The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth, and deregulation of this pathway is associated with tumorigenesis. p53, and its less investigated family member p73, have been shown to interact closely with mTOR pathways through the transcriptional regulation of different target genes. To investigate the metabolic changes that occur upon inhibition of the mTOR pathway and the role of p73 in this response primary mouse embryonic fibroblast from control and TAp73(-/-) were treated with the macrocyclic lactone rapamycin. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analysis were used to obtain a rapamycin-dependent global metabolome profile from control or TAp73(-/-) cells. In total 289 metabolites involved in selective pathways were identified; 39 biochemical metabolites were found to be significantly altered, many of which are known to be associated with the cellular stress response.
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http://dx.doi.org/10.4161/cc.25450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841324PMC
August 2013

Detection of QTL for flowering time in multiple families of elite maize.

Theor Appl Genet 2012 Nov 17;125(7):1539-51. Epub 2012 Jul 17.

State Plant Breeding Institute, University of Hohenheim, 70593, Stuttgart, Germany.

Flowering time is a fundamental quantitative trait in maize that has played a key role in the postdomestication process and the adaptation to a wide range of climatic conditions. Flowering time has been intensively studied and recent QTL mapping results based on diverse founders suggest that the genetic architecture underlying this trait is mainly based on numerous small-effect QTL. Here, we used a population of 684 progenies from five connected families to investigate the genetic architecture of flowering time in elite maize. We used a joint analysis and identified nine main effect QTL explaining approximately 50 % of the genotypic variation of the trait. The QTL effects were small compared with the observed phenotypic variation and showed strong differences between families. We detected no epistasis with the genetic background but four digenic epistatic interactions in a full 2-dimensional genome scan. Our results suggest that flowering time in elite maize is mainly controlled by main effect QTL with rather small effects but that epistasis may also contribute to the genetic architecture of the trait.
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http://dx.doi.org/10.1007/s00122-012-1933-4DOI Listing
November 2012

Comparison of biometrical approaches for QTL detection in multiple segregating families.

Theor Appl Genet 2012 Sep 23;125(5):987-98. Epub 2012 May 23.

Crop Genetics and Breeding Department, China Agricultural University, Beijing 100193, China.

Detection of QTL in multiple segregating families possesses many advantages over the classical QTL mapping in biparental populations. It has thus become increasingly popular, and different biometrical approaches are available to analyze such data sets. We empirically compared an approach based on linkage mapping methodology with an association mapping approach. To this end, we used a large population of 788 elite maize lines derived from six biparental families genotyped with 857 SNP markers. In addition, we constructed genetic maps with reduced marker densities to assess the dependency of the performance of both mapping approaches on the marker density. We used cross-validation and resample model averaging and found that while association mapping performed better under high marker densities, this was reversed under low marker densities. In addition to main effect QTL, we also detected epistatic interactions. Our results suggest that both approaches will profit from a further increase in marker density and that a cross-validation should be applied irrespective of the biometrical approach.
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http://dx.doi.org/10.1007/s00122-012-1889-4DOI Listing
September 2012

Differential signature of the centrosomal MARK4 isoforms in glioma.

Anal Cell Pathol (Amst) 2011 ;34(6):319-38

Department of Medicine, Surgery and Dentistry, Ospedale San Paolo, Medical Genetics, Università degli studi di Milano, Italy.

Background: MAP/microtubule affinity-regulating kinase 4 (MARK4) is a serine-threonine kinase expressed in two spliced isoforms, MARK4L and MARK4S, of which MARK4L is a candidate for a role in neoplastic transformation.

Methods: We performed mutation analysis to identify sequence alterations possibly affecting MARK4 expression. We then investigated the MARK4L and MARK4S expression profile in 21 glioma cell lines and 36 tissues of different malignancy grades, glioblastoma-derived cancer stem cells (GBM CSCs) and mouse neural stem cells (NSCs) by real-time PCR, immunoblotting and immunohistochemistry. We also analyzed the sub-cellular localisation of MARK4 isoforms in glioma and normal cell lines by immunofluorescence.

Results: Mutation analysis rules out sequence variations as the cause of the altered MARK4 expression in glioma. Expression profiling confirms that MARK4L is the predominant isoform, whereas MARK4S levels are significantly decreased in comparison and show an inverse correlation with tumour grade. A high MARK4L/MARK4S ratio also characterizes undifferentiated cells, such as GBM CSCs and NSCs. Accordingly, only MARK4L is expressed in brain neurogenic regions. Moreover, while both MARK4 isoforms are localised to the centrosome and midbody in glioma and normal cells, the L isoform exhibits an additional nucleolar localisation in tumour cells.

Conclusions: The observed switch towards MARK4L suggests that the balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. Moreover, the MARK4L nucleolar localisation in tumour cells features this MARK4 isoform as a nucleolus-associated tumour marker.
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http://dx.doi.org/10.3233/ACP-2011-0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605669PMC
August 2012