Publications by authors named "Hebatallah Hassan"

19 Publications

  • Page 1 of 1

Emergence of Nosocomial Pneumonia Caused by Colistin-Resistant in Patients Admitted to Chest Intensive Care Unit.

Antibiotics (Basel) 2021 Feb 24;10(3). Epub 2021 Feb 24.

Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.

(1) Background: Colistin is a last-resort antibiotic used in treating multidrug-resistant Gram-negative infections. The growing emergence of colistin resistance in represents a serious health threat, particularly to intensive care unit (ICU) patients. (2) Methods: In this work, we investigated the emergence of colistin resistance in 140 nosocomial isolated from patients with pneumonia and admitted to the chest ICU over 36 months. Virulence and resistance-related genes and pathotypes in colistin-resistant and colistin-sensitive isolates were determined. (3) Results: Colistin resistance was observed in 21/140 (15%) of the nosocomial isolates. The MIC of the resistant strains was 4 mg/L, while MIC was 16 mg/L. Colistin-resistant isolates were also co-resistant to amoxicillin, amoxicillin/clavulanic, aztreonam, ciprofloxacin, and chloramphenicol. The mechanism of colistin resistance was represented by the presence of in all resistant strains. Respectively, 42.9% and 36.1% of colistin-resistant and colistin-sensitive groups were extended-spectrum β-lactamase (ESBL) producers, while 23.8% and 21% were metallo β-lactamase (MBL) producers. was the most frequently detected ESBL gene, while was the most common MBL in both groups. Importantly, most resistant strains showed a significantly high prevalence of (76.2%), (76.2%), and (52.4%) virulence-related genes. Enteroaggregative (76%) was the most frequently detected genotype among the colistin-resistant strains. (4) Conclusion: The high colistin resistance rate observed in strains isolated from patients with nosocomial pneumonia in our university hospital is worrisome. These isolates carry different drug resistance and virulence-related genes. Our results indicate the need for careful monitoring of colistin resistance in our university hospital. Furthermore, infection control policies restricting the unnecessary use of extended-spectrum cephalosporins and carbapenems are necessary.
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http://dx.doi.org/10.3390/antibiotics10030226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996192PMC
February 2021

Surveillance Study of Acute Neurological Manifestations among 439 Egyptian Patients with COVID-19 in Assiut and Aswan University Hospitals.

Neuroepidemiology 2021 25;55(2):109-118. Epub 2021 Feb 25.

Department of Neuropsychiatry, Assiut University Hospital, Faculty of Medicine, Aswan, Egypt.

Background: COVID-19 can be accompanied by acute neurological complications of both central and peripheral nervous systems (CNS and PNS). In this study, we estimate the frequency of such complications among hospital inpatients with COVID-19 in Assiut and Aswan university hospitals.

Materials And Methods: We screened all patients with suspected COVID-19 admitted from 1 June to 10 August 2020 to the university hospitals of Assiut and Aswan in Upper Egypt. Clinical and laboratory tests, CT/MRI of the chest and brain, and neurophysiology study were performed for each patient if indicated.

Results: 439 patients had confirmed/probable COVID-19; neurological manifestations occurred in 222. Of these, 117 had acute neurological disease and the remainder had nonspecific neuropsychiatric symptoms such as headache, vertigo, and depression. The CNS was affected in 75 patients: 55 had stroke and the others had convulsions (5), encephalitis (6), hypoxic encephalopathy (4), cord myelopathy (2), relapse of multiple sclerosis (2), and meningoencephalitis (1). The PNS was affected in 42 patients: the majority had anosmia and ageusia (31) and the others had Guillain-Barré syndrome (4), peripheral neuropathy (3), myasthenia gravis (MG, 2), or myositis (2). Fever, respiratory symptoms, and headache were the most common general symptoms. Hypertension, diabetes mellitus, and ischemic heart disease were the most common comorbidities in patients with CNS affection.

Conclusion: In COVID-19, both the CNS and PNS are affected. Stroke was the most common complication for CNS, and anosmia and/or ageusia were common for PNS diseases. However, there were 6 cases of encephalitis, 2 cases of spinal cord myelopathy, 2 cases of MG, and 2 cases of myositis.
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http://dx.doi.org/10.1159/000513647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018217PMC
April 2021

Induction of heparanase via IL-10 correlates with a high infiltration of CD163+ M2-type tumor-associated macrophages in inflammatory breast carcinomas.

Matrix Biol Plus 2020 May 29;6-7:100030. Epub 2020 Feb 29.

Department of Zoology, Faculty of Science, Cairo University, Giza, 12613, Egypt.

Inflammatory breast cancer (IBC) is the most aggressive and lethal form of breast cancer, characterized by a high infiltration of tumor-associated macrophages and poor prognosis. To identify new biomarkers and to elucidate the molecular mechanisms underlying IBC pathogenesis, we investigated the expression pattern of heparanase (HPSE) and its activator cathepsin L (CTSL). First, we quantitated the and mRNA levels in a cohort of breast cancer patients after curative surgery (20 IBC and 20-non-IBC). We discovered that both and mRNA levels were significantly induced in IBC tissue vis-à-vis non-IBC patients ( <0 .05 and  <0 .001, respectively). According to the molecular subtypes, mRNA levels were significantly higher in carcinoma tissues of triple negative (TN)-IBC as compared to TN-non-IBC ( <0 .05). Mechanistically, we discovered that pharmacological inhibition of HPSE activity resulted in a significant reduction of invasiveness in the IBC SUM149 cell line. Moreover, siRNA-mediated HPSE knockdown significantly downregulated the expression of the metastasis-related gene MMP2 and the cancer stem cell marker CD44. We also found that IBC tumors revealed robust heparanase immune-reactivity and CD163+ M2-type tumor-associated macrophages, with a positive correlation of both markers. Moreover, the secretome of axillary tributaries blood IBC CD14+ monocytes and the cytokine IL-10 significantly upregulated mRNA and protein expression in SUM149 cells. Intriguingly, massively elevated mRNA expression with a trend of positive correlation with mRNA expression was detected in carcinoma tissue of IBC. Our findings highlight a possible role played by CD14+ monocytes and CD163+ M2-type tumor-associated macrophages in regulating expression possibly via IL-10. Overall, we suggest that heparanase, cathepsin L and CD14+ monocytes-derived IL-10 may play an important role in the pathogenesis of IBC and their targeting could have therapeutic implications.
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http://dx.doi.org/10.1016/j.mbplus.2020.100030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852308PMC
May 2020

Inflammatory Breast Carcinoma: Elevated microRNA miR-181b-5p and Reduced miR-200b-3p, miR-200c-3p, and miR-203a-3p Expression as Potential Biomarkers with Diagnostic Value.

Biomolecules 2020 07 16;10(7). Epub 2020 Jul 16.

Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt.

Inflammatory breast cancer (IBC) is a rare yet aggressive breast cancer variant, associated with a poor prognosis. The major challenge for IBC is misdiagnosis due to the lack of molecular biomarkers. We profiled dysregulated expression of microRNAs (miRNAs) in primary samples of IBC and non-IBC tumors using human breast cancer miRNA PCR array. We discovered that 28 miRNAs were dysregulated (10 were upregulated, while 18 were underexpressed) in IBC vs. non-IBC tumors. We identified 128 hub genes, which are putative targets of the differentially expressed miRNAs and modulate important cancer biological processes. Furthermore, our qPCR analysis independently verified a significantly upregulated expression of miR-181b-5p, whereas a significant downregulation of miR-200b-3p, miR-200c-3p, and miR-203a-3p was detected in IBC tumors. Receiver operating characteristic (ROC) curves implied that the four miRNAs individually had a diagnostic accuracy in discriminating patients with IBC from non-IBC and that miR-203a-3p had the highest diagnostic value with an AUC of 0.821. Interestingly, a combination of miR-181b-5p, miR-200b-3p, and miR-200c-3p robustly improved the diagnostic accuracy, with an area under the curve (AUC) of 0.897. Intriguingly, qPCR revealed that the expression of zinc finger E box-binding homeobox 2 () mRNA, the putative target of miR-200b-3p, miR-200c-3p, and miR-203a-3p, was upregulated in IBC tumors. Overall, this study identified a set of miRNAs serving as potential biomarkers with diagnostic relevance for IBC.
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http://dx.doi.org/10.3390/biom10071059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407124PMC
July 2020

Evaluation of the effect of abdominal sacrocolpopexy (ASC) on urethral anatomy and continence mechanism using dynamic MRI.

Int Urol Nephrol 2020 Aug 16;52(8):1429-1435. Epub 2020 Mar 16.

Radiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Introduction: Treatment of pelvic organ prolapse (POP) associated with stress urinary incontinence (SUI) is a surgical challenge. Surgeons may perform combined prolapse and incontinence surgery or may correct prolapse first and evaluate incontinence afterwards. We present a prospective study to evaluate the effect of abdominal sacrocolpopexy (ASC) on urethral anatomy and continence using dynamic magnetic resonance imaging (MRI).

Methods: Twenty females with concomitant apical prolapse and SUI due to urethral hypermobility were included. Patients with intrinsic sphincteric deficiency (ISD) were excluded. All patients underwent ASC operation as a sole treatment without anti-incontinence procedure. Patients were informed they may need anti-incontinence procedure afterwards. Symptom-specific questionnaires assessing prolapse, incontinence, sexual function and quality of life (QoL), dynamic MRI and pressure flow urodynamic study were administered before and after surgery.

Results: Mean age was 53 years. All patients had apical prolapse; four with cystocele, and five with rectocele. Urethral hypermobility was positive in all patients. After performing ASC, all patients reported significant improvement of all prolapse and incontinence questionnaires as well as QoL and sexual function. Significant improvement of incontinence parameters on dynamic MRI (bladder neck descent, posterior urethrovesical angle and urethral inclination angle) was observed after ASC. Similarly, significant change in the position of the leading edge of prolapse and anorectal junction was observed.

Conclusions: In patients with prolapse and urethral hypermobility, ASC may return bladder neck and urethral anatomy towards normal as proved by dynamic MRI. However, further studies on larger number of patients with longer follow-up period are required.
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http://dx.doi.org/10.1007/s11255-020-02444-8DOI Listing
August 2020

The immunomodulatory role of tumor Syndecan-1 (CD138) on ex vivo tumor microenvironmental CD4+ T cell polarization in inflammatory and non-inflammatory breast cancer patients.

PLoS One 2019 30;14(5):e0217550. Epub 2019 May 30.

Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.

Herein, we aimed to identify the immunomodulatory role of tumor Syndecan-1 (CD138) in the polarization of CD4+ T helper (Th) subsets isolated from the tumor microenvironment of inflammatory breast cancer (IBC) and non-IBC patients. Lymphocytes and mononuclear cells isolated from the axillary tributaries of non-IBC and IBC patients during modified radical mastectomy were either stimulated with the secretome as indirect co-culture or directly co-cultured with control and Syndecan-1-silenced SUM-149 IBC cells. In addition, peripheral blood mononuclear cells (PBMCs) of normal subjects were used for the direct co-culture. Employing flow cytometry, we analyzed the expression of the intracellular IFN-γ, IL-4, IL-17, and Foxp3 markers as readout for basal and co-cultured Th1, Th2, Th17, and Treg CD4+ subsets, respectively. Our data revealed that IBC displayed a lower basal frequency of Th1 and Th2 subsets than non-IBC. Syndecan-1-silenced SUM-149 cells significantly upregulated only Treg subset polarization of normal subjects relative to controls. However, Syndecan-1 silencing significantly enhanced the polarization of Th17 and Treg subsets of non-IBC under both direct and indirect conditions and induced only Th1 subset polarization under indirect conditions compared to control. Interestingly, qPCR revealed that there was a negative correlation between Syndecan-1 and each of IL-4, IL-17, and Foxp3 mRNA expression in carcinoma tissues of IBC and that the correlation was reversed in non-IBC. Mechanistically, Syndecan-1 knockdown in SUM-149 cells promoted Th17 cell expansion via upregulation of IL-23 and the Notch ligand DLL4. Overall, this study indicates a low frequency of the circulating antitumor Th1 subset in IBC and suggests that tumor Syndecan-1 silencing enhances ex vivo polarization of CD4+ Th17 and Treg cells of non-IBC, whereby Th17 polarization is possibly mediated via upregulation of IL-23 and DLL4. These findings suggest the immunoregulatory role of tumor Syndecan-1 expression in Th cell polarization that may have therapeutic implications for breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542534PMC
February 2020

Inflammatory breast cancer: Activation of the aryl hydrocarbon receptor and its target CYP1B1 correlates closely with Wnt5a/b-β-catenin signalling, the stem cell phenotype and disease progression.

J Adv Res 2019 Mar 8;16:75-86. Epub 2018 Dec 8.

Department of Zoology, Faculty of Science, Cairo University, Cairo University, Giza 12613, Egypt.

The aim of the present study was to evaluate the expression levels of the aryl hydrocarbon receptor (AHR) and its target gene and to correlate their expression with Wnt5a/b-β-catenin, the CD44/CD24 cancer stem cell (CSC) subset and factors associated with poor prognosis in inflammatory breast cancer (IBC) and non-IBC patients. The methods of analysis used were quantitative real-time PCR, western blotting, immunohistochemistry and flow cytometry. Compared to non-IBC tissues, IBC tissues exhibited the overexpression of AHR and its target gene/protein CYP1B1. and mRNA levels were associated with the poor clinical prognosis markers tumour grade, lymphovascular invasion, cell proliferation and lymph node metastasis. Furthermore, AHR expression correlated with the expression of Wnt5a/b and β-catenin signalling molecules, and mRNA expression was downregulated in the SUM149 human IBC cell line and the MDA-MB-231 non-IBC cell line upon inhibition of AHR. gene knockout (CRISPR-Cas9) inhibits and expression in the IBC cell line. The CD44/CD24 subset was significantly correlated with the expression of AHR, CYP1B1, Wnt5a/b and β-catenin in IBC tissues. The overexpression of AHR and its target CYP1B1 correlated with the expression of Wnt5a/b and β-catenin, CSCs, and poor clinical prognostic factors of IBC. Thus, targeting AHR and/or its downstream target molecules CYP1B1 and Wnt5a/b may represent a therapeutic approach for IBC.
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http://dx.doi.org/10.1016/j.jare.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413307PMC
March 2019

Tumor microenvironmental plasmacytoid dendritic cells contribute to breast cancer lymph node metastasis via CXCR4/SDF-1 axis.

Breast Cancer Res Treat 2019 Apr 10;174(3):679-691. Epub 2019 Jan 10.

Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt.

Purpose: Plasmacytoid dendritic cells (PDCs) infiltration into breast cancer tissues is associated with poor prognosis. Also, CXCR4 shows compelling evidences to be exploited by cancer cells to migrate to distant sites. The present study investigated lymph node metastasis in the light of PDCs infiltration and the potential cross talk with CXCR4/SDF-1 chemokine axis.

Methods: We assessed circulating PDCs proportions drained from the axillary tributaries, and the in situ expression of both CD303 and CXCR4 in breast cancer patients with positive lymph nodes (pLN) and negative lymph nodes (nLN) using immunohistochemistry and flow cytometry. We also analyzed the expression of SDF-1 in lymph nodes of pLN and nLN patients. We studied the effect of the secretome of PDCs of pLN and nLN patients on the expression of CXCR4 and activation of NF-κB in human breast cancer cell lines SKBR3 and MCF-7. TNF-α mRNA expression level in PDCs from both groups was determined by qPCR.

Results: Our findings indicate increased infiltration of PDCs in breast cancer tissues of pLN patients than nLN patients, which correlates with CXCR4 cells percentage. Interestingly, SDF-1 is highly immunostained in lymph nodes of pLN patients compared to nLN patients. Our in vitro experiments demonstrate an upregulation of NF-κB expression and CXCR4 cells upon stimulation with PDCs secretome of pLN patients than those of nLN patients. Also, PDCs isolated from pLN patients exhibited a higher TNF-α mRNA expression than nLN patients. Treatment of MCF-7 cell lines with TNF-α significantly upregulates CXCR4 expression.

Conclusions: Our findings suggest a potential role for microenvironmental PDCs in breast cancer lymph node metastasis via CXCR4/SDF-1 axis.
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http://dx.doi.org/10.1007/s10549-019-05129-8DOI Listing
April 2019

Fat Necrosis of the Breast: Magnetic Resonance Imaging Characteristics and Pathologic Correlation.

Acad Radiol 2018 08 13;25(8):985-992. Epub 2018 Feb 13.

Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Alexandria University, Champollion Street, El Azareeta, Alexandria, Egypt; Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany.

Rationale And Objectives: This study aims to describe the magnetic resonance imaging (MRI) features of fat necrosis on magnetic resonance mammography, which may downstage a suspicious lesion to a merely benign finding.

Materials And Methods: This prospective study included 82 female patients (mean age 50 years) who were diagnosed to have suspicious lesions by mammography, ultrasonography or both. All patients underwent MRI including diffusion-weighted imaging and spectroscopy. Image postprocessing and analysis included signal intensity, enhancement characteristics, diffusion restriction, and spectroscopic analysis. All patients underwent histopathological analysis for confirmation. Sensitivity, specificity, positive predictive value (PPV), and negative (NPV) predictive value were calculated.

Results: To label a lesion as fat necrosis on MRI analysis, presence of fat signal in a lesion revealed sensitivity of 98.04%, specificity of 100%, PPV of 100%, and NPP of 96.88%, whereas nonenhancement of the lesion itself revealed sensitivity of 96.08%, specificity of 100%, PPV of 100%, and NPP of 93.94%. However, adding both the nonrestriction on diffusion analysis and the lack of tCholine at 3.22 ppm increased the sensitivity and specificity to 100%, as well as PPV of 100% for fat necrosis and hence a NPV for malignancy of 100%.

Conclusions: MRI proved to be of value in differentiating fat necrosis from malignancy based on the molecular composition of fat necrosis, clearly depicted by MRI without the need for invasive confirmation by biopsy.
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http://dx.doi.org/10.1016/j.acra.2017.12.019DOI Listing
August 2018

Assessment of the cochlear nerve to facial nerve size ratio using MR multiplanar reconstruction of the internal auditory canal in patients presenting with acquired long-standing hearing loss.

Br J Radiol 2017 May 3;90(1073):20160870. Epub 2017 Apr 3.

1 Institute for Diagnostic and Interventional Radiology, Frankfurt University Hospital, Frankfurt, Germany.

Objective: To test using the facial nerve as a reference for assessment of the cochlear nerve size in patients with acquired long-standing sensorineural hearing loss (SNHL) using MRI multiplanar reconstruction.

Methods: The study was retrospectively performed on 86 patients. Group 1 (study group, n = 53) with bilateral long-standing SNHL. Group 2 (control group, n = 33) without hearing loss. The nerve size was measured by drawing a region of interest around the cross-sectional circumference of the nerve in multiplanar reconstruction images.

Results: No significant correlation was noted between the cochlear nerve and facial nerve size, and the patient's age, gender and weight (p > 0.05). In Group 1, the mean ratio of the cochlear to facial nerve size was 0.99 ± 0.30 (range: 0.52-1.86) and 1.12 ± 0.35 (range: 0.34-2.3) for the right and left sides, respectively. In Group 2, it was 1.18 ± 0.23 (range: 0.78-1.71) and 1.25 ± 0.25 (range: 0.85-1.94) for the right and left sides, respectively. The cochlear nerve size was statistically (p = 0.0004) smaller in Group 1 than in Group 2.

Conclusion: The cochlear nerve size and the cochlear to facial nerve size ratio are significantly smaller in patients with acquired long-standing SNHL. Advances in knowledge: The facial nerve can be used as a reference for assessment of the cochlear nerve in patients with acquired long-standing SNHL.
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http://dx.doi.org/10.1259/bjr.20160870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605108PMC
May 2017

Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways.

Mol Cancer 2017 03 7;16(1):57. Epub 2017 Mar 7.

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149, Münster, Germany.

Background: Inflammatory breast cancer (IBC), a particularly aggressive form of breast cancer, is characterized by cancer stem cell (CSC) phenotype. Due to a lack of targeted therapies, the identification of molecular markers of IBC is of major importance. The heparan sulfate proteoglycan Syndecan-1 acts as a coreceptor for growth factors and chemokines, modulating inflammation, tumor progression, and cancer stemness, thus it may emerge as a molecular marker for IBC.

Methods: We characterized expression of Syndecan-1 and the CSC marker CD44, Notch-1 & -3 and EGFR in carcinoma tissues of triple negative IBC (n = 13) and non-IBC (n = 17) patients using qPCR and immunohistochemistry. Impact of siRNA-mediated Syndecan-1 knockdown on the CSC phenotype of the human triple negative IBC cell line SUM-149 and HER-2-overexpressing non-IBC SKBR3 cells employing qPCR, flow cytometry, Western blotting, secretome profiling and Notch pharmacological inhibition experiments. Data were statistically analyzed using Student's t-test/Mann-Whitney U-test or one-way ANOVA followed by Tukey's multiple comparison tests.

Results: Our data indicate upregulation and a significant positive correlation of Syndecan-1 with CD44 protein, and Notch-1 & -3 and EGFR mRNA in IBC vs non-IBC. ALDH1 activity and the CD44CD24 subset as readout of a CSC phenotype were reduced upon Syndecan-1 knockdown. Functionally, Syndecan-1 silencing significantly reduced 3D spheroid and colony formation. Intriguingly, qPCR results indicate downregulation of the IL-6, IL-8, CCL20, gp130 and EGFR mRNA upon Syndecan-1 suppression in both cell lines. Moreover, Syndecan-1 silencing significantly downregulated Notch-1, -3, -4 and Hey-1 in SUM-149 cells, and downregulated only Notch-3 and Gli-1 mRNA in SKBR3 cells. Secretome profiling unveiled reduced IL-6, IL-8, GRO-alpha and GRO a/b/g cytokines in conditioned media of Syndecan-1 knockdown SUM-149 cells compared to controls. The constitutively activated STAT3 and NFκB, and expression of gp130, Notch-1 & -2, and EGFR proteins were suppressed upon Syndecan-1 ablation. Mechanistically, gamma-secretase inhibition experiments suggested that Syndecan-1 may regulate the expression of IL-6, IL-8, gp130, Hey-1, EGFR and p-Akt via Notch signaling.

Conclusions: Syndecan-1 acts as a novel tissue biomarker and a modulator of CSC phenotype of triple negative IBC via the IL-6/STAT3, Notch and EGFR signaling pathways, thus emerging as a promising therapeutic target for IBC.
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http://dx.doi.org/10.1186/s12943-017-0621-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341174PMC
March 2017

Modified MR defecography without rectal filling in obstructed defecation syndrome: Initial experience.

Eur J Radiol 2016 Sep 24;85(9):1673-81. Epub 2016 Jun 24.

Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Alexandria University, Egypt; Institute for Diagnostic and Interventional Radiology, Goethe University Hospital, Frankfurt am Main, Germany.

Objective: To evaluate the role of dynamic MR defecography before rectal filling in detecting occult anterior compartment prolapse in patients with obstructed defecation.

Methods: This prospective study was approved by the ethics committee. Seventy six females with obstructed defecation underwent dynamic MR defecography before and after rectal filling. Pre-rectal and post-rectal filling sequences were interpreted separately by two radiologists on two different settings with a time interval of one week. Statistical analysis was performed using Wilcoxon's-matched-pairs signed rank test and t-test for matched pairs; differences were considered statistically significant at p<0.05.

Results: Fifty eight females of 76 showed additional anterior compartment derangement, with 27 diagnosed only in pre-rectal filling sequence (27/58=46.55%). Following rectal filling detected cystocele in 27 patients was not identified in 14 cases and downgraded in 13. Similarly, detected uterine prolapse in 17 patients was not visualized in 14 patients and downgraded in 3. Furthermore, rectocele was identified in 7 cases before gel enema, additional 32 detected after rectal filling. Significant statistical difference in the detection of both cystocele (p=0.0001) and uterine prolapse (p=0.0013) was identified in the non-filled sequence.

Conclusion: Pelvic floor imaging before rectal filling is significantly better for detection of anterior compartment prolapse.
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http://dx.doi.org/10.1016/j.ejrad.2016.06.014DOI Listing
September 2016

Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression.

J Adv Res 2016 Sep 30;7(5):661-70. Epub 2016 Jun 30.

Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt.

Hormonal-receptor positive (HRP) breast cancer patients with positive metastatic axillary lymph nodes are characterized by poor prognosis and increased mortality rate. The mechanisms by which cancer cells invade lymph nodes have not yet been fully explored. Several studies have shown that expression of IL-6 and the proteolytic enzyme cathepsin B (CTSB) was associated with breast cancer poor prognosis. In the present study, the effect of different concentrations of recombinant human IL-6 on the invasiveness capacity of HRP breast cancer cell line MCF-7 was tested using an in vitro invasion chamber assay. The impact of IL-6 on expression and activity of CTSB was also investigated. IL-6 treatment promoted the invasiveness potential of MCF-7 cells in a dose-dependent manner. Furthermore, MCF-7 cells displayed elevated CTSB expression and activity associated with loss of E-cadherin and upregulation of vimentin protein levels upon IL-6 stimulation. To validate these results in vivo, the level of expression of IL-6 and CTSB in the carcinoma tissues of HRP-breast cancer patients with positive and negative axillary metastatic lymph nodes (pLNs and nLNs) was assessed. Western blot and immunohistochemical staining data showed that expression of IL-6 and CTSB was higher in carcinoma tissues in HRP-breast cancer with pLNs than those with nLNs patients. ELISA results showed carcinoma tissues of HRP-breast cancer with pLNs exhibited significantly elevated IL-6 protein levels by approximately 2.8-fold compared with those with nLNs patients (P < 0.05). Interestingly, a significantly positive correlation between IL-6 and CTSB expression was detected in clinical samples of HRP-breast cancer patients with pLNs (r = 0.78, P < 0.01). Collectively, this study suggests that IL-6-induced CTSB may play a role in lymph node metastasis, and that may possess future therapeutic implications for HRP-breast cancer patients with pLNs. Further studies are necessary to fully identify IL-6/CTSB axis in different molecular subtypes of breast cancer.
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http://dx.doi.org/10.1016/j.jare.2016.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957008PMC
September 2016

Prediction of O-glycosylation Sites Using Random Forest and GA-Tuned PSO Technique.

Bioinform Biol Insights 2015 5;9:103-9. Epub 2015 Jul 5.

Department of Computer Science, College of Computing and Information Technology, Arab Academy for Science and Technology and Maritime Transport (AASTMT), Cairo, Egypt.

O-glycosylation is one of the main types of the mammalian protein glycosylation; it occurs on the particular site of serine (S) or threonine (T). Several O-glycosylation site predictors have been developed. However, a need to get even better prediction tools remains. One challenge in training the classifiers is that the available datasets are highly imbalanced, which makes the classification accuracy for the minority class to become unsatisfactory. In our previous work, we have proposed a new classification approach, which is based on particle swarm optimization (PSO) and random forest (RF); this approach has considered the imbalanced dataset problem. The PSO parameters setting in the training process impacts the classification accuracy. Thus, in this paper, we perform parameters optimization for the PSO algorithm, based on genetic algorithm, in order to increase the classification accuracy. Our proposed genetic algorithm-based approach has shown better performance in terms of area under the receiver operating characteristic curve against existing predictors. In addition, we implemented a glycosylation predictor tool based on that approach, and we demonstrated that this tool could successfully identify candidate glycosylation sites in case study protein.
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http://dx.doi.org/10.4137/BBI.S26864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494626PMC
August 2015

MicroRNA regulation of proteoglycan function in cancer.

FEBS J 2014 Nov 6;281(22):5009-22. Epub 2014 Nov 6.

Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.

MicroRNAs are small noncoding RNAs acting as physiological regulators of gene expression at the post-transcriptional level. In cancer, the expression of microRNAs is dysregulated compared to healthy tissue, suggesting a mechanistic role in disease progression. Recent experimental evidence supports the important molecular role of proteoglycans as microRNA targets in this process. Misexpression of specific microRNAs results in aberrant expression patterns of proteoglycans, as well as their biosynthetic enzymes. Consequently, cell proliferation and apoptosis, adhesion, migration, invasiveness, epithelial-to-mesenchymal transition and cancer stem cell properties are affected as a result of the multifunctional properties of proteoglycans. A pharmacological targeting of the microRNA-proteoglycan axis emerges as a new therapeutic concept in cancer.
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http://dx.doi.org/10.1111/febs.13026DOI Listing
November 2014

MicroRNA-dependent targeting of the extracellular matrix as a mechanism of regulating cell behavior.

Biochim Biophys Acta 2014 Aug 23;1840(8):2609-20. Epub 2014 Jan 23.

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany. Electronic address:

Background: MicroRNAs are small noncoding RNAs which regulate gene expression at the posttranscriptional level by inducing mRNA degradation or translational repression. MicroRNA-dependent modulation of the extracellular matrix and its cellular receptors has emerged as a novel mechanism of regulating numerous matrix-dependent processes, including cell proliferation and apoptosis, cell adhesion and migration, cell differentiation and stem cell properties.

Scope Of Review: In this review, we will present different mechanisms by which microRNAs and extracellular matrix constituents mutually regulate their expression, and we will demonstrate how these expression changes affect cell behavior. We will also highlight the importance of dysregulated matrix-related microRNA expression for the pathogenesis of inflammatory and malignant disease, and discuss the potential for diagnostic and therapeutic applications.

Major Conclusions: MicroRNAs and matrix-dependent signal transduction processes form novel regulatory circuits, which profoundly affect cell behavior. As misexpression of microRNAs targeting extracellular matrix constituents is observed in a variety of diseases, a pharmacological intervention with these processes has therapeutic potential, as successfully demonstrated in vitro and in advanced animal models. However, a deeper mechanistic understanding is required to address potential side effects prior to clinical applications in humans.

General Significance: A full understanding of the role and function of microRNA-dependent regulation of the extracellular matrix may lead to new targeted therapies and new diagnostics for malignant and inflammatory diseases in humans. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
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http://dx.doi.org/10.1016/j.bbagen.2014.01.022DOI Listing
August 2014

Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling.

PLoS One 2013 31;8(12):e85737. Epub 2013 Dec 31.

Department of Gynecology and Obstetrics, University Hospital Münster, Münster, Germany.

Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085737PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877388PMC
August 2014

Syndecan-1 modulates β-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation.

FEBS J 2013 May 31;280(10):2216-27. Epub 2013 Jan 31.

Department of Gynecology and Obstetrics, University Hospital Münster, Germany.

Syndecan-1 is a cell surface heparan sulfate proteoglycan with various biological functions relevant to tumor progression and inflammation, including cell-cell adhesion, cell-matrix interaction, and cytokine signaling driving cell proliferation and motility. Syndecan-1 is a prognostic factor in breast cancer, and has a predicitive value for neodadjuvant chemotherapy. It is still poorly understood how syndecan-1 integrates matrix-dependent and cytokine-dependent signaling processes in the tumor microenvironment. Here, we evaluated the potential role of syndecan-1 in modulating matrix-dependent breast cancer cell migration in the presence of interleukin-6, and its potential involvement in resistance to irradiation in vitro. MDA-MB-231 breast cancer cells were transiently transfected with syndecan-1 small interfering RNA or control reagents, and this was followed by stimulation with interleukin-6 or irradiation. Cellular responses were monitored by adhesion, migration and colony formation assays, as well as analysis of cell signaling. Syndecan-1 depletion increased cell adhesion to fibronectin. Increased migration on fibronectin was significantly suppressed by interleukin-6, and GRGDSP peptides inhibited both adhesion and migration. Interleukin-6-induced activation of focal adhesion kinase and reduction of constitutive nuclear factor kappaB signaling were decreased in syndecan-1-deficient cells. Focal adhesion kinase hyperactivation in syndecan-1-depleted cells was associated with dramatically reduced radiation sensitivity. We conclude that loss of syndecan-1 leads to enhanced activation of β1 -integrins and focal adhesion kinase, thus increasing breast cancer cell adhesion, migration, and resistance to irradiation. Syndecan-1 deficiency also attenuates the modulatory effect of the inflammatory microenvironment constituent interleukin-6 on cancer cell migration.
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http://dx.doi.org/10.1111/febs.12111DOI Listing
May 2013

Targeting of syndecan-1 by micro-ribonucleic acid miR-10b modulates invasiveness of endometriotic cells via dysregulation of the proteolytic milieu and interleukin-6 secretion.

Fertil Steril 2013 Mar 30;99(3):871-881.e1. Epub 2012 Nov 30.

Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.

Objective: To study the function of syndecan-1 (SDC1) and its potential regulator miR-10b in endometriosis.

Design: Experimental laboratory study.

Setting: University medical center.

Patient(s): Not applicable.

Intervention(s): The human endometriotic cell line 12Z was transiently transfected with SDC1 small interfering RNA or miR-10b precursors and investigated for changes in cell behavior and gene expression. 12Z and primary eutopic endometrial stroma cells of two American Society for Reproductive Medicine class III endometriosis patients were transfected with miR-10b precursors to investigate posttranscriptional regulation of SDC1.

Main Outcome Measure(s): Quantitative polymerase chain reaction, Western blotting, flow cytometry, 3' untranslated region luciferase assays, and zymography were used to measure miR-10b-dependent targeting of SDC1 and SDC1-dependent expression changes of proteases and interleukin-6. Altered cell behavior was monitored by Matrigel invasion assays, cell viability assays, and mitogen-activated protein kinase activation blots.

Result(s): Knockdown of SDC1 inhibited Matrigel invasiveness by >60% but did not affect cell viability. Interleukin-6 secretion, matrix metalloproteinase-9 expression, and matrix metalloproteinase-2 activity were reduced, whereas plasminogen activator inhibitor-1 protein expression was up-regulated. miR-10b overexpression significantly down-regulated SDC1, reduced Matrigel invasiveness by 20% and cell viability by 14%, and decreased mitogen-activated protein kinase activation in response to hepatocyte growth factor.

Conclusion(s): Syndecan-1, a target of miR-10b, inhibits epithelial endometriotic cell invasiveness through down-regulation of metalloproteinase activity and interleukin-6.
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http://dx.doi.org/10.1016/j.fertnstert.2012.10.051DOI Listing
March 2013