Publications by authors named "Mohamed El-Shinawi"

39 Publications

IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling.

Biochim Biophys Acta Mol Cell Res 2021 May 2;1868(6):118995. Epub 2021 Mar 2.

Zoology Department, Faculty of Science, Cairo University, Giza 12613, Egypt; Director of Biotechnology program, Faculty of Science, Galala University, 43511 Suez, Egypt. Electronic address:

Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8.
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http://dx.doi.org/10.1016/j.bbamcr.2021.118995DOI Listing
May 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

Non-operative management of blunt abdominal solid organ trauma in adult patients.

Afr J Emerg Med 2020 Sep 5;10(3):123-126. Epub 2020 May 5.

Department of Emergency Medicine, Yale University School of Medicine, New Haven, CT, USA.

Introduction: Despite agreement in the literature that "stable" blunt trauma patients may be managed conservatively, in Egypt many such patients receive operative management. This paper presents the results of a pragmatic, prospective, observational study to evaluate outcomes of non-operative (NOP) versus operative (OP) management of blunt abdominal solid organ trauma in hemodynamically stable adults admitted to Tanta University Emergency Hospital (TUH) in Egypt.

Methods: A prospective observational study enrolled adult blunt abdominal trauma patients with solid organ injury at TUH over a 3-year period (June 2014-June 2017). Inclusion criteria were age ≥18 yr, mean arterial pressure >65 mm Hg, heart rate <110 bpm, hematocrit ≥7 mg/dl, and abdominal organ injury diagnosed by ultrasound or computed tomography (CT). Excluded patients were those with pelvis and femur fractures; patients with penetrating abdominal trauma; predominate burn injuries, children and pregnant women. All patients were assigned to non-operative or operative management based on clinician preference. Outcomes of interest were 30-day mortality, blood transfusion volume, and length of stay. Descriptive statistics and χ were used to compare outcomes.

Results: During the study period, 4254 trauma patients presented to TUH. Of these, 790 had blunt abdominal trauma and 111 (14.1%) met inclusion criteria. Injury severity scores for each group were comparable (24 ± 10 - NOP vs. 28 ± 11 - OP,  = 0.126). NOP received less transfused blood (213.41 ± 360.3 ml [NOP] vs.1155.17 ± 380.4 ml [OP] ( < 0.0001)) but had a longer length of stay (8.29 ± 2.8 [NOP] vs. 6.45 ± 1.97 days [OP] ( = 0.012)). There was no difference in mortality between groups ( = 0.091).

Conclusion: Our study demonstrated that non-operative management in Egypt of blunt abdominal trauma was safe and resulted in fewer procedures, fewer units of blood transfused, and no increase in mortality. Longer length of stay for non-operative patients might reflect treating physician caution in their management.
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http://dx.doi.org/10.1016/j.afjem.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474228PMC
September 2020

Harnessing inter-disciplinary collaboration to improve emergency care in low- and middle-income countries (LMICs): results of research prioritisation setting exercise.

BMC Emerg Med 2020 08 31;20(1):68. Epub 2020 Aug 31.

Division of Emergency Medicine, University of Cape Town, F51 Old Main Building, Groote Schuur Hospital Observatory, Cape Town, South Africa.

Background: More than half of deaths in low- and middle-income countries (LMICs) result from conditions that could be treated with emergency care - an integral component of universal health coverage (UHC) - through timely access to lifesaving interventions.

Methods: The World Health Organization (WHO) aims to extend UHC to a further 1 billion people by 2023, yet evidence supporting improved emergency care coverage is lacking. In this article, we explore four phases of a research prioritisation setting (RPS) exercise conducted by researchers and stakeholders from South Africa, Egypt, Nepal, Jamaica, Tanzania, Trinidad and Tobago, Tunisia, Colombia, Ethiopia, Iran, Jordan, Malaysia, South Korea and Phillipines, USA and UK as a key step in gathering evidence required by policy makers and practitioners for the strengthening of emergency care systems in limited-resource settings.

Results: The RPS proposed seven priority research questions addressing: identification of context-relevant emergency care indicators, barriers to effective emergency care; accuracy and impact of triage tools; potential quality improvement via registries; characteristics of people seeking emergency care; best practices for staff training and retention; and cost effectiveness of critical care - all within LMICs.

Conclusions: Convened by WHO and facilitated by the University of Sheffield, the Global Emergency Care Research Network project (GEM-CARN) brought together a coalition of 16 countries to identify research priorities for strengthening emergency care in LMICs. Our article further assesses the quality of the RPS exercise and reviews the current evidence supporting the identified priorities.
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http://dx.doi.org/10.1186/s12873-020-00362-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457362PMC
August 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

IL-8 and MCP-1/CCL2 regulate proteolytic activity in triple negative inflammatory breast cancer a mechanism that might be modulated by Src and Erk1/2.

Toxicol Appl Pharmacol 2020 08 5;401:115092. Epub 2020 Jun 5.

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

Inflammatory breast cancer (IBC) is a highly metastatic and lethal breast cancer. As many as 25-30% of IBCs are triple negative (TN) and associated with low survival rates and poor prognosis. We found that the microenvironment of IBC is characterized by high infiltration of tumor associated macrophages (TAMs) and by over-expression of the cysteine protease cathepsin B (CTSB). TAMs in IBC secrete high levels of the cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared to non-IBC patients. Herein, we tested the roles of IL-8 and MCP-1/CCL2 in modulating proteolytic activity and invasiveness of TN-non-IBC as compared to TN-IBC and addressed the underlying molecular mechanism(s) for both cytokines. Quantitative real time PCR results showed that IL-8 and MCP-1/CCL2 were significantly overexpressed in tissues of TN-IBCs. IL-8 and MCP-1/CCL2 induced CTSB expression and activity of the p-Src and p-Erk1/2 signaling pathways relevant for invasion and metastasis in TN-non-IBC, HCC70 cells and TN-IBC, SUM149 cells. Dasatinib, an inhibitor of p-Src, and U0126, an inhibitor of p-Erk1/2, down-regulated invasion and expression of CTSB by HCC70 and SUM149 cells, a mechanism that is reversed by IL-8 and MCP-1/CCL2. Our study shows that targeting the cytokines IL-8 and MCP-1/CCL2 and associated signaling molecules may represent a promising therapeutic strategy in TN-IBC patients.
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http://dx.doi.org/10.1016/j.taap.2020.115092DOI Listing
August 2020

Factors associated with injuries among preschool children in Egypt: demographic and health survey results, 2014.

BMC Public Health 2020 May 1;20(1):595. Epub 2020 May 1.

Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Background: Childhood injuries are a significant and growing global public health problem, often with high morbidity and, at times, mortality. A large proportion of injuries in preschool children occur in or around the home. We aimed to identify socioeconomic and demographic factors associated with preschool children injuries in Egypt.

Methods: Secondary data analysis were done for the Egyptian Demographic and Health Surveys (EDHS), 2014. Potential associated factors were measured from data on child welfare and questions on the prevalence of accidents and injuries of preschool children. These data were linked to the children demographic data, maternal age at marriage, working status of the mother, and questions on childcare arrangements.

Results: Out of the 634 injured children, 520 (83.4%) children required medical care for their injuries. The most common reported injury was an open wound 288 (45.5%), followed by fractures 237 (35.7%), burns 124 (19.7%), electrical shock 12 (1.9%) and other unknown types of injury 15 (2.4%). There was a positive correlation between injury and child's age, household wealth, mother's age at marriage, and unsupervised children or children left in the care of a minor.

Conclusion: Leaving children unsupervised or in the presence of other young children is significantly associated with the occurrence of child injuries.
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http://dx.doi.org/10.1186/s12889-020-08658-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193349PMC
May 2020

Financial and food security challenges of Egyptian women undergoing breast cancer treatment.

Support Care Cancer 2020 Dec 27;28(12):5787-5794. Epub 2020 Mar 27.

Department of General Surgery, Ain Shams University, Cairo, Egypt.

Background: Breast cancer treatment is an established cause of financial toxicity, and associated costs may contribute to higher mortality and morbidity rates. In Egypt, breast cancer incidence and mortality rates are among the highest in the Middle East. Late-stage diagnosis is common, and disease occurs at an earlier age than in Europe and North America. Out-of-pocket payments are the primary means of financing healthcare in Egypt, and socioeconomic factors have been shown to significantly impact access to cancer screening and treatment.

Methods: An observational cross-sectional study was conducted among breast cancer patients at Ain Shams University Hospitals in Cairo from 2013 to 2015.

Results: One hundred women with breast cancer participated. There was a high need for financial assistance (66.0%) and patients with financial needs had great difficulty affording medications (80.0%). A number of patients had lost their jobs following diagnosis, with 32.7% employed prior to diagnosis and 15.3% afterwards. Nearly one-half of participants were classified as food insecure, and nearly one-third reported difficulty affording transportation costs.

Conclusions: This is the first study to describe socioeconomic needs and financial impact among a cohort of Egyptian women undergoing breast cancer treatment. The findings highlight the financial impact of breast cancer treatment on a cohort of Egyptian breast cancer patients and the need for a multidisciplinary approach to help them access and mitigate the costs of treatment. Recommendations include implementing patient financial navigation services and producing printed materials to inform patients of resources to help mitigate the treatment's financial impact.
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http://dx.doi.org/10.1007/s00520-020-05426-9DOI Listing
December 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

Characterization of inflammatory breast cancer: a vibrational microspectroscopy and imaging approach at the cellular and tissue level.

Analyst 2018 Dec;143(24):6103-6112

Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et de Biologie Moléculaire, UFR de Médecine, Reims, France.

Inflammatory breast cancer (IBC) has a poor prognosis because of the lack of specific biomarkers and its late diagnosis. An accurate and rapid diagnosis implemented early enough can significantly improve the disease outcome. Vibrational spectroscopy has proven to be useful for cell and tissue characterization based on the intrinsic molecular information. Here, we have applied infrared and Raman microspectroscopy and imaging to differentiate between non-IBC and IBC at both cell and tissue levels. Two human breast cancer cell lines (MDA-MB-231 and SUM-149), 20 breast cancer patients (10 non-IBC and 10 IBC), and 4 healthy volunteer biopsies were investigated. Fixed cells and tissues were analyzed by FTIR microspectroscopy and imaging, while live cells were studied by Raman microspectroscopy. Spectra were analyzed by hierarchical cluster analysis (HCA) and images by common k-means clustering algorithms. For both cell suspensions and single cells, FTIR spectroscopy showed sufficient high inter-group variability to delineate MDA-MB-231 and SUM-149 cell lines. Most significant differences were observed in the spectral regions of 1096-1108 and 1672-1692 cm-1. Analysis of live cells by Raman microspectroscopy gave also a good discrimination of these cell types. The most discriminant regions were 688-992, 1019-1114, 1217-1375 and 1516-1625 cm-1. Finally, k-means cluster analysis of FTIR images allowed delineating non-IBC from IBC tissues. This study demonstrates the potential of vibrational spectroscopy and imaging to discriminate between non-IBC and IBC at both cell and tissue levels.
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http://dx.doi.org/10.1039/c8an01292jDOI Listing
December 2018

Concomitance of downregulated active caspase-3 and upregulated X-chromosome linked inhibitor of apoptosis protein as a sensitive diagnostic approach for breast cancer.

Mol Cell Biochem 2019 May 16;455(1-2):159-167. Epub 2018 Nov 16.

General Surgery Department, Faculty of Medicine, Ain Shams University, Abbassia, 11566, Cairo, Egypt.

We aimed to explore the efficacy of active caspase-3 and X-chromosome linked inhibitor of apoptosis protein (XIAP) as diagnostic markers for breast cancer. Furthermore, we examined the relationship between the examined parameters and clinicopathological factors. The current study involved 96 patients diagnosed with breast cancer and 40 patients had benign breast diseases. The expression of active caspase-3 was analyzed by both ELISA and Western blot, whereas the expression of XIAP was determined by ELISA in cell lysates. Active caspase-3 was significantly downregulated, while XIAP was markedly upregulated in patients with breast cancer in comparison to benign group. A significant negative correlation was observed between active caspase-3 and XIAP in breast cancer patients. Low active caspase-3 expression was associated with high grade, whereas, the high XIAP level was correlated with poorly differentiated tumors and late tumor stages. The sensitivity and specificity were 73.96% and 80.0% for active caspase-3, and, 70.83% and 82.5% for XIAP. A combination of active caspase-3 and XIAP provided a promising sensitivity of 88.54% and specificity of 90.0%. Our data indicate that active caspase-3 and XIAP could be substantial diagnostic markers for breast cancer patients.
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http://dx.doi.org/10.1007/s11010-018-3479-5DOI Listing
May 2019

Risk and survival of chronic myeloid leukemia after breast cancer: A population-based study.

Curr Probl Cancer 2019 06 3;43(3):213-221. Epub 2018 Sep 3.

General Surgery Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Background: We aimed to investigate the risk and survival of chronic myeloid leukemia (CML) after breast cancer (BC) diagnosis.

Methods: We used the Surveillance, Epidemiology, and End Results 'SEER' database. Females, diagnosed with BC between 1992 and 2014, were selected and followed for the development of CML after a 6-month latency period from BC diagnosis. We used the Multiple Primary Standardized Incidence Ratios session of the SEER*Stat software (version 8.3.4) to calculate the Observed/Expected (O/E) ratios with 95% confidence intervals (CI). To calculate the overall survival, we performed an unadjusted Kaplan-Meier analysis using the SPSS software.

Results: We included 474,866 females with BC, of which 178 were later diagnosed with CML. We found the risk of CML to increase significantly after BC diagnosis (O/E = 1.26, 95% CI: 1.08-1.45) and the risk was specifically higher within the first 5 years of diagnosis (O/E = 1.45, 95% CI: 1.16-1.8). When the risk was stratified by cancer stage, localized BC was associated with a significant increase in CML risk within 5 years of diagnosis (O/E = 1.4, 95% CI: 1.06-1.82), while regional BC was associated with a significant increase in CML risk after more than 5 years of diagnosis (O/E = 1.59, 95% CI: 1.09-2.25). Moreover, radiotherapy, chemotherapy, and presence of hormonal receptors were associated with a significant increase in CML risk in BC patients. The median overall survival of CML after BC was 28 months.

Conclusion: Breast cancer patients have an increased risk of developing CML and further investigation is required to establish the causes of this finding.
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http://dx.doi.org/10.1016/j.currproblcancer.2018.08.005DOI Listing
June 2019

IL-10 correlates with the expression of carboxypeptidase B2 and lymphovascular invasion in inflammatory breast cancer: The potential role of tumor infiltrated macrophages.

Curr Probl Cancer 2018 Mar - Apr;42(2):215-230. Epub 2018 Jan 10.

Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt; Breast-Gynecological International Cancer Society, Cairo, Egypt. Electronic address:

Pro-carboxypeptidase B2 (pro-CPB2) or thrombin-activatable fibrinolysis inhibitor (TAFI) is a glycoprotein encoded by the CPB2 gene and deregulated in several cancer types, including breast cancer. Thrombin binding to thrombomodulin (TM), encoded by THBD, is important for TAFI activation. CPB2 gene expression is influenced by genetic polymorphism and cytokines such as interleukin 10 (IL-10). Our previous results showed that tumor infiltrating monocytes/macrophages (CD14/CD16) isolated from inflammatory breast cancer (IBC) patients' secrete high levels of IL-10. The aim of the present study is to test genetic polymorphism and expression of CPB2 in healthy breast tissues and carcinoma tissues of non-IBC and IBC patients. Furthermore, to investigate whether IL-10 modulates the expression of CPB2 and THBD in vivo and in-vitro. We tested CPB2 Thr325Ile polymorphism using restriction fragment length polymorphism, (RFLP) technique in healthy and carcinoma breast tissues. The mRNA expression of CPB2, THBD and IL10 were assessed by RT-qPCR. Infiltration of CD14 cells was assessed by immunohistochemistry. In addition, we investigated the correlation between infiltration of CD14 cells and expression of IL10 and CPB2. Furthermore, we correlated IL10 expression with the expression of both CPB2 and THBD in breast carcinoma tissues. Finally, we validated the role of recombinant IL-10 in regulating the expression of CPB2 and THBD using different breast cancer cell lines. Our results showed that CPB2 genotypes carrying the high-risk allele [Thr/Ile (CT) and Ile/Ile (TT)] were more frequent in both IBC and non-IBC patients compared to control group. CPB2 genotypes did not show any statistical correlation with CPB2 mRNA expression levels or patients' clinical pathological properties. Interestingly, CPB2 and IL10 expression were significantly higher and positively correlated with the incidence of CD14 cells in carcinoma tissues of IBC as compared to non-IBC. On the other hand, THBD expression was significantly lower in IBC carcinoma versus non-IBC tissues. Based on molecular subtypes, CPB2 and IL10 expression were significantly higher in triple negative (TN) as compared to hormonal positive (HP) carcinoma tissues of IBC. Moreover, CPB2 expression was positively correlated with presence of lymphovascular invasion and the expression of IL10 in carcinoma tissues of IBC patients. Furthermore, recombinant human IL-10 stimulated CPB2 expression in SUM-149 (IBC cell line) but not in MDA-MB-231 (non-IBC cell line), while there was no significant effect THBD expression. In conclusion, carcinoma tissues of IBC patients are characterized by higher expression of CPB2 and lower expression of THBD. Moreover, CPB2 positively correlates with IL10 mRNA expression, incidence of CD14 cells and lymphovascular invasion in IBC patients. IL-10 stimulated CPB2 expression in TN-IBC cell line suggests a relevant role of CPB2 in the aggressive phenotype of IBC.
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http://dx.doi.org/10.1016/j.currproblcancer.2018.01.009DOI Listing
April 2019

Restraint use among selected hospitalized elderly patients in Cairo, Egypt.

BMC Res Notes 2017 Nov 28;10(1):633. Epub 2017 Nov 28.

Charles McC. Mathias Jr., National Study Center for Trauma and Emergency Medical Systems, University of Maryland School of Medicine, Baltimore, MD, USA.

Objective: This study's primary objective was to investigate the prevalence of physical and chemical restraint use in selected elderly hospitalized patients.

Results: This study was conducted in April 2014 in four major acute care hospitals. Trained data collectors assessed the use of physical and chemical restraint among all admitted elderly patients. There were 287 elderly patients (median age 64 years, 46% women). 32 patients were restrained. The overall prevalence of restraints was 11.1%, with physical restraint use alone at 3.2% and chemical restraints use alone at 7.3%. Restraint use varied by hospital type, with the highest at the private hospital (22.9%) and the lowest at the two university hospitals (< 6%). In conclusion the prevalence of physical and chemical restraint use among admitted elderly patients in Egypt is comparable to that seen in developed countries. However, the use appears to vary widely by hospital type. The use of restraints in the elderly remains an important question considering the increasing number of elderly.
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http://dx.doi.org/10.1186/s13104-017-2978-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704368PMC
November 2017

Inflammatory breast cancer: High incidence of GCC haplotypes (-1082A/G, -819T/C, and -592A/C) in the interleukin-10 gene promoter correlates with over-expression of interleukin-10 in patients' carcinoma tissues.

Tumour Biol 2017 Jul;39(7):1010428317713393

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

Interleukin-10 is involved in carcinogenesis by supporting tumor escape from the immune response. The aim of this study was to assess the single nucleotide polymorphisms, -1082A/G, -819T/C and -592A/C, in interleukin-10 gene promoter in inflammatory breast cancer compared to non-inflammatory breast cancer and association of these polymorphisms with interleukin-10 gene expression. We enrolled 105 breast cancer tissue (72 non-inflammatory breast cancer and 33 inflammatory breast cancer) patients and we determined the three studied single nucleotide polymorphisms in all samples by polymerase chain reaction restriction fragment length polymorphism and investigated their association with the disease and with various prognostic factors. In addition, we assessed the expression of interleukin-10 gene by real-time quantitative reverse transcription polymerase chain reaction and the correlation between studied single nucleotide polymorphisms and interleukin-10 messenger RNA expression. We found co-dominant effect as the best inheritance model (in the three studied single nucleotide polymorphisms in non-inflammatory breast cancer and inflammatory breast cancer samples), and we didn't identify any association between single nucleotide polymorphisms genotypes and breast cancer prognostic factors. However, GCC haplotype was found highly associated with inflammatory breast cancer risk (p < 0.001, odds ratio = 43.05). Moreover, the expression of interleukin-10 messenger RNA was significantly higher (p < 0.001) by 5.28-fold and 8.95-fold than non-inflammatory breast cancer and healthy control, respectively, where GCC haplotype significantly increased interleukin-10 gene expression (r = 0.9, p < 0.001).
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http://dx.doi.org/10.1177/1010428317713393DOI Listing
July 2017

Leptin is overexpressed in the tumor microenvironment of obese patients with estrogen receptor positive breast cancer.

Exp Ther Med 2017 May 30;13(5):2235-2246. Epub 2017 Mar 30.

Department of Zoology, Cancer Biology Research Laboratory (CBRL), Faculty of Science, Cairo University, Giza 12613, Egypt.

The present study aimed to investigate the potential role of leptin in the progression of breast cancer and the associated cell proliferation signalling pathway(s). A total of 44 female patients diagnosed with breast cancer and 24 healthy donors from Ain Shams University Hospitals (Cairo, Egypt) were enrolled in the present study. The present study assessed leptin expression in breast cancer tissues at the gene and protein level using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. The results demonstrate that the expression of leptin was significantly higher in tissue of breast cancer samples from obese patients than overweight and control samples (P<0.001). ELISA results indicated a significant increase (P<0.001) of leptin expression in obese patients. To investigate whether there is any difference in leptin expression between the peripheral and tumor microenvironment blood of patients with breast cancer, the concentration of leptin was assessed in plasma from both using ELISA assays. The results demonstrated a statistically significant increase in the level of leptin in plasma samples from the tumor microenvironment of obese patients with estrogen receptor positive (ER+) breast cancer, compared with peripheral plasma samples. Furthermore, the leptin gene was overexpressed in obese ER+ breast cancer tissue. RT-qPCR was also performed to assess the expression of genes involved in proliferation pathways including leptin receptor (LEPR), aromatase, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3). A positive association between leptin expression, LEPR, aromatase, MAPK and STAT3 was detected in tissue samples of patients with breast cancer. The current study concluded that leptin may enhance breast cancer progression by inducing the expression of JAK/STAT3, ERK1/2 and estrogen pathways in obese patients breast cancer.
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http://dx.doi.org/10.3892/etm.2017.4291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443182PMC
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

The KIP/CIP family members p21^{Waf1/Cip1} and p57^{Kip2} as diagnostic markers for breast cancer.

Cancer Biomark 2017 ;18(4):413-423

Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

Objective: We examined the expression status of p21^{Waf1/Cip1} and p57^{Kip2} in breast cancer as well as their relationship with clinicopathological factors. Moreover, the diagnostic value of gene promoter methylation of p21^Waf1/Cip1 and p57^Kip2 was assessed in breast cancer patients.

Methods: This study involved 85 patients diagnosed with breast cancer and 36 patients with benign breast lesions. The expression of p21^{Waf1/Cip1} and p57^{Kip2} in cell lysates was analyzed by ELISA and Western blot, respectively. The gene promoter methylation of p21^Waf1/Cip1 and p57^Kip2 was examined in cell lysates by methylation specific PCR.

Results: p21^{Waf1/Cip1} expression was higher while p57^{Kip2} level was lower in breast cancer patients compared to patients with benign breast lesions. The combined use of p21^{Waf1/Cip1} and p57^{Kip2} provided sensitivity and specificity of 82.35% and 86.11%, respectively. None of the malignant and benign breast tumors were found to be hypermethylated at p21^Waf1/Cip1 gene promoter. However, aberrant methylation of p57^Kip2 gene promoter was detected in 49 of 85 (57.65%) of breast cancer tumors. High p21^{Waf1/Cip1} level was associated with high grade, late stages and lymph node involvement, whereas low p57^{Kip2} level was correlated with high grade and HER2 overexpressing breast cancer. Moreover, hypermethylated p57^Kip2 gene promoter was associated with high grade.

Conclusion: Our findings show that the overexpression of p21^{Waf1/Cip1}, down-expression of p57^{Kip2} and gene promoter methylation of p57^Kip2 could be considered as promising diagnostic markers for breast cancer.
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http://dx.doi.org/10.3233/CBM-160308DOI Listing
March 2018

Secretome of tumor-associated leukocytes augment epithelial-mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-κB/p65 signaling pathway.

Tumour Biol 2016 Sep 22;37(9):12441-12453. Epub 2016 Jun 22.

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

Epithelial-mesenchymal transition (EMT) is an essential process in breast cancer metastasis. The aim of the present study was to determine the role of secretions of tumor-associated leukocytes (TALs) isolated from negative and positive lymph nodes (nLNs and pLNs, respectively) breast cancer patients in regulating EMT mechanism and the associated signaling pathways. We found an increased infiltration of TALs, which was associated with downregulation of E-cadherin and over-expression of vimentin in the breast carcinoma tissues of pLNs as compared to nLNs patients and normal breast tissues obtained from healthy volunteers during mammoplasty. Furthermore, TALs isolated from pLNs breast cancer patients secreted an elevated panel of cytokines by up to 2-5-fold when compared with those isolated from nLNs patients. Secretome of TALs of pLNs possessed higher TARC, IGF-1, IL-3, TNF-β, IL-5, G-CSF, IL-4, and IL-1α with more than a fivefold compared to those of nLNs. Using the human breast cancer cell lines MCF-7 and MDA-MB-231, we found that cytokines secreted by TALs isolated from nLNs and pLNs breast cancer patients promoted EMT via upregulation of TGF-β and vimentin and downregulation of E-cadherin at messenger RNA (mRNA) levels in both cell lines and at protein level in MCF-7. While TGF-β is over-expressed by MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. The downstream TGF-β signaling transcription factors, Snail, Slug, and Twist, known to be associated with EMT mechanism were over-expressed by MCF-7 and MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. Acquisition of EMT in MCF-7 cells is mechanistically attributed to the activation of EGFR and NF-κB/p65 signaling which are significantly highly expressed by MCF-7 cells seeded in media conditioned by secretome of TALs isolated from pLNs compared to nLNs patients. Overall, this study provides implications of secretome of TALs and activated EGFR and NF-κB/p65 in EMT process that may be considered a therapeutic strategy to inhibit lymph node metastasis in breast cancer patients.
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http://dx.doi.org/10.1007/s13277-016-5123-xDOI 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

Assessing the Awareness of Egyptian Medical Students about Responsible Conduct of Research and Research Ethics: Impact of an Educational Campaign.

Account Res 2016 ;23(4):199-218

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

This is a quasi-experimental pre-post assessment study utilizing an anonymous self-administered questionnaire to assess Egyptian medical students' awareness about responsible conduct of research (RCR) and research ethics. Students' were assessed before and after an RCR awareness campaign. Our results showed that most of the pre-campaign respondents were not familiar with the basic principles and terms of RCR. An increase in the awareness about RCR across all discussed topics was noted following the campaign. We concluded that an educational awareness campaign is effective in increasing medical students' awareness about RCR and should be incorporated into current medical school curricula in Egypt.
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http://dx.doi.org/10.1080/08989621.2015.1127762DOI Listing
February 2017

Inflammatory and Non-inflammatory Breast Cancer: A Potential Role for Detection of Multiple Viral DNAs in Disease Progression.

Ann Surg Oncol 2016 Feb 27;23(2):494-502. Epub 2015 Oct 27.

Cancer Biology Research Lab, Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.

Background: Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. Multiple viral infections in IBC tissues were found to be associated with disease pathogenesis.

Objective: The aim of the present study was to correlate the incidence of viral DNA with breast cancer progression.

Materials And Methods: Overall, 135 women diagnosed with breast cancer were enrolled in this study. Using polymerase chain reaction and sequencing assays, we determined the incidence of human papillomavirus types 16 and 18 (HPV-16 and -18), human cytomegalovirus (HCMV), Epstein-Barr virus, human herpes simplex virus type 1 and 2, and human herpes virus type 8 (HHV-8) in breast carcinoma tissue biopsies. We also assessed the expression of the cell proliferation marker Ki-67 by immunohistochemistry in association with the incidence of viral DNA.

Results: HCMV and HPV-16 were the most detected viral DNAs in breast carcinoma tissues; however, the frequency of HCMV and HHV-8 DNA were significantly higher in IBC than non-IBC tissues. Moreover, the prevalence of multiple viral DNAs was higher in IBC than non-IBC tissues. The incidence of multiple viral DNAs positively correlates with tumor size and number of metastatic lymph nodes in both non-IBC and IBC patients. The expression of Ki-67 was found to be significantly higher in both non-IBC and IBC tissues in which multiple viral DNAs were detected.

Conclusions: The incidence of multiple viral DNAs in IBC tissues was higher compared with non-IBC tissues. The present results suggest the possibility of a functional relationship between the presence of multiple viral DNAs and disease pathogenesis.
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http://dx.doi.org/10.1245/s10434-015-4888-2DOI Listing
February 2016

Inflammatory breast cancer: New factors contribute to disease etiology: A review.

J Adv Res 2014 Sep 14;5(5):525-36. Epub 2013 Jun 14.

Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.

Inflammatory breast cancer (IBC) is a highly metastatic and fatal form of breast cancer. In fact, IBC is characterized by specific morphological, phenotypic, and biological properties that distinguish it from non-IBC. The aggressive behavior of IBC being more common among young women and the low survival rate alarmed researchers to explore the disease biology. Despite the basic and translational studies needed to understand IBC disease biology and identify specific biomarkers, studies are limited by few available IBC cell lines, experimental models, and paucity of patient samples. Above all, in the last decade, researchers were able to identify new factors that may play a crucial role in IBC progression. Among identified factors are cytokines, chemokines, growth factors, and proteases. In addition, viral infection was also suggested to participate in the etiology of IBC disease. In this review, we present novel factors suggested by different studies to contribute to the etiology of IBC and the proposed new therapeutic insights.
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http://dx.doi.org/10.1016/j.jare.2013.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294279PMC
September 2014

Developing sustainable trauma care education in Egypt: sequential trauma education program, steps to success.

J Surg Educ 2015 Jul-Aug;72(4):e29-32. Epub 2015 Jan 16.

Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland; Charles McC. Mathias Jr. National Study Center for Trauma and EMS, Baltimore, Maryland.

Introduction: As one of the leading causes of death and disability in the world, human trauma and injury disproportionately affects individuals in developing countries. To meet the need for improved trauma care in Egypt, the Sequential Trauma Emergency/Education ProgramS (STEPS) course was created through the collaborative effort of U.S. and Egyptian physicians. The objective of course development was to create a high-quality, modular, adaptable, and sustainable trauma care course that could be readily adopted by a lower- or middle-income country.

Methods: We describe the development, transition, and host nation sustainability of a trauma care training course between a high-income Western nation and a lower-middle-income Middle Eastern/Northern African country, including the number of physicians trained and the challenges to program development and sustainability.

Results: STEPS was developed at the University of Maryland, based in part on World Health Organization's Emergency and Trauma Care materials, and introduced to the Egyptian Ministry of Health and Population and Ain Shams University in May 2006. To date, 639 physicians from multiple specialties have taken the 4-day course through the Ministry of Health and Population or public/governmental universities. In 2008, the course transitioned completely to the leadership of Egyptian academic physicians. Multiple Egyptian medical schools and the Egyptian Emergency Medicine Board now require STEPS or its equivalent for physicians in training.

Conclusions: Success of this collaborative educational program is demonstrated by the numbers of physicians trained, the adoption of STEPS by the Egyptian Emergency Medicine Board, and program continuance after transitioning to in-country leadership and trainers.
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http://dx.doi.org/10.1016/j.jsurg.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469532PMC
April 2016

Positive lymph-node breast cancer patients – activation of NF-κB in tumor-associated leukocytes stimulates cytokine secretion that promotes metastasis via C-C chemokine receptor CCR7.

FEBS J 2015 Jan 20;282(2):271-82. Epub 2014 Nov 20.

Department of Zoology, Cairo University, Giza, Egypt.

Tumor metastasis to lymph nodes is most deadly complication among breast cancer patients. Herein, we investigated the molecular mechanism by which tumor-associated leukocytes (TALs) mediate lymph node metastasis. The density of different leukocyte subtypes infiltrating the tumor microenvironment of negative and positive lymph nodes (nLNs, pLNs) in breast cancer patients was measured using immunohistochemistry. In addition, we isolated TALs from blood drained from the axillary tributaries of nLN and pLN patients during breast surgery. Secretions of TALs were subjected to cytokine profiling using a cytokine antibody array. Our results showed an increase in the number of infiltrated CD45+ cells in the carcinoma tissues of pLN patients with the major proportion being myeloid subsets compared with nLN patients. Furthermore, TALs of pLN patients show a significant fivefold increase in the secretion of interleukin (IL)-1α, interferon-γ, IL-5, IL-3 and tumor necrosis factor-β, and are characterized by enhanced constitutive NF-κB/p65 signaling compared with TALs isolated from nLN patients. Using an invasion assay, cytokines secreted by TALs of pLN patients were shown to augment the invasive phenotype of breast cancer MCF-7 and SKBR3 cells compared with nLN patients. Using flow cytometry, we found that C-C chemokine receptor 7 (CCR7) is significantly overexpressed in breast carcinoma of pLN patients compared with nLNs patients. Intriguingly, CCR7, a mechanistic clue for metastasis, is upregulated in MCF-7 cells upon stimulation with TAL-conditioned media of pLN patients. Our findings show that the molecular cues secreted by TALs alone or in combination with CCR7 may emerge as future therapeutic targets for lymph node metastasis in breast cancer patients.
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http://dx.doi.org/10.1111/febs.13124DOI Listing
January 2015

Inflammatory breast cancer: high incidence of detection of mixed human cytomegalovirus genotypes associated with disease pathogenesis.

Front Oncol 2014 11;4:246. Epub 2014 Sep 11.

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

Inflammatory breast cancer (IBC) is a highly metastatic, aggressive, and fatal form of breast cancer. Patients presenting with IBC are characterized by a high number of axillary lymph node metastases. Recently, we found that IBC carcinoma tissues contain significantly higher levels of human cytomegalovirus (HCMV) DNA compared to other breast cancer tissues that may regulate cell signaling pathways. In fact, HCMV pathogenesis and clinical outcome can be statistically associated with multiple HCMV genotypes within IBC. Thus, in the present study, we established the incidence and types of HCMV genotypes present in carcinoma tissues of infected non-IBC versus IBC patients. We also assessed the correlation between detection of mixed genotypes of HCMV and disease progression. Genotyping of HCMV in carcinoma tissues revealed that glycoprotein B (gB)-1 and glycoprotein N (gN)-1 were the most prevalent HCMV genotypes in both non-IBC and IBC patients with no significant difference between patients groups. IBC carcinoma tissues, however, showed statistically significant higher incidence of detection of the gN-3b genotype compared to non-IBC patients. The incidence of detection of mixed genotypes of gB showed that gB-1 + gB-3 was statistically significantly higher in IBC than non-IBC patients. Similarly, the incidence of detection of mixed genotypes of gN showed that gN-1 + gN-3b and gN-3 + gN-4b/c were statistically significant higher in the carcinoma tissues of IBC than non-IBC. Mixed presence of different HCMV genotypes was found to be significantly correlated with the number of metastatic lymph nodes in non-IBC but not in IBC patients. In IBC, detection of mixed HCMV different genotypes significantly correlates with lymphovascular invasion and formation of dermal lymphatic emboli, which was not found in non-IBC patients.
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http://dx.doi.org/10.3389/fonc.2014.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160966PMC
October 2014

Validation of analytical breast cancer microarray analysis in medical laboratory.

Med Oncol 2014 Oct 3;31(10):201. Epub 2014 Sep 3.

Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, 11381, Egypt.

A previously reported microarray data analysis by RISS algorithm on breast cancer showed over-expression of the growth factor receptor (Grb7) and it also highlighted Tweety (TTYH1) gene to be under expressed in breast cancer for the first time. Our aim was to validate the results obtained from the microarray analysis with respect to these genes. Also, the relationship between their expression and the different prognostic indicators was addressed. RNA was extracted from the breast tissue of 30 patients with primary malignant breast cancer. Control samples from the same patients were harvested at a distance of ≥5 cm from the tumour. Semi-quantitative RT-PCR analysis was done on all samples. There was a significant difference between the malignant and control tissues as regards Grb7 expression. It was significantly related to the presence of lymph node metastasis, stage and histological grade of the malignant tumours. There was a significant inverse relation between expression of Grb7 and expression of both oestrogen and progesterone receptors. Grb7 was found to be significantly related to the biological classification of breast cancer. TTYH1 was not expressed in either the malignant or the control samples. The RISS by our group algorithm developed was laboratory validated for Grb7, but not for TTYH1. The newly developed software tool needs to be improved.
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http://dx.doi.org/10.1007/s12032-014-0201-7DOI Listing
October 2014