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  • 1.
    Alghfeli, Latifa
    et al.
    Univ Sharjah, U Arab Emirates.
    Parambath, Divyasree
    Univ Sharjah, U Arab Emirates.
    Eldeen, Loaa A. Tag
    Suez Canal Univ, Egypt.
    El-Serafi, Ibrahim
    Ajman Univ, U Arab Emirates; Port Said Univ, Egypt.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Univ Sharjah, U Arab Emirates; Suez Canal Univ, Egypt.
    Non-additive effect of the DNA methylation inhibitor, 5-Aza-dC, and glass as a culture surface on osteogenic differentiation2022In: Heliyon, E-ISSN 2405-8440, Vol. 8, no 12, article id e12433Article in journal (Refereed)
    Abstract [en]

    The clinical need for bone regenerative solutions is expanding with increasing life expectancy and escalating incidence of accidents. Several strategies are being investigated to enhance the osteogenic differentiation of stem cells. We previously reported two different approaches for this purpose, in monolayer and three-dimensional cell culture. The first approach was based on pretreating cells with 5-Aza-dC, a DNA methylation inhibitor, before the applying the differentiation media. The second approach was based on culturing cells on a glass surface during differentiation. In this study, we investigated the potential effect of combining both methods. Our results sug-gested that both approaches were associated with decreasing global DNA methylation levels. Cells cultured as a monolayer on glass surface showed enhancement in alkaline phosphatase activity at day 10, while 5-Aza-dC pretreatment enhanced the activity at day 5, irrespective of the culture surface. In three-dimensional pellet cul-ture, 5-Aza-dC pretreatment enhanced osteogenesis through Runx-2 and TGF-beta 1 upregulation while the glass surface induced Osterix.Furthermore, pellets cultured on glass showed upregulation of a group of miRNAs, including pro-osteogenesis miR-20a and miR-148b and anti-osteogenesis miR-125b, miR-31, miR-138, and miR-133a. Interestingly, 5-Aza-dC was not associated with a change of miRNAs in cells cultured on tissue culture plastic but reverted the upregulated miRNAs on the glass to the basal level. This study confirms the two approaches for enhancing osteogenic differentiation and contradicts their combination.

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  • 2.
    El Serafi, Ibrahim Taher
    et al.
    Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
    Awad, Mohamed M.
    Department of Internal Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
    Tag Eldeen, Loaa A.
    Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
    El Serafi, Ahmed Taher
    Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
    Husin, Marwa
    Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
    Effect of interleukin-6 and insulin resistance on early virological response of Egyptian chronic hepatitis C patients to combined pegylated interferon plus ribavirin therapy2013In: Egyptian Liver Journal, ISSN 2090-6218, Vol. 3, no 2, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Background and aim: Response to hepatitis C virus (HCV)-specific therapy is variable but might be influenced by host factors. We studied whether interleukin-6 (IL-6) level, IL-6–174G>C gene polymorphism, and insulin resistance affect the response to antiviral treatment in HCV-infected patients.

    Patients and methods: Fifty-five chronic hepatitis C patients and 13 healthy individuals as controls were included in this study. Liver function tests, HCV RNA titer, ultrasonography, and histopathological examination of liver tissues were performed for all patients. Pretreatment plasma IL-6 levels and homeostasis model assessment-insulin resistance were estimated. The IL-6–174G>C polymorphism was detected by the PCR/RFLP method. After 12 weeks of combined pegylated interferon-α and ribavirin therapy, patients were classified into responders or nonresponders according to whether they achieved an early virological response.

    Results: The responders had significantly high IL-6 levels (P=0.01), low mean stage of fibrosis (P=0.03), and low viral load (P=0.04) compared with nonresponders. Although not significant, patients with the IL-6–174 CC genotype reported a higher response rate (81%) compared with those with the CG genotype (50%) and GG genotype (62%). IL-6 level at a cutoff point of 2.15 pg/ml had 81.1% sensitivity and 72.7% specificity and showed significant relation with early virological response (P=0.04).

    Conclusion: Estimation of basal IL-6 level could be used as a predictor of response to pegylated interferon-α and ribavirin therapy in CHC patients.

  • 3.
    El-Huneidi, Waseem
    et al.
    Univ Sharjah, U Arab Emirates.
    Shehab, Naglaa G.
    Dubai Pharm Coll, U Arab Emirates; Cairo Univ, Egypt.
    Bajbouj, Khuloud
    Univ Sharjah, U Arab Emirates.
    Vinod, Arya
    Univ Sharjah, U Arab Emirates.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Suez Canal Univ, Egypt.
    Shafarin, Jasmin
    Univ Sharjah, U Arab Emirates.
    Malhab, Lara J. Bou
    Univ Sharjah, U Arab Emirates.
    Abdel-Rahman, Wael M.
    Univ Sharjah, U Arab Emirates.
    Abu-Gharbieh, Eman
    Univ Sharjah, U Arab Emirates.
    Micromeria fruticosa Induces Cell Cycle Arrest and Apoptosis in Breast and Colorectal Cancer Cells2020In: Pharmaceuticals, E-ISSN 1424-8247, Vol. 13, no 6, article id 115Article in journal (Refereed)
    Abstract [en]

    Micromeria fruticosa (L.) Druce subs p.serpyllifolia (Lamiaceae) has been used widely in folk medicine to alleviate various ailments such as abdominal pains, diarrhea, colds, eye infections, heart disorders and wounds. A few reports have confirmed different therapeutic potentialities of its extracts, including the anti-inflammatory, gastroprotective, analgesic, antiobesity and antidiabetic activities. This study aimed to investigate the mechanistic pathway of the antiproliferative activity of the ethanolic extract ofM. fruticosaon two different cancer cell lines, namely human breast (mammary carcinoma F7 (MCF-7)) and human colorectal (human colon tumor cells (HCT-116)) cell lines. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay, Annexin V-FITC/PI, caspases 8/9 and cell cycle analyses, qRT-PCR and Western blot were used to assess the effect of M. fruticosaon cytotoxicity, apoptosis, cell cycle, cell cycle-related genes and protein expression profiles in MCF-7 and HCT-116. The extract inhibits cell proliferation in a time- and dose-dependent manner. The half-maximal inhibitory concentration (IC50) for both cell lines was found to be 100 mu g/mL. Apoptosis induction was confirmed by Annexin V-FITC/PI, that was related to caspases 8 and 9 activities induction. Furthermore, the cell cycle analysis revealed arrest at G2/M phase. The underlying mechanism involved in the G2/M arrest was found to be associated with the downregulation of CDK1, cyclin B1 and survivin that was confirmed by qRT-PCR and Western blotting.

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  • 4.
    El-Serafi, Ahmed
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Suez Canal Univ, Egypt.
    He, Rui
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Zheng, Wenyi
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Benkossou, Fadwa
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Oerther, Sandra
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Zhao, Ying
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Mellgren, Karin
    Sahlgrens Univ Hosp, Sweden.
    Gustafsson, Britt
    Karolinska Inst, Sweden.
    Heilmann, Carsten
    Natl Univ Hosp, Denmark.
    Kanerva, Jukka
    HUS Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Lotfi, Kourosh
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology.
    Toporski, Jacek
    Skane Univ Hosp, Sweden.
    Sundin, Mikael
    Karolinska Inst, Sweden; Astrid Lindgren Childrens Hosp, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    Mattsson, Jonas
    Univ Toronto, Canada; Princess Margaret Canc Ctr, Canada; Karolinska Inst, Sweden.
    El-Serafi, Ibrahim
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Hassan, Moustapha
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study2021In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 56, p. 807-817Article in journal (Refereed)
    Abstract [en]

    Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

  • 5.
    El-Serafi, Ahmed T.
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    El-Serafi, Ibrahim
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Ajman Univ, U Arab Emirates.
    Steinvall, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    A Systematic Review of Keratinocyte Secretions: A Regenerative Perspective2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 14, article id 7934Article, review/survey (Refereed)
    Abstract [en]

    Cell regenerative therapy is a modern solution for difficult-to-heal wounds. Keratinocytes, the most common cell type in the skin, are difficult to obtain without the creation of another wound. Stem cell differentiation towards keratinocytes is a challenging process, and it is difficult to reproduce in chemically defined media. Nevertheless, a co-culture of keratinocytes with stem cells usually achieves efficient differentiation. This systematic review aims to identify the secretions of normal human keratinocytes reported in the literature and correlate them with the differentiation process. An online search revealed 338 references, of which 100 met the selection criteria. A total of 80 different keratinocyte secretions were reported, which can be grouped mainly into cytokines, growth factors, and antimicrobial peptides. The growth-factor group mostly affects stem cell differentiation into keratinocytes, especially epidermal growth factor and members of the transforming growth factor family. Nevertheless, the reported secretions reflected the nature of the involved studies, as most of them focused on keratinocyte interaction with inflammation. This review highlights the secretory function of keratinocytes, as well as the need for intense investigation to characterize these secretions and evaluate their regenerative capacities.

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  • 6.
    El-Serafi, Ahmed Taher
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    El Serafi, Ibrahim Taher
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    The potentiality of histone deacetylase inhibitors for diabetes and obesity2020In: Histone Modifications in Therapy / [ed] Pedro Castelo-Branco, Carmen Jeronimo, San Diego, United states: Elsevier, 2020, p. 361-371Chapter in book (Other academic)
    Abstract [en]

    Diabetes, obesity, and metabolic syndrome represent the current global epidemic. In spite of the continuous development of related pharmaceuticals, complications of these conditions lower the patient's life quality and cause a burden on the health economy. Histone deacetylase inhibitors are slowly emerging as a line of management for several medical conditions. Many studies have described their potential role in diabetes, in terms of enhancing insulin secretion and decreasing insulin resistance. In obesity, these agents showed a very interesting role in converting white fat cells to their brown counterpart, as well as shifting the metabolic pathways toward less adiposity. Although these effects are characterized at the cellular and preclinical levels, few clinical studies have been reported. This chapter includes an overview of the relation between histone deacetylation and the development of diabetes and obesity, as well as the possible future role of histone deacetylase inhibitors in the management of these conditions.

  • 7.
    El-Serafi, Ibrahim
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Loy, Orlaith
    Karolinska Inst, Sweden.
    Zhao, Ying
    Karolinska Inst, Sweden.
    Oerther, Sandra
    Karolinska Inst, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Sweden; Oslo Univ Hosp, Norway.
    Pre-formulation investigations for establishing a protocol for treosulfan handling and activation2019In: Pharmaceutical development and technology (Print), ISSN 1083-7450, E-ISSN 1097-9867, Vol. 24, no 5, p. 639-648Article in journal (Refereed)
    Abstract [en]

    Introduction: Treosulfan is an alkylating agent that is used for the treatment of ovarian cancer and for conditioning prior to stem cell transplantation. It is a prodrug that is activated non-enzymatically to two active epoxides. Objectives: To optimize a protocol for both in vivo samples handling and in vitro drug preparation. Treosulfan stability was tested in biological fluids at different conditions as well as for its cytotoxicity on cell lines. Results: Plasma samples can be safely frozen for a short period up to 8 h, however; for longer periods, samples should be acidified. Urine samples and cell culture media can be safely frozen regardless their pH. For in vitro investigations, incubation of treosulfan at 37 degrees C for 24 h activated 100% of the drug. Whole blood acidification should be avoided for the risk of hemolysis. Finally; treosulfan cytotoxicity on HL-60 cells has increased following pre-incubation for 24 h at 37 degrees C compared to K562 cell line. Conclusion: The stability profiling of treosulfan provided a valuable reference for handling of biological samples for both in vivo and in vitro studies. These results can be utilized for further investigations concerning the drug kinetics and dynamics in addition to the development of new pharmaceutical formulations.

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  • 8.
    El-Serafi, Ibrahim
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Remberger, Mats
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    El-Serafi, Ahmed
    Karolinska Inst, Sweden; Univ Sharjah, U Arab Emirates.
    Benkessou, Fadwa
    Karolinska Inst, Sweden.
    Zheng, Wenyi
    Karolinska Inst, Sweden.
    Martell, Eva
    Karolinska Univ Hosp, Sweden.
    Ljungman, Per
    Karolinska Univ Hosp, Sweden.
    Mattsson, Jonas
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Hassan, Moustapha
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 8293Article in journal (Refereed)
    Abstract [en]

    Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P amp;lt; 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure). In conclusion: NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.

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  • 9.
    El-Serafi, Ibrahim
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Remberger, Mats
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Ringden, Olle
    Karolinska Inst, Sweden.
    Torlen, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Sundin, Mikael
    Karolinska Inst, Sweden; Astrid Lindgren Childrens Hosp, Sweden.
    Bjorklund, Andreas
    Karolinska Univ Hosp, Sweden.
    Winiarski, Jacek
    Karolinska Inst, Sweden; Astrid Lindgren Childrens Hosp, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Sweden; Univ Toronto, Canada; Univ Toronto, Canada.
    Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan-Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation2020In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 13, no 2, p. 293-300Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients supportive care was changed in order to reduce the regimen-related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of Bu was initiated in 2000, and the use of liver supportive drugs, such as ursodeoxycholic acid and N-acetyl-L-cysteine, were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995-1999 (16.2%) compared with 2.3% during 2010-2015. Overall survival for patients with SOS was 62%, 46%, and 27% at 100 days, 1 year, and 5 years after HSCT, respectively, compared with 92%, 77%, and 66% for those who did not develop SOS (P amp;lt; 0.001). In conclusion, the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and, hence, improve the clinical outcome.

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  • 10.
    Elsharkawi, Ibrahim
    et al.
    Univ Sharjah, U Arab Emirates.
    Parambath, Divyasree
    Univ Sharjah, U Arab Emirates.
    Saber-Ayad, Maha
    Univ Sharjah, U Arab Emirates; Cairo Univ, Egypt.
    Khan, Amir Ali
    Univ Sharjah, U Arab Emirates.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Univ Sharjah, U Arab Emirates; Suez Canal Univ, Egypt.
    Exploring the effect of epigenetic modifiers on developing insulin-secreting cells2020In: HUMAN CELL, ISSN 1749-0774, Vol. 33, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Diabetes is a worldwide health problem with increasing incidence. The current management modalities did not succeed to decrease comorbidities. This study aimed at enhancing the regenerative solution for diabetes by improving the differentiation of mesenchymal stromal cells (MSC) into glucose-sensitive, insulin-secreting cells through an epigenetic modification approach. A 3-day treatment protocol with the epigenetic modifiers, either decitabine (5-aza-2 -deoxycytidine; Aza); a DNA methylation inhibitor or Vorinostat (suberoylanilide hydroxamic acid; SAHA); a histone deacetylase inhibitor was added to two different human stem cell lines. The cells followed a multi-step differentiation protocol that provided the critical triggers in a temporal approach. Aza-pretreated group showed higher intracellular expression of insulin and the transcription factor PDX-1. The cells responded to the high glucose challenge by secreting insulin in the media, as shown by ELISA. Gene expression showed induction of the genes for insulin, the glucose transporter 2, glucokinase, as well as the transcription factors MafA and NKX6.1. Although SAHA showed upregulation of insulin secretion, in comparison to control, the cells could not respond to the high glucose challenge. Interestingly, Aza-treated cells showed a significant decrease in the global DNA methylation level at the end of the culture. In conclusion, this additional step with Aza could enhance the response of MSC to the classical differentiation protocol for insulin-secreting cells and may help in establishing a regenerative solution for patients with diabetes.

  • 11.
    Guimei, Maha
    et al.
    Alexandria Univ, Egypt; Univ Sharjah, U Arab Emirates.
    Alrouh, Sana
    Univ Sharjah, U Arab Emirates.
    Saber-Ayad, Maha
    Univ Sharjah, U Arab Emirates; Cairo Univ, Egypt.
    Hafezi, Shirin A.
    Univ Sharjah, U Arab Emirates.
    Vinod, Arya
    Univ Sharjah, U Arab Emirates.
    Rawat, Surendra
    Univ Sharjah, U Arab Emirates.
    Wardeh, Yazan
    Univ Sharjah, U Arab Emirates.
    Bakkour, Tala Mohamad
    Univ Sharjah, U Arab Emirates.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Univ Sharjah, U Arab Emirates; Suez Canal Univ, Egypt.
    Inhibition of Yes-Associated Protein-1 (YAP1) Enhances the Response of Invasive Breast Cancer Cells to the Standard Therapy2020In: Breast Cancer: Targets and Therapy, E-ISSN 1179-1314, Vol. 12, p. 189-199Article in journal (Refereed)
    Abstract [en]

    Purpose: The deregulation of the Hippo pathway results in translocation ofYes-associated protein-1 (YAP1) to the nucleus to exert an oncogenic effect. This effect has been demonstrated in several malignancies, yet, in breast cancer (BC), it remains controversial. The present study aimed to investigate the significance of YAP1 expression in BC, its relation to cancer stem cells (CSCs), and the effect of its inhibition on tumor cell survival. Patients and Methods: We evaluated the expression of YAP1 protein and gene using immunohistochemistry (IHC) and RT-qPCR in FFPE tissue from normal and breast cancer cases. We also studied its association with CSC expression (OCT4, NANOG, and SOX2) and with different clinicopathologic characteristics. Two BC cell lines (MCF7 and MDA-MB -231) were exposed to different concentrations of YAP1 inhibitor "verteporfin" and cell viability was subsequently assessed. Results: YAP1 mRNA was higher in BC compared to the normal breast tissue (p-value=0.040) and was higher in luminal tumors compared to triple-negative breast cancer (TNBC) (p-value= 0.017). Its expression in tumors was significantly associated with the expression of pluripotency markers (OCT4 and NANOG) (p-value= 0.030 and 0.035, respectively) and its inhibition resulted in a significant reduction of CSC expression in both MCF-7 and MDA-MB-231 cells. YAP1 nuclear expression by IHC, which signifies its activation, was more evident in invasive carcinomas compared to normal breast tissue and in-situ foci where the expression was limited to the cytoplasm. The pretreatment of BC cells (MCF7 and MDA-MB-231) with YAP1 inhibitor "verteporfin" resulted in their sensitization to the effect of tamoxifen and doxorubicin, respectively, and significantly decreased tumor cell proliferation and survival. Conclusion: Our results imply that YAP1 is highly expressed and activated in BC and its inhibition could represent a possible novel therapeutic strategy that should be further explored and investigated to improve the outcome of breast cancer patients.

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  • 12.
    Karlsson, Matilda
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Olofsson, Pia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Thorfinn, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Åstrand, Liselott
    Sharjah Institute for Medical Research, University of Sharjah, UAE.
    Fayiz, Safa
    Sharjah Institute for Medical Research, University of Sharjah, UAE.
    Khalaf, Ahmed
    Sharjah Institute for Medical Research, University of Sharjah, UAE.
    Divyasree, Parambath
    Sharjah Institute for Medical Research, University of Sharjah, UAE.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Sharjah Institute for Medical Research, University of Sharjah, UAE; Suez Canal University, Ismailia, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sprayed cultured autologous keratinocytes in the treatment of severe burns: a retrospective matched cohort study.2020In: Annals of burns and fire disasters, ISSN 1592-9558, Vol. 33, no 2, p. 134-142Article in journal (Refereed)
    Abstract [en]

    The standard treatment of burns is early excision followed by autologous skin grafting. The closure of extensive deep burns poses a considerable challenge. Cultured autologous keratinocytes have been used since 1981 in an effort to improve healing. However, the time required to culture the cells and the lack of a dermal component limit the expectations of outcome. Our aim was to compare the duration of hospital stay between patients who were treated with autologous skin grafts and cultured autologous keratinocytes and those who were treated with autologous skin grafting without cultured autologous keratinocytes. In this retrospective study all patients treated with cultured autologous keratinocytes between 2012 and 2015 were matched by size and depth of burn with patients not treated with cultured autologous keratinocytes. Multivariable regression was used to analyse associations between duration of hospital stay and treatment adjusted for age, mortality, size and depth of the burn. Then, we investigated the possibility of differentiation of human bone marrow stem cell line to keratinocyte- like cells as a future direction. The regression analysis showed a coefficient of 17.36 (95% CI -17.69 to 52.40), p= 0.32, for hospital stay in the treatment group, compared with the matched group. Our results showed no difference in the duration of hospital stay between the two treatments. Autologous stem cells should be considered as a future modality of burn management, although further studies are needed.

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  • 13.
    Khan, Amir Ali
    et al.
    Univ Sharjah, Saudi Arabia.
    Huat, Tee Jong
    Natl Univ Singapore, Singapore; Univ Sains Malaysia Hlth Campus, Malaysia.
    Al Mutery, Abdullah
    Univ Sharjah, U Arab Emirates.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Kacem, Hassen Hadj
    Univ Sharjah, Saudi Arabia.
    Abdallah, Sallam Hasan
    Univ Sharjah, Saudi Arabia.
    Reza, Muhammed Faruque
    Univ Sains Malaysia Hlth Campus, Malaysia.
    Abdullah, Jafri Malin
    Univ Sains Malaysia Hlth Campus, Malaysia; Univ Sains Malaysia Hlth Campus, Malaysia.
    Jaafar, Hasnan
    Univ Sains Malaysia Hlth Campus, Malaysia.
    Significant transcriptomic changes are associated with differentiation of bone marrow-derived mesenchymal stem cells into neural progenitor-like cells in the presence of bFGF and EGF2020In: Cell & Bioscience, ISSN 2045-3701, Vol. 10, no 1, article id 126Article in journal (Refereed)
    Abstract [en]

    IntroductionMesenchymal stem cells (MSCs) isolated from bone marrow have different developmental origins, including neural crest. MSCs can differentiate into neural progenitor-like cells (NPCs) under the influence of bFGF and EGF. NPCs can terminally differentiate into neurons that express beta-III-tubulin and elicit action potential. The main aim of the study was to identify key genetic markers involved in differentiation of MSCs into NPCs through transcriptomic analysis.MethodTotal RNA was isolated from MSCs and MSCs-derived NPCs followed by cDNA library construction for transcriptomic analysis. Sample libraries that passed the quality and quantity assessments were subjected to high throughput mRNA sequencing using NextSeq (R) 500. Differential gene expression analysis was performed using the DESeq2 R package with MSC samples being a reference group. The expression of eight differentially regulated genes was counter validated using real-time PCR.ResultsIn total, of the 3,252 differentially regulated genes between MSCs and NPCs with two or more folds, 1,771 were upregulated genes, whereas 1,481 were downregulated in NPCs. Amongst these differential genes, 104 transcription factors were upregulated, and 45 were downregulated in NPCs. Neurogenesis related genes were upregulated in NPCs and the main non-redundant gene ontology (GO) terms enriched in NPCs were the autonomic nervous system, cell surface receptor signalling pathways), extracellular structure organisation, and programmed cell death. The main non-redundant GO terms enriched in MSCs included cytoskeleton organisation cytoskeleton structural constituent, mitotic cell cycle), and the mitotic cell cycle process Gene set enrichment analysis also confirmed cell cycle regulated pathways as well as Biocarta integrin pathway were upregulated in MSCs. Transcription factors enrichment analysis by ChEA3 revealed Foxs1 and HEYL, amongst the top five transcription factors, inhibits and enhances, respectively, the NPCs differentiation of MSCs.ConclusionsThe vast differences in the transcriptomic profiles between NPCs and MSCs revealed a set of markers that can identify the differentiation stage of NPCs as well as provide new targets to enhance MSCs differentiation into NPCs.

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  • 14.
    Lagerwall, Cathrine
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Shahin, Hady
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Abdallah, Sallam
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Steinvall, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Suez Canal University, Egypt.
    Xeno-free workflow exhibits comparable efficiency and quality of keratinocytes isolated from human skin biopsies2021In: Regenerative Therapy, ISSN 2352-3204, Vol. 18, p. 401-407Article in journal (Refereed)
    Abstract [en]

    Introduction Regenerative solutions of the skin represent a hope for burn victims with extensive skin loss and chronic wound patients. The development of xeno-free workflow is crucial for clinical application in compliance with the directives of the European Medicines Agency. This study aimed at evaluating the outcome of the xeno-free isolation workflow of keratinocytes from human skin biopsy. Methods Skin biopsies were obtained from volunteers. The epidermis was digested with TrypLE™ Select, which was deactivated by dilution or with trypsin, deactivated by media with fetal bovine serum. Freshly isolated cells were compared for total cell number, viability, activity of caspase 3, gene expression and the presence of the keratinocyte surface markers cytokeratin 14. The cells were cultured in xeno-free conditions for one week and characterized regarding the number and viability as well as the metalloproteinase secretion. Results The number of obtained cells was similar in both workflows. The cell viability was less in the TrypLE group, with slight reduction of the cell surface marker cytokeratin 14. Caspase 3 activity was comparable as well as the gene expression of the apoptotic markers BAX, BCL2 and SLUG, as well as the keratinocyte markers cytokeratin 14, stratifin and filaggrin. Upon culture, the number of keratinocytes, their viability and secretion of matrix metalloproteinases 1 and 10 were equal in both groups. Conclusion This study reports the possibility of isolating functioning and viable keratinocytes through a xeno-free workflow for clinical application.

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  • 15.
    Mansour, Mona Farouk
    et al.
    Suez Canal Univ, Egypt.
    Greish, Sahar Mansour
    Suez Canal Univ, Egypt; Badr Univ Cairo, Egypt.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Suez Canal Univ, Egypt.
    Abdelall, Howayda
    Suez Canal Univ, Egypt.
    El-Wazir, Yasser Mohamed
    Suez Canal Univ, Egypt.
    Therapeutic potential of human umbilical cord derived mesenchymal stem cells on rat model of liver fibrosis2019In: American Journal of Stem Cells, ISSN 2160-4150, Vol. 8, no 1Article in journal (Refereed)
    Abstract [en]

    End-stage liver disease is a worldwide cause of morbidity and mortality, which is associated with a considerable economic burden. As the disease progresses, fibrosis will replace the hepatic architecture and compromise liver functions. The regenerative approach for the injured liver can provide a hope for these patients; however, it is still facing many challenges. In the current study, we aimed at (1) assessing hepatic regenerative capacity of mesenchymal stem cells, isolated from human umbilical cord blood (HMSCs), in a rat model of carbon-tetrachloride (CCL4) induced liver fibrosis, (2) comparing the therapeutic effects with other cell populations derived from umbilical cord blood and (3) evaluating the host response to the human-derived cells. Fifteen rats received either the whole mononuclear cell fraction (HMNCs), CD34-ve subpopulation or HMSCs. A fourth group did not receive any treatment and another group was left without induction of fibrosis as positive and negative controls. All groups that received cellular treatment showed homing of the human cells and improvement of the liver architecture and functional capacity. The groups received CD34-ve cells and HMSCs had the most efficient improvement in liver functions, microscopic regenerative markers and histological appearance while the least immune reaction was noted with HMSCs. HUCB-MSCs showed significant immunemodulatory effect on rat immune cells. This study can provide a clue about a simple and effective method for the management of fibrotic liver diseases.

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  • 16.
    Nugud, Ahmed
    et al.
    Aljalila Children Hosp, U Arab Emirates.
    Alghfeli, Latifa
    Univ Sharjah, U Arab Emirates.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    El-Serafi, Ibrahim
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Ajman Univ, U Arab Emirates.
    El-Serafi, Ahmed T.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Biomaterials as a Vital Frontier for Stem Cell-Based Tissue Regeneration2022In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 713934Article, review/survey (Refereed)
    Abstract [en]

    Biomaterials and tissue regeneration represent two fields of intense research and rapid advancement. Their combination allowed the utilization of the different characteristics of biomaterials to enhance the expansion of stem cells or their differentiation into various lineages. Furthermore, the use of biomaterials in tissue regeneration would help in the creation of larger tissue constructs that can allow for significant clinical application. Several studies investigated the role of one or more biomaterial on stem cell characteristics or their differentiation potential into a certain target. In order to achieve real advancement in the field of stem cell-based tissue regeneration, a careful analysis of the currently published information is critically needed. This review describes the fundamental description of biomaterials as well as their classification according to their source, bioactivity and different biological effects. The effect of different biomaterials on stem cell expansion and differentiation into the primarily studied lineages was further discussed. In conclusion, biomaterials should be considered as an essential component of stem cell differentiation strategies. An intense investigation is still required. Establishing a consortium of stem cell biologists and biomaterial developers would help in a systematic development of this field.

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  • 17.
    Saber-Ayad, Maha
    et al.
    College of Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates; College of Medicine, Cairo University, Egypt.
    Manzoor, Shaista
    College of Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates.
    El Serafi, Ahmed Taher
    College of Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates; College of Medicine, Suez Canal University, Egypt .
    Mahmoud, Ibrahim
    College of Medicine, University of Sharjah, United Arab Emirates.
    Hammoudeh, Sarah
    College of Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates.
    Rani, Aghila
    Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates.
    Abusnana, Salah
    College of Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates.
    Sulaiman, Nabil
    College of Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, United Arab Emirates.
    The FTO rs9939609 “A” allele is associated with impaired fasting glucose and insulin resistance in Emirati population2019In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 681, p. 93-98Article in journal (Refereed)
    Abstract [en]

    Background: Fat mass and obesity-associated protein gene variants have shown diverse influence on body weight and metabolism across different populations. Overweight, obesity and metabolic syndrome are multifactorial major health problems in the UAE and worldwide. Insulin resistance represents the link between overweight and development of metabolic syndrome and type 2 diabetes mellitus. We investigated two (FTO) variants in Emirati population, in relation to insulin resistance and different parameters of metabolic syndrome.

    Methods: We recruited 259 Emiratis through the UAE National Diabetes and Lifestyle Project. Ethical approval was obtained. Besides basic data collection, venous blood samples were collected. Fasting blood glucose, Lipid profile, and insulin levels were measured. Genotyping for (FTO) rs9939609 (A>T) and rs9930506 (G>A) were performed using real time-PCR. Insulin resistance were identified using HOMA2-IR calculation; with a cut-off point of 1.4 for female and 1.18 for male subjects.

    Results: The study included 259 Emiratis (age range 30-53 years, mean 41.76 years, 54.4% females), 24.5% are diabetic and 30.8% are hypertensive, with body mass index of 28.4 ± 5.9 and 28.7 ± 5.7 kg/m2 in female and male subjects, respectively. Homozygous A of rs9939609 showed significantly higher fasting glucose compared to other genotypes (p = 0.04) with a trend of higher insulin level and HOMA-2IR. The A/A diabetic patients (n = 13) showed significantly higher insulin levels compared to other genotypes. G allele of rs9930506 showed a trend of higher fasting glucose and HOMA-2IR, but lower insulin level and HbA1c. No association of genotypes was detected with other components of metabolic syndrome.

    Conclusion: There is an association of FTO rs9939609 A/A genotype and impaired fasting glucose and insulin resistance. Homozygous A genotype diabetic patients may be more vulnerable to blood glucose fluctuation. Focused genotyping can help the health care providers to identify high risk groups of both normal population and diabetic patients to intervene accordingly.

  • 18.
    Schoutrop, Esther
    et al.
    Karolinska Inst, Sweden.
    El-Serafi, Ibrahim
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Poiret, Thomas
    Karolinska Inst, Sweden.
    Zhao, Ying
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Gultekin, Okan
    Karolinska Inst, Sweden.
    He, Rui
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Moyano-Galceran, Lidia
    Karolinska Inst, Sweden.
    Carlson, Joseph W.
    Karolinska Inst, Sweden.
    Lehti, Kaisa
    Karolinska Inst, Sweden; Norwegian Univ Sci & Technol, Norway.
    Hassan, Moustapha
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Magalhaes, Isabelle
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Sweden; Princess Margaret Canc Ctr, Canada; Univ Toronto, Canada; Univ Hlth Network, Canada.
    Mesothelin-Specific CAR T Cells Target Ovarian Cancer2021In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 11, p. 3022-3035Article in journal (Refereed)
    Abstract [en]

    New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV3-bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigen-dependent manner while MSLN+ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coin-hibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z- and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8(+) T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer. Significance: These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.

  • 19.
    Shahin, Hady
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Modern Sci & Arts Univ, Egypt.
    Abdallah, Sallam
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Das, Jyotirmoy
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences, Core Facility.
    He, Weihai
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    El Serafi, Ibrahim
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ajman Univ, U Arab Emirates; Port Said Univ, Egypt.
    Steinvall, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elserafy, Ahmed
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Suez Canal Univ, Egypt.
    miRNome and Proteome Profiling of Human Keratinocytes and Adipose Derived Stem Cells Proposed miRNA-Mediated Regulations of Epidermal Growth Factor and Interleukin 1-Alpha2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 5, article id 4956Article in journal (Refereed)
    Abstract [en]

    Wound healing is regulated by complex crosstalk between keratinocytes and other cell types, including stem cells. In this study, a 7-day direct co-culture model of human keratinocytes and adipose-derived stem cells (ADSCs) was proposed to study the interaction between the two cell types, in order to identify regulators of ADSCs differentiation toward the epidermal lineage. As major mediators of cell communication, miRNome and proteome profiles in cell lysates of cultured human keratinocytes and ADSCs were explored through experimental and computational analyses. GeneChip(R) miRNA microarray, identified 378 differentially expressed miRNAs; of these, 114 miRNAs were upregulated and 264 miRNAs were downregulated in keratinocytes. According to miRNA target prediction databases and the Expression Atlas database, 109 skin-related genes were obtained. Pathway enrichment analysis revealed 14 pathways including vesicle-mediated transport, signaling by interleukin, and others. Proteome profiling showed a significant upregulation of the epidermal growth factor (EGF) and Interleukin 1-alpha (IL-1 alpha) compared to ADSCs. Integrated analysis through cross-matching the differentially expressed miRNA and proteins suggested two potential pathways for regulations of epidermal differentiation; the first is EGF-based through the downregulation of miR-485-5p and miR-6765-5p and/or the upregulation of miR-4459. The second is mediated by IL-1 alpha overexpression through four isomers of miR-30-5p and miR-181a-5p.

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  • 20.
    Shahin, Hady
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Modern Sciences and Arts University, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Markland, Katrin
    Karolinska University Hospital, Sweden.
    Blomberg, Pontus
    Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Suez Canal University, Egypt.
    Human serum albumin as a clinically accepted cell carrier solution for skin regenerative application2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 14486Article in journal (Refereed)
    Abstract [en]

    The rules governing Medicinal Products in the European Union necessitates the production of cell-based therapy in good manufacturing practice facilities. The produced cells may need several hours in transportation to reach the application sites. In this study, we investigated four candidate solutions for transporting human keratinocytes. The solutions are (1) normal saline, (2) saline with 2.5% human serum albumin (Saline + HSA), (3) chemically defined, xeno-free keratinocyte media and (4) keratinocyte media with pituitary bovine extract (PBE-media). One million keratinocytes from three donors were suspended in each solution and kept at 4 °C for up to 24 h. Cells kept in Saline + HSA showed higher viability after 1, 3 and 24 h. Then, equal number of viable cells were seeded on collagenous matrix and cultured for 48 h. The adhesion and colonization were higher in the cells kept in PBE-media, while the keratinocyte surface marker, cytokeratin 14, was present in all studied groups. These results confirmed the suitability of Saline + HSA as a cell transportation solution for clinical use, which will be the choice for the planned clinical trial. Keratinocyte PBE-media can be an alternative for cells transported for research purpose, if the same media type is going to be used in the following experiments.

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  • 21.
    Shahin, Hady
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. MSA University, Egypt.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Steinvall, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Vascularization is the next challenge for skin tissue engineering as a solution for burn management2020In: Burns & trauma, ISSN 2321-3868, Vol. 8, article id tkaa022Article, review/survey (Refereed)
    Abstract [en]

    Skin regeneration represents a promising line of management for patients with skin loss, including burn victims. The current approach of spraying single cells over the defective areas results in variable success rates in different centers. The modern approach is to synthesize a multilayer skin construct that is based on autologous stem cells. One of the main complications with different types of transplants is sloughing due to the absence of proper vascularization. Ensuring proper vascularization will be crucial for the integration of skin constructs with the surrounding tissues. Combination of the right cells with scaffolds of proper physico-chemical properties, vascularization can be markedly enhanced. The material effect, pore size and adsorption of certain proteins, as well as the application of appropriate growth factors, such as vascular endothelial growth factors, can have an additive effect. A selection of the most effective protocols is discussed in this review.

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  • 22.
    Steinvall, Ingrid
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Abdelrahman, Islam
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    El-Serafi, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Fredrikson, Mats
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, ANOPIVA US. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    ABO blood group and effects on ventilatory time, length of stay and mortality in major burns a retrospective observational outcome study2022In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 48, no 4, p. 785-790Article in journal (Refereed)
    Abstract [en]

    Blood group has been found to be important in the development of many diseases and the outcome of several disease processes, especially cardiovascular morbidity and mortality, such as caused by trauma and sepsis. The main reason is claimed to be related to glycobiology and effects mediated through the endothelium. This study investigated the possible effect of blood group (ABO) on burn care outcome. Burn outcome prediction models are extremely accurate and as such can be used to identify outcome effects even in single centre settings. In this retrospective risk adjusted observational study, we investigated the effect of ABO blood group on ventilatory time, length of hospital stay (LOS), and 90 day mortality among patients with burns. RESULTS: A total of 225 patients were included (2008-2019) with median TBSA of 26%; interquartile range (IQR) of 20-37%; median age 45 years (IQR 22-65 years); median Baux score (age + TBSA%); 76 (IQR 53- 97); 168 (75%) were male; median duration of hospital stay was 31 days (IQR 19-56); a total of 138 (61%) received treatment with mechanical ventilation; and 29 (13%) died. In a multivariable regression model, we were unable to isolate any significant effect of any blood group (O, A, B, AB) on the outcome measures studied (ventilatory time, LOS, and mortality). IN SUMMARY: contrary to many other major areas of disease in which ABO blood groups affect outcome, we were unable to find any such effect on patients with burns. Given the precision of the outcome models presented (AUC 0.93) any such an effect, if missed due to the limited study cohort, may be considered limited and to have only a minor clinical impact.

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  • 23.
    Steinvall, Ingrid
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elmasry, Moustafa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Abdelrahman, Islam
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Elserafy, Ahmed Taher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Suez Canal University, Egypt.
    Sjöberg, Folke
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, ANOPIVA US.
    Addition of admission lactate levels to Baux score improves mortality prediction in severe burns.2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 18038Article in journal (Refereed)
    Abstract [en]

    Risk adjustment and mortality prediction models are central in optimising care and for benchmarking purposes. In the burn setting, the Baux score and its derivatives have been the mainstay for predictions of mortality from burns. Other well-known measures to predict mortality stem from the ICU setting, where, for example, the Simplified Acute Physiology Score (SAPS 3) models have been found to be instrumental. Other attempts to further improve the prediction of outcome have been based on the following variables at admission: Sequential Organ Failure Assessment (aSOFA) score, determinations of aLactate or Neutrophil to Lymphocyte Ratio (aNLR). The aim of the present study was to examine if estimated mortality rate (EMR, SAPS 3), aSOFA, aLactate, and aNLR can, either alone or in conjunction with the others, improve the mortality prediction beyond that of the effects of age and percentage total body surface area (TBSA%) burned among patients with severe burns who need critical care. This is a retrospective, explorative, single centre, registry study based on prospectively gathered data. The study included 222 patients with median (25th-75th centiles) age of 55.0 (38.0 to 69.0) years, TBSA% burned was 24.5 (13.0 to 37.2) and crude mortality was 17%. As anticipated highest predicting power was obtained with age and TBSA% with an AUC at 0.906 (95% CI 0.857 to 0.955) as compared with EMR, aSOFA, aLactate and aNLR. The largest effect was seen thereafter by adding aLactate to the model, increasing AUC to 0.938 (0.898 to 0.979) (p < 0.001). Whereafter, adding EMR, aSOFA, and aNLR, separately or in combinations, only marginally improved the prediction power. This study shows that the prediction model with age and TBSA% may be improved by adding aLactate, despite the fact that aLactate levels were only moderately increased. Thereafter, adding EMR, aSOFA or aNLR only marginally affected the mortality prediction.

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