Publications by authors named "Syed Faaiz Enam"

9 Publications

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Immuno-suppressive hydrogels enhance allogeneic MSC survival after transplantation in the injured brain.

Biomaterials 2021 01 28;266:120419. Epub 2020 Sep 28.

Dept. of Biomedical Engineering, Duke University, Durham, NC, 27708, USA. Electronic address:

Traumatic brain injury (TBI) triggers multiple biochemical and cellular processes that exacerbate brain tissue damage through a secondary injury. Therapies that prevent or limit the evolution of secondary injury could significantly reduce the neurological deficits associated with TBI. Mesenchymal stem cell (MSC) transplantation after TBI can ameliorate neurological deficits by modulating inflammation and enhancing the expression of neurotrophic factors. However, transplanted MSCs can be actively rejected by host immune responses, such as those mediated by cytotoxic CD8 T cells, thereby limiting their therapeutic efficacy. Here, we designed an agarose hydrogel that releases Fas ligand (FasL), a protein that can induce apoptosis of cytotoxic CD8 T cells. We studied the immunosuppressive effect of this hydrogel near the allogeneic MSC transplantation site and its impact on the survival of transplanted MSCs in the injured brain. Agarose-FasL hydrogels locally reduced the host cytotoxic CD8 T cell population and enhanced the survival of allogeneic MSCs transplanted near the injury site. Furthermore, the expression of crucial neurotrophic factors was elevated in the injury penumbra, suggesting an enhanced therapeutic effect of MSCs. These results suggest that the development of immunosuppressive hydrogels for stem cell delivery can enhance the benefits of stem cell therapy for TBI.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120419DOI Listing
January 2021

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells.

J Neuroinflammation 2020 Jun 20;17(1):197. Epub 2020 Jun 20.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Background: Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity (WMI). There already exist clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as interleukin-4 (IL-4).

Methods: To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs with synthetic IL-4 mRNA to transiently express IL-4. These IL-4 expressing MSCs (IL-4 MSCs) were characterized for expression and functionality and then delivered in a modified mouse TBI model of closed head injury. Groups were assessed for functional deficits and MR imaging. Brain tissue was analyzed through flow cytometry, multi-plex ELISA, qPCR, histology, and RNA sequencing.

Results: We observed that IL-4 MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression after TBI. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes, or improvements in WMI on MR imaging. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists despite acute enrichment of M2-like macrophages in the brain.

Conclusion: The results demonstrate that MSCs can be engineered to induce a stronger M2-like macrophage response in vivo. However, they also suggest that acute enrichment of only M2-like macrophages after diffuse TBI cannot orchestrate neurogenesis, axonal regeneration, or improve WMI. Here, we also discuss our modified TBI model and methods to assess severity, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.
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http://dx.doi.org/10.1186/s12974-020-01860-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306141PMC
June 2020

Use of Preoperative Apparent Diffusion Coefficients to Predict Brain Tumor Grade.

Cureus 2018 Mar 7;10(3):e2284. Epub 2018 Mar 7.

Medical College, The Aga Khan University.

Introduction The apparent diffusion coefficient (ADC) sequence is based on the diffusion properties of water molecules within tissues and correlates with tissue cellularity. ADC may have a role in predicting tumor grade for gliomas, and may in turn assist in identifying tumor biopsy sites. The purpose of this investigation was to assess the competence of preoperative ADC values in predicting tumor grades. Methods This was a retrospective investigation. We calculated the ADC values in the areas of greatest restriction in solid tumor components, and we recorded the pattern of contrast enhancement. Pathology reports masked to the imaging results were reviewed independently. We calculated the differences in the mean values of different tumor grades and high-grade and low-grade gliomas. A receiver operator curve (ROC) analysis assessed the predictive potential of ADC values for low-grade gliomas. Results Forty-eight cases of glioma were included in our study. We noted a statistically significant difference in the lowest mean ADC values for the tumor regions of Grade IV lesions (333.83 ± 295.47) compared with Grade I lesions (653.20 ± 145.07). On ROC analysis, we noted an area under the curve (AUC) of 0.80 for the lowest ADC value in the whole tumor region, which was a predictor of low-grade glioma with 95 % confidence interval (CI) of 0.675-0.926. The sensitivity of the lowest ADC value was 84.5% for high-grade lesions. Conclusion Given our findings that the means of the lowest ADC value are significantly different between low and high-grade gliomas with an AUC of 0.80 for ADC as a predictor of low-grade lesions and a sensitivity of 84.5% for high-grade lesions, ADC values contain some predictive properties of tumor grading. ADC values may be a valuable parameter in the assessment and treatment of tumors.
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http://dx.doi.org/10.7759/cureus.2284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938001PMC
March 2018

The importance of Evolutionary Medicine in developing countries: A case for Pakistan's medical schools.

Evol Med Public Health 2018 29;2018(1):26-33. Epub 2018 Jan 29.

Greater Manchester Mental Health Trust, Manchester M25 3BL, UK.

Evolutionary Medicine (EM) is a fundamental science exploring why our bodies are plagued with disease and hindered by limitations. EM views the body as an assortment of benefits, mistakes, and compromises molded over millennia. It highlights the role of evolution in numerous diseases encountered in community and family medicine clinics of developing countries. It enables us to ask informed questions and develop novel responses to global health problems. An understanding of the field is thus crucial for budding doctors, but its study is currently limited to a handful of medical schools in high-income countries. For the developing world, Pakistan's medical schools may be excellent starting posts as the country is beset with communicable non-communicable diseases that are shaped by evolution. Remarkably, Pakistani medical students are open to studying and incorporating EM into their training. Understanding the principles of EM could empower them to tackle growing health problems in the country. Additionally, some difficulties that western medical schools face in integrating EM into their curriculum may not be a hindrance in Pakistan. We propose solutions for the remaining challenges, including obstinate religious sentiments. Herein, we make the case that incorporating EM is particularly important in developing countries such as Pakistan and that it is achievable in its medical student body.
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http://dx.doi.org/10.1093/emph/eoy004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822701PMC
January 2018

Enrichment of endogenous fractalkine and anti-inflammatory cells via aptamer-functionalized hydrogels.

Biomaterials 2017 Oct 10;142:52-61. Epub 2017 Jul 10.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Early recruitment of non-classical monocytes and their macrophage derivatives is associated with augmented tissue repair and improved integration of biomaterial constructs. A promising therapeutic approach to recruit these subpopulations is by elevating local concentrations of chemoattractants such as fractalkine (FKN, CX3CL1). However, delivering recombinant or purified proteins is not ideal due to their short half-lives, suboptimal efficacy, immunogenic potential, batch variabilities, and cost. Here we report an approach to enrich endogenous FKN, obviating the need for delivery of exogenous proteins. In this study, modified FKN-binding-aptamers are integrated with poly(ethylene glycol) diacrylate to form aptamer-functionalized hydrogels ("aptagels") that localize, dramatically enrich and passively release FKN in vitro for at least one week. Implantation in a mouse model of excisional skin injury demonstrates that aptagels enrich endogenous FKN and stimulate significant local increases in Ly6CCX3CR1 non-classical monocytes and CD206 M2-like macrophages. The results demonstrate that orchestrators of inflammation can be manipulated without delivery of foreign proteins or cells and FKN-aptamer functionalized biomaterials may be a promising approach to recruit anti-inflammatory subpopulations to sites of injury. Aptagels are readily synthesized, highly customizable and could combine different aptamers to treat complex diseases in which regulation or enrichment of multiple proteins may be therapeutic.
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http://dx.doi.org/10.1016/j.biomaterials.2017.07.013DOI Listing
October 2017

Predicting outcomes of decompressive craniectomy: use of Rotterdam Computed Tomography Classification and Marshall Classification.

Br J Neurosurg 2016 1;30(2):258-63. Epub 2016 Feb 1.

a Department of Surgery, Section of Neurosurgery , Aga Khan University Hospital , Karachi , Pakistan.

Background: Data on the evaluation of the Rotterdam Computed Tomography Classification (RCTS) as a predictor of outcomes in patients undergoing decompressive craniectomy (DC) for trauma is limited and lacks clarity.

Objective: To explore the role of RCTS in predicting unfavourable outcomes, including mortality in patients undergoing DC for head trauma.

Methods: This was an observational cohort study conducted from 1 January 2009 to 31 March 2013. CT scans of adults with head trauma prior to emergency DC were scored according to RCTS. A receiver operating characteristic curve analysis was performed to identify the optimal cut-off RCTS for predicting unfavourable outcomes [Glasgow outcome scale (GOS) = 1-3]. Binary logistic regression analysis was performed to evaluate the relationship between RCTS and unfavourable outcomes including mortality.

Results: One hundred ninety-seven patients (mean age: 31.4 ± 18.7 years) were included in the study. Mean Glasgow coma score at presentation was 8.1 ± 3.6. RCTS was negatively correlated with GOS (r = -0.370; p < 0.001). The area under the curve was 0.687 (95% CI: 0.595-0.779; p < 0.001) and 0.666 (95% CI: 0.589-0.742; p < 0.001) for mortality and unfavourable outcomes, respectively. RCTS independently predicted both mortality (adjusted odds ratio for RCTS >3 compared with RCTS ≤3: 2.792, 95% CI: 1.235-6.311) and other unfavourable outcomes (adjusted odds ratio for RCTS >3 compared with RCTS ≤3: 2.063, 95% CI: 1.056-4.031).

Conclusion: RCTS is an independent predictor of unfavourable outcomes and mortality among patients undergoing emergency DC.
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http://dx.doi.org/10.3109/02688697.2016.1139047DOI Listing
January 2017

Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells.

Bioconjug Chem 2015 Dec 20;26(12):2336-49. Epub 2015 Oct 20.

Regenerative Bioscience Center, ADS Complex, The University of Georgia , 425 River Road, Athens, Georgia 30602, United States.

Neural stem cells (NSCs) possess great potential for neural tissue repair after traumatic injuries to the central nervous system (CNS). However, poor survival and self-renewal of NSCs after injury severely limits its therapeutic potential. Sulfated chondroitin sulfate glycosaminoglycans (CS-GAGs) linked to CS proteoglycans (CSPGs) in the brain extracellular matrix (ECM) have the ability to bind and potentiate trophic factor efficacy, and promote NSC self-renewal in vivo. In this study, we investigated the potential of CS-GAG hydrogels composed of monosulfated CS-4 (CS-A), CS-6 (CS-C), and disulfated CS-4,6 (CS-E) CS-GAGs as NSC carriers, and their ability to create endogenous niches by enriching specific trophic factors to support NSC self-renewal. We demonstrate that CS-GAG hydrogel scaffolds showed minimal swelling and degradation over a period of 15 days in vitro, absorbing only 6.5 ± 0.019% of their initial weight, and showing no significant loss of mass during this period. Trophic factors FGF-2, BDNF, and IL10 bound with high affinity to CS-GAGs, and were significantly (p < 0.05) enriched in CS-GAG hydrogels when compared to unsulfated hyaluronic acid (HA) hydrogels. Dissociated rat subventricular zone (SVZ) NSCs when encapsulated in CS-GAG hydrogels demonstrated ∼88.5 ± 6.1% cell viability in vitro. Finally, rat neurospheres in CS-GAG hydrogels conditioned with the mitogen FGF-2 demonstrated significantly (p < 0.05) higher self-renewal when compared to neurospheres cultured in unconditioned hydrogels. Taken together, these findings demonstrate the ability of CS-GAG based hydrogels to regulate NSC self-renewal, and facilitate growth factor enrichment locally.
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http://dx.doi.org/10.1021/acs.bioconjchem.5b00397DOI Listing
December 2015

Congenital malignant melanoma of the scalp in a 25-day-old neonate.

BMJ Case Rep 2014 Apr 23;2014. Epub 2014 Apr 23.

Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Sindh, Pakistan.

We present a case of congenital malignant melanoma of the scalp in a neonate. The child was born through caesarean section with a swelling, the size of a tennis ball, on the posterior scalp. At presentation to the clinic at 25 days after birth, the swelling had significantly increased in size and ulcerated. An excision was carried out but, because of extensive haemorrhage and haemodynamic instability, the procedure was limited to subtotal resection. Later on, completion of the excision and flap coverage of the wound were performed. After an initial stable course of a few months, the child came back with local recurrence. A re-excision was planned but the child developed pneumonia resulting in sepsis leading to the demise of the child. The report adds to the literature by describing a rare entity and challenges of managing large vascular scalp lesions with complete excision and defect coverage.
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http://dx.doi.org/10.1136/bcr-2013-202588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009829PMC
April 2014

Sampling bacterial biodiversity from a highly contaminated stream flowing through a densely populated urban area in Karachi.

J Ayub Med Coll Abbottabad 2011 Apr-Jun;23(2):147-51

Background: Few studies have attempted to understand the complexity of microbial populations in Pakistan where infectious diseases are prevalent. This study was undertaken to assess bacterial biodiversity in Nehr-e-Khayyam a heavily polluted stream connected to the Arabian Gulf, which runs through a densely populated urban area in Karachi, Pakistan.

Methods: Employing a universal pair of oligonucleotides capable of amplifying species-specific segments of 16S rRNA gene from all Eubacteria, we generated a library of PCR products using total DNA purified from the collected sample, cloned the amplifers into pGEM-T-Easy and sequenced each recombinant clone. The obtained DNA sequences were subjected to bio-informatic analyses.

Results: A total of 71 recombinant clones were obtained from the amplified 16S rDNA products and sequenced. Bioinformatics analyses revealed that 54 (out of 71) were unique sequences from which 42 shared > 97% and 12 shared < 97% homology to their database counterparts. One sequence originated from the plastid DNA of eukaryote Pyramimonas disomata. From the remaining 53 sequences, 45 were Proteo-bacteria and 8 Fermicute in origin. Among 71 sequences, Alpha-, Beta- and Gamma-proteobacteria species constituted -86% of Proteo-bacteria identified in the sample while only -13% were Fermicutes.

Conclusions: The microbial niche in Nehr-e-Khayyam is occupied predominantly by heterotrophic Proteo-bacterial and Firmicute strains, some of which are known human pathogens.
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June 2014
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