Publications by authors named "David Allan"

312 Publications

MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis.

Stem Cell Rev Rep 2021 Jul 27. Epub 2021 Jul 27.

Stem Cells, Canadian Blood Services, Ottawa, ON, Canada.

Background And Objective: Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair.

Methods: English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF).

Results: Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8-28.5%, p < 0.001) and NBF (26.1% MD; 10.3-41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20).

Conclusion: Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies. Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs.
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http://dx.doi.org/10.1007/s12015-021-10208-9DOI Listing
July 2021

Impact of Exercise Training on Hematological Outcomes Following Hematopoietic Cell Transplantation: A Scoping Review.

Clin Invest Med 2021 06 14;44(2):E19-26. Epub 2021 Jun 14.

Department of Medicine, University of Ottawa, Ottawa, ON, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute and Transplantation and Cell Therapy Program, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.

Purpose: Hematopoietic cell transplantation (HCT) is associated with significant risk prior to hematopoietic engraftment. Endurance exercise can modify the bone marrow microenvironment, alter hematopoiesis and accelerate hematopoietic regeneration in mouse models of transplantation.

Methods: A systematic review was conducted to clarify the impact of exercise on clinically relevant hemato-logical outcomes in patients following HCT.

Results: A systematic search of the literature identified 13 studies (total of 615 participants; 313 in study arms). Studies included exercise regimens that were primarily low-to-moderate intensity. A total of five studies re-ported on engraftment and length of stay, which were largely unchanged with intervention. Rates of graft-ver-sus host disease were reported in six studies whereas red cell and platelet transfusion needs were reported in four studies, neither of which was different with exercise. Survival was reported in four studies and was significantly improved by exercise in one study.

Conclusions: Exercise in patients receiving HCT appears feasible and safe. Heterogeneity in type and intensity of exercise was observed and few studies examined high intensity exercise. Outcome reporting was inconsis-tent regarding transplant-related outcomes. Standardized hematological outcome measures are needed to clarify the impact of higher intensity exercise on HCT.
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http://dx.doi.org/10.25011/cim.v44i2.36369DOI Listing
June 2021

A Timely CIBMTR Analysis of How Cryopreservation Impacts Allogeneic Hematopoietic Cell Transplantation to Apply in the COVID Era.

Authors:
David S Allan

Transplant Cell Ther 2021 06;27(6):446-447

Transplant & Cellular Therapy, The Ottawa Hospital, Ottawa Hospital Research Institute, University of Ottawa and Stem Cells, Canadian Blood Services, Ottawa, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtct.2021.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205308PMC
June 2021

Pressure-and temperature induced phase transitions, piezochromism, NLC behaviour and pressure controlled Jahn-Teller switching in a Cu-based framework.

Chem Sci 2020 Jul 30;11(33):8793-8799. Epub 2020 Jul 30.

School of Molecular Sciences and Centre for Microscopy, Characterisation and Analysis, University of Western Australia 35 Stirling Highway, Crawley Perth 6005 Western Australia Australia

single-crystal diffraction and spectroscopic techniques have been used to study a previously unreported Cu-framework bis[1-(4-pyridyl)butane-1,3-dione]copper(ii) (CuPyr-I). CuPyr-I was found to exhibit high-pressure and low-temperature phase transitions, piezochromism, negative linear compressibility, and a pressure induced Jahn-Teller switch, where the switching pressure was hydrostatic media dependent.
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http://dx.doi.org/10.1039/d0sc03229hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163414PMC
July 2020

Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

Transplantation 2021 May 25. Epub 2021 May 25.

Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada. Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, ON, Canada. Department of Pathology, University of Pittsburgh, Pittsburgh, PA. Department of Medical Imaging, University Health Network, Toronto, ON, Canada. Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.

Background: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance.

Methods: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection and cryopreserved. Immunoablation using busulfan, cyclophosphamide and rabbit anti-thymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic and clinical evidence of rejection while off immunosuppression at 2 years post-aHSCT.

Results: Two of the 5 patients achieved operational tolerance with no clinical or histological evidence of PSC progression or allo-rejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now more than 3 years after aHSCT. A fourth patient was weaned off immunosuppression but died 212 days after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T cell clones, loss of autoantibodies and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors.

Conclusions: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed renders this specific protocol unsuitable for clinical adoption.
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http://dx.doi.org/10.1097/TP.0000000000003829DOI Listing
May 2021

Iron-withdrawing anti-infectives for new host-directed therapies based on iron dependence, the Achilles' heel of antibiotic-resistant microbes.

Environ Chem Lett 2021 Apr 23:1-20. Epub 2021 Apr 23.

Department of Microbiology and Immunology, Dalhousie University, 5859 College St., Halifax, NS B3H 1X5 Canada.

The iron dependence of antibiotic-resistant microbes represents an Achilles' heel that can be exploited broadly. The growing global problem of antibiotic resistance of microbial pathogens wherein microbes become resistant to the very antibiotics used against them during infection is linked not only to our health uses but also to agribusiness practices and the changing environment. Here we review mechanisms of microbial iron acquisition and host iron withdrawal defense, and the influence of iron withdrawal on the antimicrobial activity of antibiotics. Antibiotic-resistant microbes are unaltered in their iron requirements, but iron withdrawal from microbes enhances the activities of various antibiotics and importantly suppresses outgrowth of antibiotic-exposed resistant microbial survivors. Of the three therapeutic approaches available to exploit microbial iron susceptibility, including (1) use of gallium as a non-functional iron analogue, (2) Trojan horse conjugates of microbial siderophores carrying antibiotics, and (3) new generation iron chelators, purposely designed as anti-microbials, the latter offers various advantages. For instance, these novel anti-microbial chelators overcome the limitations of conventional clinically-used hematological chelators which display host toxicity and are not useful antimicrobials. 3-Hydroxypyridin-4-one-containing polymeric chelators appear to have the highest potential. DIBI (developmental code name) is a well-developed lead candidate, being a low molecular weight, water-soluble copolymer with enhanced iron binding characteristics, strong anti-microbial and anti-inflammatory activities, low toxicity for animals and demonstrated freedom from microbial resistance development. DIBI has been shown to enhance antibiotic efficacy for antibiotic-resistant microbes during infection, and it also prevents recovery growth and resistance development during microbe exposure to various antibiotics. Because DIBI bolsters innate iron withdrawal defenses of the infected host, it has potential to provide a host-directed anti-infective therapy.
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http://dx.doi.org/10.1007/s10311-021-01242-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062846PMC
April 2021

Therapeutic effects of micro-RNAs in preclinical studies of acute kidney injury: a systematic review and meta-analysis.

Sci Rep 2021 Apr 27;11(1):9100. Epub 2021 Apr 27.

Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 1967 Riverside Drive, Rm. 535, Ottawa, ON, K1H 7W9, Canada.

AKI has a high mortality rate, may lead to chronic kidney disease, and effective therapies are lacking. Micro-RNAs (miRNAs) regulate biologic processes by potently inhibiting protein expression, and pre-clinical studies have explored their roles in AKI. We conducted a systematic review and meta-analysis of miRNAs as therapeutics in pre-clinical AKI. Study screening, data extraction, and quality assessments were performed by 2 independent reviewers. Seventy studies involving 42 miRNA species were included in the analysis. All studies demonstrated significant effects of the miRNA intervention on kidney function and/or histology, with most implicating apoptosis and phosphatase and tensin homolog (PTEN) signaling. Fourteen studies (20.0%) examined the effect of miRNA-21 in AKI, and meta-analysis demonstrated significant increases in serum creatinine and kidney injury scores with miR-21 antagonism and pre-conditioning. No studies reported on adverse effects of miRNA therapy. Limitations also included lack of model diversity (100% rodents, 61.4% ischemia-reperfusion injury), and predominance of male sex (78.6%). Most studies had an unclear risk of bias, and the majority of miRNA-21 studies were conducted by a single team of investigators. In summary, several miRNAs target kidney function and apoptosis in pre-clinical AKI models, with data suggesting that miRNA-21 may mediate protection and kidney repair.Systematic review registration ID: CRD42019128854.
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http://dx.doi.org/10.1038/s41598-021-88746-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079678PMC
April 2021

MSC-Derived Extracellular Vesicles to Heal Diabetic Wounds: a Systematic Review and Meta-Analysis of Preclinical Animal Studies.

Stem Cell Rev Rep 2021 Apr 24. Epub 2021 Apr 24.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Introduction: Extracellular vesicles from mesenchymal stromal cells (MSC-EVs) have shown promise in wound healing. Their use in diabetic wounds specifically, however, remains pre-clinical and their efficacy remains uncertain less clear. A systematic review of preclinical studies is needed to determine the efficacy of MSC-EVs in the treatment of diabetic wounds to accelerate the clinical translation of this cell-based therapy.

Methods: PubMed and Embase were searched (to June 23, 2020). All English-language, full-text, controlled interventional studies comparing MSC-EVs to placebo or a "no treatment" arm in animal models of diabetic wounds were included. Study outcomes, including wound closure (primary outcome), scar width, blood vessel number and density, and re-epithelialisation were pooled using a random effects meta-analysis. Risk of bias (ROB) was assessed using the SYRCLE tool for pre-clinical animal studies.

Results: A total of 313 unique records were identified from our search, with 10 full text articles satisfying inclusion criteria (n = 136 animals). The administration of MSC-EVs improved closure of diabetic wounds compared to controls with a large observed effect (Standardized Mean Difference (SMD) 5.48, 95% Confidence Interval (CI) 3.55-8.13). Healing was further enhanced using MSC-EVs enriched in non-coding RNAs or microRNAs compared to controls (SMD 9.89, 95%CI 7.32-12.46). Other outcomes, such as blood vessel density and number, scar width, and re-epithelialisation were improved with the administration of MSC-EVs, with a large effect. ROB across studies was unclear.

Conclusion: MSC-EVs, particularly following enrichment for specific RNAs, are a promising treatment for diabetic wounds in pre-clinical studies and translation to the clinical domain appears warranted.

Registration: PROSPERO #CRD42020199327 [248]. Forest plot demonstrating increased wound closure rates of diabetic wounds receiving genetically modified MSC-EVs that were enriched for specific RNAs. DFO = deferoxamine. Control groups were inactive (no treatment or saline) except for 3 studies which used hydrogels without MSC-EVs as control (Li M 2016; Shi 2017; Tao 2016).
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http://dx.doi.org/10.1007/s12015-021-10164-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064883PMC
April 2021

Mesenchymal Stromal Cell-derived Extracellular Vesicles in Preclinical Animal Models of Tumor Growth: Systematic Review and Meta-analysis.

Stem Cell Rev Rep 2021 Apr 15. Epub 2021 Apr 15.

Clinical Epidemiology, Ottawa Hospital Research Institute, Box 704, 501 Smyth Rd, ON, K1H 8L6, Ottawa, Canada.

Background: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials.

Methods: A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed.

Results: We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD - 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied.

Conclusions: MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia.
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http://dx.doi.org/10.1007/s12015-021-10163-5DOI Listing
April 2021

Validation of a non-invasive imaging photoplethysmography device to assess plantar skin perfusion, a comparison with laser speckle contrast analysis.

J Med Eng Technol 2021 Apr 22;45(3):170-176. Epub 2021 Mar 22.

Centre for Biomechanics and Rehabilitation Technologies, Staffordshire University, Stoke-on-Trent, UK.

Assessing skin perfusion is an established and reliable method to study impaired lower limb blood flow. Laser Speckle Contrast Analysis (LASCA) has been identified as the current gold standard to measure skin perfusion. Imaging photoplethysmography (iPPG) is a new low-cost imaging technique to assess perfusion. However, it is unclear how results obtained from this technique compare against that of LASCA at plantar skin. Therefore, the aim of this study was to investigate the association between the skin perfusion at the plantar surface of the foot using iPPG and LASCA. Perfusion at six plantar locations (Hallux, 1st 3rd 5th metatarsal heads, midfoot, heel) was simultaneously measured using LASCA and iPPG in 20 healthy participants. Skin thickness and skin temperature were also collected at the same plantar locations. Spearman's rank tests showed significant associations with medium strength between the perfusion values measured with LASCA and iPPG for most tested sites. No improvement in the relationship between iPPG and LASCA data was observed when controlling for either skin thickness or skin temperature. Skin perfusion values obtained using iPPG were found to be significantly associated with the corresponding values obtained using the gold standard LASCA device. Additionally, the measurement of perfusion using iPPG is shown to be robust.
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http://dx.doi.org/10.1080/03091902.2021.1891309DOI Listing
April 2021

RNA-Seq Analysis Reveals CCR5 as a Key Target for CRISPR Gene Editing to Regulate In Vivo NK Cell Trafficking.

Cancers (Basel) 2021 Feb 19;13(4). Epub 2021 Feb 19.

National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.

A growing number of natural killer (NK) cell-based immunotherapy trials utilize ex vivo expansion to grow and activate allogenic and autologous NK cells prior to administration to patients with malignancies. Recent data in both murine and macaque models have shown that adoptively infused ex vivo expanded NK cells have extensive trafficking into liver tissue, with relatively low levels of homing to other sites where tumors often reside, such as the bone marrow or lymph nodes. Here, we evaluated gene and surface expression of molecules involved in cellular chemotaxis in freshly isolated human NK cells compared with NK cells expanded ex vivo using two different feeder cells lines: Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) or K562 cells with membrane-bound (mb) 4-1BB ligand and interleukin (IL)-21. Expanded NK cells had altered expression in a number of genes that encode chemotactic ligands and chemotactic receptors that impact chemoattraction and chemotaxis. Most notably, we observed drastic downregulation of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of C-C chemokine receptor type 5 (CCR5) transcription and phenotypic expression. clustered regularly interspaced short palindromic repeats (CRISPR) gene editing of CCR5 in expanded NK cells reduced cell trafficking into liver tissue and increased NK cell presence in the circulation following infusion into immunodeficient mice. The findings reported here show that ex vivo expansion alters multiple factors that govern NK cell homing and define a novel approach using CRISPR gene editing that reduces sequestration of NK cells by the liver.
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http://dx.doi.org/10.3390/cancers13040872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922167PMC
February 2021

Persistence of CRISPR/Cas9 gene edited hematopoietic stem cells following transplantation: A systematic review and meta-analysis of preclinical studies.

Stem Cells Transl Med 2021 Jul 5;10(7):996-1007. Epub 2021 Mar 5.

Canadian Blood Services, Stem Cells and Centre for Innovation, Ottawa, Ontario, Canada.

Gene editing blood-derived cells is an attractive approach to cure selected monogenic diseases but remains experimental. A systematic search of preclinical controlled studies is needed to determine the persistence of edited cells following reinfusion. All studies identified in our systematic search (to 20 October 2020) examining the use of CRISPR/Cas9 gene editing in blood-derived cells for transplantation were included. Meta-analysis was performed to determine the engraftment and persistence of gene edited cells. A total of 3538 preclinical studies were identified with 15 published articles meeting eligibility for meta-analysis. These in vivo animal studies examined editing of hemoglobin to correct sickle cell disease (eight studies), inducing resistance to acquired immunodeficiency syndrome (two studies), and six other monogenic disorders (single studies). CRISPR-Cas9 edited hematopoietic stem and progenitor cells demonstrated equivalent early engraftment compared to controls in meta-analysis but persistence of gene-edited cells was reduced at later time points and in secondary transplant recipients. Subgroup analysis in studies targeting the hemoglobin gene revealed a significant reduction in the persistence of gene-edited cells whether homology-directed repair or nonhomologous end-joining were used. No adverse side effects were reported. Significant heterogeneity in study design and outcome reporting was observed and the potential for bias was identified in all studies. CRISPR-Cas9 gene edited cells engraft similarly to unedited hematopoietic cells. Persistence of gene edited cells, however, remains a challenge and improved methods of targeting hematopoietic stem cells are needed. Reducing heterogeneity and potential risk of bias will hasten the development of informative clinical trials.
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http://dx.doi.org/10.1002/sctm.20-0520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235122PMC
July 2021

Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing expansion.

Mol Ther Methods Clin Dev 2021 Mar 20;20:559-571. Epub 2021 Jan 20.

Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Transduction of primary human natural killer (NK) cells with lentiviral vectors has historically been challenging. We sought to evaluate multiple parameters to optimize lentiviral transduction of human peripheral blood NK cells being expanded to large numbers using a good manufacturing practice (GMP)-compliant protocol that utilizes irradiated lymphoblastoid (LCL) feeder cells. Although prestimulation of NK cells with interleukin (IL)-2 for 2 or more days facilitated transduction with vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped lentivirus, there was a subsequent impairment in the capacity of transduced NK cells to proliferate when stimulated with LCL feeder cells. In contrast, incubation of human NK cells with LCL feeder cells plus IL-2 before transduction in the presence of the TBK1 inhibitor BX795 resulted in efficient lentiviral integration (mean of 23% transgene NK cells) and successful subsequent proliferation of the transduced cells. Investigation of multiple internal promoter sequences within the same lentiviral vector revealed differences in percentage and level of transgene expression per NK cell. Bicistronic lentiviral vectors encoding both GFP and proteins suitable for the isolation of transduced cells with magnetic beads led to efficient transgene expression in NK cells. The optimized approaches described herein provide a template for protocols that generate large numbers of fully functional and highly purified lentivirus-transduced NK cells for clinical trials.
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http://dx.doi.org/10.1016/j.omtm.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890427PMC
March 2021

Autologous Hematopoietic Stem Cell Transplantation for Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Can J Neurol Sci 2021 Feb 26:1-7. Epub 2021 Feb 26.

Division of Neurology, The Ottawa Hospital, University of Ottawa, Ottawa, Canada.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to conventional therapy can lead to marked disability and represents a therapeutic challenge.

Objective: To report five cases of treatment-refractory disabling CIDP treated with autologous hematopoietic stem cell transplantation (AHSCT).

Methods: This was a retrospective cohort study from a tertiary care referral center for both neuromuscular disease and AHSCT. Patients with CIDP treated with AHSCT between 2008 and 2020 were included. All patients had major persistent and disabling neuropathic deficits despite combinations of intensive immunosuppressive therapy. The primary outcome measures were: Medical Research Council sum score, Overall Neuropathy Limitations Scale and requirement for ongoing CIDP immunotherapy after transplantation. We also analyzed safety outcomes by documenting all severe AHSCT-related complications.

Results: Five patients with refractory CIDP underwent AHSCT. Three were classified as manifesting a typical syndrome, two were classified as the multifocal Lewis Sumner variant. The mean age at time of CIDP diagnosis was 33.4 years (range 24-46 years), with a median delay of 46 months (range 21-135 months) between diagnosis and AHSCT. The median follow-up period was 41 months. All five patients were able to wean off CIDP-related immunotherapy. Marked improvements in Medical Research Council scale and overall Neuropathy Limitations Scale were noted in 4/5 patients. One patient with longstanding neurogenic atrophy showed no improvement in disability scales. There were no treatment-related deaths or critical illnesses.

Conclusions: AHSCT can achieve marked sustained clinical improvement of refractory CIDP and may allow for weaning off long-term complex immunotherapies.
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http://dx.doi.org/10.1017/cjn.2021.30DOI Listing
February 2021

MRI-traceable theranostic nanoparticles for targeted cancer treatment.

Theranostics 2021 1;11(2):579-601. Epub 2021 Jan 1.

Department of Chemical Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, AL 36849, USA.

Current cancer therapies, including chemotherapy and radiotherapy, are imprecise, non-specific, and are often administered at high dosages - resulting in side effects that severely impact the patient's overall well-being. A variety of multifunctional, cancer-targeted nanotheranostic systems that integrate therapy, imaging, and tumor targeting functionalities in a single platform have been developed to overcome the shortcomings of traditional drugs. Among the imaging modalities used, magnetic resonance imaging (MRI) provides high resolution imaging of structures deep within the body and, in combination with other imaging modalities, provides complementary diagnostic information for more accurate identification of tumor characteristics and precise guidance of anti-cancer therapy. This review article presents a comprehensive assessment of nanotheranostic systems that combine MRI-based imaging (T1 MRI, T2 MRI, and multimodal imaging) with therapy (chemo-, thermal-, gene- and combination therapy), connecting a range of topics including hybrid treatment options ( combined chemo-gene therapy), unique MRI-based imaging ( combined T1-T2 imaging, triple and quadruple multimodal imaging), novel targeting strategies ( dual magnetic-active targeting and nanoparticles carrying multiple ligands), and tumor microenvironment-responsive drug release ( redox and pH-responsive nanomaterials). With a special focus on systems that have been tested , this review is an essential summary of the most advanced developments in this rapidly evolving field.
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http://dx.doi.org/10.7150/thno.48811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738852PMC
January 2021

Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics.

PLoS One 2020 30;15(12):e0243901. Epub 2020 Dec 30.

Department of Drug Discovery and Development, Auburn University, Auburn, AL, United States of America.

Whereas recent clinical studies report metastatic melanoma survival rates high as 30-50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2β) functions as a partial agonist at ErbB4. NRG2β/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z' > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243901PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773179PMC
February 2021

Multimedia resources to support the recruitment of committed hematopoietic stem cell donors: Perspectives of the most-needed donors.

Transfusion 2021 01 2;61(1):274-285. Epub 2020 Dec 2.

Stem Cell Club, Toronto, Ontario, Canada.

Background: Recruitment of committed unrelated hematopoietic stem cell donors from the most-needed demographics remains a challenge for donor recruitment organizations worldwide. Multimedia resources are gaining attention as a modality to support recruitment efforts; however, there is a lack of guidance for the development of such tools. This qualitative study explores the perspectives of eligible stem cell donors on an educational whiteboard video about stem cell donation, generating insights into how whiteboard videos and related multimedia may be optimized for donor recruitment.

Study Design And Methods: Eight semistructured focus groups were conducted with 38 potential donors from the most-needed demographics (young, male, and non-Caucasian) after they had watched a 3.5-minute whiteboard video explaining key concepts in stem cell donation (https://youtu.be/V4fVBtxnWfM). Constructivist grounded theory was used to identify themes and to develop a framework for understanding participants' preferred features of recruitment multimedia.

Results: Participants identified a range of features contributing to the effectiveness of recruitment multimedia, adding that the whiteboard video is an effective, integrated, and readily accessible format for supporting donor recruitment. Topics that participants felt are important to address include knowledge gaps regarding donation procedures, concerns about donor safety, and the particular need for specific donor demographics. Suggested avenues for improvement include the addition of donor/recipient/patient personal experiences, attention-grabbing hooks, and a call to action including opportunities for further learning.

Conclusions: Several considerations were generated to inform the development of future multimedia for donor education/recruitment and are relevant to donor recruitment organizations worldwide.
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http://dx.doi.org/10.1111/trf.16186DOI Listing
January 2021

Preclinical Studies of MSC-Derived Extracellular Vesicles to Treat or Prevent Graft Versus Host Disease: a Systematic Review of the Literature.

Stem Cell Rev Rep 2021 Apr 7;17(2):332-340. Epub 2020 Nov 7.

Department of Medicine (Blood and Marrow Transplantation), The Ottawa Hospital, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.

Introduction: Treating and preventing graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT) remains a significant challenge. The use of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) appears promising and a systematic review of preclinical studies is needed to accelerate the design of translational studies.

Methods: We identified 4 eligible studies from a systematic review performed on December 1, 2018. In brief, eligible studies included the treatment or prevention of GVHD in animal models and the use of MSC-EVs. Study design and outcome data were extracted and reporting was evaluated using the SYRCLE tool to identify potential bias.

Results: Two studies assessed the efficacy of MSC-EVs in treatment of GVHD and 2 studies address prevention. Mice treated with MSC-EVs showed improved median survival, GVHD clinical scores and histology scores as compared to untreated mice with GVHD. Prophylactic treatment with MSC-EVs attenuated GVHD severity and improved median survival as compared to no treatment or saline.

Conclusion: Our systematic review provides important insight regarding the potential of MSC-EVs to treat or prevent GVHD. Although few studies were identified, improved survival and attenuated histologic findings of GVHD were observed in mice after MSC-EV administration for the treatment and prevention of GVHD. Dosing of EVs and route of administration remain inconsistent, however, and scalability of EV isolation for clinical studies remains a challenge. Standardized outcome reporting is needed to pool results for metanalysis. Graphical abstract.
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http://dx.doi.org/10.1007/s12015-020-10058-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648545PMC
April 2021

Chemotherapy in the Intensive Care Unit: An Evaluation of Context and Outcomes.

Can J Hosp Pharm 2020 1;73(4):279-287. Epub 2020 Oct 1.

, MD, MHA, FRCPC, is with The Ottawa Hospital, Ottawa, Ontario.

Background: Administration of chemotherapy to highly vulnerable, critically ill patients in the intensive care unit (ICU) is becoming more common, but the process requires significantly more resources than chemotherapy administration in specialized oncology settings.

Objective: To describe the context, complications, and outcomes of chemotherapy administration for cancer-related indications in ICU patients.

Methods: For this retrospective observational study, consecutive patients receiving parenteral chemotherapy in the ICU at the General Campus of The Ottawa Hospital between January 1, 2014, and December 31, 2017, were identified using pharmacy records. The clinical characteristics of these patients, details of their chemotherapy regimens, and outcomes were analyzed.

Results: A total of 32 patients were included in the study. Of these, 27 patients (84%) had a hematological malignancy, 16 (50%) had a documented infection at the time of chemotherapy administration, and 29 (91%) received their first cycle of chemotherapy on an urgent basis during the ICU admission rather than as a scheduled or planned treatment. Severity of illness was high both at ICU admission and at the time of chemotherapy treatment; regimen modifications, drug interactions, and adverse events were common. Remission and survival data were available for 28 patients at 12 months. Eighteen (56%) of the 32 patients survived to hospital discharge, and 12 (38%) survived to 6 months; at 12 months, survival was 25% (7 of 28 patients with available data). About one-quarter of the patients were in remission at 6 and 12 months.

Conclusion: Administering chemotherapy in the ICU is feasible, but the process is resource-intensive. Patients with aggressive hematological cancers who require treatment on an urgent basis represent the most commonly observed scenario. This study highlights the complexity of management and the importance of multidisciplinary care teams for this patient population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556399PMC
October 2020

Diabetes Status is Associated With Plantar Soft Tissue Stiffness Measured Using Ultrasound Reverberant Shear Wave Elastography Approach.

J Diabetes Sci Technol 2020 Oct 23:1932296820965259. Epub 2020 Oct 23.

Department of Engineering, Medical Imaging Laboratory, Pontificia Universidad Catolica del Peru, Lima, Peru.

Introduction: The purpose of this study was to investigate the association between the mechanical properties of plantar soft tissue and diabetes status.

Method: 51 (M/F: 21/30) participants with prediabetes onset (fasting blood sugar [FBS] level > 100 mg/dL), age >18 years, and no lower limb amputation were recruited after ethical approval was granted from Pontificia Universidad Catolica del Peru ethical review board. Ultrasound reverberant shear wave elastography was used to assess the soft tissue stiffness at the 1st metatarsal head (MTH), 3rd MTH, and the heel at both feet.

Results: Spearman's rank-order correlation (rho) test indicated a significant ( < .05) positive correlations between FBS level and the plantar soft tissue shear wave speed at the 1st MTH: = 0.402 (@400 Hz), = 0.373 (@450 Hz), = 0.474 (@500 Hz), = 0.395 (@550 Hz), and = 0.326 (@600 Hz) in the left foot and = 0.364 (@450 Hz) in the right foot. Mann-Whitney U test indicated a significantly ( < .05) higher shear wave speed in the plantar soft tissue with the following effect sizes (r) at the 1st MTH of the left foot at all tested frequencies: = 0.297 (@450 Hz), = 0.345 (@500 Hz), = 0.322 (@550 Hz), and = 0.275 (@600 Hz), and at the 1st MTH of right foot = 0.286 (@400 Hz) in diabetes as compared with the age and body mass index matched prediabetes group.

Conclusion: An association between fasting blood sugar level and the stiffness of the plantar soft tissue with higher values of shear wave speed in diabetes versus prediabetes group was observed. This indicated that the proposed approach can improve the assessment of the severity of diabetic foot complications with potential implications in patient stratification.
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http://dx.doi.org/10.1177/1932296820965259DOI Listing
October 2020

Factors associated with registrant availability for unrelated adult donor hematopoietic stem cell donation: Analysis of the stem cell registry at Canadian Blood Services.

Transfusion 2021 01 21;61(1):24-28. Epub 2020 Oct 21.

Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Greater use of unrelated donors to support hematopoietic cell transplantation can be hampered by unavailability of registrants when identified as potential candidates for donation.

Methods: Multivariate analysis was performed to identify donor factors associated with availability for verification of human leukocyte antigen typing (VT) needed before donor activation. All VT requests for registrants on the Canadian Blood Services Stem Cell Registry between 1 January and 31 December 2018 were reviewed (n = 1358).

Results: Potential donors identified by transplant centers were categorized as available at the time of VT but ineligible for medical or other reasons (n = 130 and excluded from further analysis), available (n = 622) or unavailable (n = 566) due to scheduling, loss of interest, and/or inability to contact. With multivariate analysis, registrants who previously donated blood, those recruited online or from blood donation clinics, and a shorter interval between registration and VT request were significantly correlated with increased donor availability. Donor sex and geographic location, however, displayed no correlation.

Conclusion: Online registration and recruitment at whole blood donation centers should be enhanced to increase the availability of registrants at VT. More insight is needed to maintain registrant availability following community in-person recruitment events, especially if the interval between registration and activation is prolonged. Recruitment of male registrants who are well informed should not negatively impact availability.
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http://dx.doi.org/10.1111/trf.16129DOI Listing
January 2021

Augmentation of NK Cell Proliferation and Anti-tumor Immunity by Transgenic Expression of Receptors for EPO or TPO.

Mol Ther 2021 01 20;29(1):47-59. Epub 2020 Sep 20.

Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Many investigational adoptive immunotherapy regimens utilizing natural killer (NK) cells require the administration of interleukin-2 (IL-2) or IL-15, but these cytokines cause serious dose-dependent toxicities. To reduce or preclude the necessity for IL-2 use, we investigated whether genetic engineering of NK cells to express the erythropoietin (EPO) receptor (EPOR) or thrombopoietin (TPO) receptor (c-MPL) could be used as a method to improve NK cell survival and function. Viral transduction of NK-92 cells to express EPOR or c-MPL receptors conveyed signaling via appropriate pathways, protected cells from apoptosis, augmented cellular proliferation, and increased cell cytotoxic function in response to EPO or TPO ligands in vitro. In the presence of TPO, viral transduction of primary human NK cells to express c-MPL enhanced cellular proliferation and increased degranulation and cytokine production toward target cells in vitro. In contrast, transgenic expression of EPOR did not augment the proliferation of primary NK cells. In immunodeficient mice receiving TPO, in vivo persistence of primary human NK cells genetically modified to express c-MPL was higher compared with control NK cells. These data support the concept that genetic manipulation of NK cells to express hematopoietic growth factor receptors could be used as a strategy to augment NK cell proliferation and antitumor immunity.
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http://dx.doi.org/10.1016/j.ymthe.2020.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791015PMC
January 2021

Development and evaluation of stem cell collection procedure diagrams to support the education and recruitment of committed stem cell donors.

Vox Sang 2021 Feb 24;116(2):239-248. Epub 2020 Sep 24.

Canadian Blood Services, Ottawa, ON, Canada.

Background: Diagrams which allow potential unrelated stem cell donors to visualize the stem cell collection process were hypothesized to support the recruitment and education of committed stem cell donors.

Study Design And Methods: A series of bone marrow and peripheral blood stem cell collection procedure diagrams were developed, featuring young adult male donors of varied ethnic backgrounds. Post-implementation, surveys were conducted to evaluate stakeholder perspective on the diagrams' utility. A quality improvement project was conducted at five stem cell drives from 2017 to 2018 at which recruiters did or did not show the diagrams to potential donors. Following the drives, registrants were invited to complete a survey exploring their experience, knowledge and attitude towards donation.

Results: The diagrams were implemented in Canada in 07/2016. Of 293 participating registrants (24·7% non-Caucasian males) recruited at five drives between 2017 and 2018, 76% (n = 197) were shown the diagrams. Participants who were shown the diagrams were significantly more likely to report that the recruiters appeared very knowledgeable (89% vs. 76%, P = 0·019) and to report improved self-reported knowledge of stem cell donation (P = 0·010) compared to participants not shown the diagram. Data are also shown demonstrating that stakeholders in donor recruitment used and valued the diagrams and that use of the diagrams was associated with improved donor recruitment outcomes in Canada.

Conclusion: This report is the first evaluation of stem cell collection diagrams in the literature. The diagrams are relevant to donor registries, recruitment organizations and transplant centres worldwide, and their use may support efforts to educate and recruit committed, ethnically diverse donors.
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http://dx.doi.org/10.1111/vox.13010DOI Listing
February 2021

Plerixafor in combination with chemotherapy and/or hematopoietic cell transplantation to treat acute leukemia: A systematic review and metanalysis of preclinical and clinical studies.

Leuk Res 2020 10 27;97:106442. Epub 2020 Aug 27.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Canada; Department of Medicine (Hematology), Faculty of Medicine, University of Ottawa, Canada. Electronic address:

Leukemia-initiating cells localize to bone marrow niches via cell surface CXCR4 binding to stromal-derived factor 1 (SDF-1). Plerixafor, a CXCR4 antagonist, can mobilize and sensitize leukemia cells to cytotoxic therapy, and/or enhance the engraftment of healthy donor stem cells in the context of hematopoietic cell transplantation (HCT). A systematic review of preclinical and clinical studies was performed (updated May 1, 2020) to inform the design of definitive clinical trials and identified 19 studies. Pooled data from 10 preclinical in-vivo studies of AML and ALL in mouse models of leukemia revealed significant mobilization of leukemia cells into the peripheral circulation, decreased total blast burden and increased survival with plerixafor in addition to cytotoxic treatment compared to control animals. Two of 9 clinical studies compared outcomes to a control group. Plerixafor appears well tolerated and safe and can mobilize leukemia cells into the peripheral circulation. In patients with AML undergoing HCT, plerixafor given with the conditioning regimen appears safe and well tolerated. Engraftment, relapse and survival were not different from controls after limited follow-up. Studies in high risk patients with AML with longer follow-up are needed to understand the influence on relapse following treatment and on donor cell engraftment following HCT.
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http://dx.doi.org/10.1016/j.leukres.2020.106442DOI Listing
October 2020

Evaluation of commercial soft contact lenses for ocular drug delivery: A review.

Acta Biomater 2020 10 25;115:60-74. Epub 2020 Aug 25.

Department of Chemical Engineering, Auburn University, Auburn, AL, United States. Electronic address:

Soft contact lenses have generated growing interest in ocular drug delivery due to their potential to enhance drug bioavailability in ocular tissues. Commercially available soft contact lenses offer several advantages for ocular drug delivery as they are manufactured on a large scale, which guarantees the availability of a consistent and reproducible product, and their favorable safety profile is well-established through broad clinical use. Here we review the rationale for using commercially available soft contact lenses for ocular drug delivery; summarize the evolution of the materials used in contact lens fabrication; and explore various methods used to improve the drug release characteristics and its tissue penetration. While significant progress has been made, several issues still require further attention for the commercial launch of a viable drug-eluting contact lens product, including control of initial burst release, shelf-life stability, and drug loss during processing or storage.
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http://dx.doi.org/10.1016/j.actbio.2020.08.025DOI Listing
October 2020

A Scoping Review of Registered Clinical Trials of Convalescent Plasma for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence (FAST Evidence).

Transfus Med Rev 2020 07 15;34(3):158-164. Epub 2020 Jul 15.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology and Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

Many parallel studies of convalescent plasma with modest enrolment projections have been launched for the treatment of COVID-19. By pooling data from multiple parallel studies that are similar, we can increase the effective sample size and achieve enough statistical power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials of convalescent plasma for COVID-19 was conducted to assess the feasibility of performing a rapid and timely meta-analysis that will support accelerated review for approval and implementation. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized convalescent plasma to treat or prevent COVID-19. Forty-eight registered trials (projected to enroll more than 5000 subjects) of convalescent plasma were identified and included for analysis. The majority of studies (33 studies with 4440 projected enrolment) will address the treatment of severe and/or critical cases of COVID-19. Twenty-nine studies are controlled and 17 of these are reported as actively recruiting. The combined enrolment of patients from similar studies should be sufficient to determine meaningful improvements in mortality, rates of admission to intensive care and need for mechanical ventilation by the end of 2020-sooner than any individual study could determine effectiveness. Accessing supplemental outcome data from investigators may be needed; however, to align reporting of some outcomes from these studies. Heterogeneity in product potency due to different antibody titers is anticipated and studies using conventional treatment as controls instead of placebo may complicate our understanding of efficacy. Convalescent plasma is being tested in ongoing controlled studies, largely to treat severe and/or critical cases of COVID-19. Sufficient combined power to detect clinically important reductions in multiple outcomes, including mortality, is expected by September 2020. Regulatory approval, funding and implementation by blood operators could be accelerated by planned meta-analysis as study results become available.
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http://dx.doi.org/10.1016/j.tmrv.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362798PMC
July 2020

Probing the structural and electronic response of Magnus green salt compounds [Pt(NHR)][PtCl] (R = H, CH) to pressure.

Phys Chem Chem Phys 2020 Aug 29;22(31):17668-17676. Epub 2020 Jul 29.

EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.

Despite possessing the desirable crystal packing and short PtPt stacking distances required for a large piezoresistive response, the conductivity-pressure response of the Magnus green salt [Pt(NH)][PtCl] is extremely sluggish. Through a combination of high-pressure X-ray diffraction and hybrid-DFT solid state calculations this study demonstrates that the poor conductivity-pressure response is due to a low volumetric compression anisotropy, a relatively large ambient pressure band gap and a lack of dispersion in the conduction band. Ligand modification (from NH to NHCH) does not enhance the piezoresistive response, causing even lower anisotropy of the volumetric compression and an unexpected phase transition at above 2 GPa. This study demonstrates that consideration of frontier band dispersion is a key design criterion, alongside crystal packing and PtPt stacking distances, for piezoresistive materials.
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http://dx.doi.org/10.1039/d0cp03280hDOI Listing
August 2020

An Analysis of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Preclinical Use.

ACS Nano 2020 08 4;14(8):9728-9743. Epub 2020 Aug 4.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can reduce inflammation, promote healing, and improve organ function, thereby providing a potential "cell-free" therapy. Prior to clinical translation, it is critical to synthesize existing evidence on preclinical methods and efficacy. To address these issues, we used gold standard systematic review methodology to consolidate information from all published animal studies investigating MSC-EVs as an intervention. A systematic search of MEDLINE and Embase identified 206 studies. Data were extracted in duplicate for methodology, experimental design, interventional traits, modifications, and outcomes. MSC-EVs were used to treat a variety of diseases and demonstrated benefits in 97% of studies. Adverse effects were reported in only three studies, two demonstrating tumor growth. A quarter of articles modified EVs to enhance efficacy, with 72% leading to markedly improved outcomes as compared to unmodified EVs. However, several key methodological concerns were evident. Only 60% of studies used nomenclature consistent with the size definitions of EVs. Ultracentrifugation (70%) and isolation kits (23%) were the most common isolation techniques with noted differences in yield and purity. EVs were inconsistently dosed by protein (68%) or particle concentration (16%). Two-thirds of studies administered xenogeneic EVs, suggesting immunocompatibility. Less than 25% of studies assessed EV biodistribution. Approaches for determining size, protein markers, and morphology were highly heterogeneous, with only 12 and 4 studies meeting the MISEV 2014 and 2018 recommendations, respectively. Knowledge gaps identified from this systematic review highlight important opportunities to improve preclinical design and methodology in the rapidly growing field of EV therapeutics.
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http://dx.doi.org/10.1021/acsnano.0c01363DOI Listing
August 2020

A Scoping Review of Registered Clinical Trials of Cellular Therapy for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence-FAST Evidence.

Transfus Med Rev 2020 07 27;34(3):165-171. Epub 2020 Jun 27.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Clinical Epidemiology and Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada. Electronic address:

The urgent need for safe and effective treatments for COVID-19 has fueled the launch of many parallel complex studies of cellular therapies with small to modest enrolment projections. By pooling data from multiple studies that are similar, we can increase the ability to achieve sufficient power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials using cell-based interventions for COVID-19 was conducted to identify candidate studies for meta-analysis that could support an accelerated regulatory review. ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized cell or cell-derived products to treat or prevent COVID-19. Fifty-four registered cellular therapy trials were identified and included for analysis. Studies of mesenchymal stromal cells (MSCs; 41 studies; 1129 subjects projected to receive cells) and natural killer (NK) cells (5 studies; 135 projected to received cells) were observed most commonly. A subset of studies are controlled (34 studies, or 63%), including 27 studies of MSCs and 3 of NK cells. While heterogeneity in study design exists, the cumulative projected enrolment of patients from similar studies appears sufficient to allow the detection of meaningful differences in clinically important outcomes such as mortality, admission to intensive care and need for mechanical ventilation by September 2020-sooner than any individual study could determine effectiveness. MSCs are the predominant cell type in registered trials for severe or critical COVID-19 and represent the most promising candidates for future meta-analysis. Sufficient pooled sample size to detect clinically important reductions in multiple outcomes, including mortality, is anticipated by September 2020, but may require accessing supplementary data to align outcome reporting. Regulatory approval, funding and implementation by cell manufacturing partners will be accelerated by our framework for rapid meta-analysis.
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http://dx.doi.org/10.1016/j.tmrv.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320662PMC
July 2020

Human endothelial colony-forming cells in regenerative therapy: A systematic review of controlled preclinical animal studies.

Stem Cells Transl Med 2020 11 18;9(11):1344-1352. Epub 2020 Jul 18.

Clinical Epidemiology and Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Endothelial colony-forming cells (ECFCs) hold significant promise as candidates for regenerative therapy of vascular injury. Existing studies remain largely preclinical and exhibit marked design heterogeneity. A systematic review of controlled preclinical trials of human ECFCs is needed to guide future study design and to accelerate clinical translation. A systematic search of Medline and EMBASE on 1 April 2019 returned 3131 unique entries of which 66 fulfilled the inclusion criteria. Most studies used ECFCs derived from umbilical cord or adult peripheral blood. Studies used genetically modified immunodeficient mice (n = 52) and/or rats (n = 16). ECFC phenotypes were inconsistently characterized. While >90% of studies used CD31+ and CD45-, CD14- was demonstrated in 73% of studies, CD146+ in 42%, and CD10+ in 35%. Most disease models invoked ischemia. Peripheral vascular ischemia (n = 29), central nervous system ischemia (n = 14), connective tissue injury (n = 10), and cardiovascular ischemia and reperfusion injury (n = 7) were studied most commonly. Studies showed predominantly positive results; only 13 studies reported ≥1 outcome with null results, three reported only null results, and one reported harm. Quality assessment with SYRCLE revealed potential sources of bias in most studies. Preclinical ECFC studies are associated with benefit across several ischemic conditions in animal models, although combining results is limited by marked heterogeneity in study design. In particular, characterization of ECFCs varied and aspects of reporting introduced risk of bias in most studies. More studies with greater focus on standardized cell characterization and consistency of the disease model are needed.
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http://dx.doi.org/10.1002/sctm.20-0141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581447PMC
November 2020
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