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Tan H.H.,Blood Services Group | Wong C.Y.,Singapore General Hospital | Thike A.A.,Singapore General Hospital | Tan P.H.,Singapore General Hospital | Ho G.H.,The Surgical Center
Clinical Cancer Research | Year: 2013

Purpose: There is a quest for novel noninvasive diagnostic markers for the detection of breast cancer. The goal of this study is to identify circulating microRNA (miRNA) signatures using a cohort of Asian Chinese patients with breast cancer, and to compare miRNA profiles between tumor and serum samples. Experimental Design: miRNA from paired breast cancer tumors, normal tissue, and serum samples derived from 32 patients were comprehensively profiled using microarrays or locked nucleic acid real-time PCR panels. Serum samples from healthy individuals (n=22) were also used as normal controls. Significant serum miRNAs, identified by logistic regression, were validated in an independent set of serum samples from patients (n = 132) and healthy controls (n = 101). Results: The 20 most significant miRNAs differentially expressed in breast cancer tumors included miRNA (miR)-21, miR-10b, and miR-145, previously shown to be dysregulated in breast cancer. Only 7 miRNAs were overexpressed in both tumors and serum, suggesting that miRNAs may be released into the serum selectively. Interestingly, 16 of the 20 most significant miRNAs differentially expressed in serum samples were novel. MiR-1, miR-92a, miR-133a, and miR-133b were identified as the most important diagnostic markers, and were successfully validated; receiver operating characteristic curves derived from combinations of these miRNAs exhibited areas under the curves of 0.90 to 0.91. Conclusion: The clinical use of miRNA signatures as a noninvasive diagnostic strategy is promising, but should be further validated for different subtypes of breast cancers. © 2013 American Association for Cancer Research.


Suck G.,Blood Services Group | Oei V.Y.S.,Blood Services Group | Oei V.Y.S.,National University of Singapore | Linn Y.C.,Singapore General Hospital | And 6 more authors.
Experimental Hematology | Year: 2011

Objective: Interleukin (IL)-15 is a promising novel cytokine for natural killer (NK) cell activation and survival. We studied the effects of IL-15 compared to IL-2 on NK cells in long-term cultures for clinical translation. Materials and Methods: CD56 +CD3 - NK cells were expanded with IL-2 or IL-15 for 2 to 4 weeks within lymphokine-activated killer (LAK) cell cultures (LAK-NK) in serum-enriched AIM V or CellGro Stem Cell Growth Medium (SCGM). Cell growth, viability, and NK cell content were monitored and cytotoxicity assessed in a flow cytometric cytotoxicity assay. Results: IL-15 (100-1000 U/mL) could replace IL-2 (1000 U/mL) in AIM V cultures to achieve efficient LAK cell expansion. However, IL-15-stimulated LAK cells exceeded cytotoxicity of IL-2-stimulated LAK cells against K562, notably at later culture points. In the powerful CellGro SCGM, LAK cells expanded over 28 days an average of 905-fold ± 320-fold standard error of the mean (SEM) for IL-2 (500 U/mL) and 484-fold ± 98-fold SEM for IL-15 (500 U/mL), and NK cells within such LAK cultures expanded an average of 2320-fold ± 975-fold SEM for IL-2 and 1084-fold ± 309-fold SEM for IL-15. Importantly, such IL-15-activated LAK-NK cells retained enhanced cytotoxicity at later culture points against K562 as well. IL-15-stimulated effectors were also highly cytotoxic against hematological targets MOLT-4 and KU812 and nontoxic against autologous nonmalignant cells. Interestingly, IL-15-LAK-NK cells showed overall significant upregulation of the main activating and inhibitory NK cell receptors after long-term cytokine stimulation. Conclusions: Our results demonstrate the potential for IL-15 to support large-scale expansion of clinical-grade LAK-NK effectors, which could retain enhanced longer-term potency and preserve activation receptors in therapy of hematological malignancies. Protocols are readily clinically translatable. © 2011 ISEH - Society for Hematology and Stem Cells.


PubMed | Khoo Teck Puat Hospital, National University Hospital Singapore, KK Womans & Childrens Hospital, Tan Tock Seng Hospital and 4 more.
Type: Journal Article | Journal: Vox sanguinis | Year: 2016

A common national MTP was jointly implemented in 2011 by the national blood service (Blood Services Group) and seven participating acute hospitals to provide rapid access to transfusion support for massively haemorrhaging patients treated in all acute care hospitals.Through a systematic clinical workflow, blood components are transfused in a ratio of 1:1:1 (pRBC: whole blood-derived platelets: FFP), together with cryoprecipitate for fibrinogen replacement. The composition of components for the MTP is fixed, although operational aspects of the MTP can be adapted by individual hospitals to suit local hospital workflow. The MTP could be activated in support of any patient with critical bleeding and at risk of massive transfusion, including trauma and non-trauma general medical, surgical and obstetric patients.There were 434 activations of the MTP from October 2011 to October 2013. Thirty-nine per cent were for trauma patients, and 30% were for surgical patients with heavy intra-operative bleeding, with 25% and 6% for patients with gastrointestinal bleeding and peri-partum haemorrhage, respectively. Several hospitals reported reduction in mean time between request and arrival of blood. Mean transfusion ratio achieved was one red cell unit: 08 FFP units: 08 whole blood-derived platelet units: 04 units of cryoprecipitate. Although cryoprecipitate usage more than doubled after introduction of MTP, there was no significant rise in overall red cells, platelet and FFP usage following implementation.This successful collaboration shows that shared transfusion protocols are feasible and potentially advantageous for hospitals sharing a central blood provider.


Leemhuis T.,University of Cincinnati | Padley D.,Human Cellular Therapy Laboratory Mayo Clinic | Keever-Taylor C.,Medical College of Wisconsin | Niederwieser D.,University of Leipzig | And 7 more authors.
Bone Marrow Transplantation | Year: 2014

The Graft Processing subcommittee of the Worldwide Network for Blood and Marrow Transplantation wrote this guideline to assist physicians and laboratory technologists with the setting up of a cell processing laboratory (CPL) to support a hematopoietic stem cell transplant program, thereby facilitating the start-up of a transplant program in a new location and improving patient access to transplantation worldwide. This guideline describes the minimal essential features of designing such a laboratory and provides a list of equipment and supply needs and staffing recommendations. It describes the typical scope of services that a CPL is expected to perform, including product testing services, and discusses the basic principles behind the most frequent procedures. Quality management (QM) principles specific to a CPL are also discussed. References to additional guidance documents that are available worldwide to assist with QM and regulatory compliance are also provided. © 2014 Macmillan Publishers Limited All rights reserved.


Koh M.B.C.,Blood Services Group | Koh M.B.C.,St Georges Hospital and Medical School | Suck G.,Blood Services Group
Biologicals | Year: 2012

Cellular immunotherapy has been widely accepted as a new powerful modality of cancer treatment. The last 2 decades have seen impressive results in its application against haemato-oncologic malignancies, melanomas and prostate carcinoma. Cellular immunotherapy has since found applicability beyond cancer into autoimmunity and continues to expand in its clinical applicability. The discovery that stem cells have the ability to differentiate into more mature cell types, like neurones and myocardium, has focused research on using exogenous cells to repair damaged tissues. This led to numerous clinical trials using stem cells in myocardial infarction, cardiomyopathy and spinal cord damage. Results have ranged from modest to significant clinical outcomes with continuing debate on the exact process of regeneration achieved. The intertwining between cell therapy and transfusion medicine now includes research on progenitor cells for the production of mature red cells. It is also clear that cell therapy has enabled an improved understanding of the pathogenesis and clinical course of many diseases, while perhaps its role in regenerative medicine is most enticing. However, the critical role of manufacturing in terms of cost, complexity, reproducibility, and regulatory matters remains a central issue in the consideration of whether cell therapy has met all of its promise. © 2012 The International Alliance for Biological Standardization.


Linn Y.-C.,Singapore General Hospital | Niam M.,Blood Services Group | Chu S.,Blood Services Group | Choong A.,Blood Services Group | And 9 more authors.
Bone Marrow Transplantation | Year: 2012

We performed a Phase I/II clinical trial to study the feasibility, toxicity and efficacy of allogeneic cytokine-induced killer (CIK) cell expansion, and treatment for patients with haematological malignancies who relapsed after allogeneic haemopoietic SCT (allo-HSCT). Allogeneic CIK cells were successfully generated for a total of 24 patients, including those from patients' own leukapheresis products in 5 patients who had no access to further donor cells. The median CD3 T-cell expansion was 9.33 (1.3-38.97) fold, and CD3 CD56 natural killer (NK)-like T-cell expansion was 27.77 (2.59-438.93) fold. A total of 55 infusions were done for 16 patients who had either failed or progressed after initial response to various individualized chemotherapy regimens and donor lymphocyte infusion (DLI), at doses ranging from 10 to 200 million CD3 cells/kg. Response attributable to CIK cell infusion was observed in five patients. These included two with ALL, two with Hodgkin's disease (HD) and one with AML, and two of whom had a response sustained for more than 2 years. Acute GVHD occurred in three and was easily treatable. This study provides some evidence suggestive of the efficacy of allogeneic CIK cells even after failure of DLI in some cases. © 2012 Macmillan Publishers Limited.


Low S.-L.,11 Health | Lam S.,Blood Services Group | Wong W.-Y.,11 Health | Teo D.,Blood Services Group | And 2 more authors.
American Journal of Tropical Medicine and Hygiene | Year: 2015

Routine national notifications of dengue cases typically do not reflect the true dengue situation due to large proportion of unreported cases. Serosurveys, when conducted periodically, could shed light on the true dengue infections in the population. To determine the magnitude of dengue infections of the adult population in Singapore following the outbreak in 2007, we performed a cross-sectional study on blood donor samples from December 2009 to February 2010. The residual blood of 3,995 donors (aged 16-60 years) was screened for the presence of dengue-specific immunoglobulin G (IgG) and IgM using enzyme-linked immunosorbent assay (ELISA) kits. The age-weighted IgG prevalence of residents was 50.8% (N = 3,627, 95% confidence interval [CI] = 49.4-52.3%). Dengue IgG prevalence increased with age, with the lowest in 16-20 years age group (16.1%) and the highest in 56-60 years age group (86.6%). Plaque reduction neutralization test (PRNT) on samples of young resident adults (aged 16-30 years) revealed lower prevalence of neutralizing antibodies to each serotype, ranging from 5.4% to 20.3% compared with the older age groups. The level of exposure to dengue among the young adults is relatively low despite the endemicity of the disease in Singapore. It partially explains the population's susceptibility to explosive outbreaks and the high incidence rate among young adults. Copyright © 2015 by The American Society of Tropical Medicine and Hygiene.


Li P.,Agency for Science, Technology and Research Singapore | Wong J.J.-Y.,Agency for Science, Technology and Research Singapore | Sum C.,Agency for Science, Technology and Research Singapore | Sin W.-X.,Agency for Science, Technology and Research Singapore | And 4 more authors.
Blood | Year: 2011

Robust and rapid induction of interferon-β (IFN-β) in monocytes after pathogenic stimulation is a hallmark of innate immune responses. Here, we reveal the molecular mechanism underlying this key property that is exclusive to human blood monocytes.We found that IFN-β was produced rapidly in primary human monocytes as a result of cooperation between the myeloid-specific transcription factor IRF8 and the ubiquitous transcription factor IRF3. Knockdown of IRF8 in monocytes abrogated IFN-β transcription, whereas reintroduction of IRF8 into the IRF8-/- 32Dcl3 murine myeloid cell line reinstated IFN-β transcription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element of the IFN-β promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-β production, as a previously un-indentified interaction partner of IRF8. We mapped the proteinprotein interacting regions of IRF3 and IRF8, and found that their interaction was independent of the DNA-binding domain and the IRF association domain of IRF8 and IRF3, respectively. Therefore, we propose a model for the rapid induction of IFN-β in monocytes, whereby IRF8 and PU.1 form a scaffold complex on the IFN-β promoter to facilitate the recruitment of IRF3, thus enabling rapid IFN-β transcription. © 2011 by The American Society of Hematology.


Koh M.B.C.,St Georges Hospital and Medical School | Koh M.B.C.,Blood Services Group | Lao Z.T.,Singapore General Hospital | Rhodes E.,St Georges Hospital and Medical School
Best Practice and Research: Clinical Obstetrics and Gynaecology | Year: 2013

The management of patients with pre-existing haematological diseases during pregnancy can be particularly challenging. The potential maternal and foetal toxicities from treatment regimens including chemotherapy for malignant haematological disorders mean that joint management between obstetricians and haematologists is essential for achieving good outcomes for both mother and baby. Patients with inherited or acquired disorders of haemostasis including platelets (essential thrombocythaemia) and coagulation (antiphospholipid syndrome) resulting in a pro-thrombotic state also require special consideration as pregnancy is generally considered to be a pro-thrombotic condition which could exacerbate the pre-existing disorder. The choice, timing and duration of anticoagulation or anti-platelet therapy require careful coordination during the antenatal, perinatal as well as postnatal periods to ensure that both maternal and foetal risks are taken into consideration. Pregnancy in women with sickle cell disease has long been identified as high risk with medical and pregnancy related risks being more common compared to women without it. A range of foetal risks have also been reported but improvement in outcomes has been seen with better obstetric and haematological care and the emphasis on multidisciplinary teamwork. The meticulous management of iron overload and risks associated with repeated blood transfusions extends into the care of pregnant women with other haemoglobinopathies like thalassemias.© 2013 Published by Elsevier Ltd. All rights.


PubMed | Blood Services Group
Type: Journal Article | Journal: Biologicals : journal of the International Association of Biological Standardization | Year: 2012

Cellular immunotherapy has been widely accepted as a new powerful modality of cancer treatment. The last 2 decades have seen impressive results in its application against haemato-oncologic malignancies, melanomas and prostate carcinoma. Cellular immunotherapy has since found applicability beyond cancer into autoimmunity and continues to expand in its clinical applicability. The discovery that stem cells have the ability to differentiate into more mature cell types, like neurones and myocardium, has focused research on using exogenous cells to repair damaged tissues. This led to numerous clinical trials using stem cells in myocardial infarction, cardiomyopathy and spinal cord damage. Results have ranged from modest to significant clinical outcomes with continuing debate on the exact process of regeneration achieved. The intertwining between cell therapy and transfusion medicine now includes research on progenitor cells for the production of mature red cells. It is also clear that cell therapy has enabled an improved understanding of the pathogenesis and clinical course of many diseases, while perhaps its role in regenerative medicine is most enticing. However, the critical role of manufacturing in terms of cost, complexity, reproducibility, and regulatory matters remains a central issue in the consideration of whether cell therapy has met all of its promise.

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