Methodologic quality assessment of red blood cell transfusion guidelines and the evidence base of more restrictive transfusion thresholds

Significance Statement

The World Health Organization indicates that every second someone in the world needs a blood transfusion. Blood transfusions therefore save many lives every year, and patients can die when they don’t receive a transfusion when necessary. However, transfusions also carry certain risks, and therefore should not be performed unless really necessary.

In recent years, a lot of emphasis has been put on this second consideration, which has been more broadly rebranded as “patient blood management” (PBM). PBM is a worthwhile effort, but should be evidence-based and not based on other considerations, be it religious (e.g., refusing of an allogenic blood transfusion as a Jehovah Witness) or commercial (e.g., receiving sponsorships by commercial companies who promote RBC replacing products).

It is therefore important that transfusion guidelines are of high quality, and based on the best scientific evidence. Our analysis of the quality of the most widely used transfusion guidelines, using an internationally used tool (AGREE II), indicates that guidelines recommending red blood cell transfusion as of Hb levels of 7 to 8 g/dL are based on high quality evidence, whereas the more recent guidelines recommending red blood cell transfusion only at Hb thresholds of ≤6 g/dL are not based on solid evidence.

The methodological robustness of the published transfusion guidelines is variable and has room for improvement. Furthermore, guideline developers and reviewers should always be transparent about conflicts of interest, whether religious or commercial, which was, based on other available information, not always the case in these guidelines.

About The Author

Hans Van Remoortel, PT/PhD, physiotherapist, is staff member in the Centre for Evidence-Based Practice of the Belgian Red Cross-Flanders. After obtaining a Master in Rehabilitation Sciences and Physiotherapy in 2005, Hans worked for three years (2005-2008) as a clinical physiotherapist in cardiac rehabilitation programs in 2 Belgian hospitals (University Hospital of Leuven and Imelda Hospital Bonheiden). After working in a clinical setting, he obtained his PhD degree at the Faculty of Rehabilitation Sciences and Kinesiology at the University of Leuven (Belgium) with a project entitled ‘Physical activity and comorbidities in patients with chronic obstructive pulmonary disease’ (2009-2013).

He has published about 20 articles in peer reviewed journals, mainly in the field of exercise, physical activity, pulmonology and evidence-based medicine. In his current job, Hans is a methodologist working on the development of systematic reviews and guidelines within the relevant themes of the Belgian Red Cross, i.e. from humanitarian aid to blood supply. In his spare moments, Hans enjoys to spend time with his family, is a recreational sporter (squash, soccer, running, cycling) and enjoys to attend live music concerts.

About The Author

Philippe Vandekerckhove, M.D./PhD, pathologist, is the CEO of the Belgian Red Cross-Flanders.

Prior to this position Philippe worked as Clinical Director of the University Hospital Leuven from where he also obtained his M.D./PhD and Pathology degree. His clinical and pathology training was further carried out in South Africa (Baragwanath – University of Johannesburg, and Groote Schuur Hospital – University of Cape Town), the US (Woods Hole Marine Biology Laboratory, University of Hawaii, New York University), and The Netherlands (Erasmus University, Rotterdam).

In addition, Philippe studied healthcare management at INSEAD (France) and general management at Harvard Business School. He has published about 60 articles in peer reviewed journals, and 5 chapters in textbooks, mainly in the field of immunology, hematology, blood banking and evidence-based medicine.

Philippe is associate professor at the Faculties of Medicine of the University of Leuven and the University of Ghen. He holds non-executive positions as president of the European Blood Alliance, president of GAP, member of the governing board of the International Federation of Red Cross and Red Crescent Societies, and of the investment committee of Flanders’ Care Invest (Flemish government). In his spare moments, he enjoys jogging, natural horsemanship and time and travel spent in natural surroundings.

Journal Reference

Transfusion. 2016 Feb;56(2):472-80.

Van Remoortel H¹, De Buck E¹, Dieltjens T¹, Pauwels NS¹, Compernolle V^1,2, Vandekerckhove P^1,2,3.

Show Affiliations

1. BelgianRed Cross-Flanders, Mechelen, Belgium.
2. Faculty of Medicine, University of Ghent, Ghent, Belgium.
3. Department of Public Health and Primary Care, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium.

Abstract

BACKGROUND:

Recent literature suggests that more restrictive red blood cell (RBC) transfusion practices are equivalent or better than more liberal transfusion practices. The methodologic quality of guidelines recommending more restrictive transfusion thresholds and their underlying scientific evidence is unclear. Therefore, we aimed to evaluate the quality of the development process of red blood cell transfusion guidelines and to investigate the underlying evidence of guidelines recommending a more restrictive hemoglobin (Hb) threshold.

STUDY DESIGN AND METHODS:

Via systematic literature screening of relevant databases (NGC, GIN, Medline, and Embase), red blood cell transfusion guidelines recommending a more restrictive Hb level (<6, <7, or <8 g/dL) were included. Four assessors independently evaluated the methodologic quality by scoring the rigor of development domain (AGREE II checklist). The level of evidence served as a reference for the quality of the underlying evidence.

RESULTS:

The methodologic quality of 13 red blood cell transfusion guidelines was variable (18%-72%) but highest for those developed by Advancing Transfusion and Cellular Therapies Worldwide (72%), the Task Force of Advanced Bleeding Care in Trauma (70%), and the Dutch Institute for Healthcare Improvement (61%). A Hb level of less than 7 g/dL (intensive care unit patients) or less than 8 g/dL (postoperative patients) were the only thresholds based on high-quality evidence. Only four of 32 recommendations had a high-quality evidence base.

CONCLUSION:

Methodologic quality should be guaranteed in future RBC transfusion guideline development to ensure that the best available evidence is captured when recommending restrictive transfusion strategies. More high-quality trials are needed to provide a stronger scientific basis for RBC transfusion guidelines that recommend more restrictive transfusion thresholds.

© 2015 AABB.

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Modulation of the gene expression of annulus fibrosus-derived stem cells using poly(ether carbonateurethane)urea scaffolds of tunable elasticity

Significance Statement

Annulus fibrosus (AF) injuries lead to substantial intervertebral disc deterioration which characterizes degenerative disc diseases. Repair of AF, however, remains challenging due to the tremendous heterogeneity of Annulus fibrosus tissue. Since the differentiation of stem cells significantly relies on the elasticity of substrate, a series of biodegradable poly(ether carbonate urethane)urea (PECUU) materials whose elasticity resembled that of native Annulus fibrosus tissue were synthesized in this study. When Annulus fibrosus-derived stem cells (AFSCs) were cultured on electrospun PECUU fibrous scaffolds, the gene expression and protein production of major matrix components, including collagen-I, collagen-II and aggrecan, and cell traction forces gradually changed with the elasticity of PECUU. Such substrate elasticity-dependent modulation of Annulus fibrosus-derived stem cells was similar to the gradual transition in the genetic, biochemical, and biomechanical characteristics of cells from inner to outer regions of native Annulus fibrosus tissue. This work has, for the first time, revealed that Annulus fibrosus-derived stem cells are able to present different gene expression patterns simply as a result of the elasticity of scaffold material. Findings from this study will help develop adequate materials for Annulus fibrosus regeneration.

About The Author

Professor Bin Li is the director of the Biomaterials and Cell Mechanics Laboratory (BCML) of Orthopedic Institute at Soochow University, Suzhou, China. He received the bachelor degree in 1996 and PhD degree in Materials Science from Tsinghua University in 2001. He then joined the Institute of Materials Research and Engineering, Singapore as a Research Associate until 2004. After that he consecutively pursued research training at Carnegie Mellon University, University of Pittsburgh, and Harvard University until 2009, when he took the current position as a full professor at Soochow University. He is the recipient of the Orthopaedics Research Award (1st prize) from Chinese Orthopaedic Association, Xu Guangqi Program from the French Embassy in China, and France Talent Innovation from the Consulate General of France in Shanghai. He currently serves as the chair of China Development Committee of International Chinese Musculoskeletal Research Society (ICMRS). He is a fellow of Chinese Orthopaedic Research Society (CORS), Chinese Association of Orthopaedic Surgeons (CAOS), Chinese Association of Rehabilitation Medicine (CARM), and International Society of Orthopaedic Surgery and Traumatology (SICOT). He has delivered about 40 invited and is the author of over 70 publications and 9 book chapters. He now leads a multidisciplinary research group studying biomaterials for bone and cartilage repair, stem cells and tissue engineering, smart molecular recognition and controlled release, surface modification and functionalization, and cellular biomechanics and mechanobiology.

About The Author

Dr. Caihong Zhu is a research associate and a member of the Biomaterials and Cell Mechanics Laboratory (BCML) of Orthopedic Institute at Soochow University. She received the bachelor degree in Polymer Chemistry from Nanjing University in 2001 and PhD degree in Polymer Chemistry from Soochow University in 2010. She joined Soochow University in 2012. Her research interests include biomaterials for bone and intervertebral disc regeneration and controlled drug delivery.

  

About The Author

Dr. Jun Li is an orthopaedic surgeon who received his PhD degree at the Soochow University. Currently, he is a postdoctoral researcher at Shenzhen University. His major research interests include bone and cartilage regeneration via stem cell transplantation and osteoporosis.

Journal Reference

Acta Biomater. 2016;29:228-38.

Caihong Zhu, Jun Li, Chen Liu, Pinghui Zhou, Huilin Yang, Bin Li.

Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China.

These authors contributed equally to this study. Email: binli@suda.edu.cn

Abstract

Annulus fibrosus (AF) injuries commonly lead to substantial deterioration of the intervertebral disc (IVD). While tissue engineering has recently evolved into a promising approach for AF regeneration, it remains challenging due to the cellular, biochemical, and mechanical heterogeneity of AF tissue. In this study, we explored the use of AF-derived stem cells (AFSCs) to achieve diversified differentiation of cells for AF tissue engineering. Since the differentiation of stem cells relies significantly on the elasticity of the substrate, we synthesized a series of biodegradable poly(ether carbonate urethane)urea (PECUU) materials whose elasticity approximated that of native AF tissue. When AFSCs were cultured on electrospun PECUU fibrous scaffolds, the gene expression of collagen-I in the cells increased with the elasticity of scaffold material, whereas the expression of collagen-II and aggrecan genes showed an opposite trend. At the protein level, the content of collagen-I gradually increased with substrate elasticity, while collagen-II and GAG contents decreased. In addition, the cell traction forces (CTFs) of AFSCs gradually decreased with scaffold elasticity. Such substrate elasticity-dependent changes of AFSCs were similar to the gradual transition in the genetic, biochemical, and biomechanical characteristics of cells from inner to outer regions of native AF tissue. Together, findings from this study indicate that AFSCs, depending on the substrate elasticity, have strong tendencies to differentiate into various types of AF-like cells, thereby providing a solid foundation for the tissue engineering applications of AFSCs.

Copyright © 2016. Published by Elsevier B.V.

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Human telomerase reverse transcriptase binds to a pre-organized hTR in vivo exposing its template

About The Author

Dr. Georgeta Zemora studied Biochemistry at the Gene Center, Ludwig Maximilians University, Munich. She completed her PhD in Molecular Biology at the University of Vienna. During her PhD at MFPL Vienna she was guided by her mentor, Dr Christina Waldsich who introduced her into the fascinating field of RNA folding in vivo. Her research focused on deciphering the structure of human telomerase RNA (hTR) in vivo as well as its interaction with the human telomerase reverse transcriptase (hTERT). 

Journal Reference

Nucleic Acids Res. 2016 Jan 8;44(1):413-25.

Zemora G¹, Handl S², Waldsich C².

Show Affiliations

1. Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Dr Bohrgasse 9/5, A-1030 Vienna, Austria georgeta.zemora@univie.ac.at.
2. Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Dr Bohrgasse 9/5, A-1030 Vienna, Austria.

Abstract

Telomerase is a specialized reverse transcriptase that is responsible for telomere length maintenance. As in other organisms, the minimal components required for an active human telomerase are the template-providing telomerase RNA (hTR) and the enzymatic entity telomerase reverse transcriptase (hTERT). Here, we explored the structure of hTR and the hTERT-induced conformational changes within hTR in living cells. By employing an in vivo DMS chemical probing technique, we showed that the pseudoknot and associated triple helical scaffold form stably in vivo independently of hTERT. In fact, the dimethyl-sulfate (DMS) modification pattern suggests that hTR alone is capable of adopting a conformation that is suited to interact with hTERT. However, in the absence of hTERT the template region of hTR is only weakly accessible to DMS-modifications. The predominant change after binding of hTERT to hTR is the exposure of the template region.

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells

Significance Statement

Immune systems protect our body from threats by various infectious pathogens, including bacteria, virus, helminth, and fungi. In the immune systems, CD4⁺ helper T cells (Th) play central roles to exert appropriate immune reactions to such innumerable sorts of pathogens. However, if the function of Th are wrongly directed to self-antigens or non-harmful antigens, including pollens, food antigens, and commensals, it will be concluded to serious inflammatory diseases like autoimmune diseases and allergies. On the other hand, immune system has an important cell subset, regulatory T (Treg) cells, which suppress such wrong immune reactions. Treg cells have been known to be critical in suppression of inflammatory diseases, however, how Treg cell lineage was properly maintained in our body had not been clarified in depth yet. In this study, we discovered that Nr4a family of nuclear orphan receptors play critical roles in the maintenance of the Treg cell lineage. Nr4a-deficient Treg cells showed a global reduction of Treg cell-associated gene expressions, compared with those in wildtype Treg cells. Although wildtype Treg cells properly suppressed immune reactions elicited by Th2 and Tfh cells, it was revealed that Nr4a-deficient Treg cells have lost such suppressive activities. We also found that Nr4a-deficient Treg cells aberrantly convert to cells which have characteristics of inflammatory Th cells. Mice in which Nr4a factors were deleted specifically in Treg cells develop symptoms including allergic asthma and autoimmune diseases. Collectively, our work revealed that Nr4a factors play essential roles in Treg cell biology, thus present attractive therapeutic targets for treatment of various immune disorders, including atopic allergies and asthma. 

About The Author

Dr. Takashi Sekiya received his Bachelor of Science degree in 1999 from University of Tokyo. He obtained his Ph.D. from Graduate School of Agricultural and Life Sciences, The University of Tokyo in 2004. Then, he moved to Fox Chase Cancer Center as a postdoctoral fellow at Dr. Ken Zaret’s laboratory. In 2008, he moved back to Japan, and joined Dr. Akihiko Yoshimura’s lab in Keio University School of Medicine, there he has been working on mechanisms of immune tolerance, focusing on developmental programs of CD4 T cells. 

Journal Reference

J Exp Med. 2015;212(10):1623-40.

Sekiya T¹, Kondo T², Shichita T², Morita R², Ichinose H³, Yoshimura A⁴.

Show Affiliations

1. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan yoshimura@a6.keio.jpt-sekiya@z7.keio.jp.
2. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
3. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
4. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology, Chiyoda-ku, Tokyo 102-0075, Japan yoshimura@a6.keio.jpt-sekiya@z7.keio.jp.

Abstract

Regulatory T (T reg) cells are central mediators of immune suppression. As such, T reg cells are characterized by a distinct pattern of gene expression, which includes up-regulation of immunosuppressive genes and silencing of inflammatory cytokine genes. Although an increasing number of transcription factors that regulate T reg cells have been identified, the mechanisms by which the T reg cell-specific transcriptional program is maintained and executed remain largely unknown. The Nr4a family of nuclear orphan receptors, which we recently identified as essential for the development of T reg cells, is highly expressed in mature T reg cells as well, suggesting that Nr4a factors play important roles even beyond T reg cell development. Here, we showed that deletion of Nr4a genes specifically in T reg cells caused fatal systemic immunopathology. Nr4a-deficient Treg cells exhibited global alteration of the expression of genes which specify the T reg cell lineage, including reduction of Foxp3 and Ikzf4. Furthermore, Nr4a deficiency abrogated T reg cell suppressive activities and accelerated conversion to cells with Th2 and follicular helper T (Tfh) effector-like characteristics, with heightened expression of Th2 and Tfh cytokine genes. These findings demonstrate that Nr4a factors play crucial roles in mature T reg cells by directly controlling a genetic program indispensable for T reg cell maintenance and function.

© 2015 Sekiya et al.

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The development of statin-based therapy for patients with hepatitis C virus (HCV) infection using human induced pluripotent stem (iPS) cell technology

Significance Statement

Human induced pluripotent stem cells (hiPSCs) have been expected to transform drug discovery by providing physiologically relevant cells for toxic compound identification and compound screening. When Shimada M et al. (J Hepatol. 2012;56: 299-300) considered two reports (Moriguchi H et al.; Hepatology. 2010; 51: 344–345 and 351–352) published in 2010 investigating the antiviral efficacy of pitavastatin against hepatitis C virus (HCV) infection in vitro, they conducted a randomized controlled trial (J Hepatol. 2012;56: 299-300). As a result, the results of 2010 proof-of-concept studies of the antiviral efficacies and safety of pitavastatin against HCV infection using a replicon system and human hepatocyte-like cells from hiPSCs (Moriguchi H et al.; Hepatology. 2010; 51: 344–345 and 351–352) were confirmed in a randomized controlled trial published by Shimada M et al. in 2012 (J Hepatol. 2012;56: 299-300). Therefore, this series of studies (Moriguchi H et al.; Hepatology. 2010; 51: 344–345 and 351–352, Shimada M et al.; J Hepatol. 2012; 56: 299-300) would be the first to report clinical applications of hiPSCs. Furthermore, after the clinical trial by Shimada M et al. (J Hepatol. 2012; 56: 299-300), the antiviral efficacies and safeties of pitavastatin against HCV infection were more confirmed in the two clinical studies (Kohjima M et al.; J Med Virol. 2013: 85: 250-260 and Yokoyama S et al.; Aliment Pharmacol Ther. 2014; 39: 443-444). Therefore, to investigate the antiviral efficacies and safety of pitavastatin against HCV infection using a replicon system and human hepatocyte-like cells from hiPSCs (Moriguchi H et al.; Hepatology. 2010; 51: 344–345 and 351–352) would be a rational approach as new drug discovery. 

About The Author

Dr. Moriguchi H obtained his Ph.D. from the University of Tokyo in 2007. He was a visiting associate professor (full time) from 2000 to 2006 and a project professor from 2006 to 2009 at the University of Tokyo. He is currently at Oak Clinic company. His research focuses on clinical epidemiology (1996, Gut, etc), clinical decision analysis (2012, Hepatology, etc), stem cell research (2011, Cell Mol Life Sci, etc) and reproductive medicine (2012, Hum Reprod, etc) in Gastroenterology, Hepatology, cancers, stem cell research and reproductive medicine.

Journal Reference

Clin Res Hepatol Gastroenterol. 2015;39(5):541-3.

Moriguchi H.

Oak Clinic, 2-7-9, Tamade-Nishi, Nishinari-ku, 557-0045 Osaka, Japan. Electronic address: moriguchi_h@oakclinic-group.com.

Abstract

Human induced pluripotent stem (iPS) cells may transform drug discovery. Here I show an example of the development of statin (HMG-CoA reductase inhibitors)-based therapy for patients with hepatitis C virus (HCV) infection using human iPS cell technology. When Shimada et al. considered the two reports on the antiviral effects of pitavastatin for HCV infection in vitro by Moriguchi et al., they conducted a randomized controlled trial. As a result, a proof-of-concept for the antiviral effect of pitavastatin against HCV infection using human iPS cell technology by Moriguchi et al. was confirmed in the randomized controlled trial by Shimada et al. in 2012. Therefore, above-mentioned a series of studies became to the first to report the clinical application of human iPS cells. Furthermore, here I propose that new clinical research methods using human iPS cell technology will be able to circumvent the limitations of conventional randomized controlled trials (RCTs) for the purpose of personalized medicine in the clinical setting.

Copyright © 2015 Elsevier Masson SAS. All rights reserved.

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Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites

Journal Reference

Mol Pharmacol. 2015 Dec;88(6):970-81.

Ozer U¹, Barbour KW¹, Clinton SA¹, Berger FG².

Show Affiliations

1. Department of Biological Sciences, and Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
2. Department of Biological Sciences, and Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina fgberger@mailbox.sc.edu.

Abstract

Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2′-deoxyuridine-5′-monophosphate (dUMP) by N(5),N(10)-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of Thymidylate synthase have been widely used in the treatment of neoplastic disease. A number of fluoropyrimidine and folate analogs have been developed that lead to inhibition of the enzyme, resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-electron reduction of O2 to generate superoxide (O2 (●-)), is a significant source of increased ROS levels in drug-treated cells. However, gene expression profiling revealed a number of other redox-related genes that may contribute to ROS generation. Thymidylate synthase inhibitors also induce a protective response, including activation of the transcription factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of defense against oxidative and electrophilic stress. Our results show that exposure to Thymidylate synthase inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death.

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

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Effective use of the TSPY gene-specific copy number in determining fetal DNA in the maternal blood of cynomolgus monkeys

Journal Reference

Anim Sci J. 2015 Sep 30.

Yasmin L, Takano JI, Sankai T.

Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan.

Abstract

Since the available concentration of single-copy fetal genes in maternal blood DNA is sometimes lower than detection limits by PCR methods, the development of specific and quantitative PCR detection methods for fetal DNA in maternal blood is anticipated, which may broaden the methods that can be used to monitor pregnancy. We used the TaqMan qPCR amplification for DYS14 multi-copy sequence and the SRY gene in maternal blood plasma (cell-free DNA) and fractional precipitated blood cells (cellular DNA) from individual cynomolgus monkeys at 22 weeks of pregnancy. The availability of cell-free fetal DNA was higher in maternal blood plasma than that of cellular DNA from fractional precipitated blood cells. There was a significantly higher (P < 0.001) mean copy number of fetal male DYS14 from maternal plasma (4.4 × 10⁴ copies/mL) than that of detected fetal cellular DNA from fractional blood cell pellets. The sensitivity of the DYS14 PCR assay was found to be higher than that of the SRY assay for the detection of fetal DNA when its presence was at a minimum. The DYS14 assay is an improved method for quantifying male fetal DNA in circulating maternal blood in the primate model.

© 2015 Japanese Society of Animal Science.

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Effect of decellularized tissue powders on a rat model of acute myocardial infarction

Journal Reference

Mater Sci Eng C Mater Biol Appl. 2015 Nov 1;56:494-500.

Tabuchi M¹, Negishi J², Yamashita A³, Higami T¹, Kishida A⁴, Funamoto S⁵. 

Show Affiliations

1. Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan.
2. Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan; Japan Society for the Promotion of Science 8 Ichibancho, Chiyoda-ku, Tokyo 102-8472, Japan; Department of Material-based Medical Engineering, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
3. Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543, Japan; Department of Material-based Medical Engineering, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
4. Department of Material-based Medical Engineering, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
5. Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, South of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: sfunamoto.atrm@tmd.ac.jp.

Abstract

Many research groups are currently investigating new treatment modalities for myocardial infarction. Numerous aspects need to be considered for the clinical application of these therapies, such as low cell integration and engraftment rates of cell injection techniques. Decellularized tissues are considered good materials for promoting regeneration of traumatic tissues. The properties of the decellularized tissues are sustained after processing to powder form. In this study, we examined the use of decellularized tissue powder in a rat  model of acute myocardial infarction.  The decellularized tissue powders, especially liver powder, promoted cell integration and neovascularization both in vitro and in vivo. Decellularized liver powder induced neovascularization in the infarct area, resulting in the suppression of myocardial necrosis. The results of this study suggest that decellularized liver powder has good potential for application as a blood supply material for the treatment of myocardial infarction.

Copyright © 2015 Elsevier B.V. All rights reserved.

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Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Significance Statement

A large body of research has shown the importance of the canonical myomiRs in muscle development and maintenance, but more recently mis-expression of one or more myomiRs has been found important in a variety of cancers.  Whilst most myomiR dysregulation in cancer suggests a tumor-suppressor function, in a significant number of cancers a tumor-enhancer role is seen. This duality of roles is similar to that seen with a number of other important cancer-related miRNAs in different cancer types. This review collates the large body of evidence of myomiR functions in a wide variety of normal tissues and organs and relates these functions to their biological effects on validated target genes during the enhancement of cancer progression.

About The Author

KEITH MITCHELSON Has undertaken research in molecular biology, genetics, and biotechnology in the UK, Australia and China.  Until recently undertook research and business at the National Engineering Research Centre for Biochip Technology in Beijing. 

About The Author

WENYAN QIN Has undertaken research in biogenesis and progression of cancer at Tsinghua University School of Medicine, China. Currently undertake research at Capitalbio Technology Co. Ltd. 

Journal Reference

World J Biol Chem. 2015;6(3):162-208.

Mitchelson KR, Qin WY.

Keith Richard Mitchelson, Wen-Yan Qin, National Engineering Research Centre for Beijing Biochip Technology, Beijing 102206, China.

Abstract

MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/tissue regeneration/tissue inflammation responses, and cancer development.

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Modeling and Prediction of Solvent Effect on Human Skin Permeability using Support Vector Regression and Random Forest

Journal Reference

Pharm Res. 2015 Nov;32(11):3604-17.

Baba H^1,2, Takahara J³, Yamashita F⁴, Hashida M^4,5

Show Affiliations

1. Kyoto R&D Center, Maruho Co., Ltd., 93 Awata-cho, Chudoji, Shimogyo-ku, 600-8815, Kyoto, Japan. baba_dfq@mii.maruho.co.jp.
2. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida-shimoadachicho, Sakyo-ku, Kyoto, 606-8501, Japan. baba_dfq@mii.maruho.co.jp.
3. Kyoto R&D Center, Maruho Co., Ltd., 93 Awata-cho, Chudoji, Shimogyo-ku, 600-8815, Kyoto, Japan.
4. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida-shimoadachicho, Sakyo-ku, Kyoto, 606-8501, Japan.
5. Institute for Integrated Cell-Material Sciences, Kyoto University, 46-29, Yoshida-shimoadachicho, Sakyo-ku, Kyoto, 606-8501, Japan.

Abstract

PURPOSE:

The solvent effect on skin permeability is important for assessing the effectiveness and toxicological risk of new dermatological formulations in pharmaceuticals and cosmetics development. The solvent effect occurs by diverse mechanisms, which could be elucidated by efficient and reliable prediction models. However, such prediction models have been hampered by the small variety of permeants and mixture components archived in databases and by low predictive performance. Here, we propose a solution to both problems.

METHODS:

We first compiled a novel large database of 412 samples from 261 structurally diverse permeants and 31 solvents reported in the literature. The data were carefully screened to ensure their collection under consistent experimental conditions. To construct a high-performance predictive model, we then applied   support vector regression (SVR) and random forest (RF) with greedy stepwise descriptor selection to our database. The models were internally and externally validated.

RESULTS:

The support vector regression achieved higher performance statistics than random forest. The (externally validated) determination coefficient, root mean square error, and mean absolute error of support vector regression were 0.899, 0.351, and 0.268, respectively. Moreover, because all descriptors are fully computational, our method can predict as-yet unsynthesized compounds.

CONCLUSION:

Our high-performance prediction model offers an attractive alternative to permeability experiments for pharmaceutical and cosmetic candidate screening and optimizing skin-permeable topical formulations.

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