Center For Translational Medicine Research Articles

Suppression of Microtubule Acetylation Mediates Theanti-Leukemic Effect of CDK9 Inhibition

Suppression of Microtubule Acetylation Mediates the Anti-Leukemic Effect of CDK9 Inhibition Xi Xie1, BaoyuanZhang1, Ping Liu1, Ruibao Ren1,2 1. Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. International Center for Aging and Cancer, Hainan Medical University, Haikou, Hainan Province, China. Cyclin-dependent kinase 9 (CDK9) is a crucial component of transcription and potential target for anti-cancer therapies, particularly for hematological malignancies. However, the precise mechanisms underlying the therapeutic effects of CDK9 inhibitors remain not fully understood. Here, we found that inhibiting CDK9 either pharmacologically or through gene downregulation, significantly reduced the levels of α-tubulin protein in a time- and dose-dependent manner. We further discovered that CDK9 inhibition led to increased susceptibility of α-tubulin to proteasomal degradation due to reduced acetylation at lysine 40 (K40), an important modification for microtubule stability. An acetylation-mimicking mutant of α-tubulin mitigated the anti-tumor effects of CDK9 inhibition. Mechanically, we identified that CDK9 inhibition downregulated the expression of ATAT1, the acetyltransferase responsible for α-tubulin acetylation, further compromising microtubule stability. Our study unravels a novel molecular mechanism by which CDK9 inhibition disrupts α-tubulin stability and provides valuable insights for exploring effective treatment regimens involving CDK9 inhibitors.

Meet the First Authors.

Meet the First Authors.

IVF characteristics and the molecular luteal features of random start IVF cycles are not different from conventional cycles in cancer patients.

Are the IVF parameters and the steroidogenic luteal characteristics of random-start IVF cycles different from conventional cycles in cancer patients? No; controlled ovarian stimulation cycles randomly started at late follicular phase (LFP) and luteal phase (LP) are totally comparable to those conventional IVF cycles started at early follicular phase (EFP) in terms of the expression of the enzymes involved in cholesterol utilization and steroid hormone biosynthesis pathways, gonadotropin receptor expression and, estradiol (E2) and progesterone (P4) production in addition to the similarities in ovarian response to gonadotropin stimulation, oocyte yield, fertilization rate and embryo development competency in cancer patients. Random start ovarian stimulation protocols are commonly employed for oocyte and embryo freezing for fertility preservation in cancer patients with time constraints who do not have sufficient time to undergo ovarian stimulation initiated conventionally at EFP of the next cycle. No data is available regarding the molecular steroidogenic features of these cycles analyzed together with the clinical IVF characteristics in cancer patients. We aimed to address this question in this study to help understand how similar the random start cycles are to the conventional start ones. A clinical translational research study conducted in 62 cancer patients undergoing IVF for fertility preservation between the years 2017 and 2022. Sixty-two patients who were diagnosed with different types of cancer and underwent ovarian stimulation for oocyte (n = 41) and embryo (n = 21) cryopreservation using GnRH antagonist protocol and human menopausal gonadotropins before receiving cancer treatment/surgery were enrolled in the study. For patients with breast cancer and endometrial cancer the aromatase inhibitor letrozole was used with gonadotropin stimulation. Ovarian stimulation was initiated conventionally at EFP in 22 patients and served as control while it was started at LFP in 20, and mid-LP in the other 20 patients. The luteinized granulosa cells (GCs) were recovered from follicular aspirates during oocyte retrieval procedure and used for the experiments separately for each individual patient. The expression of the enzymes involved in sex steroid biosynthesis (StAR, 3β-HSD, Aromatase) and cholesterol synthesis (3-hydroxy 3-methylglutaryl Co-A reductase (HMG-Co-A reductase)), utilization (hormone sensitive lipase (HSL)), and storage (Acetyl-Coenzyme A acetyltransferase 1 (ACAT-1)), and gonadotropin receptor expression status were analyzed using immunoblotting and RT-PCR methods. Laser confocal immunofluorescence imaging was applied to analyze and compare the expression patterns of the steroidogenic enzymes and their relation with mitochondria. In vitro E2 and P4 production by the cells were compared among the groups. Baseline demographic and IVF characteristics of the patients undergoing the conventional start and random start IVF cycles were similar. Duration of gonadotropin stimulation was significantly longer in LFP and LP start cycles in comparison to the conventional ones. Ovarian response to gonadotropin stimulation, mature and total oocyte yield, fertilization and Day 5 blastulation rates of the embryos were comparable between the conventional versus random start cycles. When the luteal GCs of these random start cycles were analyzed we could not find any gross differences between these cycles in terms of the viability index and gross light microscopic morphologic features. More detailed analysis of the molecular luteal characteristics of the cells using RT-PCR, immunoblotting methods revealed that the expression profiles of the gonadotropin receptors, and the enzymes involved in sex steroid biosynthesis and cholesterol synthesis/utilization, and the steroidogenic activity of the luteal GCs of the random start cycles are almost identical to those of the conventional start cycles. Confocal image analysis demonstrated similar patterns in the signal expression profiles of the steroidogenic enzymes and their co-localization within mitochondria. N/A. Caution should be exercised when interpreting our data and counseling cancer patients seeking fertility preservation because it is still unclear if previous exposure to cancer drugs, different ovarian pathologies or infertility etiologies, previous ovarian surgery and/or any other underlying diseases that are concomitantly present with cancer may cause a difference between conventional and random start stimulation protocols in terms of IVF parameters, luteal function and reproductive outcome. Relatively low number of patients in each stimulation protocol and pooling of luteal GCs for each patient rather than individual analysis of each follicle and oocyte are additional limitations of our study. Our findings provide reassurance that random start protocol offers cancer patients an equally good prospect of fertility preservation as conventional IVF. Funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest. N/A.

Translational Medicine and Exercise Prescription (TMEP): Advancing the Era of Exercise Medicine

Translational Medicine and Exercise Prescription (TMEP): Advancing the Era of Exercise Medicine

Meet the First Author.

HomeCirculation ResearchVol. 126, No. 3Meet the First Author Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Author Originally published30 Jan 2020https://doi.org/10.1161/RES.0000000000000324Circulation Research. 2020;126:296–297is related toFunctional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and AdipocytesAge-Associated Mitochondrial Dysfunction Accelerates AtherogenesisA Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyteis related toInterleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase EnrichmentDuration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific MortalityVascular Aging, Mitochondria, and Atherogenesis (p 298)Download figureDownload PowerPointDr Dan Tyrrell is a postdoctoral fellow in Dr Daniel Goldstein’s laboratory at the University of Michigan. He completed his PhD in Dr Anthony Molina’s laboratory in Integrative Physiology and Pharmacology at Wake Forest School of Medicine. Dan’s recent work demonstrates a positive feedback loop of increased IL-6 and mitochondrial dysfunction within the aging aorta that accelerates atherogenesis. His long-term goal is to determine how mitochondria and inflammation interact in multiple vascular beds with aging, and how these changes enhance disease. Dan enjoys running and biking when he isn’t spending time with his family (ie, chasing after his two young sons). He can be found on Twitter @dantyrr.IL-10 Deficiency Impairs EPC Exosome Function (p 315)Download figureDownload PowerPointDr Yujia Yue earned her BS in Medicine from Fudan University in China. She became interested in life sciences and basic biomedical research while earning her MD. She came to the US in 2014 and completed her PhD in May 2019 (mentor, Dr Raj Kishore) at the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, focusing on stem cell-derived exosome in cardiac regeneration. After earning her PhD, Yujia joined Merck as an Associate Scientist. She is interested in furthering her scientific pursuit of translational medicine and drug discovery and plans to continue her scientific career in industry.CRISPR Screen for Genes Affecting Insulin Resistance (p 330)Download figureDownload PowerPointDr Zhifen Chen is a postdoctoral fellow in Dr Chad Cowan’s group at the Harvard Stem Cell Institute, where her research focuses on functional genomics of polygenic traits, including insulin resistance and glucose levels. She earned her PhD from Technical University of Munich (TUM) in 2016 and her MS from Tsinghua University, Beijing, in 2012. She was mentored by Dr Karl-Ludwig Laugwitz, focussing on cardiac disease modelling using patient-induced pluripotent stem cell (iPSC)-derived cardiomyocytes, including a type of long QT syndrome and a case of familial dilated cardiomyopathy. The goal of her research is to identify unknown genes contributing to adipose insulin resistance and test their therapeutic potentials for obesity or type 2 diabetes and their related cardiometabolic comorbidities. Outside of the lab, she enjoys dancing, biking, and discussing life experiences and diverse fields of science. She plans to establish her own lab in the near future.Desmin and the Nucleus (p e10)Download figureDownload PowerPointJulie Heffler is a doctoral candidate at the University of Pennsylvania in the lab of Dr Ben Prosser. She began her career as an undergraduate at the University of Houston, where she earned her BS in Biochemistry. During her time at UH, she worked in the lab of Dr Kevin Morano at UT Health researching chaperones and protein misfolding. Currently, her research at UPenn has focused on the attachment of the cytoskeleton to the nucleus in adult cardiomyocytes and how these cells sense mechanical signals, continuing her long-held interest in cell sensing and signal transduction. She can be found on Twitter @julieheffler.Antibiotics and Risk of Mortality (p 364)Download figureDownload PowerPointDr Yoriko Heianza is a postdoctoral research fellow in the Department of Epidemiology at Tulane University. She earned her PhD in Medicine from the University of Tsukuba, Japan. She previously earned her BS from the Doshisha Women’s College of Liberal Arts, Kyoto, Japan, where she gained a broad knowledge of nutrition. She has been exploring genetic, metabolomic, diet/lifestyle factors in the development of obesity and cardiovascular disease in Dr Lu Qi’s Lab at Tulane University, with the support of an AHA Postdoctoral Fellowship. She has also received two awards for her research from the AHA. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesFunctional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and AdipocytesZhifen Chen, et al. Circulation Research. 2020;126:330-346Interleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase EnrichmentYujia Yue, et al. Circulation Research. 2020;126:315-329Age-Associated Mitochondrial Dysfunction Accelerates AtherogenesisDaniel J. Tyrrell, et al. Circulation Research. 2020;126:298-314A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the CardiomyocyteJulie Heffler, et al. Circulation Research. 2020;126:e10-e26Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific MortalityYoriko Heianza, et al. Circulation Research. 2020;126:364-373 January 31, 2020Vol 126, Issue 3 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000324PMID: 31999534 Originally publishedJanuary 30, 2020 PDF download Advertisement

Aberrant Brain Structural-Functional Connectivity Coupling in Euthymic Bipolar Disorder

Aberrant structural (diffusion tensor imaging, DTI) and resting-state functional (rsfMRI) connectivity are core features of bipolar disorder (BD). However, few studies have explored the integrity agreement between structural and functional connectivity in BD (SC-FC coupling). Such SC-FC coupling index could potentially provide additional clinical predictive value for BD spectrum disorders besides the intra-modality network measures. Thus, we examined the structural (DTI) and resting-state functional network properties, as well as their coupling index, among 57 euthymic BD patients (age 13-28 years, 18 females) and 42 age- and gender-matched healthy controls (age 13-28 years, 16 females). We found that compared to controls, BD patients showed increased structural rich club connectivity as well as decreased functional modularity. Importantly, the coupling strength between structural and functional connectome was decreased in BD patients compared to controls, which emerged as the most powerful feature discriminating the two groups. Our findings suggest that structural-functional coupling strength could serve as a valuable biological trait marker for bipolar disorder over and above the intra-modality network measures. Such measure can have important clinical implications for early identification of BD individuals, and inform strategies for prevention of BD onset and relapse. Funding: This study was funded by the National Natural Science Foundation of China (NSFC: 81471375,81671347), Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders (201805010009), and Guangzhou Municipal Psychiatric Disease Clinical Transformation Laboratory (201805010009), which had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. Declaration of Interest: We declare no competing interests. Ethical Approval: This study was approved by the Institutional Review Board of the Guangzhou Brain Hospital.

LOEWE Workshop Particle Characterization in Medicine and Biology

The workshop “Particle Characterization in Medicine and Biology” jointly organized by the LOEWE research center for Translational Medicine and Pharmacology and Malvern Panalytical Ltd. was held at the University Hospital, Goethe University in Frankfurt/Main on September 20th 2018. Speakers from academia and industry gave insights into particle manufacture and characterization in various environments. Further, the implications for drug delivery and clinical translation of micro and nanotherapeutics were discussed.

Effects of ApoE gene polymorphism on the efficacy of atorvastatin in the treatment of hyperlipidemia

Objective: To study the role of ApoE gene polymorphism on efficacy of atorvastatin in lowering the lipid and its clinical significance. Methods: A total of 962 patients with hypercholesterolemia were selected between January 1 st and December 31 st 2014. The ApoE genepolymorphism in patients with hyperlipidemia was performed by using polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) method in translational medicine center of Huaihe Hospital. Patients with ApoE genotype E3/3 and E3/4 were selected and treated with atorvastatin 10 mg/d for 4 weeks. Before and after treatment, triglycerides (TG) and total cholesterol (TC) was detected by enzyme colorimetry method. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were performed by Clearance method. Lipoprotein(a) (Lp(a)) was performed by turbidimetric inhibition immunoassay. ApoE gene expression was performed by real-time PCR. Results: In the 6 gene types, the frequencies of E3/4 and E3/3 were 30.6% (294 cases) and 59.1% (569 cases) respectively. After treatment with atorvastatin, the change percent of TC, LDL-C, HDL-C, TG, Lp(a) in E3/4 and E3/3 group were -(23.0±4.7)% vs -(12.0±3.1)% (P<0.001), -(33.0±4.8)% vs -(20.0±3.9)% (P<0.001), (18.0±3.8)% vs (6.0±2.6)% (P<0.001), -(23.0±3.9)% vs -(13.0±2.7)% (P<0.001), -(21.5±4.5)% vs -(20.9±4.0)% (P=0.054), respectively. ApoE gene expression in E3/3 and E3/4 groups were down-regulated in both groups, and the change in E3/3 group was obvious than that of E3/4 group. Conclusion: After treatment with atorvastatin, levels of lipids and ApoE gene expression in ApoE genotype E3/3 patients decreased, which were more evident than E3/4 patients.

Targeted Inhibition of Leucine-Rich Repeat and Immunoglobulin Domain-Containing Protein 1 in Transplanted Neural Stem Cells Promotes Neuronal Differentiation and Functional Recovery in Rats Subjected to Spinal Cord Injury.

Leucine-rich repeat and immunoglobulin domain-containing protein (LINGO)-1 is expressed in neural stem cells, and its neutralization results in sustained neuronal immaturity. Thus, targeted inhibition of LINGO-1 via RNA interference may enhance transplanted neural stem cell survival and neuronal differentiation in vivo. Furthermore, LINGO-1 RNA interference in neural stem cells represents a potential therapeutic strategy for spinal cord injury. Department of Spine Surgery, First Affiliated Hospital of Sun Yat-sen University. Translational Medicine Center Research Laboratory, First Affiliated Hospital of Sun Yat-sen University. Female Sprague-Dawley rats. The animals were divided into three groups that underwent laminectomy and complete spinal cord transection accompanied by transplantation of control-RNA interference-treated or LINGO-1-RNA interference-treated neural stem cells at the injured site in vivo. In vitro, neural stem cells were divided into four groups for the following treatments: control, control RNA interference lentivirus, LINGO-1 RNA interference lentivirus and LINGO-1 complementary DNA lentivirusand the Key Projects of the Natural Science Foundation of Guangdong Province (No. S2013020012818). Neural stem cells in each treatment group were examined for cell survival and neuronal differentiation in vitro and in vivo via immunofluorescence and Western blot analysis. Axonal regeneration and tissue repair were assessed via retrograde tracing using Fluorogold, electron microscopy, hematoxylin-eosin staining and MRI. Rats were also examined for functional recovery based on the measurement of spinal cord-evoked potentials and the Basso-Beattie-Bresnahan score. LINGO-1-RNA interference-treated neural stem cell transplantation increased tissue repair and functional recovery of the injured spinal cord in rats. Similarly, LINGO-1 RNA interference increased neural stem cell survival and neuronal differentiation in vitro. The mechanism underlying the effect of LINGO-1 RNA interference on the injured rat spinal cord may be that the significant inhibition of LINGO-1 expression in neural stem cells inactivated the RhoA and Notch signaling pathways, which act downstream of LINGO-1. Our findings indicate that transplantation of LINGO-1-RNA interference-treated neural stem cells facilitates functional recovery after spinal cord injury and represents a promising potential strategy for the repair of spinal cord injury.

Response to the letter “No evidence to support high-intensity statin in Chinese patients with coronary heart disease”

a Research Center for Translational Medicine, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai 200120, China b Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong c Department of Cardiac Surgery, Shanghai East Hospital, Tongji University, Shanghai, China d Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan

Tapering of TNF-α Inhibitors is Feasible for Rheumatoid Arthritis Patients who have Achieved Remission

1Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan 2Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan 3Faculty of Medicine, National Yang Ming University, Taipei, Taiwan 4Institute of Biomedical Science and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan *Corresponding author: Dr. Der-Yuan Chen, Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, No. 1650, Sec. 4, Taiwan Boulevard, Taichung 40705, Taiwan, Tel: +886-4-23593354; E-mail: dychen@vghtc.gov.tw

Walter J. Koch: two decades, one mission.

Temple University Professor and Chairman of Pharmacology Walter J. (“Wally”) Koch, PhD, has been on a career-long mission to elucidate molecular mechanisms of heart failure. Studying a family of kinases that regulate adrenergic receptors and other G protein-coupled receptors (GPCRs) in the heart, Koch has focused on one such kinase, GRK2,1 which at high levels impairs myocytes and promotes cell death. Two decades of basic and preclinical work with GRK2 have put the 54-year-old Koch and his colleagues on the threshold of human trials using adeno-associated viral-mediated myocardial gene delivery to try to reverse heart failure.2–4 Koch has also shed new light on GRK5, including showing how this enzyme enters a heart cell’s nucleus, where it contributes to hypertrophy.5,6 Koch, a native of Bryan, Ohio, first pursued his interest in science by following a friend’s path to pharmacy school at the University of Toledo. Koch earned his PhD in pharmacology and cell biophysics from the University of Cincinnati, completed a Howard Hughes Medical Institute fellowship at Duke University, joined the Duke faculty, and advanced to a tenured professor of surgery. In 2003 he moved to Philadelphia to launch Thomas Jefferson University’s Center for Translational Medicine, and in 2012 established the Center for Translational Medicine at Temple. In 1995, when Koch started his own lab, he knew he wanted to be the “champion” of GRK2 in the heart and develop GRK2 inhibitors for heart failure. “Twenty years later,” he says in describing his journey, “we’re almost there.” Walter J. Koch My father was a truck driver, a World War II veteran. He hauled steel between Cleveland and Chicago, so he was not home during the week. My mom stayed home. There were five kids; I’m the baby. I went to Catholic grade school and …

Practice and thinking of hospital translational medicine development

Establish translational medicine platform,including consortium of clinical medical research platform,translational medicine center,and health services community etc.Focus on translational medicine sources; establish medical thinking to promote the translational medical personnel training.Promoting the basic medical research transform into clinical practice and health policy. Key words: practice; translational medicine; hospital

Construction of Y376C-FGFR4 eukaryotic expression plasmid and its biological activity in HEK293 cell

Jing Huang1, Liuxin Feng1, Hongli An2, and Tao Zhang1* School of Pharmaceutical Sciences, Xi’an Jiaotong University, Xi’an 710061, China Center for Translational Medicine, The First Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an 710061, China These authors are equal first author. *Correspondence address. Tel: þ86-29-82656788; Fax: þ86-29-82655451; E-mail: taozhang@mail.xjtu.edu.cn

Genetic Research Provides Insights Into Age-Related Macular Degeneration

WITH NO CURE AND A PREVAlence twice that of Alzheimer disease, age-related macular degeneration (AMD) is increasingly being recognized as a serious condition that leads to vision loss in a growing number of elderly persons. While a clear heritable component to the disease has been known for years, only recently have investigators begun to tease out the alterations in genetic pathways—particularly those involving complement and to some extent cholesterol—that play a role. Researchers have also learned that individuals who are genetically predisposed can take steps to ward off the disease. Studies indicate that a combination of environmental and hereditary risk factors confer a greater risk of AMD than that conferred by each risk factor individually. Experts are optimistic that this wealth of new information will spur additional discoveries that could ultimately delay or prevent AMD, making it one of the first major chronic diseases to benefit from pharmacogenetics and personalized medicine. “Twenty years ago, there was nothing we could do about AMD,” said Gregory Hageman, PhD, the John A. Moran Presidential Professor of Ophthalmology and Visual Sciences and director of the Moran Center for Translational Medicine at the University of Utah in Salt Lake City. “Now I’d say it’s the best understood complex trait disease out there, and I believe that in 2 to 3 years out we’ll be delivering some real benefits to patients,” he added. More than 85% of all individuals with intermediate or advanced AMD have the dry form of the disease, which occurs when the light-sensitive cells in the macula slowly break down and gradually blur central vision. Among patients with advanced AMD, about twothirds have the wet form of the disease,

Commentary: Advancing the Research Mission in an Academic Department: The Creation of a Center for Translational Medicine

Multidisciplinary research centers have multiplied in academic medical centers over the past decade and several recent reports have described their structure, strengths and limitations, and the difficulties that they may face. However, little attention has been paid to the role of a multidisciplinary center in the context of a single academic department. In 2003, the Department of Medicine at Jefferson Medical College launched the Center for Translational Medicine in order to facilitate multidisciplinary research, optimally utilize space and resources, enhance the educational experience for trainees, link basic investigation with clinical research programs, and develop a program of research excellence. Herein, we describe the structure of the Center and provide evidence of its success. The development of the Center has resulted in increased total funding, an increased number of students and residents pursuing translational research, a more effective utilization of space, the development of multidisciplinary research projects, and a significant increase in the number of individual and programmatic federally funded grants. Though the creation of the Center was not without challenges, the overall benefits for the department and the university have been substantial. The concept of a translational medicine center may be useful for many departments of academic medical centers.

Heart Failure Gene Therapy: Closer to Reality

Professor Walter Koch is currently a Director at the Center for Translational Medicine and Vice Chairman for Research in the Department of Medicine at Jefferson Medical College, Thomas Jefferson University, PA, USA. Professor Koch started his career as a Research Associate at the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA. His work is based around heart failure and the molecular mechanisms involved in the regulation of signaling through cardiovascular adrenergic receptors, the study of G-proteincoupled receptor function and signaling, and heart failure gene therapy. His current studies are investigating into the use of novel viral-mediated myocardial gene delivery for use in congestive heart failure, with an aim at developing reproducible surgical means of gene therapy. He is also involved in research to understand novel molecular signaling mechanisms responsible for reversible cardiac injury and potential repair.

Mechanisms of Cardiac Dysfunction Associated With Tyrosine Kinase Inhibitor Cancer Therapeutics

Treatment of patients with cancer has changed radically over the last several years with the advent of “targeted therapeutics.” Whereas traditional chemotherapy was directed at all rapidly dividing cells, whether cancerous or not, today’s anticancer drugs are increasingly tailored to the specific genetics of each cancer. This targeted approach, predominantly via inhibition of tyrosine kinase activity, has markedly improved the management of cancers including chronic myeloid leukemia (CML), breast cancer, gastrointestinal stromal tumor (GIST), renal cell carcinoma (RCC), and colon carcinoma.1–5 Inhibitors of tyrosine kinases are of 2 classes: monoclonal antibodies (mAbs), typically targeting growth factor receptor tyrosine kinases, and small molecules, referred to as tyrosine kinase inhibitors (TKIs), targeting both receptor and nonreceptor tyrosine kinases. The goal of targeted therapy is to improve antitumor activity with fewer toxic side effects than traditional anticancer therapies; given the initial success of this approach, the number of targeted therapy drugs entering into development in the last 5 years has increased dramatically.6,7 However, several recent studies have revealed unanticipated side effects of targeted therapy, including left ventricular (LV) dysfunction and heart failure, the primary manifestations of cardiotoxicity we will be examining here.5,8,9 Herein, we will examine the potential risk of LV dysfunction of targeted therapy and the molecular mechanisms that underlie that risk. We will review the importance of tyrosine kinase signaling pathways both for oncogenesis and for the survival of normal cardiomyocytes. To understand basic mechanisms of cardiomyopathy of TKIs, it is critical to understand 2 general classes of toxicity. The first is “on-target” toxicity, wherein the tyrosine kinase target regulating cancer cell survival and/or proliferation (and therefore a good target in cancer therapy) also serves an important role in normal cardiomyocyte survival, and thus inhibition leads to myocardial dysfunction. “Off-target” toxicity occurs when a TKI leads to toxicity …

Not All Hypertrophy Is Created Equal

See related article, pages 1164–1174 Cardiac hypertrophy is the natural response of myocardium to various stressors, including neurohormonal stimuli, hemodynamic overload, and injury. In the face of continued stress, pathological hypertrophy progresses to a loss of cardiomyocytes, the development of fibrosis, and, ultimately, heart failure. Emerging evidence has shown that glycogen synthase kinase-3β (GSK-3β) is an important negative regulator of cardiomyocyte hypertrophy, yet inhibition of GSK-3β has been shown to reduce cell death after ischemia reperfusion. Therefore, it has been difficult to predict what the consequences of chronic inhibition of GSK-3 in the heart would be because it might be a balance between the potential for the aggravation of cardiac hypertrophy versus antiapoptotic effects. In this issue of Circulation Research , Hirotani and colleagues report that sustained inhibition of GSK-3β in postneonatal hearts results in well-compensated “physiologic” cardiac hypertrophy and, most intriguingly, exerts protective effects against the development of “pathological” hypertrophy and heart failure with pressure overload.1 Although there are a number of concerns that need to be addressed before targeting GSK-3 for the treatment of heart failure, this “best of both worlds” outcome provides an interesting and favorable rationale for such intervention. The GSK-3 family of protein kinases is encoded by 2 genes, α and β. They are highly conserved throughout evolution and are critical to the regulation of diverse biological processes ranging from organ development to cell death, including cell growth, cell cycling, cytoskeletal organization, and metabolism.2,3 Furthermore, dysregulation of GSK-3β has been implicated in the pathogenesis of many human diseases including Alzheimer disease, diabetes, and tumorgenesis.4–8 GSK-3α (51 kDa) is the larger of the two and has a glycine-rich N terminus of unknown function. GSK-3β (47 kDa) and α share significant sequence homology (97%) in their kinase domains, however the homology between the …

The yin and yang of increased β-adrenergic signaling: β1-adrenergic genetic polymorphism and protection against acute myocardial ischemic injury

significant improvements in the treatment and prevention of cardiac diseases have led to declining morbidity and mortality over the past three decades ([2][1]), and drugs targeting adrenergic signaling have played a key role in the beneficial effects recently afforded to these patients. However,