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| 1 | Antibacterial photodynamic therapy:overview of a promising approach to fight antibiotic-resistant bacterial infections显示文摘Antibacterial photodynamic therapy(APDT)has drawn increasing attention from the scientific society for its potential to effectively kill multidrug-resistant pathogenic bacteria and for its low tendency to induce drug resistance that bacteria can rapidly develop against traditional antibiotic therapy.The review summarizes the mechanism of action of APDT,the photosensitizers,the barriers to PS localization,the targets,the in vitro-,in vivo-,and clinical evidence,the current developments in terms of treating Gram-positive and Gram-negative bacteria,the limitations,as well as future perspectives.Relevance for patients:A structured overview of all important aspects of APDT is provided in the context of resistant bacterial species.The information presented is relevant and accessible for scientists as well as clinicians,whose joint effort is required to ensure that this technology benefits patients in the post-antibiotic era. | Yao Liu Rong Qin Sebastian A.J.Zaat Eefjan Breukink Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，3： | 8 |
| 2 | Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity:current understanding and future perspectives显示文摘Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling.Their central role in energy metabolism,as well as their high abundance in hepatocytes,make them important targets for drug-induced hepatotoxicity.This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen,diclofenac,anti-tuberculosis drugs such as rifampin and isoniazid,anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids.The utilization of circulating mitochondrialspecific biomarkers in understanding mechanisms of toxicity in humans will also be examined.In summary,it is well-established that mitochondria are central to acetaminophen-induced cell death.However,the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis,In contrast,the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans.Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.Relevance for patients:This review focuses on the role of mitochondrial dysfunction in liver injury mechanisms of clinically important drugs like acetaminophen,diclofenac,rifampicin,isoniazid,amiodarone and others.A better understanding of the mechanisms in animal models and their translation to patients will be critical for the identification of new therapeutic targets. | Anup Ramachandran Luqi Duan Jephte Y.Akakpo Hartmut Jaeschke | 2018 | Journal of Clinical & Translational Research2018，4，1： | 8 |
| 3 | Circulating extracellular RNAs,myocardial remodeling,and heart failure in patients with acute coronary syndrome显示文摘Background:Given high on-treatment mortality in heart failure(HF),identifying molecular pathways that underlie adverse cardiac remodeling may offer novel biomarkers and therapeutic avenues.Circulating extracellular RNAs(ex-RNAs)regulate important biological processes and are emerging as biomarkers of disease,but less is known about their role in the acute setting,particularly in the setting of HF.Methods:We examined the ex-RNA profiles of 296 acute coronary syndrome(ACS)survivors enrolled in the Transitions,Risks,and Actions in Coronary Events Center for Outcomes Research and Education Cohort.We measured 374 ex-RNAs selected a priori,based on previous findings from a large population study.We employed a two-step,mechanism-driven approach to identify ex-RNAs associated with echocardiographic phenotypes(left ventricular[LV]ejection fraction,LV mass,LV end-diastolic volume,left atrial[LA]dimension,and LA volume index)then tested relations of these ex-RNAs with prevalent HF(N=31,10.5%).We performed further bioinformatics analysis of microRNA(miRNAs)predicted targets’genes ontology categories and molecular pathways.Results:We identified 44 ex-RNAs associated with at least one echocardiographic phenotype associated with HF.Of these 44 exRNAs,miR-29-3p,miR-584-5p,and miR-1247-5p were also associated with prevalent HF.The three microRNAs were implicated in the regulation p53 and transforming growth factor-βsignaling pathways and predicted to be involved in cardiac fibrosis and cell death;miRNA predicted targets were enriched in gene ontology categories including several involving the extracellular matrix and cellular differentiation.Conclusions:Among ACS survivors,we observed that miR-29-3p,miR-584-5p,and miR-1247-5p were associated with both echocardiographic markers of cardiac remodeling and prevalent HF.Relevance for Patients:miR-29c-3p,miR-584-5p,and miR-1247-5p were associated with echocardiographic phenotypes and prevalent HF and are potential biomarkers for adverse cardiac remodeling in HF. | Khanh-Van Tran Kahraman Tanriverdi Gerard P.Aurigemma Darleen Lessard Mayank Sardana Matthew Parker Amir Shaikh Matthew Gottbrecht Zachary Milstone Selim Tanriverdi Olga Vitseva John F.Keaney Catarina I.Kiefe David D.McManus Jane E.Freedman | 2019 | Journal of Clinical & Translational Research2019，5，1： | 7 |
| 4 | Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology显示文摘Acetaminophen(APAP)overdose is the most common cause of acute liver failure in the United States and mechanisms of liver injury induced by APAP overdose have been the focus of extensive investigation.Studies in the mouse model,which closely reproduces the human condition,have shown that hepatotoxicity is initiated by formation of a reactive metabolite N-acetyl-p-benzoquinone imine(NAPQI),which depletes cellular glutathione and forms protein adducts on mitochondrial proteins.This leads to mitochondrial oxidative and nitrosative stress,accompanied by activation of c-jun N-terminal kinase(JNK)and its translocation to the mitochondria.This then amplifies the mitochondrial oxidant stress,resulting in translocation of Bax and dynamin related protein 1(Drp1)to the mitochondria,which induces mitochondrial fission,and ultimately induction of the mitochondrial membrane permeability transition(MPT).The induction of MPT triggers release of intermembrane proteins such as apoptosis inducing factor(AIF)and endonuclease G into the cytosol and their translocation to the nucleus,causing nuclear DNA fragmentation and activation of regulated necrosis.Though these cascades of events were primarily identified in the mouse model,studies on human hepatocytes and analysis of circulating biomarkers from patients after APAP overdose,indicate that a number of mechanistic events are identical in mice and humans.Circulating biomarkers also seem to be useful in predicting the course of liver injury after APAP overdose in humans and hold promise for significant clinical use in the near future.Relevance for patients:This review focuses on the mechanisms behind APAP-induced hepatotoxicity and the relevance of these to the human pathophysiology.Current investigations on various biomarkers which may be useful in clinical management of APAP overdose patients are also discussed. | Anup Ramachandran Hartmut Jaeschke | 2017 | Journal of Clinical & Translational Research2017，3，1： | 6 |
| 5 | Site-specific pharmaco-laser therapy:A novel treatment modality for refractory port wine stains显示文摘Despite extensive efforts to optimize laser therapy,i.e.,the current gold standard treatment,a majority of port wine stain(PWS)patients responds suboptimally to laser therapy.This paper describes the niceties of a novel PWS treatment modality termed site-specific pharmaco-laser therapy(SSPLT).In contrast to the classic approach of enhancing the extent of intravascular photocoagulation(the photothermal response),SSPLT focuses on optimization of post-irradiation thrombus formation(i.e.,the hemodynamic response)by combining conventional laser therapy with the administration of thermosensitive drug delivery systems that encapsulate prothrombotic and antifibrinolytic drugs.The aim of SSPLT is to instill complete lumenal occlusion in target vessels,which has been linked to optimal PWS blanching.Relevance for patients:The current treatment options for PWS patients are limited in efficacy.Novel therapeutic modalities are needed to more effectively treat patients with recalcitrant PWSs.SSPLT is an experimental-stage treatment modality that could serve as an adjuvant to pulsed dye laser therapy for a selected group of patients whose PWS is ill-responsive to standard treatment.The expected clinical result of SSPLT is improved lesional blanching. | M.Ingmar van Raath Jojanneke E.van Amesfoort Martin Hermann Yasin Ince Maurice J.Zwart Agustina V.Echague Yan Chen Baoyue Ding Xuan Huang Gert Storm Michal Heger | 2019 | Journal of Clinical & Translational Research2019，5，1： | 4 |
| 6 | Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity显示文摘Background:Obesity is often associated with nonalcoholic fatty liver disease(NAFLD),which refers to a large spectrum of hepatic lesions including fatty liver,nonalcoholic steatohepatitis(NASH)and cirrhosis.Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs.Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD.Aim:The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity.For this purpose,we performed a data-mining analysis using different queries including drug-induced liver injury(or DILI),drug-induced hepatotoxicity,fatty liver,nonalcoholic fatty liver disease(or NAFLD),steatosis and obesity.The main data from the collected articles are reported in this review and when available,some pathophysiological hypotheses are put forward.Relevance for patients:Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen,halothane,methotrexate,rosiglitazone,stavudine and tamoxifen.For some of these drugs,experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD.Other drugs such as pentoxifylline,phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not.Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes,hyperlipidemia and coronary heart disease,it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening. | Julie Massart Karima Begriche Caroline Moreau Bernard Fromenty | 2017 | Journal of Clinical & Translational Research2017，3，1： | 4 |
| 7 | Importance of intellectual property generated by biomedical research at universities and academic hospitals显示文摘Biomedical research has many different facets.Researchers and clinicians study disease biology and biochemistry to discover novel therapeutic targets,unravel biochemical pathways and identify biomarkers to improve diagnosis,or devise new approaches to clinically manage diseases more effectively.In all instances,the overall goal of biomedical research is to ensure that results thereof(such as a therapy,a device,or a method which may be broadly referred to as“inventions”)are clinically implemented.Most of the researchers’efforts are centered on the advance of technical and scientific aspects of an invention.The development and implementation of an invention can be arduous and very costly.Historically,it has proven to be crucial to protect intellectual property rights(IPR)to an invention(i.e.,a patent)to ensure that companies can obtain a fair return on their investment that is needed to develop an academic invention into a product for the benefit of patients.However,the importance of IPR is not generally acknowledged among researchers at academic institutions active in biomedical research.Therefore this paper aims to(1)raise IP awareness amongst clinical and translational researchers;(2)provide a concise overview of what the patenting trajectory entails;and(3)highlight the importance of patenting for research and the researcher.Importance for patients:Adequate patent protection of inventions generated through biomedical research at academic institutions increases the probability that patients will benefit from these inventions,and indirectly enables the financing of clinical studies,mainly by opening up funding opportunities(e.g.specific grants aimed at start-ups,pre-seed and seed capital)that otherwise would not be accessible.As a consequence,patented inventions are more likely to become clinically tested and reach the market,providing patients with more treatment options. | Joris J.Heus Elmar S.de Pauw Mirjam Leloux Margherita Morpurgo Michael R Hamblin Michal Heger | 2017 | Journal of Clinical & Translational Research2017，3，2： | 3 |
| 8 | Hemoporfin-mediated photodynamic therapy on normal vasculature:implications for phototherapy of port-wine stain birthmarks显示文摘Background:Port-wine stain(PWS)birthmarks currently are treated using a pulsed dye laser(PDL)combined with transient cooling of the epidermis.PDL treatment protocols utilize short pulses of light(585 or 595 nm wavelength)to heat selectively the microvasculature due to absorption by intravascular hemoglobin.Although most patients respond to PDL therapy,few experience complete removal of the PWS.An alternate treatment option to PDL therapy of PWS is photodynamic therapy(PDT).Research groups have reported on various photosensitizers for PDT of PWS,including Hemoporfin,Benzoporphyrin Derivative monoacid ring A,and talaporfin sodium.Aim:Our aim was to evaluate,with an established preclinical in-vivo model,the efficacy of photodynamic therapy(PDT)with Hemoporfin to achieve persistent vascular shutdown.Methods:To monitor the microvasculature,a dorsal window chamber was surgically installed on 24 adult mice.The PDT excitation source emitted 150mW of 532nm light,with an irradiance of 100mW/cm^2.A retroorbital injection of Hemoporfin(2 mg/kg)was performed to deliver the drug into the bloodstream.Laser irradiation was initiated immediately after injection.To monitor blood-flow dynamics in response to PDT,we used laser speckle imaging.We employed a dose–response experimental design to study the efficacy of Hemoporfin-mediated PDT to achieve persistent vascular shutdown observed on Day 7 after PDT.Results:We observed four general hemodynamic responses to PDT:(1)At low radiant exposures,we did not observe any persistent vascular shutdown;(2)at intermediate radiant exposures,we observed delayed vascular shutdown effect with significant change to the vascular structure;(3)at intermediate radiant exposures,we observed an acute vascular shutdown effect with gradual restoration of blood flow and no significant changes to the vascular structure;and(4)at high radiant exposures,we observed acute vascular shutdown that persisted during the entire 7-day monitoring period,with no change in vascular structure.With light dose–response analysis,we estimated a characteristic radiant exposure of 359 J/cm^2 that was required to achieve persistent vascular shutdown observed on Day 7 after PDT. | Wesley JMoy Gang Ma Kristen MKelly Bernard Choi | 2016 | Journal of Clinical & Translational Research2016，2，3： | 3 |
| 9 | The need for reporting negative results–a 90 year update显示文摘In January of 1927, Dr. Richard D. Mudd of Detroit publisheda letter in the Journal of the American Medical Association,seeking to vindicate his grandfather, Dr. Samuel A. Mudd,against charges of conspiring in a murder [1]. The victim wasU.S. President Abraham Lincoln;the murderer, actor JohnWilkes Booth (see Appendix). In this editorial, I, an erstwhileactor, would like to vindicate my own grandfather, Dr. JohnRosslyn Earp, for a letter he published on the same day, justone column over, in the very same issue of the journal [2]. ButI mean “vindicate” in its other sense—to prove correct—as weshall see. | Brian D.Earp | 2017 | Journal of Clinical & Translational Research2017，3，4： | 3 |
| 10 | The publication symmetry test:a simple editorial heuristic to combat publication bias显示文摘Premier academic journals—that is, the journals in whichmany researchers must publish their work in order to maintainor advance their careers—have historically tended to rejectpapers reporting “negative” or null findings, including thosederived from “failed” attempts to replicate prior results [1–3].This tendency was likely due to three main factors. First, thelimited space available for publishing articles when journalswere printed exclusively on paper. Second, the prestige-relateddesire of “top” journals to publish new and exciting findings—i.e., “discoveries” (often taken to imply a demonstrationthat something “works,” as opposed to “fails to work”). Andthird, the difficulty posed by negative findings in terms of howthey should be interpreted: do they suggest that there is noeffect of interest to be found, or rather that the experiment,whether in its design or execution, was simply inadequate toshow the effect even though it is real [4–6]? | Brian D.Earp Dominic Wilkinson | 2017 | Journal of Clinical & Translational Research2017，3，4： | 3 |
| 11 | Inflammatory bowel disease: role of diet, microbiota, life style显示文摘 | Manuela G. Neuman Radu M. Nanau | 2012 | Translational Research2012，，1： | 2 |
| 12 | Genome-Wide Association Studies of Hypertension: Have They Been Fruitful?显示文摘 | Sajjad Rafiq Sonia Anand Robert Roberts | 2010 | Journal of Cardiovascular Translational Research2010，，3： | 2 |
| 13 | Immune mechanisms of idiosyncratic drug-induced liver injury显示文摘Idiosyncratic drug reactions(IDRs)continue to be an important issue.Specifically,idiosyncratic drug-induced liver injury(IDILI)is the most likely IDR to lead to drug withdrawal,and it accounts for a significant portion of all cases of acute liver failure.In addition,IDRs are unpredictable and their mechanisms are not well understood.There is increasing clinical evidence that most IDILI is immune mediated.Several immune mediated mechanistic hypotheses exist such as the hapten and danger hypothesis;however,they do not completely explain the idiosyncratic nature of these reactions.Extensive mechanistic studies are needed to better understand these reactions;however,it is impossible to do controlled experiments in humans,and previous animal models did not properly model IDILI.If IDILI is immune mediated and the major factor preventing liver injury in patients is immune tolerance,then a plausible method to develop an animal model of IDILI would be to impair immune tolerance.This hypothesis has shown promise in developing valid animal models of IDILI as demonstrated by a halothane induced liver injury mouse model developed by depleting myeloid derived suppressor cells(MDSCs),as well as an amodiaquine-,isoniazid-and nevirapine-induced liver injury mouse model developed by impairing immune tolerance by blocking PD-1 and CTLA-4,two immune checkpoint inhibitors.Further characterization and validation of these models is required;however,it is likely that they will make it possible to perform mechanistic studies that have been impossible in the past.Relevance for patients:Idiosyncratic drug-induced liver injury can be serious leading to liver transplantation or death.Their idiosyncratic nature makes mechanistic studies very difficult.However,with the development of the first animal model that is similar to the liver injury that occurs in humans,it will be possible to study the mechanisms involved.With a better mechanistic understanding it should be possible to test drug candidates and produce safer drugs.In addition,it should be possible to design better treatments when drug-induced liver injury does occur. | Alastair Mak Jack Uetrecht | 2017 | Journal of Clinical & Translational Research2017，3，1： | 2 |
| 14 | The impact of sterile inflammation in acute liver injury显示文摘Background:The liver has a number of functions in innate immunity.These functions predispose the liver to innate immune-mediated liver injury when inflammation goes unchecked.Significant progress has been made in the last 25 years on sterile inflammatory liver injury in a number of models;however,a great deal of controversy and many questions about the nature of sterile inflammation still exist.Aim:The goal of this article is to review sterile inflammatory liver injury using both a basic approach to what constitutes the inflammatory injury,and through examination of current models of liver injury and inflammation.This information will be tied to human patient conditions when appropriate.Relevance for patients:Inflammation is one of the most critical factors for managing in-patient liver disease in a number of scenarios.More information is needed for both scientists and clinicians to develop rational treatments. | Benjamin L.Woolbright Hartmut Jaeschke | 2017 | Journal of Clinical & Translational Research2017，3，1： | 2 |
| 15 | Bone marrow stromal cells as replacement cells for Parkinson’s disease: generation of an anatomical but not functional neuronal phenotype显示文摘 | Meghan G. Thomas Leah Stone Lauren Evill Syerna Ong Mel Ziman Livia Hool | 2011 | Translational Research2011，，2： | 2 |
| 16 | Antisense Technology: An Emerging Platform for Cardiovascular Disease Therapeutics显示文摘 | Richard G. Lee Jeff Crosby Brenda F. Baker Mark J. Graham Rosanne M. Crooke | 2013 | Journal of Cardiovascular Translational Research2013，，6： | 2 |
| 17 | Platelet aggregation but not activation and degranulation during the acute post-ischemic reperfusion phase in livers with no underlying disease显示文摘Background:Platelets and P-selectin(CD62P)play an unequivocal role in the pathology of hepatic ischemia/reperfusion(I/R)injury.Inhibition or knock-out of P-selectin or immunodepletion of platelets results in amelioration of post-ischemic inflammation,reduced hepatocellular damage,and improved survival.However,P-selectin expression on platelets and endothelial cells,which concurs with platelet activation,has never been clearly demonstrated in I/R-subjected livers.Aims:To determine whether platelets become activated and degranulate in the acute phase of liver I/R and whether the platelets interact with neutrophils.Methods:Hepatic I/R was induced in male C57BL/6J mice(N=12)using 37.5-min ischemia time.Platelets,endothelial cells,and neutrophils were fluorescently labeled by systemic administration of non-blocking antibodies.Cell kinetics were monitored by intravital spinning disk confocal microscopy during 90 min of reperfusion.Image analysis and quantification was performed with dedicated software.Results:Platelets adhered to sinusoids more extensively in post-ischemic livers compared to livers not subjected to I/R and formed aggregates,which occurred directly after ischemia.Platelets and endothelial cells did not express P-selectin in post-ischemic livers.There was no interaction between platelets and neutrophils.Conclusions:Platelets aggregate but do not become activated and do not degranulate in post-ischemic livers.There is no platelet-neutrophil interplay during the early reperfusion phase in a moderate model of hepatic I/R injury.The mechanisms underlying the biological effects of platelets and P-selectin in this setting warrant further investigation.Relevance for patients:I/R in surgical liver patients may compromise outcome due to post-ischemic oxidative stress and sterile inflammation.Both processes are mediated in part by platelets.Understanding platelet function during I/R is key to developing effective interventions for I/R injury and improving clinical outcomes. | Rowan F.van Golen Katarzyna M.Stevens Pina Colarusso Hartmut Jaeschke Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，2： | 2 |
| 18 | Translational research: understanding the continuum from bench to bedside显示文摘 | Brian C. Drolet Nancy M. Lorenzi | 2011 | Translational Research2011，，1： | 2 |
| 19 | Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy显示文摘 | Megan Jack Douglas Wright | 2012 | Translational Research2012，，5： | 2 |
| 20 | Osteosarcoma cell proliferation and migration are partly regulated by redox-activated NHE-1显示文摘Background:Osteosarcoma(OS)is the most common primary malignant bone tumor in children and adolescents.OS is associated with locally aggressive growth and high metastatic potential.The mechanisms that underlie these processes are currently elusive.Reactive oxygen species(ROS)and Na+/H+exchanger 1(NHE1)have been suggested to regulate proliferation and migration of tumor cells.However,the relationship between NHE1 and ROS in OS proliferation and migration has not been investigated before.Aim:To investigate the role of NHE1 and ROS in the proliferation and migration of OS.Methods:ROS levels and NHE1 expression were studied in cultured human OS cells and human OS xenografts in nude mice.In vitro,OS cells were treated with different doses of tert-butyl hydroperoxide(tBHP),a ROS inducer,and cariporide,an NHE1 inhibitor,to study the effect on cell proliferation and migration.In vivo,nude mice bearing OS cells were administrated with NHE1 inhibitor or antioxidant and the tumor weights were measured.Results:This study reported for the first time that the expression of NHE1 and intracellular ROS level were both increased in OS tissues and cells.Exposure of OS cell to ROS derived from tBHP was able to accelerate cell proliferation and migration and also up-regulate NHE1 protein expression.Moreover,tBHP significantly increased intracellular pH(pHi),decreased extracellular pH(pHe)and induced upregulation of ERK,MMP2,and MMP9.Lowering of ROS levels with the anti-oxidant DMTU or inhibiting NHE1 activity via cariporide abolished the stimulatory effect of tBHP.However,there cariporide did not affect intracellular ROS levels.In vivo study we further confirmed that cariporide could inhibit tumor growth in the nude mouse xenografts of OS cells.Conclusions:The data demonstrate that up-regulation of NHE1 was induced by low concentrations of ROS contributes to the regulation of tumor proliferation and invasion of OS.Relevance for patients:There is potential application for cariporide as an effective antitumor agent during the development of human osteosarcoma.In addition,redox modulation on proton transport may represent a novel target of osteosarcoma prevention,and open a new avenues for future research. | Hua Bai Guojing Chen Congwen Fang Xuekang Yang Sixun Yu Chunxu Hai | 2015 | Journal of Clinical & Translational Research2015，1，3： | 2 |
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