http://www.clintransmed.com The latest research articles published by Clinical and Translational Medicine 2013-06-17T00:00:00Z Background: Previous studies of epidermal kinetics in psoriasis have relied on invasive biopsy procedures or the use of radioactive labels. We previously developed a non-invasive method for measuring keratin synthesis in human skin using deuterated water labeling, serial collection of tape strips and measurement of deuterium enrichment in protein by mass spectrometry. This powerful method can be applied to measure other skin proteins and lipids collected by tape stripping. Here, for the first time, we apply this technique to investigate the epidermal kinetics of psoriasis, the first step in defining a kinetic profile for normal skin versus activated or quiescent psoriatic skin. Methods: Psoriatic subjects were given 2H2O orally as twice-daily doses for 16--38 days. Affected and unaffected skin was sampled by tape stripping and washing (modified Pachtman method). Proteins were isolated from the tape strips by a method that enriches for keratin. Turnover times were determined by gas chromatography/mass spectrometry. Kinetic data were compared to transepidermal water loss (TEWL). Results: Deuterium-labeled protein from lesional psoriatic skin appeared at the skin surface within 3--8 days of label administration, whereas labeled protein from non-lesional skin requires 10--20 days to appear. Psoriatic skin had similar rate of growth despite varying anatomic location. Proteins recovered from tape strips were identified by nanoscale liquid chromatography/tandem mass spectrometry. Isolated peptides were >98% from keratin in uninvolved skin and >72% keratin in psoriatic skin. Revealing that one-quarter of all newly synthesized proteins in psoriatic skin are antimicrobial defense and other immune-related proteins. TEWL values were greater in lesional than non-lesional skin, suggesting barrier compromise in psoriatic skin despite increased clinical thickness. Conclusions: This simple, elegant, and non-invasive method for measuring epidermal protein synthesis, which can also be adapted to measure epidermal lipids, provides a metric that may reveal new insights into the mechanisms and dynamic processes underlying psoriasis and may also provide an objective scale for determining response to therapeutic agents in pre-clinical and clinical trials. This opens a pathway to the non-invasive study of kinetics of protein formation in psoriasis or other skin diseases. http://www.clintransmed.com/content/2/1/12 Claire Emson Sarah Fitzmaurice Glen Lindwall Kelvin Li Marc Hellerstein Howard Maibach Wilson Liao Scott Turner Clinical and Translational Medicine 2013, null:12 2013-06-17T00:00:00Z doi:10.1186/2001-1326-2-12 /content/figures/2001-1326-2-12-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 12 2013-06-17T00:00:00Z PDF The kidney has key roles in maintaining human health. There is an escalating medical crisis in nephrology as growing numbers of patients suffer from kidney diseases that culminate in organ failure. While dialysis and transplantation provide life-saving treatments, these therapies are rife with limitations and place significant burdens on patients and healthcare systems. It has become imperative to find alternative ways to treat existing kidney conditions and preemptive means to stave off renal dysfunction. The creation of innovative medical approaches that utilize stem cells has received growing research attention. In this review, we discuss the regenerative and maladaptive cellular responses that occur during acute and chronic kidney disease, the emerging evidence about renal stem cells, and some of the issues that lie ahead in bridging the gap between basic stem cell biology and regenerative medicine for the kidney. http://www.clintransmed.com/content/2/1/11 Yue Li Rebecca Wingert Clinical and Translational Medicine 2013, null:11 2013-05-21T00:00:00Z doi:10.1186/2001-1326-2-11 /content/figures/2001-1326-2-11-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 11 2013-05-21T00:00:00Z XML Our current health research enterprise is painstakingly slow and cumbersome, and its results seldom translate into practice. The slow pace of health research contributes to findings that are less relevant and potentially even obsolete. To produce more rapid, responsive, and relevant research, we propose approaches that increase relevance via greater stakeholder involvement, speed research via innovative designs, streamline review processes, and create and/or better leverage research infrastructure. Broad stakeholder input integrated throughout the research process can both increase relevance and facilitate study procedures. More flexible and rapid research designs should be considered before defaulting to the traditional two-arm randomized controlled trial (RCT), but even traditional RCTs can be designed for more rapid findings. Review processes for grant applications, IRB protocols, and manuscript submissions can be better streamlined to minimize delays. Research infrastructures such as rapid learning systems and other health information technologies can be leveraged to rapidly evaluate new and existing treatments, and alleviate the extensive recruitment delays common in traditional research. These and other approaches are feasible but require a culture shift among the research community to value not only methodological rigor, but also the pace and relevance of research. http://www.clintransmed.com/content/2/1/10 William Riley Russell Glasgow Lynn Etheredge Amy Abernethy Clinical and Translational Medicine 2013, null:10 2013-05-10T00:00:00Z doi:10.1186/2001-1326-2-10 /content/figures/2001-1326-2-10-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 10 2013-05-10T00:00:00Z XML Two direct-acting antivirals (DAAs) against hepatitis C virus (HCV): telaprevir and boceprevir, are now available in combination with peginterferon plus ribavirin for the treatment of chronic hepatitis C infection. Although these drugs are potent inhibitors of HCV replication, they occasionally result in severe adverse events. In the present clinical trials, in their stead, several second-generation DAAs are being investigated. Most of them are being viewed with high expectations, but they also require the combination with peginterferon plus ribavirin. In the near future, we might be using all-oral DAAs and interferon-free regimens for the treatment of HCV-infected patients, and these would be potent inhibitors of HCV and have less adverse events. http://www.clintransmed.com/content/2/1/9 Tatsuo Kanda Osamu Yokosuka Masao Omata Clinical and Translational Medicine 2013, null:9 2013-04-11T00:00:00Z doi:10.1186/2001-1326-2-9 /content/figures/2001-1326-2-9-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 9 2013-04-11T00:00:00Z XML Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible “molecules binds” to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis.Further studies in these directions are necessary to better define the therapeutic implication of maspin. http://www.clintransmed.com/content/2/1/8 Rossana Berardi Francesca Morgese Azzurra Onofri Paola Mazzanti Mirco Pistelli Zelmira Ballatore Agnese Savini Mariagrazia De Lisa Miriam Caramanti Silvia Rinaldi Silvia Pagliaretta Matteo Santoni Chiara Pierantoni Stefano Cascinu Clinical and Translational Medicine 2013, null:8 2013-03-07T00:00:00Z doi:10.1186/2001-1326-2-8 /content/figures/2001-1326-2-8-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 8 2013-03-07T00:00:00Z XML Background: The objectives and goals of the Southern Swedish Malignant Melanoma (SSMM) are to develop, build and utilize cutting edge biobanks and OMICS platforms to better understand disease pathology and drug mechanisms. The SSMM research team is a truly cross-functional group with members from oncology, surgery, bioinformatics, proteomics, and genomics initiatives. Within the research team there are members who daily diagnose patients with suspect melanomas, do follow-ups on malignant melanoma patients and remove primary or metastatic lesions by surgery. This inter-disciplinary clinical patient care ensures a competence build as well as a best practice procedure where the patient benefits. Methods: Clinical materials from patients before, during and after treatments with clinical end points are being collected. Tissue samples as well as bio-fluid samples such as blood fractions, plasma, serum and whole blood will be archived in 384-high density sample tube formats. Standardized approaches for patient selections, patient sampling, sample-processing and analysis platforms with dedicated protein assays and genomics platforms that will hold value for the research community are used. The patient biobank archives are fully automated with novel ultralow temperature biobank storage units and used as clinical resources. Results: An IT-infrastructure using a laboratory information management system (LIMS) has been established, that is the key interface for the research teams in order to share and explore data generated within the project. The cross-site data repository in Lund forms the basis for sample processing, together with biological samples in southern Sweden, including blood fractions and tumor tissues. Clinical registries are associated with the biobank materials, including pathology reports on disease diagnosis on the malignant melanoma (MM) patients. Conclusions: We provide data on the developments of protein profiling and targeted protein assays on isolated melanoma tumors, as well as reference blood standards that is used by the team members in the respective laboratories. These pilot data show biobank access and feasibility of performing quantitative proteomics in MM biobank repositories collected in southern Sweden. The scientific outcomes further strengthen the build of healthcare benefit in the complex challenges of malignant melanoma pathophysiology that is addressed by the novel personalized medicines entering the market. http://www.clintransmed.com/content/2/1/7 Charlotte Welinder Göran Jönsson Christian Ingvar Lotta Lundgren Håkan Olsson Thomas Breslin Ákos Végvári Thomas Laurell Melinda Rezeli Bo Jansson Bo Baldetorp György Marko-Varga Clinical and Translational Medicine 2013, null:7 2013-02-27T00:00:00Z doi:10.1186/2001-1326-2-7 /content/figures/2001-1326-2-7-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 7 2013-02-27T00:00:00Z XML The transplant of organs and tissues is one of the greatest curative achievements of this century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the main goal of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. Cell surface molecules that induce an antigenic stimulus cause the rejection immune response to grafted tissue or organ. A wide variety of transplantation antigens have been described, including the major histocompatibility molecules, minor histocompatibility antigens, ABO blood group antigens and endothelial cell antigens. The sensitization to MHC antigens may be caused by transfusions, pregnancy, or failed previous grafts leading to development of anti-human leukocyte antigen (HLA) antibodies that are important factor responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complication Anti-HLA Abs may be present in healthy individuals. Methods for HLA typing are described, including serological methods, molecular techniques of sequence-specific priming (SSP), sequence-specific oligonucleotide probing (SSOP), Sequence based typing (SBT) and reference strand-based conformation analysis (RSCA) method. Problems with organ transplantation are reservoir of organs and immune suppressive treatments that used to decrease rate of rejection with less side effect and complications. http://www.clintransmed.com/content/2/1/6 Batool Mahdi Clinical and Translational Medicine 2013, null:6 2013-02-23T00:00:00Z doi:10.1186/2001-1326-2-6 /content/figures/2001-1326-2-6-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 6 2013-02-23T00:00:00Z XML We propose A step-by-step roadmap to integrate genetics in the Electronic Patient Record in Family Medicine and clinical research. This could make urgent operationalization of readily available genetic knowledge feasible in clinical research and consequently improved medical care.Improving genomic literacy by training and education is needed first. The second step is the improvement of the possibilities to register the family history in such a way that queries can identify patients at risk. Adding codes to the ICPC chapters “A21 Personal/family history of malignancy” and “A99 Disease carrier not described further” is proposed. Multidisciplinary guidelines for referral must be unambiguous. Electronical patient records need possibilities to add (new) family history information, including links between individuals who are family members. Automatic alerts should help general practitioners to recognize patients at risk who satisfy referral criteria. We present a familial breast cancer case with a BRCA1 mutation as an example. http://www.clintransmed.com/content/2/1/5 Elisa Houwink Annet Sollie Mattijs Numans Martina Cornel Clinical and Translational Medicine 2013, null:5 2013-02-16T00:00:00Z doi:10.1186/2001-1326-2-5 /content/figures/2001-1326-2-5-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 5 2013-02-16T00:00:00Z XML The impact of mapping the human proteomeGlobally, the health care organizations are under resource and cost constrains due to the increasing number of patients that are due to a fast increase of the 65+ age group requiring extensive medical hospitalization and treatments. Hospitals worldwide strive to seek the best cure for patients, suffering from various diseases. A consequence of these global changes, of healthy populations in relation to patients forms the basis for the build of large and centralized biobank facilities, with strategies where the search for an understanding of diseases at a molecular level is at heart. The efforts made lies within large governmental resource allocations where patient centers are collecting samples from clinical study participants in order to try to discover universal expression patterns and molecular signatures of disease and disease stages. Most developments in this area are aimed towards the discovery, and understanding diagnosis implementations. By providing the right treatment alternatives for patients care, at the right time point i.e., at a given disease stage development becomes a major goal where pharmaceutical industry, academia and the health care sector joins forces in large clinical epidemiological, population-, and disease based studies. This becomes a clear strategic link to the enhancement and prospects for personalized medicines and target directed diagnosis developments (Companion Diagnostics), which require coordinated efforts across a wide range of disciplines. Currently, companion diagnostics is at the core of the personalized medicine paradigm shift. It will identify patients who are most likely to benefit from a particular therapeutic product, as well as identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic agent. It is predicted that more than half of all new drugs will require a companion diagnostic, which opens up for an endeavor for Proteomics research implementations. http://www.clintransmed.com/content/2/1/4 György Marko-Varga Clinical and Translational Medicine 2013, null:4 2013-02-06T00:00:00Z doi:10.1186/2001-1326-2-4 /content/figures/2001-1326-2-4-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 4 2013-02-06T00:00:00Z XML Chemotherapy is one of the standard methods of treatment in many cancers. While chemotherapy is often capable of inducing cell death in tumors and reducing the tumor bulk, many cancer patients experience recurrence and ultimately death because of treatment failure. In recent years, cancer stem cells (CSCs) have gained intense interest as key tumor-initiating cells that may also play an integral role in recurrence following chemotherapy. As such, a number of mechanisms of chemoresistance have been identified in CSCs. In this review, we describe a number of these mechanisms of chemoresistance including ABC transporter expression, aldehyde dehydrogenase (ALDH) activity, B-cell lymphoma-2 (BCL2) related chemoresistance, enhanced DNA damage response and activation of key signaling pathways. Furthermore, we evaluate studies that demonstrate potential methods for overcoming chemoresistance and treating chemoresistant cancers that are driven by CSCs. By understanding how tumor-initiating cells such as CSCs escape chemotherapy, more informed approaches to treating cancer will develop and may improve clinical outcomes for cancer patients. http://www.clintransmed.com/content/2/1/3 Lissa Abdullah Edward Chow Clinical and Translational Medicine 2013, null:3 2013-01-17T00:00:00Z doi:10.1186/2001-1326-2-3 /content/figures/2001-1326-2-3-toc.gif Clinical and Translational Medicine 2001-1326 ${item.volume} 3 2013-01-17T00:00:00Z XML