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Molecular Medicine 2013

Articles from this Volume

Posted by Leah Caracappa on Nov 13, 2013 6:25 PM CST

Albert Dahan, Ann Dunne, Maarten Swartjes, Paolo L Proto, Lara Heij, Oscar Vogels, Monique van Velzen, Elise Sarton, Marieke Niesters, Martijn R Tannemaat, Anthony Cerami, and Michael Brines


Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD. 

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Posted by Leah Caracappa on Nov 13, 2013 6:21 PM CST
Tatsuo Takahashi, Sayaka Katsuta, Yusuke Tamura, Nozomi Nagase, Keita Suzuki, Masaaki Nomura, Shunji Tomatsu, Ken-ichi Miyamoto, and Shinjiro Kobayashi

Rheumatoid arthritis (RA) is a chronic inflammatory synovitis that leads to the destruction of bone and cartilage. The receptor for advanced glycation end products (RAGE) is a multiligand membrane-bound receptor for high-mobility group box-1 (HMGB1) associated with development of RA by inducing production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmembrane- bound form of RAGE (endogenous secretory RAGE [esRAGE]) functioning as a decoy receptor. We assessed its tissue distribution and therapeutic effectiveness in a murine model of collagen-induced arthritis (CIA). Acidic oligopeptide–tagged esRAGE (D6-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D6-esRAGE with a dose of 1 mg/kg to RA model mice significantly ameliorated inflammatory arthritis, synovial hyperplasia, cartilage destruction and bone destruction, while untagged esRAGE showed little effectiveness. Moreover, D6-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-α, IL-1 and IL-6, while esRAGE reduced the levels of IL-1 and IL-6 to a lesser extent, suggesting that production of IL-1 and IL-6 reduced along the blockade of HMGB1 receptor downstream signals by D6-esRAGE could be attributed to remission of CIA. These findings indicate that D6-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA. 

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Posted by Leah Caracappa on Nov 1, 2013 1:50 PM CDT
Natalya Seredkina, Johan van der Vlag, Jo Berden, Elin Mortensen, and Ole Petter Rekvig

Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complex–mediated tissue damage. Recent data suggest acquired error of renal chromatin degradation due to the loss of renal DNaseI enzyme activity is an important contributing factor to the development of lupus nephritis in lupus-prone (NZBxNZW)F1 mice and in patients with lupus nephritis. Downregulation of DNaseI expression results in reduced chromatin fragmentation and in deposition of extracellular chromatin–IgG complexes in glomerular basement membranes in individuals who produce IgG anti-chromatin autoantibodies. The main focus of the present review is to discuss whether exposed chromatin fragments in glomeruli are targeted by potentially nephritogenic anti-dsDNA autoantibodies or if the nephritogenic activity of these autoantibodies is explained by cross-reaction with intrinsic glomerular constituents or if both models coexist in diseased kidneys. In addition, the role of silencing of the renal DNaseI gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed. 

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Posted by Leah Caracappa on Nov 1, 2013 1:36 PM CDT
Eugenia Tsakou, Andreas Agathagelidis, Myriam Boudjoghra, Thorsten Raff, Antonis Dagklis, Maria Chatzouli, Tatjana Smilevska, George Bourikas, Helene Merle-Beral, Eleni Manioudaki-Kavallieratou, Achilles Anagnostopoulos, Monika Brüggemann, Frederic Davi, Kostas Stamatopoulos, and Chrysoula Belessi.

Partial versus Productive Immunoglobulin Heavy Locus Rearrangements in

Chronic Lymphocytic Leukemia: Implications for B-Cell Receptor Stereotypy. 
 

One of the authors’ names is incorrect. Andreas Agathagelidis should be given as Andreas Agathangelidis.

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Posted by Leah Caracappa on Oct 30, 2013 12:50 PM CDT
Sohel M Julovi, Kaitlin Shen, Kelly McKelvey, Nikita Minhas, Lyn March, and Christopher J Jackson

Synovial fibroblast proliferation is a hallmark of the invasive pannus in the rheumatoid joint. Activated protein C (APC) is a natural anticoagulant that exerts antiinflammatory and cyto-protective effects in various diseases via endothelial protein C receptor (EPCR) and proteinase-activated receptor (PAR)-mediated pathways. In this study, we investigated the effect and the underlying cellular signaling mechanisms of APC on proliferation of human rheumatoid synovial fibroblasts (RSFs). We found that APC stimulated proliferation of mouse dermal fibroblasts (MDFs) and normal human dermal fibroblasts (HDFs) by up to 60%, but robustly downregulated proliferation of RSFs. APC induced the phosphorylation of extracellular signal–regulated protein kinase (ERK) and enhanced expression of p21 and p27 in a dose-dependent manner in RSFs. The latter effect was inhibited by pretreatment with the ERK inhibitors PD98059 and U0126 but not by p38 inhibitor SB203580. In addition, APC significantly downregulated tumor necrosis factor (TNF)α-stimulated cell proliferation and activation of p38, c-Jun NH2-terminal kinase (JNK) and Akt in RSFs. These results provide the first evidence that APC selectively inhibits proliferation and the inflammatory signaling pathways of RSFs. Thus, APC may reduce synovial hyperplasia and pannus invasion in rheumatoid arthritis. 

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Supplemental Data

 

Posted by Leah Caracappa on Oct 24, 2013 1:41 PM CDT
Helena M Linge, Cecilia Andersson, Sara L Nordin, Anders I Olin, Ann-Cathrine Petersson, Matthias Mörgelin, Amanda Welin, Johan Bylund, Leif Bjermer, Jonas Erjefält, and Arne Egesten

Staphylococcus aureus
is sometimes isolated from the airways during acute exacerbations of chronic obstructive pulmonary disease (COPD) but more commonly recognized as a cause of ventilator-associated pneumonia (VAP). Antimicrobial proteins, among them midkine (MK), are an important part of innate immunity in the airways. In this study, the levels and possible processing of MK in relation to S. aureus infection of the airways were investigated, comparing COPD and VAP, thus comparing a state of disease with preceding chronic inflammation and remodeling (COPD) with acute inflammation (that is, VAP). MK was detected in the small airways and alveoli of COPD lung tissue but less so in normal lung tissue. MK at below micromolar concentrations killed S. aureus in vitro. Proteolytic processing of MK by the staphylococcal metalloprotease aureolysin (AL), but not cysteine protease staphopain A (SA), resulted in impaired bactericidal activity. Degradation was seen foremost in the COOH-terminal portion of the molecule that harbors high bactericidal activity. In addition, MK was detected in sputum from patients suffering from VAP caused by S. aureus but less so in sputum from COPD exacerbations associated with the same bacterium. Recombinant MK was degraded more rapidly in sputum from the COPD patients than from the VAP patients and a greater proteolytic activity in COPD sputum was confirmed by zymography. Taken together, proteases of both bacteria and the host contribute to degradation of the antibacterial protein MK, resulting in an impaired defense of the airways, in particular, in COPD where the state of chronic inflammation could be of importance. 

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Posted by Leah Caracappa on Sep 30, 2013 2:16 PM CDT
In 1986 Microsoft Corporation launched its initial public offering, and Halley’s Comet last appeared in the inner solar system. And it was the year that Jack Ross, age 29, was diagnosed with testicular cancer. Jack describes himself as “fortunate,” however, because a biomedical research program from Michigan had recently led to FDA approval for the use of cisplatin to treat testicular cancer in 1978. It would later become known as the “penicillin of cancer,” curing most forms of testicular cancer in up to 90% of cases. The story of the drug’s discovery from an experiment using platinum electrodes in bacterial cultures had become personal. Jack was cured. This experience inspired Jack and Robin Ross to devote their time, resources and passion to research and led to their founding the Ross Prize in Molecular Medicine. The Prize recognizes individuals whose scientific advances and discoveries change the way medicine is practiced. It is awarded to midcareer scientists who have made a demonstrable impact in the understanding of human disease pathogenesis and/or treatment and who hold significant promise for making even greater contributions to the general field of molecular medicine. I am proud to note here that Dan R Littman, MD, PhD, is the inaugural winner of the 2013 Ross Prize in Molecular Medicine for his seminal discoveries and ongoing research to better understand viral, immune and inflammatory diseases. Dr. Littman is the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Skirball Institute of Biomolecular Medicine at NYU School of Medicine. Molecular Medicine shares Jack and Robin Ross’s vision for this prize. Like the cure from Michigan that was implemented at Jack Ross’s bedside in New York, it is our vision that the contributions made by Ross Prize winners will impact the practice of medicine in the world community and enhance human health.

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Posted by Leah Caracappa on Sep 18, 2013 3:20 PM CDT
Monica Colombo, Giovanna Cutrona, Daniele Reverberi, Silvia Bruno, Fabio Ghiotto, Claudya Tenca, Kostas Stamatopoulos, Anastasia Hadzidimitriou, Jenny Ceccarelli, Sandra Salvi, Simona Boccardo, Maria Grazia Calevo, Amleto De Santanna, Mauro Truini, Franco Fais, and Manlio Ferrarini

Marginal zone (MZ) B cells, identified as surface (s)IgMhighsIgDlowCD23low/–CD21+CD38– B cells, were purified from human spleens, and the features of their V(D)J gene rearrangements were investigated and compared with those of germinal center (GC), follicular mantle (FM) and switched memory (SM) B cells. Most MZ B cells were CD27+ and exhibited somatic hypermutations (SHM), although to a lower extent than SM B cells. Moreover, among MZ B-cell rearrangements, recurrent sequences were observed, some of which displayed intraclonal diversification. The same diversifying sequences were detected in very low numbers in GC and FM B cells and only when a highly sensitive, gene-specific polymerase chain reaction was used. This result indicates that MZ B cells could expand and diversify in situ and also suggested the presence of a number of activation-induced cytidine deaminase (AID)-expressing B cells in the MZ. The notion of antigen-driven expansion/selection in situ is further supported by the VH CDR3 features of MZ B cells with highly conserved amino acids at specific positions and by the finding of shared (“stereotyped”) sequences in two different spleens. Collectively, the data are consistent with the notion that MZ B cells are a special subset selected by in situ antigenic stimuli. 


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Supplemental data

Posted by Leah Caracappa on Sep 17, 2013 2:19 PM CDT
Marianne Berg, Marianne Guriby, Oddmund Nordgård, Bjørn S Nedrebø, Terje C Ahlquist, Rune Smaaland, Satu Oltedal, Jon Arne Søreide, Hartwig Kørner, Ragnhild A Lothe, and Kjetil Søreide

Lymph node (LN) harvest is influenced by several factors, including tumor genetics. Microsatellite instability (MSI) is associated with improved node harvest, but the association to other genetic factors is largely unknown. Research methods included a prospective series of stage I–III colon cancer patients undergoing ex vivo sentinel-node sampling. The presence of MSI, KRAS mutations in codons 12 and 13, and BRAF V600E mutations was analyzed. Uni- and multivariate regression models for node sampling were adjusted for clinical, pathological and molecular features. Of 204 patients, 67% had an adequate harvest (≥12 nodes). Adequate harvest was highest in patients whose tumors exhibited MSI (79%; odds ratio [OR] 2.5, 95% confidence interval [CI] 1.2–4.9; P = 0.007) or were located in the proximal colon (73%; 2.8, 1.5–5.3; P = 0.002). In multiple linear regression, MSI was a significant predictor of the total LN count (P = 0.02). Total node count was highest for cancers with MSI and no KRAS/BRAF mutations. The independent association between MSI and a high LN count persisted for stage I and II cancers (P = 0.04). Tumor location in the proximal colon was the only significant predictor of an adequate LN harvest (adjusted OR 2.4, 95% CI 1.2–4.9; P = 0.01). An increase in the total number of nodes harvested was not associated with an increase in nodal metastasis. In conclusion, number of nodes harvested is highest for cancers of the proximal colon and with MSI. The nodal harvest associated with MSI is influenced by BRAF and KRAS genotypes, even for cancers of proximal location. Mechanisms behind the molecular diversity and node yield should be further explored. 
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Posted by Leah Caracappa on Sep 10, 2013 2:28 PM CDT
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