July-August 2011 l Vol 17 l No 7-8

Research Articles

Mesenchymal Stromal Cells Promote Tumor Growth through the Enhancement of Neovascularization
Kazuhiro Suzuki, Ruowen Sun, Makoto Origuchi, Masahiko Kanehira, Takenori Takahata, Jugoh Itoh, Akihiro Umezawa, Hiroshi Kijima, Shinsaku Fukuda, and Yasuo Saijo
Angiogenesis is a fundamental event in tumor growth and metastasis. Therapies targeting angiogenic growth factors secreted by tumor cells, such as VEGF-A antibody, bevacizumab, have achieved limited success in the clinic. Human mesenchymal stromal cells (MSCs) are ubiqutous components of vessel walls and are involved in tissue repair. Here, Suzuki et al. quantified the contribution to tumor growth and neovascularization of MSCs in vitro and in vivo. The authors show tumors grow best under direct cell contact with MSCs at a ratio of 1:5 (cancer cell:MSC). Even at a 1:1 ratio, direct cell contact with MSCs stimulated growth three-fold more than cancer cell contact with secreted growth factors. This data indicates interrupting MSC-cancer cell communication may be a platform for the next generation of antiangiogenic cancer therapies.
Page 579 l View article: PDF (3.9 MB)

Prestroke Proteomic Changes in Cerebral Microvessels in Stroke-Prone, Transgenic[hCETP]-Hyperlipidemic, Dahl Salt-Sensitive Hypertensive Rats
Agnes Bergerat, Julius Decano, Chang-Jiun Wu, Hyungwon Choi, Alexey I Nesvizhskii, Ann Marie Moran, Nelson Ruiz-Opazo, Martin Steffen, and Victoria LM Herrera
Stroke is the third leading cause of death with high rates of morbidity among survivors. The unequivocal need for new therapeutic approaches would benefit from unbiased proteomic analyses of experimental models of spontaneous stroke in the prestroke stage. Using proteomic analysis, Bergerat et al. tested the putative changes in cerebral cortical microvessels (cMVs) preceding the onset of stroke in a stroke-prone model. The authors show cMV prestroke proteomic changes associated with age and stroke susceptibility. Their data indicate significant molecular changes in ischemic cerebral microvasculature in the prestroke stage, which could contribute to the observed model phenotype of microhemorrhages and post-ischemic hemorrhagic transformation. These pathways comprise putative targets for translational research of much-needed diagnostic and therapeutic approaches for stroke.
Page 588 l View article: PDF (2.7 MB)
Supplementary Data View article: PDF (688 KB)

Galantamine Alleviates Inflammation and Other Obesity-Associated Complications in High-Fat Diet–Fed Mice
Sanjaya K Satapathy, Mahendar Ochani, Meghan Dancho, LaQueta K Hudson, Mauricio Rosas-Ballina, Sergio I Valdes-Ferrer, Peder S Olofsson, Yael Tobi Harris, Jesse Roth, Sangeeta Chavan, Kevin J Tracey, and Valentin A Pavlov
Obesity affects more than 50 million people in the United States and is a global epidemic.  Obesity and the associated metabolic syndrome increases the risk of developing type 2 diabetes, cardiovascular disease, respiratory diseases and osteoarthritis. Inflammation is thought to be an important contributor to obesity-associated pathological conditions. Satapathy et al. explored the use of galantamine, a clinically approved drug for Alzheimer's disease, to alleviate obesity-related inflammation and other complications. Results indicate galantamine can reduce inflammation, decrease body weight gain and abdominal adiposity, and alleviate hyperglycemia, hyperinsulinemia, hypercholesterolemia, insulin resistance and fatty liver. These results suggest a previously unexplored potential of galantamine in alleviating obesity and its associated complications.
Page 599 l View article: PDF (2.2 MB)
Supplementary Data View article: PDF (430 KB)

A Functional Variant of IC53 Correlates with the Late Onset of Colorectal Cancer
Jingzhou Chen, Yi Shi, Ziyu Li, Hui Yu, Yu Han, Xiaojian Wang, Kai Sun, Tao Yang, Kejia Lou, Yan Song, Yinhui Zhang, Yisong Zhen, Guiguo Zhang, Ying Hu, Jiafu Ji, and Rutai Hui
Colorectal cancer (CRC) is a one of the most pervasive cancers worldwide. The IC53 gene has been reported to be upregulated in colon adenocarcinoma cells. Here, Chen et al. hypothesize that IC53 can regulate colon cancer progression and that a variant in the gene could modify the incidence and onset of colon cancer. Their data indicate IC53 is a positive mediator for colon cancer progression and the variant may serve as a protective factor against the onset of colorectal cancer.
Page 607 l View article: PDF (2.6 MB)
Supplementary Data View article: PDF (1.8 MB)

Bone Marrow Stromal Cell–Derived Vascular Endothelial Growth Factor (VEGF) Rather Than Chronic Lymphocytic Leukemia (CLL) Cell–Derived VEGF Is Essential for the Apoptotic Resistance of Cultured CLL Cells
Iris Gehrke, Rajesh Kumar Gandhirajan, Simon Jonas Poll-Wolbeck, Michael Hallek, and Karl-Anton Kreuzer
Chronic lymphocytic leukemia (CLL) cells accumulate in the body as a result of their anti-apoptotic nature. Although cells undergo rapid apoptosis in vitro, they survive longer in vivo. CLL cells receive survival signals from their microenvironment, however, the nature of these signals is not completely understood. Vascular endothelial growth factor (VEGF) is considered a pro-survival factor in CLL but its source and mechanism have not been clearly identified. Here, Gehrke et al. investigate the source of VEGF and its effect on the survival of CLL cells co-cultured on bone marrow stromal cells (BMSCs). Data showed VEGF derived from BMSCs, but not CLL cells, is involved in coculture-mediated survival support of CLL cells. These results suggest targeting VEGF signaling may be a promising approach to overcome CLL cell apoptotic resistance in their natural microenvironment.
Page 619 l View article: PDF  (1.6 MB)

Fluorescence-Assisted Cytological Testing (FACT): Ex Vivo Viral Method for Enhancing Detection of Rare Cancer Cells in Body Fluids
Prasad S Adusumilli, Sepideh Gholami, Yun Shin Chun, Michael Mullerad, Mei Ki Chan, Zhenkun Yu, Leah Ben-Porat, Valerie W Rusch, and Yuman Fong
Cytology diagnosis combined with imaging-assisted staging aids cancer treatment decisions. However, cytology from bodily fluids or sputum is often difficult to interpret because reactive mesothelial cells mimic malignant cells and cytology in patients with advanced cancer rarely finds malignant cells. Here, Adusumilli et al. tested whether a modified herpes virus carrying an EGFP protein could detect rare cancer cells in body fluids. The presence of cancer cells were accurately identified by all observers irrespective of their experience with microscopy even at a concentration as low as one cancer cell in one million normal cells. This fluorescence assisted cytologic testing (FACT) method may save patients from morbidity of surgery for tissue diagnosis and eliminate the interobserver variability that often plaques the field of cytopathology.
Page 628 l View article: PDF (1.5 MB)

Overexpression of Fatty Acid Synthase in Middle Eastern Epithelial Ovarian Carcinoma Activates AKT and Its Inhibition Potentiates Cisplatin-Induced Apoptosis
Shahab Uddin, Zeenath Jehan, Maqbool Ahmed, Aisha Alyan, Fouad Al-Dayel, Azhar Hussain, Prashant Bavi, and Khawla S Al-Kuraya
Over 21,000 women are diagnosed with ovarian cancers annually in the US. Two-thirds will die of their disease. Cisplatin is the gold standard in treatment, however, cells acquire resistance leading to the patients’ demise. Previous research shows fatty acid synthanse (FASN) is overexpressed in breast, ovarian, colorectal, lung, prostate and thyroid cancer and the magnitude of expression is proportional with cancer aggressiveness and metastasis. Here, Uddin et al. used ovarian tumor samples and cell lines to investigate the FASN pathway, AKT signaling, apoptosis and cisplatin resistance. The authors found FASN overexpression was directly linked to AKT phosphorylation and protection from cisplatin-induced apoptosis. Treatment with an FASN inhibitor promoted apoptosis in cancer cells via a mitochondrial pathway. These results provide a molecular rationale to design novel therapies directed against FASN in combination with cisplatin in ovarian carcinomas.
Page 635 l View article: PDF (20.7 MB)
Supplementary Data View article: PDF (610 KB)

Targeting IL-12/IL-23 by Employing a p40 Peptide-Based Vaccine Ameliorates TNBS-Induced Acute and Chronic Murine Colitis
Qingdong Guan, Yanbing Ma, China-Li Hillman, Gefei Qing, Allan G Ma, Carolyn R Weiss, Gang Zhou, Aiping Bai, Richard J Warrington, Charles N Bernstein, and Zhikang Peng
Interleukin (IL)-12 and IL-23 both share the p40 subunit and are key cytokines in the pathogenesis of Crohn’s disease.  Guan et al. developed vaccines that develop specific antibodies against both cytokines and here, tested them in experimental models of colitis. Vaccinations resulted in significantly less body weight loss, diminished colon inflammation and fibrosis, as well as reduced levels of multiple pro-inflammatory cytokines. These findings suggest this vaccine may provide a potential approach for long-term treatment of Crohn’s disease.
Page 646 l View article: PDF (6.9 MB)

Steroidogenic Enzymes and Stem Cell Markers Are Upregulated during Androgen Deprivation in Prostate Cancer
Minja J Pfeiffer, Frank P Smit, John PM Sedelaar, and Jack A Schalken
Since the survival and growth of prostate cancer (PCa) cells are driven by androgens, androgen deprivation therapy is the first line of treatment for advanced PCa. However, despite castration, cancer often recurs and may be considered castration resistant prostate cancer (CRPC). In this work, Pfeiffer et al. hypothesize that treatment-surviving, cancer-initiating cells along with the ability to metabolize steroids from precursors may be required in order for recurrent tumors to form. The authors assessed steroidogenic enzyme expression and stem cell markers during androgen depletion in a PCa cell line as well as in clinical samples. Enzymes involved in adrenal steroid metabolism, stem/progenitor cell markers, and the androgen receptor were found to be upregulated. This evidence links steroidogenesis with cancer initiating cells in PCa and indicates that therapies targeting adrenal steroid metabolism may prove effective in preventing tumor regrowth.
Page 657 l View article: PDF  (4.4 MB)

Diverging Alternative Splicing Fingerprints in the Transforming Growth Factor-β Signaling Pathway Identified in Thoracic Aortic Aneurysms
Sanela Kurtovic, Valentina Paloschi, Lasse Folkersen, Johan Gottfries, Anders Franco-Cereceda, and Per Eriksson
Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, resulting from degeneration of extra cellular matrix and loss of smooth muscle cells in the tunica media. Impaired regulation of the transforming growth factor-β (TGFβ) signaling pathway has been linked to TAA and differential splicing potentially influences the function of proteins. Kurtovic et al. investigated the occurrence of differential splicing in the TGFβ pathway associated with TAA in patients with bicuspid (BAV) and tricuspid (TAV) aortic valve. Using Affymetrix Human Exon arrays and multivariate techniques, they demonstrated that the two different types of aorta tissues, dilated and non-dilated show different alternative splicing patterns in TGFβ pathway with respect to TAV and BAV. Their results indicate that dilatation in patients with TAV has different underlying molecular mechanisms compared with BAV patients.
Page 665l View article: PDF (2.5 MB)
Supplementary Data View article: PDF (1.4 MB)

A Superagonistic Monoclonal Antibody for CD28 Ameliorates Crescentic Glomerulonephritis in Wistar-Kyoto Rats
Yoshitsugu Takabatake, Xiao-Kang Li, Masayuki Mizui, Kenro Miyasato, Isao Matsui, Noritaka Kawada, Enyu Imai, Thomas Hünig, Shiro Takahara, Takashi Wada, Kengo Furuichi, Hiromi Rakugi, and Yoshitaka Isaka
Regulatory T (Treg) cells play an important role in the resolution of crescentic lomerulonephritis (GN), therefore, agents that increase Treg cells appear to be ideal for suppressing T-cell-mediated renal pathology. Takabatake et al. hypothesized that a superagonistic monoclonal antibody for CD28 (CD28-SA) which has been known to preferentially expand Treg cells in vivo, could prevent nephrotoxic serum-induced crescentic GN. Administration of CD28-SA attenuated crescent formation, proteinuria, and glomerular accumulation of macrophages and CD8+ T cells. These changes were accompanied by increased infiltration of Treg cells. This study demonstrates treatment with CD28-SA has a dramatic therapeutic effect on an experimental crescentic GN, potentially due to expansion and activation of Treg cells.
Page 686 l View article: PDF (5.8 MB)

Interleukin (IL)-10 Induced by CD11b+ Cells and IL-10-Activated Regulatory T Cells Play a Role in Immune Modulation of Mesenchymal Stem Cells in Rat Islet Allografts
Yang-Hee Kim, Yu-Mee Wee, Monica-Y Choi, Dong-Gyun Lim, Song-Cheol Kim, and Duck-Jong Han
Mesenchymal stem cells (MSCs) have been suggested as immune modulators because of their therapeutic potential in transplantation. MSCs have also been proposed as treatments for autoimmune diseases, such as diabetes, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. In this work, Kim et al. evaluated the therapeutic potential of autologous MSCs in the prevention of graft rejection after allogeneic islet transplantation. The authors assessed the ability of MSCs to elicit an antiproliferative response in alloreactive lymphocytes and tested the immunosuppressive effect of MSCs in allogeneic islet transplantation. Results indicate the combined use of autologous MSCs and cyclosporine A exert a synergistic immunosuppressive effect which prolongs graft survival. This suggests a role for autologous MSCs as immune modulators and may suggest a new strategy for preventing and treating rejection after transplantation.
Page 697 l View article: PDF (2.5 MB)

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis
Lei Jiang, Yiu-Kay Lai, Jinfang Zhang, Hua Wang, Marie CM Lin, Ming-liang He, and Hsiang-fu Kung
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Protein S100P has been found to be overexpressed in a number of cancers including CRC and is considered a potential target for cancer therapy. The functional role and mechanism of action of S100P are not fully understood. Here, Jiang et al. use in vitro and in vivo methods to investigate this mechanism. Their results suggest S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P may contribute to a further understanding of the downstream signaling cascade of S100P. These findings highlight new therapeutic targets for colon cancer treatment.
Page 709 l View article: PDF (2.5 MB)

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria
Constance AM Finney, Cheryl A Hawkes, Dylan C Kain, Aggrey Dhabangi, Charles Musoke, Christine Cserti-Gazdewich, Tamas Oravecz, W Conrad Liles, and Kevin C Kain
Cerebral malaria (CM) is a life-threatening complication resulting from Plasmodium falciparum infection which is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid that regulates several cellular processes affected by CM, including inflammation and vascular endothelial homeostasis. Here, Finney et al. test whether S1P signaling is affected during malarial infection in a manner that deleteriously impacts host immune responses. Median plasma S1P levels were significantly decreased in Ugandan children with CM compared to children with uncomplicated malaria. Similarly, in an experimental model, improved outcome was observed in animals with diminished S1P-degrading enzyme activity. S1P levels were associated with improved outcome. Increased survival was also observed when an S1P receptor modulator was administered. Data indicates that these treatments preserve blood-brain barrier and endothelium integrity. These results suggest treatment approaches to enhance S1P-mediated activity may have potential clinical utility as adjunctive therapeutic strategies for individuals with malaria.
Page 717 l View article: PDF (958 KB)
Supplementary Data View article: PDF (504 KB)

Altered Methylation at MicroRNA-Associated CpG Islands in Hereditary and Sporadic Carcinomas: A Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)-Based Approach
Walter Pavicic, Esa Perkiö, Sippy Kaur, and Päivi Peltomäki
MicroRNAs (miRNAs) are small noncoding RNAs that contribute to tumorigenesis by acting as oncogenes or tumor suppressor genes and may be important in the diagnosis, prognosis and treatment of cancer. Many miRNA genes have associated CpG islands, suggesting epigenetic regulation of their expression. Pavicic et al. examined over 150 patients from gastrointestinal and endometrial carcinomas to examine how methylation profiles apply to miRNA loci in cancer. The authors showed both hypermethylation and hypomethylation at classical tumor suppressor promoter in the same tumors. Methylation alterations at miRNA-associated CpG islands may have widespread biological and clinical significance.
Page 726 l View article: PDF (2.1 MB)
Supplementary Data View article: PDF (1.6 MB)

Brown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21
Dionysios V Chartoumpekis, Ioannis G Habeos, Panos G Ziros, Agathoklis I Psyrogiannis, Venetsana E Kyriazopoulou, and Athanasios G Papavassiliou
Fibroblast growth factor-21 (FGF21) is a protein involved in energy homeostasis and is mainly expressed in liver and adipose tissue. Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. While FGF21 is reportedly expressed in BAT, its role in metabolism has not been investigated. In this work, Chartoumpekis et al. examine the role of FGF21 in BAT and show both short-term exposure to the cold, as well as β3-adrenergic stimulation, cause significant induction of FGF21 mRNA in BAT. These initial findings may open the door to future therapeutics targeting FGF21 expression and BAT thermogenesis.
Page 736 l View article: PDF (225 KB)

Kinase Activity Profiling of Gram-Negative Pneumonia
Arie J Hoogendijk, Sander H Diks, Maikel P Peppelenbosch, Tom van der Poll, and Catharina W Wiel
Pneumonia is a severe disease associated with high morbidity and mortality. A major causative pathogen of pneumonia is the Gram-negative bacterium Klebsiella pneumoniae (K. pneumoniae). In this work, Hoogendijk et al. explore the signal transduction and kinase activities of K. pneumoniae using a systems biology approach and a kinase activity array. The authors identified and validated activity patterns of classic immune related kinases, such as p38 and p42 as well as other key regulators of cellular responses. This study suggests a role for SRC kinase in pneumonia and delineates a potential link of AKT and PKA with inflammatory responses. Kinase activity profiling may reveal new functional and pathogenetic mechanisms involved during various stages of pneumonia.
Page 741 l View article: PDF (1.4 MB)

Congenital Erythropoietic Porphyria: Characterization of Murine Models of the Severe Common (C73R/C73R) and Later-Onset Genotypes
David F Bishop, Sonia Clavero, Narla Mohandas, and Robert J Desnick
Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder of heme biosynthesis resulting from insufficient uroporphyrinogen III synthase (UROS) activity. Bishop et al. generated and characterized UROS knock-in models for several UROS mutations, including the most common mutation that causes CEP, C73R/C73R. Homozygous C73R mice were characterized clinically, biochemically and hematologically. The C73R/C73R mice had less than 1% residual UROS activity and severe hemolytic anemia, whereas the C73R/V99L mice, that had 10–15% residual UROS activity, were only mildly anemic. These data suggest that improving UROS activity by 10-15% may be sufficient to reverse pathology in human CEP patients.
Page 748 l View article: PDF (5.6 MB)

Fibrinogen Availability and Coagulation Function after Hemorrhage and Resuscitation in Pigs
Wenjun Z Martini
Hemorrhagic coagulopathy, a blood clotting disorder, accounts for up to 40% of deaths in both civilian and military hospitals. Coagulation involves complex interactions and the underlying mechanisms remain unclear. In this work, Dr. Martini examines coagulation function at various time points using an experimental model of hemorrhage and resuscitation. Results show hemorrhage compromises platelet counts, clot strength and fibrinogen levels. However, 24 hours after hemorrhage and resuscitation, fibrinogen levels increased and contributed to restoration of clot strength despite a sustained platelet deficit. This work demonstrates the potential role of fibrinogen in restoring coagulation function in vivo.
Page 757 l View article: PDF (147 KB)

Chemokine Expression by Small Sputum Macrophages in COPD
Marion Frankenberger, Christiane Eder, Thomas PJ Hofer, Irene Heimbeck, Kerstin Skokann, Gudrun Kaßner, Norbert Weber, Winfried Möller, and Loems Ziegler-Heitbrock
Small sputum macrophages represent highly active cells that increase in the airways in patients with inflammatory diseases like chronic obstructive pulmonary disease (COPD). It has often been reported that levels of cytokines, chemokines and proteases are increased in sputum supernatants of these patients. In COPD the small sputum macrophages may contribute to these supernatant proteins and recruit additional cells via specific chemokine expression patterns. Frankenberger et al. investigated the expression profile of chemokines in sputum macrophages obtained from COPD patients in comparison to cells from healthy donors and cells isolated after inhalation of lipolysaccharide (LPS). Results suggest an increase in small sputum macrophages in COPD patients, in asymptomatic smokers and after LPS inhalation in healthy volunteers. This indicates that small sputum macrophages may have different properties dependent on the circumstance of their induction.
Page 762 l View article: PDF (401 KB)
Supplementary Data View article: PDF (225 KB)

High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes
Cheng-Che E Lan, Ching-Shuang Wu, Shu-Mei Huang, Hsuan-Yu Kuo, I-Hui Wu, Chien-Hui Wen, Chee-Yin Chai, Ai-Hui Fang, and Gwo-Shing Chen
Diabetes mellitus (DM) patients suffer complications that include increased rates of skin infections, which are linked with elevated plasma glucose levels. This hyperglycemia effects the physiologic functions of keratinocytes, the immune competent cells forming the outermost layer of the skin. As a result, the body may be less capable of warding off microbial invasion. Lan et al. explored the effects of a high glucose environment on the innate immunity of keratinocytes by focusing on beta defensin-3 (BD3) using in vivo and in vitro approaches. The authors demonstrate that the perilesional skins of diabetic rats did not show enhanced BD3 expression after wounding. Further, high glucose treatment reduced human BD3 (hBD3) expression in cultured human keratinocytes. Together these data implicate glucose-induced downregulation of BD3 in the blunted response to wounding in patients with DM.
Page 771 l View article: PDF (1.7 MB)
Supplementary Data View article: PDF (33 KB)

Strain Differences in Alveolar Neutrophil Infiltration and Macrophage Phenotypes in an Acute Lung Inflammation Model
Yinzhong Zhang, Xinchun Lin, Kiyokazu Koga, Koichiro Takahashi, Helena M Linge, Adriana Mello, Teresina Laragione, Percio S Gulko, and Edmund J Miller
Pulmonary infection is a major cause of mortality and morbidity, and the magnitude of lung inflammation correlates with patient survival. Neutrophils are critical to the pathogenesis of acute lung injury and their migration into joints is regulated by arthritis severity quantitative trait loci (QTLs). However, it is unclear whether these QTLs contribute to the regulation of lung inflammation in pneumonias. Zhang et al. examined two experimental models, which differ in these QTLs and susceptibility to joint inflammation, and found there are significant differences in the regulation of pulmonary inflammation induced by bacterial products. These differences are associated with different alveolar macrophage phenotypes, specifically differences in MAPK signaling pathways. Their data may lead to understanding of the compartmentalization of the lung inflammatory response and tissue-specific regulation of the immune responses.
Page 780 l View article: PDF (1 MB)

Widespread Deregulation of Phosphorylation-Based Signaling Pathways in Multiple Myeloma Cells: Opportunities for Therapeutic Intervention
Gwenny Manel Fuhler, Sander Henricus Diks, Maikel Petrus Peppelenbosch, and William Garrow Kerr
Multiple myeloma (MM) is a malignancy of plasma cell origin that is largely confined to the bone marrow (BM). MM leads to renal failure, hypercalcemia and skeletal destruction resulting in a median length of survival at diagnosis of only 3-5 years. Research indicates that phosphorylation of proteins plays a pivotal role in cell growth and survival. Therefore, knowing the status of phosphorylation based signaling pathways in MM cells could provide critical information for understanding MM cell survival. Here, Fuhler et al. developed a strategy to detect enzymatic activities for the phosphorylation of different kinase substrates and applied it to primary MM isolates. The MM phosphoproteome and their normal plasma cell counterparts proved to be significantly different. Fuhler et al. used these differences to propose two therapeutic applications that target specific proteins and deregulated kinases. Such therapies may increase the survival rate for patients suffering from this deadly blood cancer.
Page 790 l View article: PDF (1.9 MB)
Supplementary Data View article: PDF (1.8 MB)

All-trans Retinoic Acid Upregulates Reduced CD38 Transcription in Lymphoblastoid Cell Lines from Autism Spectrum Disorder
Mathias Riebold, David Mankuta, Elad Lerer, Salomon Israel, Songfa Zhong, Luba Nemanov, Mikhail V Monakhov, Shlomit Levi, Nurit Yirmiya, Maya Yaari, Fabio Malavasi, and Richard P Ebstein
Deficits in social behavior associated with autistic spectrum disorder (ASD) have been connected to specific variants of CD38. CD38 transcription is highly sensitive to several cytokines and vitamins such as ATRA, and here Riebold et al. demonstrate that retinoids may play a beneficial role in the treatment of ASD. The authors explore an in vitro model in which ATRA is applied to lymphoblastoid cell (LBC) lines from ASD patients, which show reduced CD38 mRNA levels, and their parents. They showed that the addition of this retinoid increases CD38 transcription to normal levels in these cells, suggesting a novel approach for ASD treatment. In light of this work, CD38 may prove important in the diagnosis and therapy of ASD.
Page 799 l View article: PDF (401 KB)

High Mobility Group Protein B1 (HMGB1) in Asthma: Comparison of Patients with Chronic Obstructive Pulmonary Disease and Healthy Controls
Changchun Hou, Haijin Zhao, Laiyu Liu, Wenjun Li, Xiaoting Zhou, Yanhua Lv, Xiangbo Shen, Zhenyu Liang, Shaoxi Cai, and Fei Zou
Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway diseases characterized by chronic inflammation of the respiratory tract. High mobility group protein B1 (HMGB1) has been implicated as an important mediator in the pathogenesis of both of these conditions. However, HMGB1 expression in asthma and COPD patient serum and sputum have not been characterized. In this study, Hou et al. examined sputum and plasma concentrations of HMGB1 in COPD and asthmatic patients with varying disease severity. HMGB1 sputum and plasma concentrations in asthma and COPD were significantly higher compared with control subjects, and were negatively correlated with forced expiratory volume 1 s (FEV1), FEV1 (% predicted). HMGB1 sputum level in COPD patients was significantly higher than those of asthma patients. HMGB1 levels in asthmatic and COPD patients were positively correlated with neutrophil counts and percentage of neutrophils. These data support a potential role for HMGB1 as a biomarker and diagnostic tool for the differential diagnosis of asthma and COPD.
Page 807 l View article: PDF (680 KB)

Asporin Expression Is Highly Regulated in Human Chondrocytes
Elise Duval, Nicolas Bigot, Magalie Hervieu, Ikuyo Kou, Sylvain Leclercq, Philippe Galéra, Karim Boumediene, and Catherine Baugé
Osteoarthritis (OA), the most prevalent form of skeletal disease, is characterized by joint cartilage degeneration. Despite its frequency, the details of OA etiology and pathogenesis remain unclear. A genetic association between the cartilage extracellular matrix protein asporin (ASPN) and OA has been reported. In order to further understand the role of ASPN in OA, Duval et al. investigated ASPN expression in human articular chondrocytes (HAC). Results show proinflammatory cytokines downregulated ASPN, while TGFβ1 upregulated it. Additionally, the authors propose a role for the transcription factor Sp1 in the regulation of ASPN expression. These results indicate ASPN is finely regulated in cartilage and suggest a key role for Sp1 in chondrocytes.
Page 816 l View article: PDF (2.4 MB)

Molecular Pathways Differentiate Hepatitis C Virus (HCV) Recurrence from Acute Cellular Rejection in HCV Liver Recipients
Ricardo Gehrau, Daniel Maluf, Kellie Archer, Richard Stravitz, Jihee Suh, Ngoc Le, and Valeria Mas
Liver transplantation (LT) is the chosen treatment for patients with advanced liver disease and cirrhosis. Acute cellular rejection (ACR) and hepatitis C virus (HCV) infection recurrence (HCVrec) are common complications post-liver transplantation (LT) in HCV patients. ACT and HCVrec both share common clinical and histological features, increasing difficulty in the differential diagnosis. ACR rate after LT is especially controversial in HCV positive recipients because of the overlapping clinical and histological features with HCVrec. Despite some promising results, reliable diagnostic biomarkers are still lacking. Gehrau et al. investigated differential gene expression, using microarrays in liver samples from HCV transplant recipients with HCVrec disease, and ACR in the setting of HCV infection. The study identified and validated four differentially expressed genes as potential biomarkers for differential diagnosis of both complications, HCVrec and ACR.
Page 824 l View article: PDF (1.2 MB)
Supplementary Data View article: PDF (188 KB)

Intraclonal Cell Expansion and Selection Driven by B Cell Receptor in Chronic Lymphocytic Leukemia
Monica Colombo, Giovanna Cutrona, Daniele Reverberi, Sonia Fabris, Antonino Neri, Marina Fabbi, Giovanni Quintana, Giovanni Quarta, Fabio Ghiotto, Franco Fais, and Manlio Ferrarini
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and is characterized by monoclonal accumulation in the blood and peripheral lymphoid organs. Evidence indicates that antigens may play a fundamental role in expanding B cells prior to transformation and in sustaining survival/expansion of cells in the early steps of leukemogenesis, when they are not capable of independent growth. However, whether antigenic stimulation or selection contributes to the expansion of fully transformed CLL clones is unknown. In this work, Colombo et al. provide evidence of fully transformed CLL cells utilizing the process of antigenic stimulation that may lead to clonal expansion. The special features of this CLL case support the notion that antigenic stimulation continues after the process of leukemogenesis is completed and leads to the selective expansion of subclones. Further understanding this mechanism may lead to future treatment options for CLL.
Page 834 l View article: PDF (758 KB)

Adipose and Liver Expression of Interleukin (IL)-1 Family Members in Morbid Obesity and Effects of Weight Loss
Alexander R Moschen, Clemens Molnar, Barbara Enrich, Sabine Geiger, Christoph F Ebenbichler, and Herbert Tilg
Morbid obesity is associated with a state of chronic inflammation. Members of the Interleukin-1 cytokine family (IL-1F) are produced by human adipose tissue in obesity and many IL-1F members act in an antiinflammatory manner. Moschen et al. investigate over 20 severely obese patients undergoing laparoscopic adjustable gastric banding to understand the effect excessive weight loss may have on subcutaneous adipose tissue and liver expression of cytokines. Results suggest excessive weight loss significantly affects expression of IL-1F members in adipose and liver tissue, thereby potentially contributing to the improvement of insulin resistance and inflammation in our patients. Targeting proinflammatory cytokines might reveal an attractive treatment concept in obesity related inflammatory disorders.
Page 840 l View article: PDF (492 KB)
Supplementary Data View article: PDF (66 KB)

Review Articles

Regulation of Male Fertility by the Opioid System
Nerea Subirán, Luis Casis, and Jon Irazusta
Endogenous opioid peptides are substances involved in cell communication. They are present in various organs and tissues of the male and female reproductive tract. Recent studies suggest the opioid system can participate in the regulation of reproductive physiology at multiple levels. A better understanding of the implications of the opioid system in reproductive processes may contribute to clarifying the etiology of many cases of infertility, and the effect of opiate abuse on fertility. Subiran et al. reviewed current knowledge regarding the role of the opioid system in male fertility. Additionally, the authors suggest that novel biochemical tool for the diagnosis and treatment of male infertility could be based on components of the opioid system.
Page 846 l View article: PDF (684 KB)

Poly(ADP-Ribose) Polymerase-1 Inhibition: Preclinical and Clinical Development of Synthetic Lethality
Mary Leung, David Rosen, Scott Fields, Alessandra Cesano, and Daniel R Budman
The BRCA genes are commonly linked with hereditary breast and ovarian cancers with a potential lifetime risk as high as 50% and 40% respectively. Hereditary breast cancers linked to these genes exhibit defective homologous DNA repair (HR) and patients with either BRCA-1 or BRCA-2 defective genes have genomic instability. As a result, the cell depends on alternate DNA repair processes, such as base excision repair (BER), which requires Poly(ADP-ribose) polymerase 1 (PARP-1). In this review, Leung et al. discuss the current state of PARP-1 understanding and suggest ways in which inhibition of this gene may contribute to enhanced efficacy of a wide range of chemotherapeutics.
Page 854 l View article: PDF (1 MB)