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Long Shen - Top 30 Publications

Systemic manifestations of primary Sjögren's syndrome in the NOD.B10Sn-H2(b)/J mouse model.

Animal models that recapitulate human disease are crucial for the study of Sjögren's Syndrome (SS). While several SS mouse models exist, there are few primary SS (pSS) models that mimic systemic disease manifestations seen in humans. Similar to pSS patients, NOD.B10Sn-H2(b)/J (NOD.B10) mice develop exocrine gland disease and anti-nuclear autoantibodies. However, the disease kinetics and spectrum of extra-glandular disease remain poorly characterized in this model. Our objective was to characterize local and systemic SS manifestations in depth in NOD.B10 female mice at early and late disease time points. To this end, sera, exocrine tissue, lung, and kidney were analyzed. NOD.B10 mice have robust lymphocytic infiltration of salivary and lacrimal tissue. In addition, they exhibit significant renal and pulmonary inflammation. We identified numerous autoantibodies, including those directed against salivary proteins. In conclusion, the NOD.B10 model recapitulates both local and systemic pSS disease and represents an excellent model for translational studies.

JMJD3 suppresses stem cell-like characteristics in breast cancer cells by downregulation of Oct4 independently of its demethylase activity.

Epigenetic regulator JMJD3 plays an important role in both tumor progression and somatic cell reprogramming. Here, we explored the effect of JMJD3 on the stem cell-like characteristics of breast cancer and its underlying mechanism involving stemness-related transcription factor Oct4. Our data revealed that, in breast cancer cells lines and an orthotopic xenograph mouse model of breast cancer, ectopic overexpression of JMJD3 suppressed stem cell-like characteristics of breast cancer cells, whereas knockdown of JMJD3 promoted these characteristics. Oct4 mediated the suppressive effects of JMJD3 on the stemness of breast cancer cells. The inhibitory effect of JMJD3 on Oct4 was independent of demethylase activity, but mediated via degradation of PHF20. Furthermore, we applied an agonist of the vitamin D receptor, paricalcitol, and found that it induced JMJD3 in breast cancer cells. Our data showed that administration of paricalcitol suppressed stem cell-like characteristics and Oct4 expression. Taken together, JMJD3 inhibits the stem cell-like characteristics in breast cancer by suppression of stemness factor Oct4 in a PHF20-dependent manner. Administration of paricalcitol leads to upregulation of JMJD3 that suppresses Oct4 expression and the stem cell-like characteristics in breast cancer.

Evaluation of Autoantibodies in Patients with Primary and Secondary Sjogren's Syndrome.

Antibodies to salivary gland protein 1 (SP1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) were discovered in an animal model of Sjogren's syndrome (SS). Their expression was noted in patients with SS, especially those with lower focus scores on lip biopsies and those with early disease lacking antibodies to Ro and La.

Autoantibodies, detection methods and panels for diagnosis of Sjögren's syndrome.

The presence of autoantibodies is one of several hallmarks of Sjögren's Syndrome, the detection of serum autoantibodies has a central role in the diagnosis and classification of Sjögren's syndrome. In this review, we will discuss autoantibodies that are helpful in the diagnosis of Sjögren's syndrome. This includes the traditional autoantibodies for disease classification (ANA, Anti-Ro/SSA, Anti-La/SSB, RF), autoantibodies identified from mouse models (Anti-SP1, Anti- PSP, Anti-CA6, and anti-alpha fodrin) and autoantibodies associated with other autoimmune disease (ACA, AMA, and Anti-CCP). We will also review the methods for the detection of autoantibodies and associated challenges for clinical results reporting. The significance of using an autoantibody panel for the diagnosis of SS will be also be reviewed.

Several microRNAs could predict survival in patients with hepatitis B-related liver cancer.

MicroRNAs as biomarkers play an important role in the tumorigenesis process, including hepatocellular carcinomas (HCCs). In this paper, we used The Cancer Genome Atlas (TCGA) database to mine hepatitis B-related liver cancer microRNAs that could predict survival in patients with hepatitis B-related liver cancer. There were 93 cases of HBV-HCC and 49 cases of adjacent normal controls included in the study. Kaplan-Meier survival analysis of a liver cancer group versus a normal control group of differentially expressed genes identified eight genes with statistical significance. Compared with the normal liver cell line, hepatocellular carcinoma cell lines had high expression of 8 microRNAs, albeit at different levels. A Cox proportional hazards regression model for multivariate analysis showed that four genes had a significant difference. We established classification models to distinguish short survival time and long survival time of liver cancers. Eight genes (mir9-3, mir10b, mir31, mir519c, mir522, mir3660, mir4784, and mir6883) were identified could predict survival in patients with HBV-HCC. There was a significant correlation between mir10b and mir31 and clinical stages (p < 0.05). A random forests model effectively estimated patient survival times.

Analysis of novel Sjogren's syndrome autoantibodies in patients with dry eyes.

Dry eye is a common problem in Ophthalmology and may occur for many reasons including Sjogren's syndrome (SS). Recent studies have identified autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and anti-parotid secretory protein (PSP), which occur early in the course of SS. The current studies were designed to evaluate how many patients with idiopathic dry eye and no evidence of systemic diseases from a dry eye practice have these autoantibodies.

M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma.

Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL.

Central role for marginal zone B cells in an animal model of Sjogren's syndrome.

Patients with Sjogren's syndrome (SS) have been shown to have abnormal B cell function and increased numbers of marginal zone B cells (MZB and MZB precursors. The current studies utilized the Interleukin 14 alpha transgenic mouse model (IL14aTG) for SS to investigate the roles of marginal zone B cells (MZB) of the innate immune system in the pathophysiology of the disease. Eliminating MZB from IL14aTG mice by B cell specific deletion of RBP-J resulted in complete elimination of all disease manifestations of SS. Mice had normal salivary gland secretions, negative autoantibodies and normal histology of the salivary and lacrimal glands compared to IL14aTG mice at the same time points. In contrast, eliminating B1 cells by deleting btk did not ameliorate the disease. Therefore, MZB are critical for the development of SS.

JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms.

JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo, treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes.

IP3R deficit underlies loss of salivary fluid secretion in Sjögren's Syndrome.

The autoimmune exocrinopathy, Sjögren's syndrome (SS), is associated with secretory defects in patients, including individuals with mild lymphocytic infiltration and minimal glandular damage. The mechanism(s) underlying the secretory dysfunction is not known. We have used minor salivary gland biopsies from SS patients and healthy individuals to assess acinar cell function in morphologically intact glandular areas. We report that agonist-regulated intracellular Ca(2+) release, critically required for Ca(2+) entry and fluid secretion, is defective in acini from SS patients. Importantly, these acini displayed reduction in IP3R2 and IP3R3, but not AQP5 or STIM1. Similar decreases in IP3R and carbachol (CCh)-stimulated [Ca(2+)]i elevation were detected in acinar cells from lymphotoxin-alpha (LTα) transgenic (TG) mice, a model for (SS). Treatment of salivary glands from healthy individuals with LT α, a cytokine linked to disease progression in SS and IL14α mice, reduced Ca(2+) signaling. Together, our findings reveal novel IP3R deficits in acinar cells that underlie secretory dysfunction in SS patients.

Inflammatory Joint Diseases.

Investigation of novel autoantibodies in Sjogren's syndrome utilizing Sera from the Sjogren's international collaborative clinical alliance cohort.

Sjogren's syndrome (SS) is a chronic autoimmune disease mainly affecting salivary and lacrimal glands. Current diagnostic criteria for SS utilize anti-Ro and anti-La as serological markers. Animal models for SS have identified novel autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These novel antibodies are seen in the animals at an earlier stage of SS than anti-Ro and anti-La. The current studies were designed to evaluate these novel autoantibodies in the sera of well-characterized patients with dry eyes and dry mouth and lip biopsies from the Sjogren's International Collaborative Clinical Alliance (SICCA) to determine if they indeed identify SS with less severe disease than patients expressing anti-Ro and anti-La.

Update on the use of biologics in vasculitides.

Vasculitides are disease in which injury to blood vessels leads to various degrees and types of organ dysfunction. They are subdivided into different groups dependent on the size of blood vessels involved as well as other particular clinical features. Therapy is dependent upon the size of the blood vessels involved and the nature of the disease. For medium and large vessel vasculitides, glucocorticoids, cyclophosphamide, azathioprine and methotrexate have been the mainstay for induction and maintenance of remission. Because of potential for side effects from standard therapies, various biologic agents have been evaluated in the treatment of ANCA positive vasculitis (AAV), cryoglobulinemic vasculitis, Behcet's disease and Takayasu's Arteritis (TAK). In this article, we present a review on biologic agents used in various vasculitides.

Biologics in systemic sclerosis.

Systemic sclerosis (scleroderma) is a heterogeneous autoimmune disorder characterized by collagen overproduction that leads to cutaneous and internal organs sclerosis and pulmonary arterial hypertension. SSc has high morbidity and mortality. SSc pathogenesis is uncertain. At present most therapies of SSc are symptomatic. Effective therapeutic approaches are lacking. Accompanying a growing understanding of SSc pathogenesis, various key mediators are being evaluated as the therapeutic targets. This review described the effects of these key mediators in SSc.

Evaluation of salivary gland protein 1 antibodies in patients with primary and secondary Sjogren's syndrome.

Sjogren's syndrome (SS) has been associated with the expression of anti-Ro and anti-La antibodies. Anti-salivary gland protein 1 (SP1) antibodies have recently been identified in patients with SS. The current work involved a cross sectional study to determine whether anti-SP1 antibodies were identified in particular subgroups of patients with SS. The results of this study revealed that anti-SP1 antibodies were present in the sera of 52% of SS patients while anti-Ro/anti-La was present in 63% of patients. 19% of patients had anti-SP1 without anti-Ro/anti-La. Patients with SS and lymphoma expressed anti-Ro, anti-La and anti-SP1 together. In SS associated with RA, 50% had antibodies anti-SP1 while 40% had anti-Ro/anti-La. In conclusion, anti-SP1 antibodies are commonly seen in both primary and secondary SS and rarely in normal controls. Future studies are needed to determine the roles and timing of expression of anti-SP1 antibodies in Sjogren's syndrome.

Update on the use of biologics in lupus.

Systemic lupus erythematosus is more than a heterogeneous autoimmune disease. It is in fact a syndrome of many different clinical genotypes and phenotypes. This review covers the most recently studied monoclonal antibodies and those currently being investigated. The key trials are summarized, including those for biologics on the market for two decades and those just approved for lupus less than two years ago. The focus will be on the following four: Rituximab, Abatacept, Belimumab, and Epratuzumab. It is a challenge to design the perfect trial and study patients with this disease as each has his or her own unique manifestations, biological markers, and underlying genetic background. However, as our understanding of the immune mechanisms involved in lupus increases; novel therapies will emerge that can be utilized for appropriately selected patients.

Xerophthalmia of Sjogren's Syndrome Diagnosed with Anti-Salivary Gland Protein 1 Antibodies.

The purpose of this report is to describe 2 patients with persistent severe dry eyes, positive Schirmer tests for Sjogren's syndrome (SS) but lacking antibodies to either Ro or La. These patients were diagnosed to have SS by detecting antibodies to salivary gland protein 1 (Sp1) and parotid secretory protein (PSP). This report emphasizes the existence of patients with SS who lack antibodies to either Ro or La and may therefore be misdiagnosed. Detection of novel autoantibodies, including antibodies to Sp1 and PSP, are helpful in identifying these patients. Initial presentation may simply be dry eyes.

Overexpression of Oct4 suppresses the metastatic potential of breast cancer cells via Rnd1 downregulation.

Although Oct4 is known as a critical transcription factor involved in maintaining "stemness", its role in tumor metastasis is still controversial. Herein, we overexpressed and silenced Oct4 expression in two breast cancer cell lines, MDA-MB-231 and 4T1, separately. Our data showed that ectopic overexpression of Oct4 suppressed cell migration and invasion in vitro and the formation of metastatic lung nodules in vivo. Conversely, Oct4 downregulation increased the metastatic potential of breast cancer cells both in vitro and in vivo. Furthermore, we identified Rnd1 as the downstream target of Oct4 by ribonucleic acid sequencing (RNA-seq) analysis, which was significantly downregulated upon Oct4 overexpression. Chromatin immunoprecipitation assays revealed the binding of Oct4 to the promoter region of Rnd1 by ectopic overexpression of Oct4. Dual luciferase assays indicated that Oct4 overexpression suppressed transcriptional activity of the Rnd1 promoter. Moreover, overexpression of Rnd1 partially rescued the inhibitory effects of Oct4 on the migration and invasion of breast cancer cells. Overexpression of Rnd1 counteracted the influence of Oct4 on the formation of cell adhesion and lamellipodia, which implied a potential underlying mechanism involving Rnd1. In addition, we also found that overexpression of Oct4 led to an elevation of E-cadherin expression, even in 4T1 cells that possess a relatively high basal level of E-cadherin. Rnd1 overexpression impaired the promoting effects of Oct4 on E-cadherin expression in MDA-MB-231 cells. These results suggest that Oct4 affects the metastatic potential of breast cancer cells through Rnd1-mediated effects that influence cell motility and E-cadherin expression.

Anti-salivary gland protein 1 antibodies in two patients with Sjogren's syndrome: two case reports.

Current diagnostic criteria for Sjogren's syndrome developed by the American College of Rheumatology include the presence of antinuclear antibodies, rheumatoid factor, anti-Ro or anti-La autoantibodies. The purpose of this report is to describe two patients with biopsy-proven Sjogren's syndrome lacking these autoantibodies but identified by antibodies to salivary gland protein 1. Diagnosis was delayed until salivary gland tumors developed in these patients because of the lack of the classic autoantibodies. This report emphasizes the existence of patients with primary Sjogren's syndrome who lack autoantibodies anti-Ro or anti-La and may therefore be misdiagnosed. Antibodies to salivary gland protein 1 identify some of these patients.

Temporal histological changes in lacrimal and major salivary glands in mouse models of Sjogren's syndrome.

Evidence in imaging studies suggests that there may be differences in glandular involvement in Sjogren's syndrome (SS) depending on the stage of the disease. No detailed histological studies are available to show if there are any such difference in glandular involvement at various time periods and stages of SS. This cross sectional study examines the inflammatory changes in mouse models of SS at various ages.

Different stages of primary Sjogren's syndrome involving lymphotoxin and type 1 IFN.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR(-/-)) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR(-/-) mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR(-/-) mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR(-/-) mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.

Novel autoantibodies in Sjogren's syndrome.

Sjogren's syndrome (SS) is defined by autoantibodies to Ro and La. The current studies identified additional autoantibodies in SS to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP). These autoantibodies were present in two animal models for SS and occurred earlier in the course of the disease than antibodies to Ro or La. Patients with SS also produced antibodies to SP-1, CA6 and PSP. These antibodies were found in 45% of patients meeting the criteria for SS who lacked antibodies to Ro or La. Furthermore, in patients with idiopathic xerostomia and xerophthalmia for less than 2 years, 76% had antibodies to SP-1 and/or CA6 while only 31% had antibodies to Ro or La. Antibodies to SP-1, CA6 and PSP may be useful markers for identifying patients with SS at early stages of the disease or those that lack antibodies to either Ro or La.

Inhibiting Wipf2 downregulation by transgenic expression of its 3' mRNA-untranslated region improves cytotoxicity and vaccination response.

Lymphocyte activation results in profound changes in the abundance of mRNA transcripts many of which are downregulated. The Wiskott-Aldrich syndrome (WAS) protein (WASP) family is critical for productive T-cell receptor signaling and actin reorganization. The WASP signal pathway includes the WAS/WAS-like (WASL) interacting protein family 2 (WIPF2) gene also known as WIRE/WICH. We show that both human WIPF2 and mouse Wipf2 are mice, alternatively spliced within the 3' untranslated region (3'UTR) resulting in two major transcripts of approximately 4.5 and 6 kb in size. Following T-cell activation, the level of human WIPF2 and mouse Wipf2 mRNA rapidly declines. In mice, this decline is accompanied by a marked reduction in WIPF2 protein levels. Transgenic expression of a 240-bp fragment derived from a highly conserved terminal 3'UTR found within the 6-kb transcript blocks Wipf2 downregulation. These effects may be mediated by competitive inhibition of microinhibitory RNA (miRNA) regulation since the 6-kb-derived transgene and the 4.5-kb transcript share functional binding sites for miRNA146a. Blocking Wipf2 gene and protein repression resulted in improved T-cell responses to antigen immunization in vivo as well as in vitro cytotoxic T-cell killing. Collectively, these data suggest that early downregulation of this immunologically relevant gene controls the intensity of selective lymphocyte functions.

Pharmacoinvasive therapy for ST elevation myocardial infarction in China: a pilot study.

Most patients with acute ST-elevation myocardial infarction (STEMI) cannot receive timely primary percutaneous coronary intervention (PCI) because of lack of facilities or delays in patient transfer or catheterization team mobilization. In these patients, early routine post-thrombolysis PCI might be a reasonable, useful strategy. This study investigated feasibility and safety of early PCI after successful half-dose alteplase reperfusion in a Chinese population. Patients with STEMI received half-dose alteplase if expected time delay to PCI was ≥90 min. Patients who reached clinical criteria of successful thrombolysis reperfusion were recommended to undergo diagnostic angiography within 3-24 h after thrombolysis. Patients with residual stenosis ≥70% in the infarct-related artery underwent PCI, regardless of flow or patency status. Epicardial arterial flow was assessed using thrombolysis in myocardial infarction (TIMI) flow grade and TIMI frame count (CTFC). Myocardial perfusion was assessed using myocardial blush grade (MBG) and TIMI myocardial perfusion frame count (TMPFC). Forty-nine patients were enrolled and underwent diagnostic angiography 3-11.3 h (median 6.5 h) after thrombolysis. Forty-six patients underwent PCI. No procedure-related complications occurred, except two patients who had no reflow after PCI. Twenty-two (47.8%) patients had TIMI grade 3 flow before PCI and 33 (71.7%) after PCI. CTFC was significantly improved after PCI (48.5 ± 32.1 vs. 37.9 ± 25.6, P = 0.01). MBG and TMPFC exhibited a similar improving trend after PCI, and the best myocardial perfusion tended to be achieved 3-12 h after lysis. During the 30-day follow-up, there were two deaths. The composite end point of death, cardiogenic shock, heart failure, reinfarction, and recurrent ischemia occurred in four patients. TIMI minor bleeding occurred in four patients. No TIMI major bleeding and stroke occurred. Early routine PCI after half-dose alteplase thrombolysis in Chinese population appears feasible. A larger clinical trial should be designed to further elucidate its efficacy and safety. Early PCI after thrombolysis in STEMI: The EARLY-PCI pilot feasibility study, ChiCTR-TNC-11001363.

A role for lymphotoxin in primary Sjogren's disease.

The etiology of salivary gland injury in primary Sjögren's disease is not well understood. We have previously described a mouse model of Sjögren's disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren's disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA(-/-) mice, the IL14αTG.LTA(-/-) mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA(-/-) mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA(-/-) mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren's disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren's disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren's disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

TIMI myocardial perfusion frame count: a new method to assess myocardial perfusion and its predictive value for short-term prognosis.

We sought to develop a new quantitative method to evaluate the degree of myocardial perfusion.

Side population of a murine mantle cell lymphoma model contains tumour-initiating cells responsible for lymphoma maintenance and dissemination.

'Cancer stem cells' or 'tumour initiating cells' in B-cell non-Hodgkin lymphomas have not been demonstrated, although some studies focused on other cancer types suggest that such populations exist and represent tumour cells resistant to therapy and involved in relapse. These cells may also represent a putative neoplastic 'cell of origin' in lymphomas, but there is little substantive data to support this suggestion. Using cell lines derived from a recently established murine IL-14alphax c-Myc double transgenic/mantle cell lymphoma-blastoid variant model, heretofore referred to as DTG cell lines, we identified a subset of cells within the side population (SP) with features of 'tumour-initiating cells'. These features include higher expression of ABCG2 and BCL-2, longer telomere length, greater self-renewal ability and higher in vitro clonogenic and in vivo tumorigenic capacities compared with non-SP. In addition, in vitro viability studies demonstrated that the non-SP lymphoma subpopulation has a limited lifespan in comparison with the SP fraction. Syngenic transplant studies showed that non-SP derived tumours, in comparison to the SP-derived tumours, exhibit greater necrosis/apoptosis and less systemic dissemination capability. In conclusion, our data support the interpretation that the DTG SP fraction contains a cell population highly capable of tumour maintenance and systemic dissemination and lends support to the concept that 'tumour-initiating cells' occur in lymphomas.

Lanthanide-organic cation frameworks with zeolite gismondine topology and large cavities from intersected channels templated by polyoxometalate counterions.

A family of organic-inorganic hybrid frameworks, {[Ln(H(2)O)(4)(pdc)](4)} [XMo(12)O(40)].2H(2)O (Ln = La, Ce, and Nd; X = Si and Ge; H(2)pdc = pyridine-2,6-dicarboxylate), have been prepared under hydrothermal conditions and characterized by single crystal X-ray diffraction analyses, elemental analyses, IR, and thermal gravimetric analyses. Single crystal X-ray diffraction reveals that all six compounds are isostructural, and each consists of a zeolite-like four-connected three-dimensional cationic framework {[Ln(H(2)O)(4)(pdc)](4)}(4+) and ball-shaped Keggin type [XMo(12)O(40)](4-) as templates. Interesting channels exist in the cationic framework with the gismondine topology, and these channels intersect each other to form large cavities, which array in a zigzag fashion and are occupied by nanosized [XMo(12)O(40)](4-) counterions. Moreover, these compounds display strong photoluminescent properties in the solid state at room temperature.

IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans.

To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren's syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR. In addition, transgenic IL-14a mice were analyzed from 6 weeks of age to death for both histological and immunological features of Sjögren's disease. Patients with both primary and secondary Sjögren's syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop hypergammaglobulinemia, autoantibodies, infiltration of the parotid glands with lymphocytes, mild immune-complex mediated renal disease and large B cell lymphoma. In this paper we expand these observations to demonstrate that these mice develop all the clinical and immunological features of primary Sjögren's disease in the same relative time frame as patients with primary Sjögren's disease: stage 1-early hypergammaglobulinemia and autoantibody production, stage 2-decreased salivary gland function with early lymphocytic infiltration of the submandibular glands only, but antibody deposition in the submandibular and parotid glands, stage 3-lymphocytic infiltration of the submandibular, parotid and lacrimal glands with B and T lymphocytes and plasma cells along with interstitial lung disease and mild renal disease, and stage 4-large B cell lymphoma. Thus IL-14a is important in the pathophysiology of Sjögren's disease. The IL-14a transgenic mouse is a novel animal model that can be utilized to understand the pathophysiology of Sjögren's disease.

Regulation of human interleukin 14 transcription in vitro and in vivo after renal transplantation.

Alloantibodies and B lymphocytes are felt to contribute in increasingly important ways to the pathogenesis of both acute and chronic allograft injury. The mechanisms that lead to the formation of posttransplant alloantibodies despite immunosuppressive therapy have not been fully elucidated. Interleukin 14 (IL-14) or high molecular weight B cell growth factor secreted by activated T and B cells and follicular dendritic cells promotes B cell growth, survival and memory, and antibody production. The potential role of IL-14 in human transplantation has not been examined.