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BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset
No full textAbstract
Background
B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS.
Methods
Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh).
Results
Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes ( p \u2009<\u20090.01), lower values of BAFF Index (11.9\u2009\ub1\u20096.1 vs 17.5\u2009\ub1\u20095.2, p \u2009<\u20090.01), and higher CSF CXCL13 levels (27.7\u2009\ub1\u200933.5 vs 0.9\u2009\ub1\u20091.5, p \u2009<\u20090.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis ( r \u2009>\u20090.5 and p \u2009<\u20090.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB\u2212 ( p \u2009<\u20090.05) and HC ( p \u2009<\u20090.01), and correlated to CSF CXCL13 concentrations ( r 0.77, p \u2009<\u20090.001).
The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41\u2009\ub1\u20090.1 vs 2.49\u2009\ub1\u20090.1\ua0mm, p \u2009<\u20090.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB\u2212.
Conclusions
The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by ..
Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study
No full textAbstract
Background
To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients.
Methods
A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with \u22652 lines of prior therapies. The primary endpoint was progression-free survival (PFS).
Results
In the phase Ib study, 42 patients took fruquintinib 5\ua0mg for 3\ua0weeks on/1\ua0week off. The median PFS was 5.80\ua0months, and the median overall survival (OS) was 8.88\ua0months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73\ua0months; 95% confidence interval [CI] 2.86\u20135.59) versus placebo plus BSC (0.99\ua0months; 95% CI 0.95\u20131.58); (hazard ratio [HR] 0.30; 95% CI 0.15\u20130.59; P \u2009<\u20090.001). The median OS was 7.72 versus 5.52\ua0months (HR 0.71; 95% CI 0.38\u20131.34). The most common grade 3\u20134 adverse events were hypertension and hand-foot skin reaction.
Conclusions
Fruquintinib showed a significant PFS benefit of 3.7\ua0months in patients with treatment-refractory mCRC. The safety profile was consistent with that of VEGFR tyrosine kinase inhibitors. A randomized phase III confirmatory study in mCRC is underway.
Trial registration
NCT01975077 and NCT0219668
Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism
No full textAbstract
Background
The value of microRNAs (miRNAs) as novel targets for cancer therapy is now widely recognized. However, no information is currently available on the expression/functional role of miRNAs in diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional treatments, for which the development of new therapeutic strategies is urgently needed. Here, we evaluated the expression and biological effects of miR-34a\u2014one of the most widely deregulated miRNAs in cancer and for which a lipid-formulated mimic is already clinically available\u2014in a large cohort of DMPM clinical samples and a unique collection of in house-developed preclinical models, with the aim to assess the potential of a miR-34a-based approach for disease treatment.
Methods
miR-34a expression was determined by qRT-PCR in 45 DMPM and 7 normal peritoneum specimens as well as in 5 DMPM cell lines. Following transfection with miR-34a mimic, the effects on DMPM cell phenotype, in terms of proliferative potential, apoptotic rate, invasion ability, and cell cycle distribution, were assessed. In addition, three subcutaneous and orthotopic DMPM xenograft models were used to examine the effect of miR-34a on tumorigenicity. The expression of miRNA targets and the activation status of relevant pathways were investigated by western blot.
Results
miR-34a was found to be down-regulated in DMPM clinical specimens and cell lines compared to normal peritoneal samples. miR-34a reconstitution in DMPM cells significantly inhibited proliferation and tumorigenicity, induced an apoptotic response, and declined invasion ability, mainly through the down-regulation of c-MET and AXL and the interference with the activation of downstream signaling. Interestingly, a persistent activation of ERK1/2 and AKT in miR-34a-reconstituted cells was found to counteract the antiproliferative and proapoptotic effects of miRNA, yet not affecting its anti-invasive activity.
Conclusions
Our preclinical data showing impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of ..
Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients
No full textAbstract
The determinants of clinical responses after autologous hematopoietic stem cell transplantation (aHSCT) in systemic sclerosis (SSc) are still unraveled. We analyzed long-term immune reconstitution (IR) and T cell receptor (TCR) repertoire diversity in 10 SSc patients, with at least 6\ua0years simultaneous clinical and immunological follow-up after aHSCT. Patients were retrospectively classified as long-term responders (A, n \u2009=\u20095) or non-responders (B, n \u2009=\u20095), using modified Rodnan\u2019s skin score (mRSS) and forced vital capacity (FVC%). All patients had similar severe SSc before aHSCT. Number of reinjected CD34
+
cells was higher in group B versus A ( P \u2009=\u20090.02). Long-term mRSS fall >25% was more pronounced in group A ( P \u2009=\u20090.004), the only to improve long-term FVC% >10% ( P \u2009=\u20090.026). There was an overall trend toward increased of T cell reconstitution in group B versus A. B cells had a positive linear regression slope in group A (LRS\u2009=\u200911.1) and negative in group B (LRS\u2009=\u2009\u221211.6). TCR repertoire was disturbed before aHSCT and the percentage of polyclonal families significantly increased at long-term ( P \u2009=\u20090.046), with no difference between groups. Despite improved skin score after aHSCT in all SSc patients, pretransplant B cell clonal expansion and faster post-transplant T cell IR in long-term non-responder/relapsing patients call for new therapeutic protocols guided by IR analysis to improve their outcome
Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
No full textAbstract
Background
Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option.
Methods
To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry.
Results
One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54\ua0years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients\u2019 age.
Conclusions
In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1
Semaphorin 7A as a potential immune regulator and promising therapeutic target in rheumatoid arthritis
No full textAbstract
Background
Semaphorin 7A (Sema7A) is expressed by several different classes of lymphoid and myeloid cells and is a potent immunomodulator. We examined the role of Sema7A in modulating cellular immune responses and to provide experimental data validating the therapeutic potential of Sema7A in rheumatoid arthritis (RA).
Methods
Soluble Sema7A (sSema7A) levels in the serum and synovial fluid from patients with RA or osteoarthritis, as well as cytokine secretions, were analyzed with an enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema7A were evaluated in T cells and monocytes from patients with RA. The effect of Sema7A on the functions of primary T cells isolated from the peripheral blood of healthy donors was observed. Detection of the activation of the signal mediator focal adhesion kinase was performed by Western blotting. Shedding of sSema7A was evaluated in monocytes. The introduction of anti-Sema7A antibody to mice with collagen-induced arthritis (CIA) was observed in vivo.
Results
Upregulation of sSema7A levels in both the serum and synovial fluid of patients with RA was correlated with disease activity markers. sSema7A markedly increased Th1/Th17 cytokine secretion and induced evident upregulation of T-bet and retinoic acid receptor-related orphan nuclear receptor \u3b3t levels in T cells. Cell surface Sema7A was cleaved by a disintegrin and metalloprotease 17 (ADAM17) in monocytes. Interleukin-6 and tumor necrosis factor-\u3b1 stimulated ADAM17 secretion in synovial macrophages. Blocking of \u3b21-integrin abrogated the Sema7A-mediated cytokine secretion. Treatment with an anti-Sema7A antibody significantly attenuated CIA.
Conclusions
These findings indicate that Sema7A as a potent activator of T cells and monocytes in the immune response contributes to the inflammation and progression of RA, suggesting its therapeutic potential in the treatment of RA
Applying graphical oracles to evaluate image segmentation results
No full textAbstract
Segmentation plays an important role in the pattern recognition and image processing areas. Several techniques have been proposed aiming at solving generic issues or particular applications. Traditionally, these techniques have been evaluated by using the Overlap measure, which verifies the coincident and non-coincident areas between the image resulting from a segmentation process and an image considered correct. Albeit widely, this type of measure does not allow flexibility in the assessment process. We here propose an approach to evaluate segmentation techniques using concepts from content-based image retrieval and considering a methodology for testing generic programs with graphical outputs, named graphic oracle. Our approach was applied to evaluate the segmentation of mammographic images, and the results indicate a performance compatible with the traditional measure with more flexibility and precision. Thus, our approach provides a contribution to allow a more flexible segmentation assessment, according to image characteristics and application objectives
Priming increases the anti-tumor effect and therapeutic window of 177 Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1
No full textAbstract
Background
177
Lu-[DOTA
0
, Tyr
3
]-octreotate (
177
Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1 , 2 and 5 , and increase
177
Lu-octreotate uptake.
The aim of the present study was to examine the anti-tumor effect of a
177
Lu-octreotate priming dose followed 24\ua0h later by a second injection of
177
Lu-octreotate compared to a single administration of
177
Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice.
Results
Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE , BAX , CDKN1A , and GADD45A .
Conclusions
Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for
177
Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects
A novel quality assessment for visual secret sharing schemes
No full textAbstract
To
evaluate
the visual quality in visual secret sharing schemes, most of the existing metrics fail to generate fair and uniform quality scores for tested reconstructed images. We propose a new approach to measure the visual quality of the reconstructed image for visual secret sharing schemes. We developed an object detection method in the context of secret sharing, detecting outstanding local features and global object contour. The quality metric is constructed based on the object detection-weight map. The effectiveness of the proposed quality metric is demonstrated by a series of experiments. The experimental results show that our quality metric based on secret object detection outperforms existing metrics. Furthermore, it is straightforward to implement and can be applied to various applications such as performing the security test of the visual secret sharing process
DNA methyltransferases and their roles in tumorigenesis
No full textAbstract
DNA methylation plays an important role in gene expression, chromatin stability, and genetic imprinting. In mammals, DNA methylation patterns are written and regulated by DNA methyltransferases (DNMTs), including DNMT1, DNMT3A and DNMT3B. Recent emerging evidence shows that defects in DNMTs are involved in tumor transformation and progression, thus indicating that epigenetic disruptions caused by DNMT abnormalities are associated with tumorigenesis. Herein, we review the latest findings related to DNMT alterations in cancer cells and discuss the contributions of these effects to oncogenic phenotypes