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β-defensin 2 as an Adjuvant Promotes Anti-Melanoma Immune Responses and Inhibits the Growth of Implanted Murine Melanoma In Vivo  [PDF]
Han-fang Mei, Xiao-bao Jin, Jia-yong Zhu, Ai-hua Zeng, Qiang Wu, Xue-mei Lu, Xiao-bo Li, Juan Shen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031328
Abstract: β-defensin 2 is a small antimicrobial peptide of the innate immune system and has been thought to regulate anti-tumor immunity. However, little is known on whether β-defensin 2 could modulate melanoma-specific NK and T cell responses. In this study, we first cloned the murine β-defensin 2 gene by RT-PCR and generated the β-defensin 2 stably expressing B16 cells (B16-mBD2). Subsequently, we evaluated whether vaccination with irradiated B16-mBD2 could modulate the growth of implanted B16 cells and determined the potential mechanisms underlying the action of B16-mBD2 vaccine in modulating the growth of B16 tumors in C57BL/6. We found that vaccination with irradiated B16-mBD2, but not with control B16-p or parental B16, inhibited the development and progression of B16 tumors, and prolonged the survival of tumor-bearing mice. However, vaccination with irradiated B16-mBD2 failed to inhibit the development of B16 tumors in the CD4+- or CD8+-depleted recipients. Furthermore, vaccination with irradiated B16-mBD2 stimulated strong NK activity and promoted potent B16-specific CTL responses, accompanied by augmenting IFN-γ and IL-12, but not IL-4, responses in the recipient mice. Moreover, vaccination with irradiated B16-mBD2 promoted the infiltration of CD8+ and CD4+ T, NK cells and macrophages in the tumor tissues. These data suggest β-defensin 2 may act as a positive regulator, promoting anti-tumor NK and T cell responses in vivo. Therefore, β-defensin 2 may be used for the development of immunotherapy for the intervention of melanoma.
Mice Lacking Inositol 1,4,5-Trisphosphate Receptors Exhibit Dry Eye  [PDF]
Takaaki Inaba, Chihiro Hisatsune, Yasumasa Sasaki, Yoko Ogawa, Etsuko Ebisui, Naoko Ogawa, Minoru Matsui, Tsutomu Takeuchi, Katsuhiko Mikoshiba, Kazuo Tsubota
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099205
Abstract: Tear secretion is important as it supplies water to the ocular surface and keeps eyes moist. Both the parasympathetic and sympathetic pathways contribute to tear secretion. Although intracellular Ca2+ elevation in the acinar cells of lacrimal glands is a crucial event for tear secretion in both the pathways, the Ca2+ channel, which is responsible for the Ca2+ elevation in the sympathetic pathway, has not been sufficiently analyzed. In this study, we examined tear secretion in mice lacking the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3 (Itpr2?/?;Itpr3?/?double-knockout mice). We found that tear secretion in both the parasympathetic and sympathetic pathways was abolished in Itpr2?/?;Itpr3?/? mice. Intracellular Ca2+ elevation in lacrimal acinar cells after acetylcholine and epinephrine stimulation was abolished in Itpr2?/?;Itpr3?/? mice. Consequently, Itpr2?/?;Itpr3?/? mice exhibited keratoconjunctival alteration and corneal epithelial barrier disruption. Inflammatory cell infiltration into the lacrimal glands and elevation of serum autoantibodies, a representative marker for Sj?gren’s syndrome (SS) in humans, were also detected in older Itpr2?/?;Itpr3?/? mice. These results suggested that IP3Rs are essential for tear secretion in both parasympathetic and sympathetic pathways and that Itpr2?/?;Itpr3?/? mice could be a new dry eye mouse model with symptoms that mimic those of SS.
Combinatorial treatment with carboxyamidotriazole- orotate and temozolomide in sc-implanted human LOX IMVI melanoma xenografts  [cached]
Rashida A Karmali,Yulia Y. Maxuitenko,Greg S. Gorman,Zhican Qu
Journal of Solid Tumors , 2012, DOI: 10.5430/jst.v2n5p13
Abstract: Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1(4-(4-chlorobenzoyl)-3, 5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide (CAI). CTO possesses increased solubility as compared to CAI as the free base. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor-operated, calcium-channel-mediated calcium influx. CTO can inhibit calcium-sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cy, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl. Methods: Different combinations of CTO and temozolomide were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously implanted human LOX IMVI melanoma xenografts. Results: Oral CTO at doses of 513 or 342 mg/kg/dose Q1D×14 resulted in inhibition of tumor growth (p<0.001 and p=0.004). Oral TEM at doses of 90 and 60 mg/kg/dose Q4D×3 resulted in dose-dependent inhibition of tumor growth (p<0.001 and p<0.001). Oral CTO at 513 or 342 mg/kg/dose in combination with temozolomide 90 mg/kg/dose resulted in comparable tumor inhibition to temozolomide alone. However, oral CTO at 513 mg/kg/dose in combination with temozolomide 60mg/kg/dose resulted in additive antitumor activity compared to each drug alone. Also, CTO at 342 mg/kg/dose in combination with temozolomide 60mg/kg/dose had more than additive antitumor activity and was statistically different from the group treated with temozolomide 60 mg/kg/dose alone (p=0.001). Conclusions: These results suggest that this combination of previously configured therapeutic doses of temozolomide with CTO enhances the sensitivity of temozolomide and may permit use of lower temozolomide doses to obtain an optimum antitumor effect in combination therapy. This dose-dilution combinatorial strategy fulfills the need for increased tumor sensitivity and efficacy. Additionally, this strategy reduces drug resistance and toxicity associated with dose dense strategy of temozolomide treatment in this melanoma model.
Dragoslav Miljkovi?,Vanja Peci?,Milica Nestorovi?,Dragan Mihajlovi?
Acta Medica Medianae , 2011,
Abstract: Primary malignant melanoma of the anorectum is rare. It accounts for 0.2-0.3% of all malignant melanomas. Prognosis is very poor since majority of patients dies within first two years. We report a case of a 76 year-old man with anoretal melanoma. Digital rectal examination revealed a mass on the anterior wall. Biopsy report favored two possibilities, first, malignant melanoma and second, poorly differentiated carcinoma. Abdominal ultrasonography and chest X-ray did not show signs of distant metastasis. Computed tomography of abdomen and pelvis revealed presence of a large, irregular hypodense mass with heterogeneous enhancement in anal canal accompanied by enlarged lymph nodes. Abdomino-perineal resection was performed. Histopathological examination of resected specimen confirmed diagnosis of malignant melanoma. Postoperative course was uneventful. However, patient died one year after due to metastasis. Surgery is the mainstay of curative treatment of anorectal melanoma, effective systemic adjuvant therapy has been lacking. Long-term survival is rare, as most patients die of disseminated systemic disease.
Drosophila larvae lacking the bcl-2 gene, buffy, are sensitive to nutrient stress, maintain increased basal target of rapamycin (Tor) signaling and exhibit characteristics of altered basal energy metabolism  [cached]
Monserrate Jessica P,Chen Michelle Y-Y,Brachmann Carrie
BMC Biology , 2012, DOI: 10.1186/1741-7007-10-63
Abstract: Background B cell lymphoma 2 (Bcl-2) proteins are the central regulators of apoptosis. The two bcl-2 genes in Drosophila modulate the response to stress-induced cell death, but not developmental cell death. Because null mutants are viable, Drosophila provides an optimum model system to investigate alternate functions of Bcl-2 proteins. In this report, we explore the role of one bcl-2 gene in nutrient stress responses. Results We report that starvation of Drosophila larvae lacking the bcl-2 gene, buffy, decreases survival rate by more than twofold relative to wild-type larvae. The buffy null mutant reacted to starvation with the expected responses such as inhibition of target of rapamycin (Tor) signaling, autophagy initiation and mobilization of stored lipids. However, the autophagic response to starvation initiated faster in larvae lacking buffy and was inhibited by ectopic buffy. We demonstrate that unusually high basal Tor signaling, indicated by more phosphorylated S6K, was detected in the buffy mutant and that removal of a genomic copy of S6K, but not inactivation of Tor by rapamycin, reverted the precocious autophagy phenotype. Instead, Tor inactivation also required loss of a positive nutrient signal to trigger autophagy and loss of both was sufficient to activate autophagy in the buffy mutant even in the presence of enforced phosphoinositide 3-kinase (PI3K) signaling. Prior to starvation, the fed buffy mutant stored less lipid and glycogen, had high lactate levels and maintained a reduced pool of cellular ATP. These observations, together with the inability of buffy mutant larvae to adapt to nutrient restriction, indicate altered energy metabolism in the absence of buffy. Conclusions All animals in their natural habitats are faced with periods of reduced nutrient availability. This study demonstrates that buffy is required for adaptation to both starvation and nutrient restriction. Thus, Buffy is a Bcl-2 protein that plays an important non-apoptotic role to promote survival of the whole organism in a stressful situation.
A copy number variation in human NCF1 and its pseudogenes
Tiffany Brunson, Qingwei Wang, Isfahan Chambers, Qing Song
BMC Genetics , 2010, DOI: 10.1186/1471-2156-11-13
Abstract: We examined three normal populations (86 individuals). We observed the 2:2:2 pattern (NCF1B:NCF1:NCF1C) in only 26 individuals. On average, each African- American has 1.4 ± 0.8 (Mean ± SD) copies of NCF1B and 2.3 ± 0.6 copies of NCF1C; each Caucasian has 1.8 ± 0.7 copies of NCF1B and 1.9 ± 0.4 copies of NCF1C; and each Mexican has 1.6 ± 0.6 copies of NCF1B and 1.0 ± 0.4 copies of NCF1C. Mexicans have significantly less NCF1C copies than African-Americans (p = 6e-15) and Caucasians (p = 3e-11). Mendelian transmission of this CNV was observed in two CEPH pedigrees. Moreover, we cloned two alternative spliced transcripts generated from these two pseudogenes that adopt alternative exon-2 instead of their defective exon 2. The NCF1 pseudogene expression responded robustly to PMA induction during macrophage differentiation. NCF1B decreased from 32.9% to 8.3% in the cDNA pool transcribed from 3 gene copies. NCF1Ψs also displayed distinct expression patterns in different human tissues.Our results suggest that these two pseudogenes may adopt an alternative exon-2 in different tissues and in response to external stimuli. The GT deletion is insufficient to define them as functionless pseudogenes; this CNV may have biological relevance.Recent genomic studies suggested that gene duplication occurred frequently and in variable numbers during the recent history of human populations, which has led to de novo formations of copy number variation (CNV) [1]. Presumably due to positive selection, genes encoding certain protein categories are particularly enriched in CNVs, such as those involved in processes related to environmental responses [1-8]. In this process, duplicated genes are thought to be the "successful" copies; pseudogenes are those "unsuccessful" duplicates retained in the genome [1].Neutrophil cytosolic factor 1 (NCF1, also called p47phox, for phagocyte oxidase), is a crucial component of NADPH oxidase [9]. This enzyme catalyzes the production of microbicidal superoxide i
NCF1 gene and pseudogene pattern: association with parasitic infection and autoimmunity
Bernhard Greve, Peter Hoffmann, Reinhard Vonthein, Jürgen Kun, Bertrand Lell, Marcin P Mycko, Krysztof W Selmaj, Klaus Berger, Robert Weissert, Peter G Kremsner
Malaria Journal , 2008, DOI: 10.1186/1475-2875-7-251
Abstract: NCF1ΔGT/GTGT ratios were correlated with clinical parameters and ROI production during Plasmodium falciparum malaria and with susceptibility to the autoimmune disease multiple sclerosis (MS).Among Gabonese children with severe malaria, ROI production from peripheral blood tended to be higher in individuals with a ΔGT/GTGT ratio ≤ 1:1. ΔGT/GTGT ratios were not associated with susceptibility to MS, but to age-of-onset among MS patients.The genomic pattern of NCF1 and its pseudogenes might influence ROI production but only marginally influence susceptibility to and outcome of malaria and MS.The release of reactive oxygen intermediates (ROI) constitutes part of the innate immune responses against pathogens [1]. During malaria, ROI production can contribute to both faster parasite clearance and more severe disease, especially anaemia [2,3]. Furthermore, ROI are involved in cell signalling pathways [4]. In autoimmune diseases such as Multiple Sclerosis (MS), ROI have been implicated as mediators for demyelination and axonal damage [5,6], and enhanced respiratory burst activity has been detected in leukocytes of MS patients compared to control individuals [7].One of the key enzymes leading to production of ROI is the leukocyte NADPH oxidase, consisting of several subunits, which are membrane-bound or located in the cytosol. Loss-of-function-mutations within the genes of these subunits lead to the development of chronic granulomatous disease (CGD) [8]. Genetic variation in components of the leukocyte NADPH oxidase may, therefore, influence disease susceptibility to and disease course of parasitic infection and autoimmune disease. The length of a TA-repeat in the promoter region of the leukocyte NADPH oxidase subunit gp91phox is associated with severity of malaria [9]. A single nucleotide polymorphism (SNP) in the subunit neutrophil cytosolic factor (NCF) 4 (p40phox) has been shown to be associated with antibody-negative arthritis [10]. Susceptibility to animal models of aut
Primary Cilium Depletion Typifies Cutaneous Melanoma In Situ and Malignant Melanoma  [PDF]
Jinah Kim, Salma Dabiri, E. Scott Seeley
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027410
Abstract: Cutaneous melanoma is a lethal malignancy that arises spontaneously or via in situ precursor neoplasms. While melanoma in situ and locally invasive malignant melanoma can be cured surgically, these lesions can sometimes be difficult to distinguish from melanocytic nevi. Thus, the identification of histolopathologic or molecular features that distinguish these biologically distinct lesions would represent an important advance. To this end, we determined the abundance of melanocytic primary cilia in a series of 62 cases composed of typical cutaneous melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma. Primary cilia are sensory organelles that modulate developmental and adaptive signaling and notably, are substantially depleted from the neoplastic epithelium of pancreatic carcinoma at a stage equivalent to melanoma in situ. In this series, we find that while nearly all melanocytes in 22 melanocytic nevi possessed a primary cilium, a near-complete loss of this organelle was observed in 16 cases of melanoma in situ, in 16 unequivocal primary invasive melanomas, and in 8 metastatic tumors, each associated with a cutaneous primary lesion. These findings suggest that the primary cilium may be used to segregate cutaneous invasive melanoma and melanoma in situ from melanocytic nevi. Moreover, they place the loss of an organelle known to regulate oncogenic signaling at an early stage of melanoma development.
Mucosal malignant melanoma of the nasal cavity  [cached]
Bothale K,Maimoon S,Patrikar A,Mahore S
Indian Journal of Cancer , 2009,
Abstract: Mucosal malignant melanoma (MMM) of the nose is extremely rare. We report a case of MMM of the nasal cavity in a 60-year-old male patient presenting with a polypoidal mass in the right nasal cavity. It was increasing gradually and obstructing breathing. A biopsy of the lesion was done with a clinical suspicion of inverted papilloma/carcinoma. Microscopy revealed features suggestive of malignant melanoma with minimal melanin pigmentation. Subsequently wide local excision was done. Diagnosis of malignant melanoma was facilitated by histochemistry and immunohistochemistry.
Malignant Melanoma of Gastroesophageal Junction.  [PDF]
Arvind Kohli, Anita Kohli, Kuldeep Singh, Gurjeet Singh
JK Science : Journal of Medical Education & Research , 2004,
Abstract: A rare case of malignant melanoma arising from the gastroesophageal junction is being reported.Since part of the tumor was adherent with hiatus, palliative procedure in form of Mousseau Barbintube insertion was necessitated. Postoperatively patient was subjected to radiotherapy. Malignantmelanoma of gastroesophageal junction is rare accounting for only 0.1% of the lesions of this region.Surgical treatment requires a far greater margin of excision than the usual squamous cell carcinoma.Intracavitary radiotherapy has been recommended.
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