bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Complex-Bearing Follicular Dendritic Cells Deliver a Late Antigenic Signal That Promotes Somatic Hypermutation
Authors: Wu Yongzhong , Sukumar Selvakumar , El Shikh Mohey Eldin , Best Al M. , Szakal Andras K. , Tew John G. 
Published: April 2014

AbstractWe reasoned that immune complex (IC)-bearing follicular dendritic cells (FDCs) promote somatic hypermutation (SHM). This hypothesis was tested in murine germinal center reactions induced in vitro by coculturing 6-day (4-hydroxy-3-nitrophenyl) acetyl-primed but unmutated λ+ B cells, chicken γ-globulin (CGG) memory T cells, FDCs, and ICs (anti-CGG plus NP-CGG). Mutations in primed λ+ B cells were obtained only when both FDCs and immunogen were present. FDCs alone promoted B cell survival and Ab production but there were no mutations without more immunogen. Moreover, the mutation rate was enhanced when FDCs were activated. Trapped ICs ranged from 200 to 500 Å apart on FDC membranes and this correlated with the periodicity known to optimally signal BCRs. FDCs are unique in their ability to retain ICs for months and a second signal mediated by FDC-ICs appeared to be needed a week or more after immunization by immunogen persisting on FDCs. However, the time needed to detect extensive SHM could be reduced to 7 days if ICs were injected together with memory T cells in vivo. In marked contrast, no mutations were apparent after 7 days in vivo if ICs were replaced by free Ag that would not load on FDCs until Ab was produced. The data suggest that specific Ab production leads to the following events: Ab encounters Ag and ICs are formed, ICs are trapped by FDCs, B cells are stimulated by periodically arranged Ag in ICs on FDCs, and this late antigenic signal promotes SHM.
Differential Microenvironment Localization of Effector and Memory CD8 T Cells
Authors: Dauner Joseph G. , Williams Ifor R. , Jacob Joshy 
Published: April 2014

Abstract
CD8 T cells are critical for the clearance of intracellular pathogens. Upon infection, naive CD8 T cells differentiate into effector cells that target and eliminate infected cells. Following clearance of the pathogen, most effector cells die, although a small fraction survives to establish a memory population. Subsequent exposure to the same pathogen induces a rapid response of memory T cells and efficient elimination of the pathogen. Although much is known about the CD8 T cell response, the precise microenvironment location of effector and memory CD8 T cells in secondary lymphoid organs is not well characterized. In this study, we present an in situ analysis of the localization of effector and memory CD8 T cells during the murine immune response to lymphocytic choriomenginits virus. We identified the location of these cells using a transgenic mouse model system in which CD8 T cells are irreversibly tagged with yellow fluorescent protein (YFP) after activation. After infection, YFP+ CD8 T cells were initially observed within T cell zones. Later, these cells were found in the red pulp and a disruption of all CD8 T cell zones was observed. After resolution of the immune response, YFP+ memory CD8 T cells were observed primarily in T cells zones. Thus, in the spleens of mice, effector CD8 T cells localize to the red pulp and memory CD8 T cells localize to the T cell zones. Upon rechallenge, memory CD8 T cells rapidly proliferate and the secondary effector CD8 T cells are found in the red pulp.
Sequential Shrinkage and Swelling Underlie P2X7-Stimulated Lymphocyte Phosphatidylserine Exposure and Death
Authors: Taylor Simon R. J. , Gonzalez-Begne Mireya , Dewhurst Stephen , Chimini Giovanna , Higgins Christopher F. , Melvin James E. , Elliott James I. 
Published: April 2014

Abstract
Patterns of change in cell volume and plasma membrane phospholipid distribution during cell death are regarded as diagnostic means of distinguishing apoptosis from necrosis, the former being associated with cell shrinkage and early phosphatidylserine (PS) exposure, whereas necrosis is associated with cell swelling and consequent lysis. We demonstrate that cell volume regulation during lymphocyte death stimulated via the purinergic receptor P2X7 is distinct from both. Within seconds of stimulation, murine lymphocytes undergo rapid shrinkage concomitant with, but also required for, PS exposure. However, within 2 min shrinkage is reversed and swelling ensues ending in cell rupture. P2X7-induced shrinkage and PS translocation depend upon K+ efflux via KCa3.1, but use a pathway of Cl− efflux distinct from that previously implicated in apoptosis. Thus, P2X7 stimulation activates a novel pathway of cell death that does not conform to those conventionally associated with apoptosis and necrosis. The mixed apoptotic/necrotic phenotype of P2X7-stimulated cells is consistent with a potential role for this death pathway in lupus disease.
Regulation of HumanDAP10Gene Expression in NK and T Cells by Ap-1 Transcription Factors
Authors: Marusina Alina I. , Burgess Steven J. , Pathmanathan Ishani , Borrego Francisco , Coligan John E. 
Published: April 2014

AbstractHuman NKG2D/DAP10 is an activation receptor expressed by NK and subsets of T cells, whose ligands include MHC class I chain-related (MIC) protein A and protein B and UL16-binding proteins that are often up-regulated by stress or pathological conditions. DAP10 is required for NKG2D/DAP10 cell surface expression and signaling capacity. Little is known about the mechanisms that regulate DAP10 gene expression. We describe the existence of multiple transcriptional start sites upstream of DAP10 exon 1 and identify the location of the basic promoter upstream of these starting sites. The promoter is active in NK and CD8+ T cells, but not in CD4+ T cells. We demonstrate TCR-mediated up-regulation of DAP10 transcription and found that a 40 bp region within the DAP10 promoter, containing an Ap-1 binding site, is largely responsible for this increased transcription. Using pull-down and chromatin immunoprecipitation assays, we show that the DAP10 promoter interacts with Ap-1 transcription factors in primary CD8+ T and NK cells in vitro and in vivo. Overexpression of c-Jun or c-Fos in NK and T cells led to enhanced DAP10 promoter activity and DAP10 protein expression. Taken together, our data indicate that Ap-1 is an important transcription factor for regulating DAP10 gene expression in human NK and T cells, and that Ap-1 plays a key role in the transactivation of DAP10 promoter following TCR stimulation.
B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms
Authors: Rangel-Moreno Javier , Carragher Damian M. , Misra Ravi S. , Kusser Kim , Hartson Louise , Moquin Amy , Lund Frances E. , Randall Troy D. 
Published: April 2014

Abstract
Immunity to heterosubtypic strains of influenza is thought to be mediated primarily by memory T cells, which recognize epitopes in conserved proteins. However, the involvement of B cells in this process is controversial. We show in this study that influenza-specific memory T cells are insufficient to protect mice against a lethal challenge with a virulent strain of influenza in the absence of B cells. B cells contribute to protection in multiple ways. First, although non-neutralizing Abs by themselves do not provide any protection to challenge infection, they do reduce weight loss, lower viral titers, and promote recovery of mice challenged with a virulent heterosubtypic virus in the presence of memory T cells. Non-neutralizing Abs also facilitate the expansion of responding memory CD8 T cells. Furthermore, in cooperation with memory T cells, naive B cells also promote recovery from infection with a virulent heterosubtypic virus by generating new neutralizing Abs. These data demonstrate that B cells use multiple mechanisms to promote resistance to heterosubtypic strains of influenza and suggest that vaccines that elicit both memory T cells and Abs to conserved epitopes of influenza may be an effective defense against a wide range of influenza serotypes.
Impaired Phagosomal Maturation in Neutrophils Leads to Periodontitis in Lysosomal-Associated Membrane Protein-2 Knockout Mice
Authors: Beertsen Wouter , Willenborg Marion , Everts Vincent , Zirogianni Angelika , Podschun Rainer , Schröder Bernd , Eskelinen Eeva-Liisa , Saftig Paul 
Published: April 2014

Abstract
Inflammatory periodontal diseases constitute one of the most common infections in humans, resulting in the destruction of the supporting structures of the dentition. Circulating neutrophils are an essential component of the human innate immune system. We observed that mice deficient for the major lysosomal-associated membrane protein-2 (LAMP-2) developed severe periodontitis early in life. This development was accompanied by a massive accumulation of bacterial plaque along the tooth surfaces, gingival inflammation, alveolar bone resorption, loss of connective tissue fiber attachment, apical migration of junctional epithelium, and pathological movement of the molars. The inflammatory lesions were dominated by polymorphonuclear leukocytes (PMNs) apparently being unable to efficiently clear bacterial pathogens. Systemic treatment of LAMP-2-deficient mice with antibiotics prevented the periodontal pathology. Isolated PMNs from LAMP-2-deficient mice showed an accumulation of autophagic vacuoles and a reduced bacterial killing capacity. Oxidative burst response was not altered in these cells. Latex bead and bacterial feeding experiments showed a reduced ability of the phagosomes to acquire an acidic pH and late endocytic markers, suggesting an impaired fusion of late endosomes-lysosomes with phagosomes. This study underlines the importance of LAMP-2 for the maturation of phagosomes in PMNs. It also underscores the requirement of lysosomal fusion events to provide sufficient antimicrobial activity in PMNs, which is needed to prevent periodontal disease.
A Th1-Recognized Peptide P277, When Tandemly Repeated, Enhances a Th2 Immune Response toward Effective Vaccines against Autoimmune Diabetes in Nonobese Diabetic Mice
Authors: Jin Liang , Zhu Aihua , Wang Yu , Chen Qingmei , Xiong Qiyan , Li Jianping , Sun Yunxiao , Li Taiming , Cao Rongyue , Wu Jie , Liu Jingjing 
Published: April 2014

Abstract
Subunit immunogens containing tandemly repeated copies of T and B cell epitopes have been shown to be more immunogenic than the respective immunogen containing only a single copy of the sequence. To investigate whether the increased copies of the Th2-activated peptide sequence will enhance the Th2-like immune response, we compared the cytokine secreted in mice that inoculated with two immunogens containing one or six tandemly repeated copies of a Th2-activated peptide sequence P277. Immunization of mice with a 6×P277 fusion protein elicited much higher levels of Th2-type cytokines and lower Th1-type cytokines than with a fusion protein with one P277 peptide. The data of tandemly repeated peptide P277 potentiate the anti-inflammatory in NOD mice, most likely associated with a Th1 to Th2 cytokine shift specific for the autoimmune T cells, which suggested that application of multiple tandem repeats of a Th2-activated epitope is an efficient method to enhance the anti-inflammatory immune response by shifting the immune response from Th1-like to Th2-like. The subunit immunogens containing tandemly repeated copies of peptide P277 might be effective vaccines against autoimmune diabetes in NOD mice.
Integrin αDβ2 Is Dynamically Expressed by Inflamed Macrophages and Alters the Natural History of Lethal Systemic Infections
Authors: Miyazaki Yasunari , Bunting Michaeline , Stafforini Diana M. , Harris Estelle S. , McIntyre Thomas M. , Prescott Stephen M. , Frutuoso Valber S. , Amendoeira Fabio C. , de Oliveira Nascimento Danielle , Vieira-de-Abreu Adriana , Weyrich Andrew S. , Castro-Faria-Neto Hugo C. , Zimmerman Guy A. 
Published: April 2014

AbstractThe leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin αDβ2, a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. αDβ2 is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity. In response to challenge with Plasmodium berghei, a malarial pathogen that models systemic infection and inflammatory injury, new populations of αD+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of αD conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of αD−/− animals at these time points is not attributed to differences in magnitude of anemia or parasitemia or to alterations in splenic microanatomy, each of which is a key variable in the natural history of P. berghei infection, and indicated that an altered pattern of inflammatory cytokines may contribute to the difference in mortality. In contrast to the outcome in malarial challenge, death of αD−/− animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for αDβ2 in systemic infection. These studies identify previously unrecognized and unique activities of αDβ2, and macrophages that express it, in host defense and injury.
Recurrent Staphylococcal Cellulitis and Subcutaneous Abscesses in a Child with Autoantibodies against IL-6
Authors: Puel Anne , Picard Capucine , Lorrot Mathie , Pons Charlotte , Chrabieh Maya , Lorenzo Lazaro , Mamani-Matsuda Maria , Jouanguy Emmanuelle , Gendrel Dominique , Casanova Jean-Laurent 
Published: April 2014

Abstract
We investigated an otherwise healthy patient presenting two episodes of staphylococcal cellulitis and abscesses, accompanied by high fever and biological signs of inflammation but, paradoxically, with no detectable increase in serum levels of C-reactive protein (CRP), an IL-6-responsive protein synthesized in the liver. Following in vitro activation of whole blood cells from the patient with multiple cytokines, TLR agonists, heat-killed bacteria, and mitogens, we observed a profound and specific impairment of IL-6 secretion. However, the patient’s PBMCs, activated in the same conditions but in the absence of the patient’s plasma, secreted IL-6 normally. The patient’s serum contained high titers of IgG1 autoantibodies against IL-6, which specifically neutralized IL-6 production by control PBMCs as well as IL-6 responses in the human hepatocellular carcinoma cell line Hep3B. These anti-IL-6 autoantibodies were detected over a period of 4 years, in the absence of any other autoantibodies. Our results indicate that these Abs probably prevented an increase in CRP concentration during infection and that impaired IL-6-mediated immunity may have contributed to staphylococcal disease. Patients with severe bacterial infections and low serum CRP concentrations should be tested for anti-IL-6 autoantibodies, especially in the presence of other clinical and biological signs of inflammation.
IL-17RA and IL-17RC Receptors Are Essential for IL-17A-Induced ELR+ CXC Chemokine Expression in Synoviocytes and Are Overexpressed in Rheumatoid Blood
Authors: Zrioual Saloua , Toh Myew-Ling , Tournadre Anne , Zhou Yuan , Cazalis Marie-Angélique , Pachot Alexandre , Miossec Vincent , Miossec Pierre 
Published: April 2014

AbstractIL-17A is a cytokine secreted by the newly described Th17 cells implicated in rheumatoid arthritis (RA). Less is known about its receptors in synoviocytes. IL-17RA and IL-17RC were found to be overexpressed in RA peripheral whole blood and their expression was detected locally in RA synovium. In vitro, IL-17A synergized with TNF-α to induce IL-6, IL-8, CCL-20, and matrix metalloproteinase-3. Using microarrays, a specific up-regulation of Glu-Leu-Arg+ CXC chemokines was observed in IL-17A-treated synoviocytes. Using both posttranslational inhibitions by silencing interfering RNA and extracellular blockade by specific inhibitors, we showed that both IL-17RA and IL-17RC are implicated in IL-17A-induced IL-6 secretion, whereas in the presence of TNF-α, the inhibition of both receptors was needed to down-regulate IL-17A-induced IL-6 and CCL-20 secretion. Thus, IL-17A-induced IL-6, IL-8, and CCL20 secretion was dependent on both IL-17RA and IL-17RC, which are overexpressed in RA patients. IL-17A-induced pathogenic effects may be modulated by IL-17RA and/or IL-17RC antagonism.
Immunotherapy with Chimeric NKG2D Receptors Leads to Long-Term Tumor-Free Survival and Development of Host Antitumor Immunity in Murine Ovarian Cancer
Authors: Barber Amorette , Zhang Tong , Sentman Charles L. 
Published: April 2014

Abstract
Ovarian cancer is one of the leading causes of cancer death in women and the development of novel therapies is needed to complement the standard treatment options such as chemotherapy and radiation. In this study, we show that treatment with T cells expressing a chimeric NKG2D receptor (chNKG2D) was able to lead to long-term, tumor-free survival in mice bearing established ovarian tumors. Tumor-free mice were able to reject a rechallenge with ovarian tumor cells 225 days after original tumor injection. In addition, chNKG2D T cell treatment induced specific host immune responses to ovarian tumor cells, including the development of both CD8+ and CD4+ T cell tumor-specific memory responses. The chNKG2D T cells reduced the ovarian tumor burden using both cytotoxic and cytokine-dependent pathways. Specifically, chNKG2D T cell expression of perforin, GM-CSF, and IFN-γ were essential for complete antitumor efficacy.
Age at diagnosis of female breast cancer in Oman: Issues and implications
Authors: Mehdi Itrat , Monem Essam Abdul , Bahrani Bassim Jaffar Al , Kharusi Suad Al , Nada Ayman Mohammad , Lawati Jawad Al , Lawati Najla Al 
Published: April 2014

Abstract
Introduction: Female breast cancer (BC) is the most frequent malignancy diagnosed globally, about 23% of the diagnosed cancers. BC incidence varies geographically, highest in Western Europe and lowest in Africa. BC in females is strongly correlated to age, the highest incidence rate amongst older women reinforcing the importance of hormonal status. BC in young females has an aggressive phenotype. There is a shared observation amongst practicing oncologists that BC in Middle East and the developing world presents at an earlier age. Aim and Objective: The aims of this study are to evaluate the age at presentation of female BC in Oman, and to compare our data with international and regional published data. It discusses the impact of young age Breast Cancer. Materials and Methods: All diagnosed female BC cases registered from 1996-2010 all over the country, were retrieved from the National Cancer Registry, Ministry of Health. BC cases were analyzed with respect to age at presentation. The data were compared with regional and international data. Results: A total of 14,109 cancer cases were recorded during the period of study. BC was the leading malignancy as 1,294 cases (9.1%). Female BC patients were 1,230; denoting 19.2% of all female cancers. 53.5% of female BC presented below 50 years of age. Male BC constituted 5% of total, with 67% of male BC occurring over 50 years of age. Compared with data from Oman, the highest rates in UK and other Western countries are above 50 years of age. These rates are four to 10 times higher than local in different age groups. Interestingly, these rates increase with increasing age in UK from 40-45 to up to 85+, keep on increasing and go up to four times higher with higher age. This phenomenon, of increasing incidence rates with age, is not observed in our local population. Discussion: BC is significantly correlated to age as reported from Western population. BC is reported at a younger age from developing and Arab World, which need to be further studied and validated. This phenomenon of BC in younger age may have significant implications and effects ranging from screening, diagnosis, management, prognosis, and cost of treatment. Conclusion: The impact on young women diagnosed with BC is enormous, ranging from psychosocial to healthcare services and economics. There is a need to study it further in depth in developing World.
Late effects of cancer treatment in breast cancer survivors
Authors: Agrawal Sushma 
Published: April 2014

AbstractPostoperative radiation therapy (RT) and chemotherapy,both reduces the risk of local recurrence and extends overall survival in patients with breast cancer (BC). Concerns have, however, been raised about the risk of acute and chronic side effects in breast cancer survivors as the number of treated individuals is large and their expected survival is long compared to most patients with other malignant diseases. Cardiac toxicity, reproductive dysfunction, pneumonitis (RP),arm lymph edema, neuropathy, skin changes are examples of the wide range of complications that has been associated with adjuvant treatment.
Ramosetron hydrochloride for the prevention of cancer chemotherapy induced nausea and vomiting: The Indian experience
Authors: Sanmukhani Jayesh J. , Pawar Prafulla , Mittal Ravindra 
Published: April 2014

Abstract
Background: Despite the advent of 5-HT 3 antagonists, control of delayed gastrointestinal adverse events with cancer chemotherapy is still not optimal. This open label, active controlled, multicentric clinical trial was undertaken to assess the comparative efficacy and safety of ramosetron with ondansetron for the prevention of acute and delayed nausea and vomiting associated with emetogenic cancer chemotherapy in adult patients in India. Materials and Methods: Enrolled patients received treatment with ramosetron hydrochloride 0.1 mg or ondansetron hydrochloride 4 mg tablets once daily in the morning for 5 days starting 1 h before the start of chemotherapy. Severity grades of nausea and vomiting were recorded on a daily basis for a period of 5 days and complete response rate (CRR) and effective rate (ER) were calculated. Clinical adverse events were recorded and hematological and biochemical investigations were performed for safety assessment. Results: A total of 114 patients in ramosetron group and 100 patients in ondansetron group completed the study and were eligible for efficacy and safety analysis. CRR and ERs show that while ramosetron is non-inferior to ondansetron in the control of early nausea and vomiting (occurring during the first 24 h) after the treatment with emetogenic chemotherapy, it is superior to ondansetron in the control of delayed nausea and vomiting (occurring after the first 24 h). The proportion of patients achieving a cumulative complete response (for the entire study period) is significantly greater in ramosetron group as compared to ondansetron group (27.2% vs. 7.0%; P < 0.001). Ramosetron was well tolerated by all the study participants. Conclusions: Ramosetron is significantly more effective than ondansetron for the control of delayed nausea and vomiting induced by emetogenic cancer chemotherapy.
Promoting Learning Outcomes Assessment in Higher Education:
Authors: Ndoye Abdou 
Published: April 2014

Abstract
This article presents results of a study on factors that contribute to successful learning outcomes assessment practices. This qualitative study uses the case study method to analyze factors of success in higher education programs. Interviews of faculty members reveal that factors such as communication, implementing assessment as a change initiative, and using a learning community approach are identified by study participants as the main facilitators of success.