bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes
Authors: Talahalli Ramaprasad , Zarini Simona , Tang Jie , Li Guangyuan , Murphy Robert , Kern Timothy S , Gubitosi-Klug Rose A 
Published: October 2012

Abstract
Critical involvement of the leukocyte and 5-lipoxygenase metabolites in retinal capillary degeneration using a chimeric mouse model of diabetic retinopathy.
Understanding the early pathogenesis of DR may uncover new therapeutic targets to prevent or slow the progression of this sight-threatening disorder. We investigated the role of leukocyte-mediated generation of LTs in regulation of retinal capillary degeneration and inflammation in the diabetic mouse. We generated (1) chimeric mice that lacked the ability to generate LTs by transplanting 5LO−/− bone marrow cells into ND.WT mice and into SD.WT mice and (2) “control” chimeric mice by transplanting WT bone marrow cells into 5LO−/− mice or into WT mice. Retinas from diabetic chimeric mice with WT marrow demonstrated capillary degeneration to the same extent as retinas from diabetic, nonchimeric WT mice. In contrast, retinas from diabetic chimeric mice with 5LO−/− marrow developed significantly less capillary degeneration and pericyte loss (P&lt;0.05). In the retinas from chimeric mice with WT marrow, diabetes induced a rise in leukocyte adherence to the microvasculature, expression of the NF-κB p65 subunit, and ICAM1, superoxide generation, and retinal microvascular permeability, yet these characteristic responses were blunted by &gt;50% in diabetic chimeras containing 5LO−/− leukocytes (P&lt;0.05). Our data suggest the critical involvement of leukocytes and LTs in the regulation of inflammation and capillary degeneration in DR.
Selective inhibition of the gliadin-specific, cell-mediated immune response by transamidation with microbial transglutaminase
Authors: Lombardi Emanuela , Bergamo Paolo , Maurano Francesco , Bozzella Giuseppina , Luongo Diomira , Mazzarella Giuseppe , Rotondi Aufiero Vera , Iaquinto Gaetano , Rossi Mauro 
Published: October 2012

Abstract
mTGase-mediated transamidation of wheat flour reverses the T cell mediated inflammatory response in models of gliadin sensitivity.
CD is an immune-mediated enteropathy caused by the ingestion of wheat gluten. The modification of gluten by intestinal tTGase plays a crucial role in CD pathogenesis. In this study, we observed that extensive transamidation of wheat flour with K-C2H5 by mTGase yielded spf and K-gliadins fractions. By Western blot, we found that these modifications were associated with strongly reduced immune cross-reactivity. With the use of DQ8 tg mice as a model of gluten sensitivity, we observed a dramatic reduction in IFNγ production in gliadin-specific spleen cells challenged with spf and K-gliadins in vitro (n=12; median values: 813 vs. 29 and 99; control vs. spf and K-gliadins, P=0.012 for spf, and P=0.003 for K-gliadins). For spf, we also observed an increase in the IL-10/IFNγ protein ratio (n=12; median values: 0.3 vs. 4.7; control vs. spf, P=0.005). In intestinal biopsies from CD patients challenged in vitro with gliadins (n=10), we demonstrated further that K-gliadins dramatically reduced the levels of antigen-specific IFNγ mRNA in all specimens responsive to native gliadins (four of 10; P&lt;0.05). As cytotoxic effects have been described for gliadins, we also studied GST and caspase-3 activities using the enterocytic Caco-2 cell line. We found that neither activities were modified by flour transamidation. Our results indicate that K-C2H5 cross-linking via mTGase specifically affects gliadin immunogenicity, reversing the inducible inflammatory response in models of gluten sensitivity without affecting other aspects of the biological activity of gliadins.
Influenza-induced, helper-independent CD8+ T cell responses use CD40 costimulation at the late phase of the primary response
Authors: Seah Shirley G K , Brady Jamie L , Carrington Emma M , Ng Wy Ching , Sutherland Robyn M , Hancock Manuela S , La Gruta Nicole L , Brown Lorena E , Turner Stephen J , Lew Andrew M , Zhan Yifan 
Published: October 2012

Abstract
Direct costimulation of CD8+ T cells is more important than the canonical licensing of DCs by CD4 help, in influenza.
The helper-dependent pathway of priming CD8+ T cells involves “licensing” of DCs by CD40L on CD4+ T cells. The helper-independent (“helpless”) pathways elicited by many viruses, including influenza, are less widely understood. We have postulated that CD40L can be up-regulated on DCs by such viruses, and this promotes priming of CD8+ T cells via CD40. Most studies on costimulation have been performed in the presence of CD4+ T cells, and so the role of CD40L costimulation under helpless circumstances has not been fully elucidated. Here, we investigated such a role for CD40L using CD40L KO mice. Although the number of influenza-specific CD8+ T cells was unaffected by the absence of CD4+ T cells, it was markedly decreased in the absence of CD40L. Proliferation (the number of CD44+BrdU+ influenza-specific CD8+ T cells) in the primary response was diminished in CD40L KO mice at Day 8 but not at Day 5 after infection. MLR studies indicated that CD40L expression on DCs was critical for CD8+ T cell activation. Adoptive transfer of CD40 KO CD8+ T cells compared with WT cells confirmed that CD40 on such cells was critical for the generation of primary anti-influenza CD8+ T cell responses. The late effect also corresponded with the late expression of CD40 by influenza-specific CD8+ T cells. We suggest that costimulation via CD40L on DCs and CD40 on CD8+ T cells is important in optimizing primary CD8+ T cell responses during influenza infection.
Acupuncture for Cancer-Related Fatigue in Patients With Breast Cancer: A Pragmatic Randomized Controlled Trial
Authors: Molassiotis Alexander , Bardy Joy , Finnegan-John Jennifer , Mackereth Peter , Ryder David W. , Filshie Jacqueline , Ream Emma , Richardson Alison 
Published: October 2012

Purpose We aimed to assess the effectiveness of acupuncture for cancer-related fatigue (CRF) in patients with breast cancer. Patients and Methods We conducted a pragmatic, randomized controlled trial comparing acupuncture with enhanced usual care. Three hundred two outpatients with breast cancer participated. We randomly assigned 75 patients to usual care and 227 patients to acupuncture plus usual care (random assignment of 1:3 respectively) with minimization controlling for baseline general fatigue and maintenance treatment. Treatment was delivered by acupuncturists once a week for 6 weeks through needling three pairs of acupoints. The usual care group received a booklet with information about fatigue and its management. Primary outcome was general fatigue at 6 weeks, measured with the Multidimensional Fatigue Inventory (MFI). Other measurements included the Hospital Anxiety and Depression Scale, Functional Assessment of Cancer Therapy–General quality-of-life scale, and expectation of acupuncture effect. Analyses were by intention to treat. Results Two hundred forty-six of 302 patients randomly assigned provided complete data at 6 weeks. The difference in the mean General Fatigue score, between those who received the intervention and those who did not, was −3.11 (95% CI, −3.97 to −2.25; P < .001). The intervention also improved all other fatigue aspects measured by MFI, including Physical Fatigue and Mental Fatigue (acupuncture effect, −2.36 and −1.94, respectively; both at P < .001), anxiety and depression (acupuncture effect, −1.83 and −2.13, respectively; both at P < .001), and quality of life (Physical Well-Being effect, 3.30; Functional Well-Being effect, 3.57; both at P < .001; Emotional Well-Being effect, 1.93; P = .001; and Social Functioning Well-Being effect, 1.05; P < .05). Conclusion Acupuncture is an effective intervention for managing the symptom of CRF and improving patients' quality of life.
A Role for Common Genomic Variants in the Assessment of Familial Breast Cancer
Authors: Sawyer Sarah , Mitchell Gillian , McKinley Joanne , Chenevix-Trench Georgia , Beesley Jonathan , Chen Xiao Qing , Bowtell David , Trainer Alison H. , Harris Marion , Lindeman Geoffrey J. , James Paul A. 
Published: October 2012

Purpose Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear. Patients and Methods We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer–associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared. Results Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 × 10−16). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 × 10−6). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio [OR]= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk. Conclusion Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored.
Opioid Prescribing for Cancer Pain During the Last 3 Months of Life: Associated Factors and 9-Year Trends in a Nationwide United Kingdom Cohort Study
Authors: Higginson Irene J. , Gao Wei 
Published: October 2012

Purpose To determine time trends and characteristics associated with opioid analgesic prescribing to patients with cancer who are approaching the end of life. Patients and Methods This population-based cohort study used data on 29,825 patients diagnosed with five common cancers—lung (34.2%), colorectal (19.9%), female breast (21.6%), prostate (19.1%), and head and neck (5.2%)—in the United Kingdom General Practice Research Database (GPRD) who died between 2000 and 2008. Opioid prescription rates in the last 3 months of life were described. Characteristics associated with opioid prescribing were investigated by using generalized estimation equation models. Results In the last 3 months of life, 43.6% (95% CI, 43.0% to 44.2%) of patients received at least one prescription of opioids: morphine (33.4%; 95% CI, 32.8% to 33.9%), diamorphine (11.6%; 95% CI, 11.2% to 11.9%), and fentanyl family (10.2%; 95% CI, 9.8% to 10.5%). Over time, prescription rates increased for opioids predominant during specific time periods, especially oxycodone. Older patients (age > 60 years) had significantly lower chances of receiving opioids than their younger (age < 50 years) peers (prevalence ratio [PR] range, 0.14 to 0.78), even adjusted for comorbidity. Women were slightly more likely than men to receive any type of opioid (PR,1.07; 95% CI, 1.04 to 1.11). Morphine and diamorphine (PR range, 1.14 to 1.56) were more commonly prescribed for lung and colorectal cancers and fentanyl family for head and neck cancers (PR, 1.39; 95% CI, 1.19 to 1.62) compared with for prostate cancers. Conclusion Morphine and diamorphine remain the stronghold for treating cancer pain in the United Kingdom. Opioid prescription rates are increasing over time. Prescription rates are lower for older people for all opioids, suggesting that this group needs attention.
Pemetrexed Versus Pemetrexed and Carboplatin As Second-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the GOIRC 02-2006 Randomized Phase II Study and Pooled Analysis With the NVALT7 Trial
Authors: Ardizzoni Andrea , Tiseo Marcello , Boni Luca , Vincent Andrew D. , Passalacqua Rodolfo , Buti Sebastiano , Amoroso Domenico , Camerini Andrea , Labianca Roberto , Genestreti Giovenzio , Boni Corrado , Ciuffreda Libero , Di Costanzo Francesco , de Marinis Filippo , Crinò Lucio , Santo Antonio , Pazzola Antonio , Barbieri Fausto , Zilembo Nicoletta , Colantonio Ida , Tibaldi Carmelo , Mattioli Rodolfo , Cafferata Mara A. , Camisa Roberta , Smit Egbert F. 
Published: October 2012

Purpose To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS). Results From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). Conclusion Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.
Antibodies binding the ADAM10 substrate recognition domain inhibit Eph function
Authors: Atapattu Lakmali , Saha Nayanendu , Llerena Carmen , Vail Mary E. , Scott Andrew M. , Nikolov Dimitar B. , Lackmann Martin , Janes Peter W. 
Published: October 2012

Summary
The ADAM10 transmembrane metalloprotease cleaves a variety of cell surface proteins that are important in disease, including ligands for receptor tyrosine kinases of the erbB and Eph families. ADAM10-mediated cleavage of ephrins, the ligands for Eph receptors, is suggested to control Eph/ephrin-mediated cell-cell adhesion and segregation, important during normal developmental processes, and implicated in tumour neo-angiogenesis and metastasis. We previously identified a substrate-binding pocket in the ADAM10 C domain that binds the EphA/ephrin-A complex thereby regulating ephrin cleavage. We have now generated monoclonal antibodies specifically recognising this region of ADAM10, which inhibit ephrin cleavage and Eph/ephrin-mediated cell function, including ephrin-induced Eph receptor internalisation, phosphorylation and Eph-mediated cell segregation. Our studies confirm the important role of ADAM10 in cell-cell interactions mediated by both A- and B-type Eph receptors, and suggest antibodies against the ADAM10 substrate-recognition pocket as promising therapeutic agents, acting by inhibiting cleavage of ephrins and potentially other ADAM10 substrates.
Sirtuin-3 modulates Bak- and Bax-dependent apoptosis
Authors: Verma Manish , Shulga Nataly , Pastorino John G. 
Published: October 2012

Summary
Sirtuin-3 exhibits properties of a tumor suppressor partly emanating from its ability to control the state of mitochondrial metabolism, with depletion of sirt-3 increasing tumor cell survival. In the present study we demonstrate that depletion of sirtuin-3 brings about an anti-apoptotic phenotype via stimulating cyclophilin-D activity, which promotes the binding of hexokinase II to the mitochondria, thereby preventing Bak/Bax dependent mitochondrial injury and cell death. By contrast, increased expression of sirtuin-3 decreases cyclophilin-D activity, resulting in detachment of hexokinase II from the mitochondria and potentiation of Bak- and Bax-induced mitochondrial injury and loss of cell viability.
Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic reticulum
Authors: López-Sanjurjo Cristina I. , Tovey Stephen C. , Prole David L. , Taylor Colin W. 
Published: October 2012

SummaryMost intracellular Ca2+ signals result from opening of Ca2+ channels in the plasma membrane or endoplasmic reticulum (ER), and they are reversed by active transport across these membranes or by shuttling Ca2+ into mitochondria. Ca2+ channels in lysosomes contribute to endo-lysosomal trafficking and Ca2+ signalling, but the role of lysosomal Ca2+ uptake in Ca2+ signalling is unexplored. Inhibition of lysosomal Ca2+ uptake by dissipating the H+ gradient (using bafilomycin A1), perforating lysosomal membranes (using glycyl-L-phenylalanine 2-naphthylamide) or lysosome fusion (using vacuolin) increased the Ca2+ signals evoked by receptors that stimulate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] formation. Bafilomycin A1 amplified the Ca2+ signals evoked by photolysis of caged Ins(1,4,5)P3 or by inhibition of ER Ca2+ pumps, and it slowed recovery from them. Ca2+ signals evoked by store-operated Ca2+ entry were unaffected by bafilomycin A1. Video-imaging with total internal reflection fluorescence microscopy revealed that lysosomes were motile and remained intimately associated with the ER. Close association of lysosomes with the ER allows them selectively to accumulate Ca2+ released by Ins(1,4,5)P3 receptors.
Temporal artery biopsy for giant cell arteritis: retrospective audit
Authors: Saedon Habiba , Saedon Mahmud , Goodyear Steve , Papettas Trifonas , Marshall Colette 
Published: October 2012

Objectives Temporal artery biopsy (TAB) is performed in suspected cases of sight-threatening giant cell arteritis (GCA). We aimed to determine the feasibility of TAB in patients who are suspected of having GCA. Design, setting and participants A retrospective audit of all patients undergoing TAB at a single teaching hospital between 2005 and 2011, identified from the histopathology database. Main outcome measures (1) Clinical profile and biochemical criteria associated with positive histology. (2) Proportion of negative histology patients who were commenced on steroid therapy. Results One hundred and fifty-three TAB were performed (mean age 70.8 years, men:women = 3:2, 110 Caucasian: 43 Asian). Thirty-two biopsies were positive for GCA and 121 were negative. In total, 68 (61%) of 112 negative TAB patients were clinically diagnosed with GCA despite histological findings ( P < 0.001). Nine out of 153 biopsies were non-arterial. Histologically positive TAB patients were of higher mean age (77.1 [95% CI 74.5–79.7] versus 69.1 [95% CI 66.7–71.6]; P < 0.001) and had a higher erythrocyte sedimentation rate (ESR) (60 [95% CI 46.1–73.9] versus 39.8 [95% CI 34.2–45.3]; P < 0.01)] than those with negative histology. Conclusions Raised ESR and higher age may be the most useful indicators of GCA. Many histologically negative individuals were nevertheless clinically diagnosed and managed as GCA.
Socioeconomic determinants of non-communicable-diseases among the Cypriot population: questionnaire study
Authors: Kiliari Nitsa , Theodosopoulou Eleni , Papanastasiou Elena , Charalambous Andreas 
Published: October 2012

Objective To investigate the extent to which the socioeconomic status of Cypriots is associated with the lifetime prevalence of self-reported non-communicable disease (NCDs), with emphasis on those accounting for most Death and Disability-adjusted Life Years (DALYs) among the population, including cardiovascular disease (CVD), metabolic risks and neuropsychiatric disorders. Design A nationally based survey conducted through personal interviews, using a structured questionnaire design. Setting Cyprus rural and urban areas (excluding Turkish-occupied areas). Participants Four hundred and sixty-five Cypriot adults of an average age of 53 years. Main outcome measures Lifetime prevalence of self-reported NCDs. Results Most self-reported NCDs were shown to have significant associations with socioeconomic status, defined for this study by level of education and family income. Education was significantly inversely associated with CVD (18.1% at elementary education level (EE); 2.7% at high school education level (HE); and 1.7% at University/College education level (UE)), hypertension (23.4% at EE; 8.6% at HE; and 2.6% at UE), hypercholesterolaemia (12.8% at EE; 7.1% at HE; and 5.2% at UE), obesity (10.7% at EE; 4.7% at HE; and 3.5% at UE), diabetes (13.8% at EE; 2.4% at HE; and 0.9% at UE), and drug addiction (7.6% at EE; 1.6% at HE; and 0.0% at UE). Depression was more frequent amongst middle level graduates (3.2% at EE; 5.1% at HE; and 2.6% at UE). Income was significantly negatively associated with CVD ( r = –0.130, p = 0.005), stress ( r = –0.103, p = 0.028) and drug addiction ( r = –0.117, p = 0.012), and significantly positively associated with the ‘no problems'statement ( r = 0.201, p = 0.000) which was reported by almost two fifths of the population. Worth noting is stress which, demonstrating no socioeconomic discrimination, was reported by high percentages of the population (17.2% of the sample). Conclusions Although with some limitations, this study has provided initial evidence for the existence of socioeconomically determined health inequalities, which may have potentially important implications for understanding the deeper aetiology of common NCDs and for informing public policies. More research in this area is required to reveal the magnitude of NCDS–socioeconomic relation.
Assessment of Lichens' Metabolic and Degradation Products at Dornava Manor
Authors: Ropret P. , Tavzes S. , Retko K. , Legan L. , Spec T. , Ocepek N. 
Published: October 2012

Five major types of lichen were discovered in the investigated specimens from Dornava Manor. All these lichens and/or their combinations are considered common lichenous overgrowth for the region and its climate. For all of the positively identified lichen species, it is common that they are found on a wide variety of calciferous or base-rich substrata, incl. mortar, brick, roofing tiles, walls, also in large urban areas (are not particularly disturbed by pollution/eutrophication), therefore preferring neutral to basic environment. They are well adapted to sunlight (from scarce direct solar irradiation to sites with very high direct solar irradiation) and can tolerate low water accessibility. In some of the lichens parietin, an orange organic pigment, was found, indicating the sun exposed areas. Additionally, carotenoids and pulvinic acid derivatives were identified, from which the metabolic pathway of lichens can be determined. These products can also represent biomarkers that can be linked to the survival strategies of lichen communities in stressed environmental habitats. For many of the investigated samples the lichens' degradation products like oxalates were identified, mainly calcium oxalate Weddellite, while the ammonium oxalate Oxammite is also possible.