bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fc-gamma receptor polymorphisms as predictive and prognostic factors in patients receiving oncolytic adenovirus treatment
Authors: Hirvinen Mari , Heiskanen Raita , Oksanen Minna , Pesonen Saila , Liikanen Ilkka , Joensuu Timo , Kanerva Anna , Cerullo Vincenzo , Hemminki Akseli 
Published: August 2013

Abstract

Background
Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy. Polymorphisms in Fc gamma receptors (FcgRs) lead to altered binding affinity of IgG between the receptor allotypes and therefore contribute to differences in immune defense mechanisms. Associations have been identified between FcgR polymorphisms and responsiveness to different immunotherapies. Taken together with the increasing understanding that immunological factors might determine the efficacy of oncolytic virotherapy we studied whether FcgR polymorphisms would have prognostic and/or predictive significance in the context of oncolytic adenovirus treatments.

Methods
235 patients with advanced solid tumors were genotyped for two FcgR polymorphisms, FcgRIIa-H131R (rs1801274) and FcgRIIIa-V158F (rs396991), using TaqMan based qPCR. The genotypes were correlated with patient survival and tumor imaging data.

Results
In patients treated with oncolytic adenoviruses, overall survival was significantly shorter if the patient had an FcgRIIIa-VV/ FcgRIIa-HR (VVHR) genotype combination (P = 0,032). In contrast, patients with FFHR and FFRR genotypes had significantly longer overall survival (P = 0,004 and P = 0,006, respectively) if they were treated with GM-CSF-armed adenovirus in comparison to other viruses. Treatment of these patients with unarmed virus correlated with shorter survival (P < 0,0005 and P = 0,016, respectively). Treating FFHH individuals with CD40L-armed virus resulted in longer survival than treatment with other viruses (P = 0,047).

Conclusions
Our data are compatible with the hypothesis that individual differences in effector cell functions, such as NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and tumor antigen presentation by APCs caused by polymorphisms in FcgRs could play role in the effectiveness of oncolytic virotherapies. If confirmed in larger populations, FcgR polymorphisms could have potential as prognostic and predictive biomarkers for oncolytic adenovirus therapies to enable better selection of patients for clinical trials. Also, putative associations between genotypes, different viruses and survival implicate potentially important mechanistic issues.
Rule–based regulatory and metabolic model for Quorum sensing in P. aeruginosa
Authors: Schaadt Nadine S , Steinbach Anke , Hartmann Rolf W , Helms Volkhard 
Published: August 2013

AbstractBackgroundIn the pathogenP. aeruginosa, the formation of virulence factors is regulated via Quorum sensing signaling pathways. Due to the increasing number of strains that are resistant to antibiotics, there is a high interest to develop novel antiinfectives. In the combat of resistant bacteria, selective blockade of the bacterial cell–to–cell communication (Quorum sensing) has gained special interest as anti–virulence strategy. Here, we modeled thelas,rhl, andpqsQuorum sensing systems by a multi–level logical approach to analyze how enzyme inhibitors and receptor antagonists effect the formation of autoinducers and virulence factors.ResultsOur rule–based simulations fulfill the behavior expected from literature considering the external level of autoinducers. In the presence of PqsBCD inhibitors, the external HHQ and PQS levels are indeed clearly reduced. The magnitude of this effect strongly depends on the inhibition level. However, it seems that the pyocyanin pathway is incomplete.ConclusionsTo match experimental observations we suggest a modified network topology in which PqsE and PqsR acts as receptors and an autoinducer as ligand that up–regulate pyocyanin in a concerted manner. While the PQS biosynthesis is more appropriate as target to inhibit the HHQ and PQS formation, blocking the receptor PqsR that regulates the biosynthesis reduces the pyocyanin level stronger.
External Quality Assessment (EQA) program for the preanalytical and analytical immunohistochemical determination of HER2 in breast cancer: an experience on a regional scale
Authors: Terrenato Irene , Arena Vincenzo , Pizzamiglio Sara , Pennacchia Ilaria , Perracchio Letizia , Buglioni Simonetta , Ercolani Cristiana , Sperati Francesca , Costarelli Leopoldo , Bonanno Elena , Baldini Daniela , Candia Silvia , Crescenzi Anna , Dal Mas Antonella , Di Cristofano Claudio , Gomes Vito , Grillo Lucia Rosalba , Pasquini Paola , Pericoli Maria Nicoletta , Ramieri Maria Teresa , Di Stefano Domenica , Ruco Luigi , Scarpino Stefania , Vitolo Domenico , d’Amati Giulia , Paradiso Angelo , Verderio Paolo , Mottolese Marcella 
Published: August 2013

Abstract

Background
An External Quality Assessment (EQA) program was developed to investigate the state of the art of HER2 immunohistochemical determination in breast cancer (BC) in 16 Pathology Departments in the Lazio Region (Italy). This program was implemented through two specific steps to evaluate HER2 staining (step 1) and interpretation (step 2) reproducibility among participants.

Methods
The management activities of this EQA program were assigned to the Coordinating Center (CC), the Revising Centers (RCs) and the Participating Centers (PCs). In step 1, 4 BC sections, selected by RCs, were stained by each PC using their own procedures. In step 2, each PC interpreted HER2 score in 10 BC sections stained by the CC. The concordance pattern was evaluated by using the kappa category-specific statistic and/or the weighted kappa statistic with the corresponding 95% Jackknife confidence interval.

Results
In step 1, a substantial/almost perfect agreement was reached between the PCs for scores 0 and 3+ whereas a moderate and fair agreement was observed for scores 1+ and 2+, respectively.
In step 2, a fully satisfactory agreement was observed for 6 out of the 16 PCs and a quite satisfactory agreement was obtained for the remaining 10 PCs.

Conclusions
Our findings highlight that in the whole HER2 evaluation process the two intermediate categories, scores 1+ and 2+, are less reproducible than scores 0 and 3+. These findings are relevant in clinical practice where the choice of treatment is based on HER2 positivity, suggesting the need to share evaluation procedures within laboratories and implement educational programs.
Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population
Authors: de Oliveira Alvim Rafael , Santos Paulo Caleb Junior Lima , Musso Mariane Manso , de Sá Cunha Roberto , Krieger José Eduardo , Mill José Geraldo , Pereira Alexandre Costa 
Published: August 2013

AbstractBackgroundIndependent of other cardiovascular (CV) risk factors, increased arterial stiffness has been established as a predictor of morbidity and mortality. The main aim of this study was to investigate the impact of diabetes on arterial stiffness in a representative sample of an urban Brazilian population plus Amerindians.MethodsA total of 1,415 individuals from the general population were randomly selected plus 588 Amerindians from a native community in Brazil. In addition, a sub-sample of 380 individuals from the general population had 5-year follow-up data. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior, Colson; Garges les Gonesses, France) and increased arterial stiffness was defined as PWV ≥ 12 m/s.ResultsIn the overall group, diabetic individuals had higher frequencies of increased arterial stiffness and hypertension. They also had higher values of PWV, body mass index, total cholesterol, triglycerides, systolic and diastolic blood pressures compared to non-diabetic individuals (p < 0.01). In an analysis stratified by hypertension, PWV values and increased arterial stiffness frequency were higher in diabetic individuals in both groups (hypertensive and non-hypertensive) (p < 0.05). Furthermore, higher risk for increased arterial stiffness was observed in the diabetic individuals from the overall group (OR = 2.27; CI = 1.47-3.52,p < 0.001) and from the hypertensive group (OR = 2.70; CI = 1.58-4.75,p < 0.001), adjusted for covariates. Regarding the ethnic stratification, diabetic individuals from Amerindian, White, and Mulatto (mixed-race) groups had higher PWV values and a greater frequency of increased arterial stiffness compared to non-diabetic individuals. Both diabetic and non-diabetic individuals had higher PWV values after 5 years. There was no significant difference in the 5-year PWV progression in diabetic compared to non-diabetic individuals.ConclusionsThese results confirm, in a sample of Brazilian population, that the presence of diabetes is associated with increased arterial stiffness and it may contribute in part to increased cardiovascular risk in diabetic patients.
Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain
Authors: Dan Ayaho , Takahashi Muneaki , Masuda-Suzukake Masami , Kametani Fuyuki , Nonaka Takashi , Kondo Hiromi , Akiyama Haruhiko , Arai Takao , Mann David MA , Saito Yuko , Hatsuta Hiroyuki , Murayama Shigeo , Hasegawa Masato 
Published: August 2013

Abstract

Background
Intracytoplasmic inclusions composed of filamentous tau proteins are defining characteristics of neurodegenerative tauopathies, but it remains unclear why different tau isoforms accumulate in different diseases and how they induce abnormal filamentous structures and pathologies. Two tau isoform-specific antibodies, RD3 and RD4, are widely used for immunohistochemical and biochemical studies of tau species in diseased brains.

Results
Here, we show that extensive irreversible post-translational deamidation takes place at asparagine residue 279 ( N279) in the RD4 epitope of tau in Alzheimer’s disease (AD), but not corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP), and this modification abrogates the immunoreactivity to RD4. An antiserum raised against deamidated RD4 peptide specifically recognized 4R tau isoforms, regardless of deamidation, and strongly stained tau in AD brain. We also found that mutant tau with N279D substitution showed reduced ability to bind to microtubules and to promote microtubule assembly.

Conclusion
The biochemical and structural differences of tau in AD from that in 4R tauopathies found in this study may therefore have implications for prion-like propagation of tau.
Trade-offs in quality of life and survival with chemotherapy for advanced breast cancer: mature results of a randomized trial comparing single-agent mitoxantrone with combination cyclophosphamide, methotrexate, 5-fluorouracil and prednisone
Authors: Lee Chee Khoon , Gebski Val J , Coates Alan S , Veillard Anne-Sophie , Harvey Vernon , Tattersall Martin HN , Byrne Michael J , Brigham Brian , Forbes John , Simes R John 
Published: August 2013

Abstract

Background
We evaluate trade-offs between quality of life (QoL) and survival improvement for two chemotherapy regimens in advanced breast cancer. We also report on the long-term survival of patients in the ANZ 8614 clinical trial.

Methods
A total of 391 patients were randomized to mitoxantrone (14 mg/m2 intravenously every 21 days) or a combination of cyclophosphamide 100 mg/m2 and prednisone 40 mg/m2 orally days 1 to 14 plus methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously days 1 and 8 every 28 days (CMFP). QoL was self-assessed on 14 linear analog scales. We computed the mean differences between the two treatments as products of the mean differences in global QoL, progression-free survival and overall survival.

Results
CMFP led to a higher overall tumor response (39% vs. 25%, P=0.004) and longer progression-free survival (PFS) (median 5.6 vs 3.9 months, P=0.02) but with significantly more toxicity from alopecia, mucositis, diarrhea, anemia and lethargy. Overall survival (OS) was similar in the two groups (median 10.1 vs 11.6 months, P=0.81). QoL over the first 12 weeks was rated better by patients on CMFP for mood (P=0.04), nausea and vomiting (P=0.01), and feeling sick (P=0.02) but worse for hair loss (P<0.0001). A weighted combination of individual QoL items favoured CMFP (subset score mean difference 2.4, P=0.03). A global QoL score tended to favour CMFP (global score mean difference 1.7, P=0.18). Quality-adjusted PFS was significantly longer with CMFP (mean 7.208 vs 5.965 months, P=0.04), but quality-adjusted OS was not significantly different (mean 11.832 vs 11.315 months, P=0.57).

Conclusion
Despite the greater toxicity, the superior antitumor activity of CMFP led to an overall improvement in quality-adjusted PFS. In advanced breast cancer, in clinical decision making about treatment for palliative intent, the principle used to assess trade-offs between antitumor efficacy and toxicity remains relevant and applicable to all modern therapeutic agents.
SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis
Authors: Gómez-Vaquero Carmen , Corrales Alfonso , Zacarías Andrea , Rueda-Gotor Javier , Blanco Ricardo , González-Juanatey Carlos , Llorca Javier , González-Gay Miguel A 
Published: August 2013

Abstract
Introduction
Our objective was to determine which one of the two function charts available in Spain to calculate cardiovascular (CV) risk, Systematic COronary Risk Evaluation (SCORE) or Framingham-REgistre GIroní del COR (REGICOR), should be used in patients with rheumatoid arthritis (RA).

Methods
A series of RA patients seen over a one-year period without history of CV events were assessed. SCORE, REGICOR, modified (m)SCORE and mREGICOR according to the European League Against Rheumatism (EULAR) recommendations were applied. Carotid ultrasonography (US) was performed. Carotid intima-media thickness (cIMT) > 0.90 mm and/or carotid plaques were used as the gold standard test for severe subclinical atherosclerosis and high CV risk (US+). The area under the receiver operating curves (AUC) for the predicted risk for mSCORE and mREGICOR were calculated according to the presence of severe carotid US findings (US+).

Results
We included 370 patients (80% women; mean age 58.9 ± 13.7 years); 36% had disease duration of 10 years or more; rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) were positive in 68%; and 17% had extra-articular manifestations. The EULAR multiplier factor was used in 122 (33%) of the patients. The mSCORE was 2.16 ± 2.49% and the mREGICOR 4.36 ± 3.46%. Regarding US results, 196 (53%) patients were US+. The AUC mSCORE was 0.798 (CI 95%: 0.752 to 0.844) and AUC mREGICOR 0.741 (95% CI; 0.691 to 0.792). However, mSCORE and mREGICOR failed to identify 88% and 91% of US+ patients. More than 50% of patients with mSCORE ≥1% or mREGICOR >1% were US+.

Conclusions
Neither of these two function charts was useful in estimating CV risk in Spanish RA patients.
Distinct development and functions of resident and recruited liver Kupffer cells/macrophages
Authors: Ikarashi Masami , Nakashima Hiroyuki , Kinoshita Manabu , Sato Atsushi , Nakashima Masahiro , Miyazaki Hiromi , Nishiyama Kiyoshi , Yamamoto Junji , Seki Shuhji 
Published: August 2013

ABSTRACTAlthough mouse liver F4/80+ Kupffer cells consist of cytokine-producing CD11b+ cells and phagocytic CD68+ cells, an undefined CD11b− CD68− subset (30%) also exists. We herein demonstrate a more fundamental classification by adding CD32 (FcγRII), which covers most liver F4/80+ cells and the distinct functions of them. Among the F4/80+ cells, 50%, 40%, and 30% of cells were CD32+, CD68+, and CD11b+, respectively, and one-half of the CD68+ cells coexpressed CD32. CD68+ and CD32+ cells, but not CD11b+ cells, expressed a phagocytosis-related CRIg. Gy (6) irradiation depleted liver CD11b+ cells and those in the spleen, bone marrow, and peripheral blood but not liver CD32/CD68+ cells. Transfer of bone marrow cells into the irradiated mice reconstituted liver CD11b+ cells. Conversely, clodronate pretreatment depleted only liver CD32/CD68+ cells but not liver CD11b+ cells and peripheral blood or spleen CD11b+ monocytes/macrophages. Moreover, the CD32+ cells might be precursors of CD68+ cells, as a large proportion of CD32+ cells expressed the c-kit (CD117), and CD34 and CD32+ cells acquired CD68 immediately after bacteria administration. CD32/CD68+ cells, but not CD11b+ cells, expressed resident macrophage-specific MerTK and CD64 (FcγRI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68+ subset is engaged in systemic bactericidal activity, whereas the CD11b+ subset is pivotal for liver antitumor immunity. Human liver CD14+ Kupffer cells could also be classified into three similar subsets. These results suggest that liver CD68+ Kupffer cells and CD11b+ Kupffer cells/macrophages are developmentally and functionally distinct subsets.
Extrinsic and intrinsic control of macrophage inflammatory responses
Authors: Cohen Heather B , Mosser David M 
Published: August 2013

ABSTRACTMacrophages make major contributions to inflammatory immunopathology. In this work, we examine three disease scenarios, in which M1s play a major role early in the disease but eventually transitions into a population of cells with immunoregulatory activity. We propose that the transition from an inflammatory to a regulatory phenotype is a natural progression that regularly occurs in stimulated macrophages and that the timing of this transition is critical to maintaining homeostasis. In the first section of this review, we discuss the exogenous microenvironmental cues that may induce macrophages to enter a regulatory state. In the second half of this review, we discuss a novel mechanism, whereby TLR-stimulated macrophages can intrinsically induce their own regulatory activation state. They do so by secreting and synthesizing endogenous “reprogramming” signals that work in an autocrine fashion to promote a regulatory phenotype. We propose that these endogenous regulatory mechanisms exist to prevent macrophage-mediated immunopathology. Thus, macrophages can respond to endogenous and exogenous cues to regulate their activation state, and without these controlled regulatory responses, M1 would persist to the detriment of the host.
Oxygen levels determine the ability of glucocorticoids to influence neutrophil survival in inflammatory environments
Authors: Marwick John A , Dorward David A , Lucas Christopher D , Jones Katie O , Sheldrake Tara A , Fox Sarah , Ward Carol , Murray Joanna , Brittan Mairi , Hirani Nik , Duffin Rodger , Dransfield Ian , Haslett Christopher , Rossi Adriano G 
Published: August 2013

ABSTRACTGCs are highly effective in treating a wide range of inflammatory diseases but are limited in their ability to control neutrophilic lung inflammation in conditions such as COPD. Neutrophil apoptosis, a central feature of inflammation resolution, is delayed in response to microenvironmental cues, such as hypoxia and inflammatory cytokines, present at inflamed sites. GCs delay neutrophil apoptosis in vitro, and this may therefore limit the ability of GCs to control neutrophilic inflammation. This study assesses the effect GCs have on hypoxia- and inflammatory cytokine-induced neutrophil survival. Human neutrophils were treated with GCs in the presence or absence of GM-CSF or inflammatory macrophage-CM at a range of oxygen concentrations (21–1% oxygen). Neutrophil apoptosis and survival were assessed by flow cytometry and morphological analysis and neutrophil function, by stimulus-induced shape change and respiratory burst. Dexamethasone promoted neutrophil survival at 21%, 10%, and 5% oxygen but not at 1% oxygen. Interestingly, GM-CSF and inflammatory CM increased neutrophil survival significantly, even at 1% oxygen, with cells remaining functionally active at 96 h. Dexamethasone was able to reduce the prosurvival effect of GM-CSF and inflammatory CM in a hypoxic environment. In conclusion, we found that GCs do not augment neutrophil survival in the presence of severe hypoxia or proinflammatory mediators. This suggests that GCs would not promote neutrophil survival at sites of inflammation under these conditions.
Mechanical performance of spider orb webs is tuned for high-speed prey
Authors: Sensenig Andrew T. , Kelly Sean P. , Lorentz Kimberly A. , Lesher Brittany , Blackledge Todd A. 
Published: August 2013

SUMMARYSpiders in the Orbiculariae spin orb webs that dissipate the mechanical energy of their flying prey, bringing the insects to rest and retaining them long enough for the spider to attack and subdue their meals. Small prey are easily stopped by webs but provide little energetic gain. While larger prey offer substantial nourishment, they are also challenging to capture and can damage the web if they escape. We therefore hypothesized that spider orb webs exhibit properties that improve their probability of stopping larger insects while minimizing damage when the mechanical energy of those prey exceeds the web's capacity. Large insects are typically both heavier and faster flying than smaller prey, but speed plays a disproportionate role in determining total kinetic energy, so we predicted that orb webs may dissipate energy more effectively under faster impacts, independent of kinetic energy per se. We used high-speed video to visualize the impact of wooden pellets fired into orb webs to simulate prey strikes and tested how capture probability varied as a function of pellet size and speed. Capture probability was virtually nil above speeds of ~3 m s−1. However, successful captures do not directly measure the maximum possible energy dissipation by orb webs because these events include lower-energy impacts that may not significantly challenge orb web performance. Therefore, we also compared the total kinetic energy removed from projectiles that escaped orb webs by breaking through the silk, asking whether more energy was removed at faster speeds. Over a range of speeds relevant to insect flight, the amount of energy absorbed by orb webs increases with the speed of prey (i.e. the rates at which webs are stretched). Orb webs therefore respond to faster – and hence higher kinetic energy – prey with better performance, suggesting adaptation to capture larger and faster flying insect prey. This speed-dependent toughness of a complex structure suggests the utility of the intrinsic toughness of spider silk and/or features of the macro-design of webs for high-velocity industrial or military applications, such as ballistic energy absorption.