bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus
Authors: Rullo Ornella J , Woo Jennifer MP , Parsa Miriam F , Hoftman Alice DC , Maranian Paul , Elashoff David A , Niewold Timothy B , Grossman Jennifer M , Hahn Bevra H , McMahon Maureen , McCurdy Deborah K , Tsao Betty P 
Published: January 2013

Abstract
Introduction
Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity.

Methods
cOPN and cNGAL were measured in prospectively followed pSLE (n = 42) and adult SLE (aSLE; n = 23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI).

Results
Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P = 0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r = 0.51 and 0.52, P = 0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P = 0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P = 0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%).

Conclusion
High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.
Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models
Authors: Issa Amine , Gill Jason W , Heideman Marinus R , Sahin Ozgur , Wiemann Stefan , Dey Julien H , Hynes Nancy E 
Published: January 2013

Abstract
Introduction
Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As alterations in fibroblast growth factor receptor (FGFR) activity have been implicated in breast cancer, we examined in breast cancer models with autocrine FGFR activity the impact of targeting FGFRs in vivo with a selective kinase inhibitor in combination with an inhibitor of PI3K/mTOR or with a pan-ErbB inhibitor.

Methods
Using 4T1 or 67NR models of basal-like breast cancer, tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/mTOR inhibitor (NVP-BEZ235) or a pan-ErbB inhibitor (AEE788) individually or in combination. To uncover mechanisms underlying inhibitor action, signaling pathway activity was examined in tumor lysates and transcriptome analysis carried out to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P-Tyr RTK) were also used to screen 4T1 tumors.

Results
The combination of dovitinib + NVP-BEZ235 causes tumor stasis and strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. P-Tyr RTK arrays identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the tumor models revealed that the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a significant decrease in lung metastasis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity.

Conclusions
The work presented here shows that in the breast cancer models examined, the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 results in strong inhibition of tumor growth and a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and PI3K/Akt/mTOR signaling pathways. The resultant decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group, suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results have implications for targeted therapy.
Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98
Authors: Loi Sherene , Sirtaine Nicolas , Piette Fanny , Salgado Roberto , Viale Giuseppe , Van Eenoo Françoise , Rouas Ghizlane , Francis Prudence , Crown John P.A. , Hitre Erika , de Azambuja Evandro , Quinaux Emmanuel , Di Leo Angelo , Michiels Stefan , Piccart Martine J. , Sotiriou Christos 
Published: January 2013

Purpose Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes. Patients and Methods We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. Results There was no significant prognostic association in the global nor estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). Conclusion In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
Phase II Study of Gemcitabine, Carboplatin, and Bevacizumab in Patients With Advanced Unresectable or Metastatic Urothelial Cancer
Authors: Balar Arjun V. , Apolo Andrea B. , Ostrovnaya Irina , Mironov Svetlana , Iasonos Alexia , Trout Alisa , Regazzi Ashley M. , Garcia-Grossman Ilana R. , Gallagher David J. , Milowsky Matthew I. , Bajorin Dean F. 
Published: January 2013

Purpose Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. Patients and Methods Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. Results Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. Conclusion The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.
TBS (Trabecular Bone Score) and Diabetes-Related Fracture Risk
Authors: Leslie William D. , Aubry-Rozier Berengère , Lamy Olivier , Hans Didier ,   for the Manitoba Bone Density Program
Published: January 2013

AbstractContext:Type 2 diabetes is associated with increased fracture risk but paradoxically greater bone mineral density (BMD). Trabecular bone score (TBS) is derived from the texture of the spine dual x-ray absorptiometry (DXA) image and is related to bone microarchitecture and fracture risk, providing information independent of BMD.Objective:This study evaluated the ability of lumbar spine TBS to account for increased fracture risk in diabetes.Design and Setting:We performed a retrospective cohort study using BMD results from a large clinical registry for the province of Manitoba, Canada.Patients:We included 29,407 women 50 years old and older with baseline DXA examinations, among whom 2356 had diagnosed diabetes.Main Outcome Measures:Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident nontraumatic major osteoporotic fractures (mean follow-up 4.7 years).Results:Diabetes was associated with higher BMD at all sites but lower lumbar spine TBS in unadjusted and adjusted models (all P &lt; .001). The adjusted odds ratio (aOR) for a measurement in the lowest vs the highest tertile was less than 1 for BMD (all P &lt; .001) but was increased for lumbar spine TBS [aOR 2.61, 95% confidence interval (CI) 2.30–2.97]. Major osteoporotic fractures were identified in 175 women (7.4%) with and 1493 (5.5%) without diabetes (P &lt; .001). Lumbar spine TBS was a BMD-independent predictor of fracture and predicted fractures in those with diabetes (adjusted hazard ratio 1.27, 95% CI 1.10–1.46) and without diabetes (hazard ratio 1.31, 95% CI 1.24–1.38). The effect of diabetes on fracture was reduced when lumbar spine TBS was added to a prediction model but was paradoxically increased from adding BMD measurements.Conclusions:Lumbar spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD.
Tyrosyl Phosphorylated PAK1 Regulates Breast Cancer Cell Motility in Response to Prolactin through Filamin A
Authors: Hammer Alan , Rider Leah , Oladimeji Peter , Cook Leslie , Li Quanwen , Mattingly Raymond R. , Diakonova Maria 
Published: January 2013

AbstractThe p21-activated serine-threonine kinase (PAK1) is activated by small GTPase-dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation. Here, we have used human breast cancer T47D cells stably overexpressing PAK1 wild type or PAK1 Y3F mutant in which Tyr(s) 153, 201, and 285 were mutated to phenylalanines to demonstrate that phosphorylation of these three tyrosines are required for maximal PRL-dependent ruffling. In addition, phosphorylation of these three tyrosines is required for increased migration of T47D cells in response to PRL as assessed by two independent motility assays. Finally, we show that PAK1 phosphorylates serine (Ser) 2152 of the actin-binding protein filamin A to a greater extent when PAK1 is tyrosyl phosphorylated by JAK2. Down-regulation of PAK1 or filamin A abolishes the effect of PRL on cell migration. Thus, our data presented here bring some insight into the mechanism of PRL-stimulated motility of breast cancer cells.
Prolonged Infusion Antibiotics for Suspected Gram-Negative Infections in the ICU: A Before-After Study
Authors: Arnold Heather M , Hollands James M , Skrupky Lee P , Smith Jennifer R , Juang Paul H , Hampton Nicholas B , McCormick Sandra , Reichley Richard M , Hoban Alex , Hoffmann Justin , Micek Scott T , Kollef Marin H 
Published: January 2013

BACKGROUND: β-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of β-lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis.
Association Between Periodontal Disease and Chronic Obstructive Pulmonary Disease: A Reality or Just a Dogma?
Authors: Peter Kalpak Prafulla , Mute Bhumika Ramchandra , Doiphode Satish Shripad , Bardapurkar Suhas Jagannath , Borkar Mangala Sonawani , Raje Dhananjay Vasant 
Published: January 2013

Background: In the past few years, the association between chronic obstructive pulmonary disease (COPD) and periodontal disease has been promulgated. The present study is aimed at determining the association between these two diseases.Methods: This observational study includes 501 individuals consisting of 102 patients (case group) having COPD and 399 individuals as controls. Individuals in the case group were well‐functioning and ambulatory patients having COPD as determined by their history and their values of forced expiratory volume in 1 second (FEV1) and forced vital capacity. Periodontal status was evaluated by the following five indices: 1) plaque index; 2) oral hygiene index (OHI); 3) gingival index (GI); 4) probing depth (PD); and 5) clinical attachment level (CAL). Lung function test was performed by all the patients (case group), who were then graded into mild, moderate, severe, and very severe.Results: Preliminary analysis was performed to identify the covariates in this study. Individuals in the case group had significantly higher CAL, PD, and OHI (P <0.0001) compared with the control group after adjusting for covariates. A significant negative correlation was observed between FEV1 values and CAL, PD, and GI, thus indicating a trend in which severity of lung obstruction increased as these periodontal indices worsened.Conclusion: Although the present study cannot ascertain causal association, it provides substantial evidence that poor periodontal health is associated with obstructive lung disease.
Ridge Preservation Comparing Socket Allograft Alone to Socket Allograft Plus Facial Overlay Xenograft: A Clinical and Histologic Study in Humans
Authors: Poulias Evmenios , Greenwell Henry , Hill Margaret , Morton Dean , Vidal Ricardo , Shumway Brian , Peterson Thomas L. 
Published: January 2013

Background: Previous studies of ridge preservation showed a loss of ≈18% or 1.5 mm of crestal ridge width in spite of treatment. The primary aim of this randomized, controlled, masked clinical trial is to compare a socket graft to the same treatment plus a buccal overlay graft, both with a polylactide membrane, to determine if loss of ridge width can be prevented by use of an overlay graft.Methods: Twelve patients who served as positive controls received an intrasocket mineralized cancellous allograft (socket group), and 12 patients received the same socket graft procedure plus buccal overlay cancellous xenograft (overlay group). Horizontal ridge dimensions were measured with a digital caliper, and vertical ridge changes were measured from a stent. Before implant placement, at 4 months, a trephine core was obtained for histologic analysis.Results: The mean horizontal ridge width at the crest for the socket group decreased from 8.7 ± 1.0 to 7.1 ± 1.5 mm for a mean loss of 1.6 ± 0.8 mm (P <0.05), whereas the same measurement for the overlay group decreased from 8.4 ± 1.4 to 8.1 ± 1.4 mm for a mean loss of 0.3 ± 0.9 mm (P >0.05). The overlay group was significantly different from the socket group (P <0.05). Histologic analysis revealed that the socket group had 35% ± 16% vital bone, and the overlay group had 40% ± 16% (P >0.05).Conclusions: The overlay treatment significantly prevented loss of ridge width and preserved or augmented the buccal contour. The socket and overlay groups healed with a high percentage of vital bone.
Mutually algebraic structures and expansions by predicates
Authors: Laskowski Michael C. 
Published: January 2013

AbstractWe introduce the notions of a mutually algebraic structures and theories and prove many equivalents. A theory T is mutually algebraic if and only if it is weakly minimal and trivial if and only if no model M of T has an expansion (M, A) by a unary predicate with the finite cover property. We show that every structure has a maximal mutually algebraic reduct. and give a strong structure theorem for the class of elementary extensions of a fixed mutually algebraic structure.
Unbounded and dominating reals in Hechler extensions
Authors: Palumbo Justin 
Published: January 2013

AbstractWe give results exploring the relationship between dominating and unbounded reals in Hechler extensions, as well as the relationships among the extensions themselves. We show that in the standard Hechler extension there is an unbounded real which is dominated by every dominating real, but that this fails to hold in the tree Hechler extension. We prove a representation theorem for dominating reals in the standard Hechler extension: every dominating real eventually dominates a sandwich composition of the Hechler real with two ground model reals that monotonically converge to infinity. We apply our results to negatively settle a conjecture of Brendle and Löwe (Conjecture 15 of [4]). We also answer a question due to Laflamme.
Failure of treatment of impacted canines associated with invasive cervical root resorption
Authors: Becker Adrian , Abramovitz Itzhak , Chaushu Stella 
Published: January 2013

ABSTRACT

Objectives:
To propose invasive cervical root resorption (ICRR) as an unrecognized and/or overlooked etiologic factor in the failure of response of an impacted tooth to orthodontic traction and to underline the importance of cone beam computerized tomography (CBCT) for early and accurate diagnosis of ICRR.

Materials and Methods:
Fourteen patients (age 13–21 years) with impacted canines (15 canines) that had failed to respond to orthodontic forces and that exhibited ICRR formed the case series for this investigation. The initial diagnosis, treatment, clinical and radiographic expression of failure, and adverse effects on adjacent teeth were analyzed.

Results:
Initial diagnosis had been performed on plane radiographs. The orthodontist was absent during surgery in 11 patients. Nine canines had been exposed by open procedures. ICRR was not related to the severity of impaction. Its diagnosis was made on existing radiographs, new films, and/or new CBCT. The severity of the lesions was Class 3 or 4, and the teeth were finally extracted. Loss of anchorage characterized 11 patients. Apical resorption of the roots of adjacent teeth was diagnosed in 9 patients.

Conclusions:
ICRR is a frequently undiagnosed or unrecognized cause of failure of orthodontic resolution of impacted canines and should be distinguished from replacement resorption. CBCT should be used for its early detection and accurate assessment of potential damage to adjacent anchor teeth.