bluuebunny/crossref_metadata_2025_split huggingface dataset:
p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses
Authors: Hardwick Nicola R. , Carroll Mary , Kaltcheva Teodora , Qian Dajun , Lim Dean , Leong Lucille , Chu Peiguo , Kim Joseph , Chao Joseph , Fakih Marwan , Yen Yun , Espenschied Jonathan , Ellenhorn Joshua D. I. , Diamond Don J. , Chung Vincent 
Published: July 2014

AbstractPurpose: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers.Experimental Design: Three patients were vaccinated with 1.0 × 108 plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro.Results: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P = 0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent.Conclusion: p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. Clin Cancer Res; 20(17); 4459–70. ©2014 AACR.
SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies
Authors: Deckert Jutta , Wetzel Marie-Cécile , Bartle Laura M. , Skaletskaya Anna , Goldmacher Victor S. , Vallée François , Zhou-Liu Qing , Ferrari Paul , Pouzieux Stéphanie , Lahoute Charlotte , Dumontet Charles , Plesa Adriana , Chiron Marielle , Lejeune Pascale , Chittenden Thomas , Park Peter U. , Blanc Véronique 
Published: July 2014

AbstractPurpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984.Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice.Results: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells.Conclusion: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies. Clin Cancer Res; 20(17); 4574–83. ©2014 AACR.
Measurements of Form and Frictional Drags over a Rough Topographic Bank
Authors: Wijesekera H. W. , Jarosz E. , Teague W. J. , Wang D. W. , Fribance D. B. , Moum J. N. , Warner S. J. 
Published: July 2014

AbstractPressure differences across topography generate a form drag that opposes the flow in the water column, and viscous and pressure forces acting on roughness elements of the topographic surface generate a frictional drag on the bottom. Form drag and bottom roughness lengths were estimated over the East Flower Garden Bank (EFGB) in the Gulf of Mexico by combining an array of bottom pressure measurements and profiles of velocity and turbulent kinetic dissipation rates. The EFGB is a coral bank about 6 km wide and 10 km long located at the shelf edge that rises from 100-m water depth to about 18 m below the sea surface. The average frictional drag coefficient over the entire bank was estimated as 0.006 using roughness lengths that ranged from 0.001 cm for relatively smooth portions of the bank to 1–10 cm for very rough portions over the corals. The measured form drag over the bank showed multiple time-scale variability. Diurnal tides and low-frequency motions with periods ranging from 4 to 17 days generated form drags of about 2000 N m−1 with average drag coefficients ranging between 0.03 and 0.22, which are a factor of 5–35 times larger than the average frictional drag coefficient. Both linear wave and quadratic drag laws have similarities with the observed form drag. The form drag is an important flow retardation mechanism even in the presence of the large frictional drag associated with coral reefs and requires parameterization.
Equations of Atmospheric Motion in Non-Eulerian Vertical Coordinates: Vector-Invariant Form and Quasi-Hamiltonian Formulation
Authors: Dubos Thomas , Tort Marine 
Published: July 2014

Abstract
The curl form of equations of inviscid atmospheric motion in general non-Eulerian coordinates is obtained. Narrowing down to a general vertical coordinate, a quasi-Hamiltonian form is then obtained in a Lagrangian, isentropic, mass-based or z-based vertical coordinate. In non-Lagrangian vertical coordinates, the conservation of energy by the vertical transport terms results from the invariance of energy under the vertical relabeling of fluid parcels. A complete or partial separation between the horizontal and vertical dynamics is achieved, except in the Eulerian case. The horizontal–vertical separation is especially helpful for (quasi-)hydrostatic systems characterized by vanishing vertical momentum. Indeed for such systems vertical momentum balance reduces to a simple statement: total energy is stationary with respect to adiabatic vertical displacements of fluid parcels. From this point of view the purpose of (quasi-)hydrostatic balance is to determine the vertical positions of fluid parcels, for which no evolution equation is readily available. This physically appealing formulation significantly extends previous work.
The general formalism is exemplified for the fully compressible Euler equations in a Lagrangian vertical coordinate and a Cartesian (x, z) slice geometry, and the deep-atmosphere quasi-hydrostatic equations in latitude–longitude horizontal coordinates. The latter case, in particular, illuminates how the apparent intricacy of the time-dependent metric terms and of the additional forces can be absorbed into a proper choice of prognostic variables. In both cases it is shown how the quasi-Hamiltonian form leads straightforwardly to the conservation of energy using only integration by parts.
Relationships with previous work and implications for stability analysis and the derivation of approximate sets of equations and energy-conserving numerical schemes are discussed.
Hispanic residential ethnic density and depression in post–acute coronary syndrome patients: Re-thinking the role of social support
Authors: Denton Ellen-ge D , Shaffer Jonathan A , Alcantara Carmela , Clemow Lynn , Brondolo Elizabeth 
Published: July 2014

Background: The ethnic density hypothesis suggests that ethnic density confers greater social support and consequently protects against depressive symptoms in ethnic minority individuals. However, the potential benefits of ethnic density have not been examined in individuals who are facing a specific and salient life stressor. Aims: We examined the degree to which the effects of Hispanic ethnic density on depressive symptoms are explained by socioeconomic resources and social support. Methods: Patients with acute coronary syndrome (ACS, N = 472) completed the Beck Depression Inventory (BDI) and measures of demographics, ACS clinical factors and perceived social support. Neighborhood characteristics, including median income, number of single parent households and Hispanic ethnic density, were extracted from the American Community Survey Census (2005–2009) for each patient using his or her geocoded address. Results: In a linear regression analysis adjusted for demographic and clinical factors, Hispanic ethnic density was positively associated with depressive symptoms (β = .09, standard error (SE) = .04, p = .03). However, Hispanic density was no longer a significant predictor of depressive symptoms when neighborhood characteristics were controlled. The relationship of Hispanic density on depressive symptoms was moderated by nativity status. Among US-born patients with ACS, there was a significant positive relationship between Hispanic density and depressive symptoms and social support significantly mediated this effect. There was no observed effect of Hispanic density to depressive symptoms for foreign-born ACS patients. Conclusion: Although previous research suggests that ethnic density may be protective against depression, our data suggest that among patients with ACS, living in a community with a high concentration of Hispanic individuals is associated with constrained social and economic resources that are themselves associated with greater depressive symptoms. These data add to a growing body of literature on the effects of racial or ethnic segregation on health outcomes.
Low Wound Complication Rates for the Lateral Extensile Approach for Calcaneal ORIF When the Lateral Calcaneal Artery Is Patent
Authors: Bibbo Christopher , Ehrlich David A. , Nguyen Hoang M.L. , Levin L. Scott , Kovach Stephen J. 
Published: July 2014

Background: Historically, the lateral extensile approach for calcaneal fracture osteosynthesis has had relatively high rates of wound healing problems. The vascular territory (angiosome) of the lateral foot is now known to be dependent upon the lateral calcaneal branch of the peroneal artery (LCBP artery). We postulated that patency of the LCBP artery may have a profound positive impact on incisional wound healing for calcaneal open reduction and internal fixation (ORIF). Methods: Ninety consecutive calcaneal fractures that met operative criteria were preoperatively evaluated for the presence of a Doppler signal in the LCBP artery and were followed for the development of wound healing problems. Results: Among these 90 fractures, 85 had a positive preoperative Doppler signal along the course of the LCBP artery (94%) and 5 had no Doppler signal (6%). All patients underwent ORIF via a lateral extensile approach. Overall, incisional wound healing problems occurred in 6 of 90 calcaneal incisions (6.5%). All 5 feet that exhibited an absent Doppler signal in the LCPB artery developed an incisional wound healing complication (5/6, approximately 83%): 2 large apical wounds and 3 major dehiscence/slough. However, among the 84 feet that possessed a positive preoperative Doppler signal in the LCBP artery, there was only 1 (1/84, approximately 1%) incisional wound healing problem ( P < .0001, Fischer’s exact test). Smokers with a positive Doppler signal in the LCBP artery did not develop a wound healing complication. Conclusions: This study suggests a strong link to low incisional wound healing complications for the lateral extensile approach to the calcaneus when a preoperative Doppler signal is present in the LCBP artery. We believe this simple examination should be routinely performed prior to calcaneal ORIF. Level of Evidence: Level III, comparative case series.
Second-Generation Ceramic First Metatarsophalangeal Joint Replacement for Hallux Rigidus
Authors: Nagy Mathias Thomas , Walker Christopher Richard , Sirikonda Siva Prasad 
Published: July 2014

Background: Ceramic first metatarsophalangeal (MP) joint replacement has been reported for treatment of hallux rigidus, but there are no published mid- or long-term studies available. We present our midterm results using a second-generation ceramic first MP joint implant. Methods: A retrospective review of clinical data and radiographs was performed for 31 feet (24 women; mean age at surgery, 55 ± 6 years) who had first MP joint replacement with a second-generation ceramic prosthesis (primary, 29 feet; revision, 2 feet). Mean follow-up was 81 ± 27 months after surgery Results: Mean first MP passive range of motion was 32 ± 17 degrees (dorsi- and plantarflexion). Mean AOFAS score was 72 ± 19 points and Foot Function Index was 27 ± 26 points (all 31 feet). Clinical rating for 29 feet that had surgery as a primary procedure was excellent in 5 feet (17%), good in 8 feet (28%), fair in 3 feet (10%), and poor in 13 feet (45%). Patients were satisfied with the outcome in 24 feet (77%). Follow-up radiographs showed that radiolucency, change in angulation, sinkage, and malalignment of the metatarsal or proximal phalanx components were common. Complications included 1 superficial wound infection, and revision was performed in 5 feet (16%) because of loosening, sinkage, subluxation, pain, or fractured prosthesis. Implant survival was 92% at 5 years, 85% at 7 years, and 68% at 9 years. Conclusion: The results of second-generation ceramic first MP joint replacement in our series demonstrated poor clinical and radiological results with a high revision rate. Level of Evidence: Level IV, case series.
A phase I study to determine the maximum tolerated dose and safety of oral LR-103 (1α,24(S)Dihydroxyvitamin D2) in patients with advanced cancer
Authors: Wisinski Kari B , Ledesma Wendy M , Kolesar Jill , Wilding George , Liu Glenn , Douglas Jeffrey , Traynor Anne M , Albertini Mark , Mulkerin Daniel , Bailey Howard H 
Published: July 2014

Background The objective of this study was to determine the maximum tolerated dose and safety of LR-103, a Vitamin D analogue, in patients with advanced cancer. Methods In Step A, patients received oral LR-103 once daily in 14-day cycles with intra-patient dose escalation per accelerated dose escalation design. Dose limiting toxicity for Step A was defined as ≥grade 2 hypercalcemia and/or >grade 2 other toxicities. Starting dose was 5 µg/day. Step B used a 3+3 design starting at Step A maximum tolerated dose with 28-day cycles. Dose limiting toxicity was defined as ≥grade 3 hypercalcemia or any grade 3 or 4 non-hematologic toxicity, except hypercalciuria. Results Twenty-one patients were enrolled; eight were treated in Step A. At dose level 3 (15 µg/day), two patients had dose limiting toxicity. One had grade 4 hyperuricemia. The other had grade 4 GGT plus grade 3 alkaline phosphatase, fatigue and urinary tract infection (UTI). Dose level 2 (10 µg/day) was the maximum tolerated dose for Step A and was starting dose for Step B. The dose was escalated to dose level 5 (30 µg/day) with a patient experiencing grade 3 dose limiting toxicity of hypercalcemia. The study was discontinued before reaching the maximum tolerated dose due to sponsor decision. Modest increases in serum osteocalcin and calcium and decrease in parathyroid hormone were noted. Best response was stable disease; four patients were on therapy for six months or longer. Conclusion Step A dose limiting toxicities limited accelerated dose escalation. The maximum tolerated dose of LR-103 was not reached prior to study termination and this agent is no longer being developed.
The increasing incidence of thromboembolic events among hospitalized patients with inflammatory bowel disease
Authors: Kuy SreyRam , Dua Anahita , Chappidi Rohit , Seabrook Gary , Brown Kellie R , Lewis Brian , Rossi Peter J , Lee Cheong J 
Published: July 2014

Background We performed a national population-based study examining the incidence of both venous and arterial thromboembolic events in patients hospitalized with inflammatory bowel disease over the past decade. Methods A retrospective cross-sectional analysis using the Nationwide Inpatient Sample Database was performed. Patients hospitalized with Crohn’s disease and ulcerative colitis were identified using ICD-9 codes. The incidence of clinically relevant venous thromboembolic events and arterial thromboembolic events including myocardial infarction, visceral ischemia, cerebrovascular accidents, and peripheral arterial events was examined. Results During the study period, 461,415 hospitalized inflammatory bowel disease patients were identified. Among these patients, 28,820 had a diagnosis of a thromboembolic event (overall prevalence of 6%). The incidence of thromboembolic events in patients with inflammatory bowel disease rose from 5.65% in 2000 to 7.17% by 2009. There were 18,270 (3.96%) patients who had an arterial thrombotic event, the most common being myocardial infarction (50%), followed by visceral ischemia (25%), and cerebrovascular incidents (22%). There were 11,083 (2.4%) patients identified to have had a venous thrombotic event, with the most common manifestation being deep vein thrombosis (77%), pulmonary embolism (32%), and portal vein thrombosis (3.9%). Conclusion An increasing incidence of thromboembolic event in patients with inflammatory bowel disease was observed over the past decade. Interestingly, there were more arterial thrombotic events in comparison to venous thrombotic events.
Characterization of acute myeloid leukemia based on levels of global hydroxymethylation
Authors: Kroeze Leonie I. , Aslanyan Mariam G. , van Rooij Arno , Koorenhof-Scheele Theresia N. , Massop Marion , Carell Thomas , Boezeman Jan B. , Marie Jean-Pierre , Halkes Constantijn J. M. , de Witte Theo , Huls Gerwin , Suciu Stefan , Wevers Ron A. , van der Reijden Bert A. , Jansen Joop H. 
Published: July 2014

Key Points5hmC levels vary considerably in patients with AML. High levels of 5hmC independently correlate with inferior overall survival in AML.
Plasmacytomagenesis in Eμ-v-abl transgenic mice is accelerated when apoptosis is restrained
Authors: Vandenberg Cassandra J. , Waring Paul , Strasser Andreas , Cory Suzanne 
Published: July 2014

Key Points
Loss of Bim accelerated the development and increased the incidence of plasmacytomas in Eμ-v-abl transgenic mice. As in multiple myeloma, elevated expression of myc and cyclin D genes was common and p53 deregulation was rare.
Updated cost-of-care estimates for commercially insured patients with multiple sclerosis: retrospective observational analysis of medical and pharmacy claims data
Authors: Carroll Cathryn A , Fairman Kathleen A , Lage Maureen J 
Published: July 2014

Abstract

Background
For patients with multiple sclerosis (MS), previous research identified key disease sequelae as important cost drivers and suggested that among users of disease-modifying drugs (DMDs) in 2004, DMDs represented 73% of the total cost of care. More recent studies were limited to incident disease/treatment and/or excluded DMDs from cost estimates. To support contemporary pharmacoeconomic analyses, the present study was conducted to provide updated information about MS-related costs and cost drivers including DMDs.

Methods
For each of 2 years, 2006 and 2011, commercially insured, continuously eligible patients with ≥ 1 medical claim diagnosis of MS were sampled. MS-related charges were based on medical claims with MS diagnosis plus medical/pharmacy claims for DMDs. 2006 charges were adjusted to 2011 $ using the medical care component of the consumer price index (CPI). Subgroups of patients using DMDs (interferon [IFN] beta-1a intramuscular or subcutaneous, IFN beta-1b, glatiramer, natalizumab) in 2011 were identified. By-group differences were tested with bivariate statistics.

Results
Mean (standard deviation [SD]) age of 15,902 sample patients in 2011 was 47.6 (11.8) years, 76% female. Mean [SD] MS charges ($26,520 [$38,478] overall) were significantly (P < 0.001) higher for patients with common disease sequelae: malaise/fatigue (n = 2,235; $39,948 [$48,435]), paresthesia (n = 1,566; $33,648 [$45,273]), depression (n = 1,255; $42,831 [$51,693]), and abnormality of gait (n = 1,196; $48,361 [$55,472]). From 2006 to 2011, CPI-adjusted MS charges increased by 60%. Among patients treated with a single DMD in 2011, inpatient care was 6% of charges (range = 4%-8%; P = 0.155); outpatient care was 19% (range = 14%-20% except for natalizumab [29%]; P < 0.001); and DMDs were 75% (range = 67%-81%; P < 0.001).

Conclusions
Common MS sequelae remain important cost drivers. Although MS treatment costs are increasing, the proportion of MS charges due to DMDs in 2011 is similar to that reported in 2004.
Immigration status and property crime: an application of estimators for underreported outcomes
Authors: Papadopoulos Georgios 
Published: July 2014

Abstract
This paper studies the individual-level relationship between immigration and property crime in England and Wales using crime self-reports from the Crime and Justice Survey. Models that account for underreporting are used, since this is a major concern in crime self-reports. The results indicate that the reported crime is substantially underreported, but if anything, immigrants are less likely to underreport than natives. More importantly, controlling for underreporting and basic demographics, the estimates across all model specifications, although imprecise, indicate that immigration status and property crime are negatively associated. We finally find that the estimated relationship between immigration status and property crime differs across regions and ethnic groups.

JEL Codes

K42, J15, J22, C25, C51