bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Phase II Trial of Sorafenib with Temsirolimus or Tipifarnib in Untreated Metastatic Melanoma (S0438)
Authors: Margolin Kim A. , Moon James , Flaherty Lawrence E. , Lao Christopher D. , Akerley Wallace L. , Othus Megan , Sosman Jeffrey A. , Kirkwood John M. , Sondak Vernon K. 
Published: January 2012

Abstract
Purpose: Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma.
Experimental Design: This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens.
Results: On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR.
Conclusions: The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates. Clin Cancer Res; 18(4); 1129–37. ©2012 AACR.
New Gene-Immunotherapy Combining TRAIL-Lymphocytes and EpCAMxCD3 Bispecific Antibody for Tumor Targeting
Authors: Groth Ariane , Salnikov Alexei V. , Ottinger Sabine , Gladkich Jury , Liu Li , Kallifatidis Georgios , Salnikova Olga , Ryschich Eduard , Giese Nathalia , Giese Thomas , Momburg Frank , Büchler Markus W. , Moldenhauer Gerhard , Herr Ingrid 
Published: January 2012

AbstractPurpose: To enhance T-cell responsiveness toward cancer cells, we overexpressed TRAIL in lymphocytes, as this death ligand induces tumor-specific apoptosis. To increase contact time of lymphocytes with tumor cells and thereby of TRAIL with its death receptors, lymphocytes were linked to the CD3 arm of bispecific antibody EpCAMxCD3, to guide the lymphocytes to tumor cells positive for the cancer stem cell marker EpCAM/ESA.Experimental Design: Lymphocytes were transduced with TRAIL lentivirus and the antitumor effect in presence and absence of EpCAMxCD3 was evaluated in vitro and in xenograft studies using epithelial cell adhesion molecule (EpCAM)–positive pancreatic and prostate cancer cells.Results: Compared with control lymphocytes, TRAIL-lymphocytes increased cytotoxicity and further induced expression of several apoptosis-related molecules. Cotransplantation of TRAIL-lymphocytes and tumor cells in mice or peritumoral injection of TRAIL-lymphocytes in larger xenografts retarded growth and induced apoptosis. Combination of TRAIL-lymphocytes with EpCAMxCD3 potentiated tumor eradication by enhancing antiapoptotic and antiproliferative signaling and by decreasing tumor vasculature. Intratumoral cyst formation was involved and associated with enhanced chemokine secretion and infiltration of mouse macrophages, suggesting contribution of an inflammatory host response. Most importantly, tumorigenicity of pancreatic cancer cells with cancer stem cell features resistant to conventional chemotherapy was strongly reduced.Conclusions: This gene-immunotherapeutic approach may be a new tool to support endogenous immune responses toward cancer even in its advanced stages. Clin Cancer Res; 18(4); 1028–38. ©2012 AACR.
Fibroblast Growth Factor-2 Is an Important Factor that Maintains Cellular Immaturity and Contributes to Aggressiveness of Osteosarcoma
Authors: Shimizu Takatsune , Ishikawa Tomoki , Iwai Sayaka , Ueki Arisa , Sugihara Eiji , Onishi Nobuyuki , Kuninaka Shinji , Miyamoto Takeshi , Toyama Yoshiaki , Ijiri Hiroshi , Mori Hajime , Matsuzaki Yumi , Yaguchi Tomonori , Nishio Hiroshi , Kawakami Yutaka , Ikeda Yasuo , Saya Hideyuki 
Published: January 2012

AbstractOsteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal–regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma. Mol Cancer Res; 10(3); 454–68. ©2012 AACR.
Systemic-to-Pulmonary Collateral Flow, as Measured by Cardiac Magnetic Resonance Imaging, Is Associated With Acute Post-Fontan Clinical Outcomes
Authors: Glatz Andrew C. , Rome Jonathan J. , Small Adam J. , Gillespie Matthew J. , Dori Yoav , Harris Matthew A. , Keller Marc S. , Fogel Mark A. , Whitehead Kevin K. 
Published: January 2012

Background—
Systemic-pulmonary collateral (SPC) flow occurs commonly in single ventricle patients after superior cavo-pulmonary connection, with unclear clinical significance. We sought to evaluate the association between SPC flow and acute post-Fontan clinical outcomes using a novel method of quantifying SPC flow by cardiac magnetic resonance (CMR) imaging.

Methods and Results—

All patients who had SPC flow quantified by CMR imaging before Fontan were retrospectively reviewed to assess for acute clinical outcomes after Fontan completion. Forty-four subjects were included who had Fontan completion between May 2008 and September 2010. SPC flow prior to Fontan measured 1.5±0.9 L/min/m
2
, accounting for 31±11% of total aortic flow and 44±15% of total pulmonary venous flow. There was a significant linear association between natural log-transformed duration of hospitalization and SPC flow as a proportion of total aortic (rho=0.31,
P
=0.04) and total pulmonary venous flow (rho=0.29,
P
=0.05). After adjustment for Fontan type and presence of a fenestration, absolute SPC flow was significantly associated with hospital duration ≥7 days (odds ratio [OR]=9.2,
P
=0.02) and chest tube duration ≥10 days (OR=22.7,
P
=0.009). Similar associations exist for SPC flow as a percentage of total aortic (OR=1.09,
P
=0.048 for hospitalization ≥7 days; OR=1.24,
P
=0.007 for chest tube duration ≥10 days) and total pulmonary venous flow (OR=1.07,
P
=0.048 for hospitalization ≥7 days; OR=1.18,
P
=0.006 for chest tube duration ≥10 days).

Conclusions—
Increasing SPC flow before Fontan, as measured by CMR imaging, is associated with increased duration of hospitalization and chest tube following Fontan completion.
The Draf III Mucosal Grafting Technique
Authors: Conger Bryant T. , Riley Kristen , Woodworth Bradford A. 
Published: January 2012

ObjectiveThe Draf III procedure is an advanced surgical option for frontal sinus disease refractory to endoscopic frontal sinusotomy and is used to expose the anterior limit of resection of the skull base during endoscopic management of anterior skull base tumors. Our objective was to evaluate outcomes of a strategy using mucosal grafts to decrease postoperative closure.Study DesignProspective cohort.SettingTertiary care facility.Subjects and MethodsPatients requiring a Draf III procedure were prospectively enrolled in the study. Demographics, reason for the procedure, percentage graft viability, and complications were recorded. The primary outcome measure was anterior‐posterior (AP) diameter at 3 months.ResultsMucosal grafting was performed during 29 Draf III procedures from 2008 to 2011. Twenty‐seven patients (average age, 58 years) were available for measurement at 3 months (average postoperative follow‐up, 15.4 months; range, 3–30 months). Reasons for the procedure included tumor (n = 14), chronic rhinosinusitis (CRS) with frontal ostium stenosis (n = 12), and trauma (n = 1). Average intraoperative AP diameter was 11.7 mm. All patients met the definition of success (<50% reduction in diameter), maintaining a patent combined frontal sinus ostium for the duration of follow‐up (average diameter 10.8 mm at 3 months). Nine patients with CRS and frontal ostium stenosis had openings similar to the entire cohort (>1‐year follow‐up; average, 19.3 months) with significant symptom reduction (SNOT‐22 preop 62.3 ± 20.8 vs 3 months 27.8 ± 14.8 and 1 year 21.4 ± 13.6; P <. 0001).ConclusionCicatricial stenosis and osteoneogenesis are common following the Draf III procedure. This study indicates that the use of mucosal grafts may assist with postoperative stenosis and should be considered a routine strategy for preventing closure.
Jones Fracture Fixation
Authors: Orr Justin D. , Glisson Richard R. , Nunley James A. 
Published: January 2012

Background: Stabilization of fifth metatarsal Jones fractures with intramedullary screw fixation is the most common method for surgical fixation when operative treatment is indicated. Conventional partially threaded screws of various diameters are routinely used for Jones fracture fixation. Recently, the use of tapered variable pitch screws has become popular, but information regarding their performance in Jones fracture fixation is limited. No previous studies have compared conventional and tapered variable pitch screws in Jones fracture fixation under physiologic cyclic loading conditions. Purpose: To determine whether biomechanical differences exist between appropriately sized conventional partially threaded screws and tapered variable pitch screws under physiologic cyclic loading conditions with regard to Jones fracture fixation. Study Design: Controlled laboratory study. Methods: Simulated Jones fractures were created in 23 matched pairs of fresh-frozen fifth metatarsals. One bone from each pair was stabilized with a conventional partially threaded screw and the contralateral bone with a tapered variable pitch screw. Initial compression, as well as fracture site compression, angulation, and bending stiffness, was compared between groups throughout 1000 physiologic cyclic loads. Results: Conventional partially threaded screws obtained significantly greater initial compression compared with tapered variable pitch screws. Significantly greater compression was maintained throughout cyclic loading with conventional screw fixation compared with tapered variable pitch screws. Fracture site angulation was significantly greater using tapered variable pitch screws from the tenth load cycle through completion of cyclic loading. Despite a trend toward increased fracture site bending stiffness when using conventional screws, no difference in fixation stiffness was demonstrable between the 2 screw types. Conclusion: In this cadaveric Jones fracture fixation model, conventional partially threaded screws provided improved fracture site compression and decreased fracture site angulation but offered no advantage in improving fracture site stiffness compared with tapered variable pitch screws. These results provide empirical evidence to guide implant selection decision making for operative fixation of Jones fractures. Clinical Relevance: While the use of tapered variable pitch screws is a potential alternative for fixation of fifth metatarsal Jones fractures, conventional partially threaded screws may provide better biomechanical stability, the effect of which on fracture healing is unknown.
Comparative efficacy and safety of fenofibrate/pravastatin plus ezetimibe triple therapy and simvastatin/ezetimibe dual therapy in type 2 diabetic patients with mixed hyperlipidaemia and cardiovascular disease
Authors: Farnier Michel , Retterstøl Kjetil , Steinmetz Armin , Császár Albert 
Published: January 2012

Background: This study was designed to compare the efficacy and safety of a fenofibrate/pravastatin 160/40 mg fixed-dose combination plus ezetimibe 10 mg triple therapy and simvastatin 20 mg plus ezetimibe 10 mg dual therapy in patients with type 2 diabetes, mixed hyperlipidaemia and cardiovascular disease. Method: After a 6-week run-in period on simvastatin 20 mg, 273 patients with non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dl or low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dl were randomised to receive 12-week treatment with triple therapy or dual therapy, followed by a 12-week safety period during which all patients received the triple therapy. Results: At week 12, similar significant decreases in non-HDL-C were observed with both treatments. The triple therapy has induced a greater decrease in triglycerides (between-treatment difference: −14.6%, p = 0.007) and the dual therapy a greater decrease in LDL-C (between-treatment difference: +5.3%, p = 0.05). Both treatments were generally well tolerated. Conclusion: The fenofibrate/pravastatin plus ezetimibe therapy improves the global atherogenic lipid profile in type 2 diabetic patients with mixed hyperlipidaemia.
Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience
Authors: Kantarjian Hagop , O'Brien Susan , Jabbour Elias , Garcia-Manero Guillermo , Quintas-Cardama Alfonso , Shan Jenny , Rios Mary Beth , Ravandi Farhad , Faderl Stefan , Kadia Tapan , Borthakur Gautam , Huang Xuelin , Champlin Richard , Talpaz Moshe , Cortes Jorge 
Published: January 2012

Abstract
A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.
Bone marrow homing and engraftment of human hematopoietic stem and progenitor cells is mediated by a polarized membrane domain
Authors: Larochelle Andre , Gillette Jennifer M. , Desmond Ronan , Ichwan Brian , Cantilena Amy , Cerf Alexandra , Barrett A. John , Wayne Alan S. , Lippincott-Schwartz Jennifer , Dunbar Cynthia E. 
Published: January 2012

AbstractManipulation of hematopoietic stem/progenitor cells (HSPCs) ex vivo is of clinical importance for stem cell expansion and gene therapy applications. However, most cultured HSPCs are actively cycling, and show a homing and engraftment defect compared with the predominantly quiescent noncultured HSPCs. We previously showed that HSPCs make contact with osteoblasts in vitro via a polarized membrane domain enriched in adhesion molecules such as tetraspanins. Here we show that increased cell cycling during ex vivo culture of HSPCs resulted in disruption of this membrane domain, as evidenced by disruption of polarity of the tetraspanin CD82. Chemical disruption or antibody-mediated blocking of CD82 on noncultured HSPCs resulted in decreased stromal cell adhesion, homing, and engraftment in nonobese diabetic/severe combined immunodeficiency IL-2γnull (NSG) mice compared with HSPCs with an intact domain. Most leukemic blasts were actively cycling and correspondingly displayed a loss of domain polarity and decreased homing in NSG mice compared with normal HSPCs. We conclude that quiescent cells, unlike actively cycling cells, display a polarized membrane domain enriched in tetraspanins that mediates homing and engraftment, providing a mechanistic explanation for the homing/engraftment defect of cycling cells and a potential new therapeutic target to enhance engraftment.
Emerging roles for multipotent, bone marrow–derived stromal cells in host defense
Authors: Auletta Jeffery J. , Deans Robert J. , Bartholomew Amelia M. 
Published: January 2012

Abstract
Multipotent, bone marrow–derived stromal cells (BMSCs, also known as mesenchymal stem cells [MSCs]), are culture-expanded, nonhematopoietic cells with immunomodulatory effects currently being investigated as novel cellular therapy to prevent and to treat clinical disease associated with aberrant immune response. Emerging preclinical studies suggest that BMSCs may protect against infectious challenge either by direct effects on the pathogen or through indirect effects on the host. BMSCs may reduce pathogen burden by inhibiting growth through soluble factors or by enhancing immune cell antimicrobial function. In the host, BMSCs may attenuate pro-inflammatory cytokine and chemokine induction, reduce pro-inflammatory cell migration into sites of injury and infection, and induce immunoregulatory soluble and cellular factors to preserve organ function. These preclinical studies provide provocative hints into the direction MSC therapeutics may take in the future. Notably, BMSCs appear to function as a critical fulcrum, providing balance by promoting pathogen clearance during the initial inflammatory response while suppressing inflammation to preserve host integrity and facilitate tissue repair. Such exquisite balance in BMSC function appears intrinsically linked to Toll-like receptor signaling and immune crosstalk.
Generic and oral quality of life is affected by oral mucosal diseases
Authors: Liu Li-Jun , Xiao Wen , He Qing-Bo , Jiang Wei-Wen 
Published: January 2012

Abstract

Background
The generic and oral health-related quality of life (QoL) has provided opportunity for investigation of the interrelations among generic health, oral health, and related outcomes. The purpose of this study was to identify the generic and oral QoL in the patients with oral mucosal disease (OMD).

Methods
Five hundred and thirty-eight OMDs were recruited in this study. The instruments applied were Chinese version of the 36-item short form health survey (SF-36) and the short-form of Oral Health Impact Profile (OHIP-14).

Results
The mean score of sum OHIP-14 was significantly higher in the patients with OMD (10.81 ± 9.01) compared with those in the healthy subjects (HS) (6.55 ± 6.73) (p < 0.001, Mann-Whitney U test). 56.51% of the OMD patients and 12.94% of the HS reported at least one oral negative impact (p < 0.001, Chi-square test). The overall mean score of SF-36 was significantly lower in the patients with OMD (74.54 ± 12.77) compared with those in the HS (77.97 ± 12.39) (p = 0.021, t-test).

Conclusions
Administration of specific and generic questionnaires of QoL can provide us a detailed picture of the impact of OMDs on patients, and both generic and oral QoL were impaired in the patients with OMD.
Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study
Authors: Jyonouchi Harumi , Geng Lee , Streck Deanna L , Toruner Gokce A 
Published: January 2012

Abstract

Introduction
There exists a small subset of children with autism spectrum disorders (ASD) characterized by fluctuating behavioral symptoms and cognitive skills following immune insults. Some of these children also exhibit specific polysaccharide antibody deficiency (SPAD), resulting in frequent infection caused by encapsulated organisms, and they often require supplemental intravenous immunoglobulin (IVIG) (ASD/SPAD). This study assessed whether these ASD/SPAD children have distinct immunological findings in comparison with ASD/non-SPAD or non-ASD/SPAD children.

Case description
We describe 8 ASD/SPAD children with worsening behavioral symptoms/cognitive skills that are triggered by immune insults. These ASD/SPAD children exhibited delayed type food allergy (5/8), treatment-resistant seizure disorders (4/8), and chronic gastrointestinal (GI) symptoms (5/8) at high frequencies. Control subjects included ASD children without SPAD (N = 39), normal controls (N = 37), and non-ASD children with SPAD (N = 12).

Discussion and Evaluation
We assessed their innate and adaptive immune responses, by measuring the production of pro-inflammatory and counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in responses to agonists of toll like receptors (TLR), stimuli of innate immunity, and T cell stimulants. Transcription profiling of PB monocytes was also assessed. ASD/SPAD PBMCs produced less proinflammatory cytokines with agonists of TLR7/8 (IL-6, IL-23), TLR2/6 (IL-6), TLR4 (IL-12p40), and without stimuli (IL-1ß, IL-6, and TNF-α) than normal controls. In addition, cytokine production of ASD/SPAD PBMCs in response to T cell mitogens (IFN-γ, IL-17, and IL-12p40) and candida antigen (Ag) (IL-10, IL-12p40) were less than normal controls. ASD/non-SPAD PBMDs revealed similar results as normal controls, while non-ASD/SPAD PBMCs revealed lower production of IL-6, IL-10 and IL-23 with a TLR4 agonist. Only common features observed between ASD/SPAD and non-ASD/SPAD children is lower IL-10 production in the absence of stimuli. Transcription profiling of PB monocytes revealed over a 2-fold up (830 and 1250) and down (653 and 1235) regulation of genes in ASD/SPAD children, as compared to normal (N = 26) and ASD/non-SPAD (N = 29) controls, respectively. Enriched gene expression of TGFBR (p < 0.005), Notch (p < 0.01), and EGFR1 (p < 0.02) pathways was found in the ASD/SPAD monocytes as compared to ASD/non-SPAD controls.

Conclusions
The Immunological findings in the ASD/SPAD children who exhibit fluctuating behavioral symptoms and cognitive skills cannot be solely attributed to SPAD. Instead, these findings may be more specific for ASD/SPAD children with the above-described clinical characteristics, indicating a possible role of these immune abnormalities in their neuropsychiatric symptoms.