bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenovirus Vector E4 Gene Promotes Angiogenesis through Modulation of Junctional Connexin 40 and 43 Expression.
Authors: Cheng Joseph , Zhang Fan , Lam George , Hackett Neil R. , Wang Shiyang , Amano Hideki , Shmelkov Sergey V. , Young Lauren M. , Hempstead Barbara , Crystal Ronald G. , Rafii Shahin 
Published: October 2019

Abstract
Gap junction channels formed of connexin (Cx) proteins provide a means for intercellular communication via direct linkage of the cytoplasm of adjacent cells and play important roles in the pathophysiology of vascular and cardiac homeostasis and disease. We have previously reported that introduction of E1/E3-deleted adenovirus (AdE4+) to endothelial cells (EC) selectively activates angiogenesis and increases cell survival via activation of the junctional adhesion molecule vascular endothelial-cadherin which targets the PI3K/Akt pathway. We now show that AdE4+ also potentiates Cx expression in EC in vitro and mouse heart tissue in vivo. Infection of EC with AdE4+, but not AdE4−, vectors resulted in time- and dose-dependent induction of Cx40 and suppression of Cx43 protein and mRNA as determined by immunoblot and Northern blot respectively. Maximal induction of Cx40 and suppression of Cx43 protein and mRNA were observed by 48 hours after infection, and between multiplicity-of-infection of 100 and 200. Immunohistochemical analysis of infected EC revealed that AdE4+ induced Cx40 expression localized to the plasma membrane at intercellular junctions, and attenuated total Cx43 expression. Cx40 expression was also markedly increased and Cx43 significantly decreased in the heart tissue of mice treated with AdE4+ via intra-tracheal administration compared to control mice. Pretreatment of EC with either PKA inhibitor (H89) or PI3K inhibitor (LY294002) abrogated the effects of AdE4+ in regulating Cx40 and Cx43, and was associated with diminished AdE4+-enhanced EC survival. Furthermore, neither PKG inhibitor (KT5823) nor guanylyl cyclase inhibitor (NS2028) affected AdE4+-modulation of Cx. It is of interest to note that cAMP has been shown to trigger Cx trafficking by way of PKA activation, as we have also observed. However, neither forskolin- nor cholera toxin-induced cAMP affected Cx expression in AdE4+-infected EC, indicating that PKA activation by AdE4+ may be independent of cAMP. Taken together, alteration of the Cx expression profile, as mediated through PKA and PI3K signaling pathways, may play a role in AdE4+-associated EC survival. These findings of Cx modulation by AdE4+ may not only explain why E4+ adenoviral vectors may induce increased survival of endothelial cells in vivo, but also may help us to understand the mechanisms of the pathophysiology of vascular and heart disorders by regulation of Cx.
Risk Factors for Bleeding in Patients with Nonvalvular Atrial Fibrillation Who Are Receiving Anticoagulant Therapy with Ximelagatran or Warfarin: Findings from the SPORTIF III and V Trials.
Authors: Douketis James D. , Arneklev Karin , Goldhaber Samuel , Spandorfer John , Halperin Frank , Horrow Jay 
Published: October 2019

Abstract
Background: Ximelagatran is a novel oral direct thrombin inhibitor that is as effective as warfarin in preventing stroke and other thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). Risk factors for bleeding with warfarin are known, but risk factors for bleeding with ximelagatran have not been described. Unlike warfarin, ximelagatran has a predictable anticoagulant effect, does not require anticoagulation monitoring, has a low potential for interactions with drugs, food, or alcohol, and is not affected by genetic polymorphisms. We undertook an exploratory analysis of a large patient database to identify conventional and novel risk factors for bleeding in ximelagatran-treated patients, in warfarin-treated patients, and in all patients, irrespective of treatment.
Methods: We undertook a pooled analysis of the SPORTIF III and V trials trials, which included 7329 patients with nonvalvular AF who received oral ximelagatran, 36 mg twice daily, or warfarin, administered to achieve a target international normalized ratio of 2.0–3.0. Patients had nonvalvular AF and 1 or more risk factors for stroke: hypertension; age ≥75 years; previous stroke, transient ischemic attack (TIA) or systemic embolism; left ventricular dysfunction; age ≥65 years and coronary artery disease; or age ≥65 years and diabetes mellitus. Major exclusion criteria were: mitral stenosis; previous heart valve surgery; transient AF; increased risk for bleeding. Multivariate logistic regression analysis was used to identify independent risk factors for major bleeding. The hazard ratio (HR) for major bleeding, and corresponding 95% confidence interval (CI), was calculated for each variable in the regression model.
Results: The Table presents risk factors in which there was a significant or a non-significant (NS) association with major bleeding in ximelagatran-treated or warfarin-treated patients, and in the combined patient population.
Risk factor Ximelagatran-treated patients, HR (95% CI) Warfarin-treated patients, HR (95% CI) Combined patient population, HR (95% CI) Aspirin use 1.65 (1.07, 2.55) 2.40 (1.69, 3.42) 1.96 (1.49, 2.58) Increasing age 1.03 (1.01, 1.05) 1.06 (1.03, 1.08) 1.04 (1.03, 1.06) Prior liver disease NS 4.96 (1.57, 15.62) NS Prior stroke or TIA 1.78 (1.16, 2.73) NS NS Diabetes mellitus 1.80 (1.18, 2.75) NS 1.39 (1.05, 1.86) Asian race NS NS 1.99 (1.16, 3.42) Statin use 0.62 (0.39, 0.97) 0.61 (0.42, 0.88) 0.62 (0.39, 0.97)
Conclusions: Overall, the bleeding risk was lower with ximelagatran compared with warfarin. Aspirin use and increasing age were associated with an increased risk of bleeding in both ximelagatran- and warfarin-treated patients. Statin use was associated with a decreased risk for bleeding in both groups.
Early Results from a Choice Based Conjoint Analysis Assessing Patient Preferences for Selected Features of Erythropoietic Agents.
Authors: Bolge Susan C. , Fastenau John M. , Howell Jamie B. , Piech Catherine T. , Donohue Jane A. 
Published: October 2019

Abstract
Background: Understanding patients’ preferences regarding treatment features is important, as they may not be aligned with those of providers. Epoetin alfa (EPO) and darbepoetin alfa (DARB) are two erythropoietic agents indicated for the treatment of chemotherapy-related anemia (CRA) to increase hemoglobin (Hb) levels and reduce transfusion requirements. These outcomes are associated with fatigue reduction and improved quality of life (QoL), but the degree of improvement and current dosing schedules for both agents may vary. Preliminary results from a comparative trial suggest EPO provides a greater early and overall Hb rise compared to DARB at the commonly prescribed doses (EPO 40,000 units weekly vs. DARB 200 mcg every two weeks) (Proc Am Soc Clin Oncol.2004;23:763 (8153)).
Objective: To assess patient preferences for two attributes, effectiveness and convenience, associated with the use of erythropoietic agents.
Methods: A cross-sectional study of adults (age 18+) with solid tumor cancers and anemia is on going. 500 planned participants are being recruited through 50 oncologists’ offices across the U.S. Information is collected via a self-administered questionnaire that is divided into two parts. The first, completed by the provider, captures clinical information; the second, completed by patients records their knowledge, experience and preferences regarding anemia and its treatments, including resource use, QoL and productivity. This preliminary analysis focuses on the choice based conjoint (CBC) section of the questionnaire that assesses effectiveness, defined as time to a noticeable relief of fatigue, and convenience, defined as number of provider visits during an 8-week period. Each attribute has three levels (4, 6, and 8 weeks or visits).
Results: 276 provider/patient-matched questionnaires have been received. 264 providers and 237 patients have completed the CBC section (96% and 86% response rates, respectively). 80% of providers view time to a noticeable relief of fatigue as being more important to patients than frequency of visits when choosing a medication to treat anemia. Similarly, patients also view time to a noticeable relief of fatigue as being the more important characteristic of anemia medications (1.8 times more important than frequency of visits). For time to a noticeable relief of fatigue, patients prefer an early onset (4 over 6 over 8 weeks). For convenience, patients prefer 8 over 6 over 4 visits during an 8-week period.
Conclusion: Providers and patients both view effectiveness as a more important attribute of anemia treatment over convenience. While patients prefer relief of fatigue as soon as possible, interestingly, their preference to see providers more frequently rather than less may be contrary to some providers’ beliefs.
Topical Progesterone Cream Does Not Increase Thrombotic and Inflammatory Factors in Postmenopausal Women.
Authors: Stephenson Kenna , Price Carol , Kurdowska Anna , Neuenschwander Pierre , Stephenson John , Pinson Barbara , Stephenson Douglas , Alfred Denita , Krupa Agnieszka , Mahoney Debra , Zava David , Bevan Mary 
Published: October 2019

Abstract
Postmenopausal women have an increased risk of cardiovascular disease, and heart disease is the leading cause of death in postmenopausal American women. Conventional hormone replacement therapy has been shown to result in an increase in thrombotic events in large prospective clinical trials including HERS I, and the recently halted Women’s Health Initiative. One possible mechanism for this observed increase is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory factors. An estimated 50 million American women are peri or postmenopausal and clinical therapies for menopausal symptoms remain a significant challenge in light of the known thrombotic risks. In this prospective blinded study, we examined the short-term effect of topical progesterone cream on menopausal symptom relief in 30 healthy postmenopausal women. Potential adverse effects of topical progesterone on hemostatic and inflammatory factors and cortisol levels were also examined. Subjects were randomized to first receive either 20 mg of topical progesterone cream or placebo cream for 4 weeks. Following a subsequent 4-week washout period, subjects were crossed over to either placebo cream or active drug for an additional 4-week period. In each case, progesterone and cortisol levels were monitored by salivary sampling. Baseline values, 4-week follow-up values and end-of-study values were also obtained for the Greene Climacteric Scale, total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6. For subjects receiving 20 mg of topical progesterone cream for 4 weeks, Greene Climacteric Scale scores were consistently and significantly improved (decreased) over baseline, demonstrating significant relief from menopausal symptoms. In addition, in a subpopulation of hypercortisolemic women, topical progesterone was associated with a favorable decrease in nocturnal cortisol. Surprisingly, and in sharp contrast to earlier studies with conventional hormone replacement therapy, topical progesterone had no effect on any of the hemostatic components examined: total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, and PAI-1 levels were all unchanged. Levels of CRP, TNFα and IL-6 also remained unchanged. From this study we conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.
Treatment of Osteopenia/Osteoporosis in Pediatric Hematopoietic Cell Transplantation.
Authors: Sanders Jean E. , Hoffmeister Paul A. , Storer Barry E. 
Published: October 2019

Abstract
The bone mineral density during childhood and the teen years is an important determinate of adult bone health. Decreased bone mineral density has been found to be a relatively common complication following adult hematopoietic cell transplantation (HCT), but has not been well studied after HCT among pediatric patients. Not surprisingly, an effective therapeutic approach to decreased bone mineral density has also not been developed for children.
Patients and Methods: The records of 196 children <18 years of age who received HCT between 1/97-6/03 who survived for 1 year or more after HCT were reviewed. Patients selected for analysis had decreased bone mineral density (Z-score of <-1 standard deviation (SD) corrected for patient sex and age) and 2 or more bone mineral density (DEXA) scans performed after HCT. Change in bone density was calculated as the difference in L2-4 lumbar spine SD score. Variables associated with change in bone density were analyzed.
Results: Among the 143 patients who had a DEXA scan performed, 82 (57%) demonstrated bone loss defined as <-1 SD Z-score. Fifty-six (68%) of these 82 patients had two or more DEXA scans and were analyzed. These 56 patients received an HCT when they were a median 10.8 (1.1–17.9) years of age, 33 were male, and 40 had chronic GVHD treated with corticosteroids and calcinurin inhibitor therapy. Patients were grouped according to treatment received for the bone loss. Nine patients changed therapy and were analyzed twice in separate treatment categories, hence there were 65 patients in 3 groups: 16 received a bisphosphonate or calcitonin (B/C), 37 calcium supplement only, and 12 no therapy. The B/C group included patients receiving pamidronate, zometa, fosamax, or calcitonin. Baseline median Z-scores were −2.6 SD for the B/C group, −2.2 SD for calcium, and −1.4 SD for no therapy. The median length of therapy was 446 days for the B/C group and 365 days for the calcium group. For the no therapy group, the time interval between DEXA scans was 324 days. Treatment with B/C or calcium compared with no therapy was significantly associated with improved bone density (p=0.0004). Corticosteroids, length of corticosteroid therapy (months), presence of chronic GVHD, gender, TBI received in preparative regimen, and patient age at therapy were not associated with change in bone mineral density. The mean change in bone mineral density per year was +1.16 SD for the B/C group, +0.16 for calcium, and +0.52 for no therapy. Although not statistically significant (p=0.44), concomitant steroid use for more than half the time interval between DEXA scans decreased therapeutic gains in the B/C group by −0.59 SD/year and −0.38 SD/year for the calcium group. The only observed side effect was hypocalcemia in one patient receiving pamidronate.
Conclusions: These data demonstrate that the greatest improvement in bone mineral density was observed in patients receiving a bisphosphonate or calcitonin. Minimal to no toxicity was observed.
Adhesion Molecule ICAM-4 Participates in Erythroblastic Island Formation.
Authors: Lee Gloria , Lo Annie , Short Sarah , Mankelow Tosti , Parsons Stephen , Spring Frances , Narla Mohandas , Anstee David , Chasis Joel Anne 
Published: October 2019

Abstract
Erythroblasts proliferate, differentiate and enucleate within erythroblastic islands, three dimensional structures comprised of developing erythroblasts surrounding a central macrophage. Collective evidence suggests that erythroblastic islands are highly specialized bone marrow subcompartments where adhesion events, in concert with cytokines, play critical roles in regulating erythropoiesis and apoptosis. ICAM-4, a recently characterized member of the immunoglobulin superfamily, is expressed early in erythroid differentiation. This adhesion molecule interacts with multiple integrin binding partners, including alpha4beta1 and alphaV integrins (alphaVbeta1, alphaVbeta3 and alphaVbeta5). Since erythroblasts express alpha4beta1 and ICAM-4 and macrophages exhibit alphaV, ICAM-4 is an attractive candidate for mediating erythroblast-erythroblast and erythroblast-macrophage attachments. A molecular model of ICAM-4 derived from the crystal structure of closely related ICAM-2 presents the extracellular region of ICAM-4 as two Ig-like domains comprised of A,B,C,D,E,F, and G strands. Employing targeted mutagenesis of surface-exposed amino acid residues, we earlier identified a patch or footprint that mediates adhesion to alphaV integrins comprised of three A strand residues and five G strand residues on N-terminal domain 1. To explore whether ICAM-4 attachments are active in erythroblastic islands we first developed a quantitative live cell assay for reforming islands from single cell suspensions of freshly harvested mouse bone marrow. Islands and their cellular components were identified and quantitated by three-color immunofluorescent microscopy employing fluoresceinated erythroid-specific TER119 antibody, macrophage-specific F4/80 antibody and a DNA probe. To determine the amount of variation in number of islands reformed from a single cell suspension of 1 x 105 cells, we counted islands at the beginning and conclusion of experiments on five different mice. The island numbers were very reproducible and equaled 1000 +/− 158. We then tested the effects of two synthetic peptides that we have previously shown block ICAM-4/alphaV adhesion: peptides FWV and ATSR, corresponding to sequences of the A and G strands of ICAM-4 domain 1, respectively. Both peptides caused a marked, concentration dependent decrease in the percentage of islands formed. 2mM ATSR inhibited island formation by 75% while 2mM FWV inhibited island formation by 70%. In marked contrast, a strand D control peptide had minimal to no effect on island formation. Our data strongly suggest that erythroblast ICAM-4 binding to macrophage alphaV is critical for erythroblastic island formation. We postulate that this newly identified receptor-counterreceptor interaction may be important not only for adhesive integrity of the island structure but also for initiating intracellular signaling essential for normal erythroid terminal differentiation.
Chimeric Anti-CD20 Monoclonal Antibody (Rituximab; Mabtheraâ) in Remission Induction and Maintenance Treatment of Relapsed /Resistant Follicular Non-Hodgkin’s Lymphoma : A Phase III Randomized Intergroup Clinical Trial.
Authors: Van Oers Marinus H.J. , Van Glabbeke Martine , Teodorovic Ivana , Rozewicz Cynthia , Klasa Richard , Marcus Robert E. , Wolf Max , Kimby Eva , Hagenbeek Anton 
Published: October 2019

Abstract
Background. In view of a) the efficacy of Rituximab (R) monotherapy in relapsed low grade lymphoma; b) the feasibility to combine R with cytostatic drugs c) the potential of such combinations to clear minimal residual disease, in 1999 we started a phase III clinical trial in patients with relapsed follicular non-Hodgkin’s lymphoma, with 2 main objectives. First: to compare CHOP and R-CHOP as to response rate and response quality. Second: to establish the effect of maintenance treatment with R on progression-free survival (PFS ).
Study design. Patients with stages III or IV follicular lymphoma at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg /m2 at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment or maintenance treatment with R (375 mg/m2 once every 3 months until relapse or for a maximum period of two years).
Results. In February 2004, a preplanned second interim analysis by the IDMC was performed. At that time 461 patients had been included. Of these, 369 could be evaluated for response (188 CHOP; 181 R-CHOP). The groups did not differ as to age, sex, performance status, time from initial diagnosis, number and type of, and best overall response to prior chemotherapy. Both treatment arms yielded similar PR rates: CHOP 53.7%; R-CHOP 52.5 %. However, there was a highly significant difference in CR rates: CHOP 18.1% versus R-CHOP 30.4 % (p=0.0004). 319 patients have been randomized for maintenance treatment. Of these, 268 were evaluable (132 observation; 136 R maintenance). 1 year and 3 year PFS were 54.9% and 31.2% respectively in the observation arm, and 80.2 % and 67.7% in patients with R maintenance treatment (p< 0.0001). There is as yet no impact on OS: the observed difference (in favor of R maintenance) was not significant for an interim analysis (p=0.03). There were no differences in toxicity between CHOP and R-CHOP induction treatments. Maintenance treatment was associated with minimal toxicity. Because the planned second interim analysis revealed that the primary endpoints for both the induction and maintenance part of the study had been reached, the formal criteria for stopping the trial have now been met.
Conclusion. In patients with relapsed/resistant follicular lymphoma R-CHOP remission induction results in a highly significant increase in CR rate as compared to CHOP. Moreover, this is the first trial to show that in these patients Rituximab maintenance treatment achieves a considerable improvement in PFS.
Id/KLH Vaccine (FavId™) Following Treatment with Rituximab: An Analysis of Response Rate Improvement (RRI) and Time-to-Progression (TTP) in Follicular Lymphoma (FL).
Authors: Koc Omer N. , Redfern Charles , Wiernik Peter H. , Rosenfelt Fred , Winter Jane N. , Guthrie Troy H. , Kaplan Lawrence , Holman Peter , Densmore John , Hainsworth John , Lin Thomas , Castillo Rene A. , Janakiraman Nalini , Bender John F. 
Published: October 2019

Abstract
Background: Id/KLH vaccine (FavId) administered as a single agent has been associated with tumor regressions in patients with relapsed/refractory (RR) FL. B-cell depletion has been demonstrated to augment the T-cell immune response to subsequent vaccine administration in mice (Qin 1998 Nat Med 4:627).
Objective: To evaluate the efficacy and safety of Id-KLH administered during the period of rituximab induced B-cell depletion.
Eligibility: FL pts who were: treatment naïve (TN); RR following chemotherapy; or relapsed following rituximab.
Treatment: Following rituximab (375mg/m2 i.v. weekly x 4) pts received Id-KLH (1 mg s.q. monthly x 6) starting on week 12. GM-CSF, 250 mcg, was administered s.q. at the Id-KLH injection site on days 1–4. Pts could continue Id-KLH until progression.
Results: 103 pts received rituximab. Response to rituximab at month 3 was 35% (3-CR; 33-PR). Eleven (11) pts were PD following rituximab (11%). Id/KLH could not be made for 4 pts (4%). Eighty-eight (88) pts were begun on Id-KLH. Among the 45 RR pts, 32 (72%) have not progressed at a median follow-up of 12 months compared with 40% of historical control pts treated with rituximab alone (Witzig 2002 JCO 20:2453). Among the 43 TN pts, 82% have not progressed after a median follow-up of 9 months. RRI (SD to PR, PR to CR after month 3) was observed in 21 pts (12-SD to PR; 9-PR to CR). Robust T-cell responses to both Id and KLH were observed (3 of 3 pts tested). Anti-KLH antibody responses were generally not seen until B-cell recovery. The most frequent adverse event was an injection site reaction. A flu-like syndrome was also observed consistent with GM-CSF administration.
Conclusion: Id/KLH vaccine (FavId), administered to pts with FL during a period of B-cell depletion induced by rituximab, can result in an anti-Id T-cell response, and appears to result in an RRI and an increased TTP compared to historical controls. A randomized, double-blind, placebo-controlled, Phase 3 trial of rituximab + FavId has been initiated.