bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis
Authors: Osmundson Evan C , Ray Dipankar , Moore Finola E , Kiyokawa Hiroaki 
Published: July 2009

Abstract
The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C) is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2), is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus)-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2), known as a negative regulator of transforming growth factor-beta (TGF-β) signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by perturbed mitotic control.
Retinal waves are likely to instruct the formation of eye-specific retinogeniculate projections
Authors: Feller Marla B 
Published: July 2009

AbstractPrior to eye-opening and the development of visual responses, the retina exhibits highly correlated spontaneous firing pattens termed retinal waves. Disruption of the normal spontaneous firing pattern either genetically or pharmacologically prevents the eye-specific refinement of retinogeniculate afferents. Here I provide the evidence that retinal waves play an instructive role in this process. In addition, I argue that a full understanding requires an identification of the features of retinal activity that drive the refinement as well as an understanding of mechanisms that transform these signals into axonal rearrangements.
Retinal waves are unlikely to instruct the formation of eye-specific retinogeniculate projections
Authors: Chalupa Leo M 
Published: July 2009

AbstractIn all mammalian species the projections of the two eyes to the dorsal lateral geniculate nucleus are initially overlapping before gradually forming the eye-specific domains evident at maturity. It is widely thought that retinal waves of neuronal activity play an instructional role in this developmental process. Here, I discuss the myriad reasons why retinal waves are unlikely to have such a role, and suggest that eye-specific molecular cues in combination with neuronal activity are most probably involved in the formation of eye-specific retinogeniculate projections.
A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases
Authors: Peineau Stéphane , Nicolas Céline S , Bortolotto Zuner A , Bhat Ratan V , Ryves W Jonathan , Harwood Adrian J , Dournaud Pascal , Fitzjohn Stephen M , Collingridge Graham L 
Published: July 2009

AbstractBackgroundThe signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons.ResultsUsing a panel of 23 inhibitors individually loaded into the recorded neurons, we can discount the involvement of at least 57 kinases, including PKA, PKC, CaMKII, p38 MAPK and DYRK1A. However, we have been able to confirm a role for the ser/thr protein kinase, glycogen synthase kinase 3 (GSK-3).ConclusionThe present study is the first to investigate the role of 58 ser/thr protein kinases in LTD in the same study. Of these 58 protein kinases, we have found evidence for the involvement of only one, GSK-3, in LTD.
Comparison of three methods of extravascular lung water volume measurement in patients after cardiac surgery
Authors: Maddison Benjamin , Wolff Christopher , Findlay George , Radermacher Peter , Hinds Charles , Pearse Rupert M 
Published: July 2009

Abstract
Introduction
Measurement of extravascular lung water (EVLW) by using the lithium-thermal (Li-thermal) and single-thermal indicator dilution methods was compared with the indocyanine green-thermal (ICG-thermal) method in humans.

Methods
Single-center observational study involving patients undergoing cardiac surgery with cardiopulmonary bypass. Paired measurements were taken 1, 2, 4, and 6 hours after surgery. Bland-Altman analysis was used to calculate bias and limits of agreement. Data are presented as mean (SD) or median (IQR).

Results
Seventeen patients were recruited (age, 69 years (54 to 87 years); Parsonnet score 10 (0 to 29)). Sixteen ICG-thermal measurements were excluded after blinded assessment because of poor-quality indicator dilution curves. EVLW volume as measured by the ICG-thermal technique was 4.6 (1.9) ml/kg, compared with 5.3 (1.4) ml/kg for the single-thermal method. Measurements taken with the Li-thermal method were clearly erroneous (-7.6 (7.4) ml/kg). In comparison with simultaneous measurements with the ICG-thermal method, single-thermal measurements had an acceptable degree of bias, but limits of agreement were poor (bias, -0.3 ml/kg (2.3)). Li-thermal measurements compared poorly with the ICG-thermal reference method (bias, 13.2 ml/kg (14.4)).

Conclusions
The principal finding of this study was that the prototype Li-thermal method did not provide reliable measurements of EVLW volume when compared with the ICG-thermal reference technique. Although minimal bias was associated with the single-thermal method, limits of agreement were approximately 45% of the normal value of EVLW volume. The Li-thermal method performed very poorly because of the overestimation of mean indicator transit time by using an external lithium ion electrode. These findings suggest that the assessment of lung water content by lithium-indicator dilution is not sufficiently reliable for clinical use in individual patients.
Unfractionated heparin and enoxaparin reduce high-stretch ventilation augmented lung injury: a prospective, controlled animal experiment
Authors: Li Li-Fu , Huang Chung-Chi , Lin Horng-Chyuan , Tsai Ying-Huang , Quinn Deborah A , Liao Shuen-Kuei 
Published: July 2009

Abstract
Introduction
Dysregulation of coagulation and local fibrinolysis found in patients with acute lung injury often results in the need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and suppression of fibrinolytic activity, but the mechanisms are unclear. We hypothesized that subcutaneous injections of unfractionated heparin and enoxaparin would decrease neutrophil infiltration, lung edema, and plasminogen-activator inhibitor-1 (PAI-1) production in mice exposed to high-tidal-volume ventilation.

Methods
Male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume (30 ml/kg) or low-tidal-volume (6 ml/kg) mechanical ventilation with room air for 1 to 5 hours after 200 IU/kg or 400 IU/kg unfractionated heparin and 4 mg/kg or 8 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet- to dry-weight ratio, histopathologic grading of epithelium, myeloperoxidase, and gene expression of PAI-1 were measured. The expression of PAI-1 was studied by immunohistochemistry.

Results
High-tidal-volume ventilation induced increased microvascular permeability, neutrophil influx, PAI-1 mRNA expression, production of PAI-1 protein, and positive staining of PAI-1 in epithelium in a dose-dependent manner. Lung injury induced by high-tidal-volume ventilation was attenuated with PAI-1-deficient mice and pharmacologic inhibition of PAI-1 activity by low-dose unfractionated heparin and enoxaparin.

Conclusions
We conclude that high-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx, lung PAI-1 mRNA expression, production of active PAI-1. The deleterious effects were attenuated by low-dose unfractionated heparin or enoxaparin treatment. Understanding the protective mechanism of unfractionated heparin and enoxaparin related to the reduction of PAI-1 may afford further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.
Myeloablative Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia: Analysis of Graft Sources and Long-Term Outcome
Authors: Tomblyn Michael B. , Arora Mukta , Baker K. Scott , Blazar Bruce R. , Brunstein Claudio G. , Burns Linda J. , DeFor Todd E. , Dusenbery Kathryn E. , Kaufman Dan S. , Kersey John H. , MacMillan Margaret L. , McGlave Philip B. , Miller Jeffrey S. , Orchard Paul J. , Slungaard Arne , Tomblyn Marcie R. , Vercellotti Gregory M. , Verneris Michael R. , Wagner John E. , Weisdorf Daniel J. 
Published: July 2009

Purpose Analysis of hematopoietic cell transplantation (HCT) for high-risk or recurrent acute lymphoblastic leukemia (ALL) using different donor sources is confounded by variable conditioning and supportive care. Patients and Methods We studied 623 consecutive ALL myeloablative HCT (1980 to 2005). Donors were autologous (n = 209), related (RD; n = 245), unrelated (URD; n = 100), and umbilical cord blood (UCB; n = 69). Results After median of 8.3 years of follow-up, 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 29% (95% CI, 26% to 32%), 26% (95% CI, 23% to 29%), and 43% (95% CI, 39% to 47%), respectively. Treatment-related mortality (TRM) at 2 years was 28% (95% CI, 25% to 31%). Mismatched URD sources yielded higher TRM (relative risk [RR], 2.2; P < .01) and lower OS (RR, 1.5; P = .05) than RD or UCB HCT. Autografting yielded significantly more relapse (68%; 95% CI, 59% to 77%; P < .01) and poorer LFS (14%; 95% CI, 10% to 18%; P = .01). HCT in first complete remission (CR1) yielded significantly better outcomes than later HCT. In a 1990 to 2005 allogeneic CR1/second complete response cohort, 5-year OS, LFS, and relapse rates were 41% (95% CI, 35% to 47%), 38% (95% CI, 32% to 44%), and 25% (95% CI, 19% to 31%), respectively; 2-year TRM was 34% (95% CI, 28% to 40%). With RD, well-matched URD and UCB sources, 5-year LFS was 40% (95% CI, 31% to 49%), 42% (95% CI, 14% to 70%), and 49% (95% CI, 34% to 64%), respectively, while relapse was 31% (95% CI, 22% to 40%), 17% (95% CI, 0% to 37%), and 27% (95% CI, 13% to 41%). Acute graft-versus-host disease was associated with fewer relapses. Since 1995, we noted progressive improvements in OS, LFS, and TRM. Conclusion Allogeneic, but not autologous, HCT for ALL results in durable LFS. Importantly, HCT using UCB led to similar outcomes as either RD or well-matched URD. HCT in early remission can best exploit the potent antileukemic efficacy of allografting from UCB, RD, or URD sources.
Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma
Authors: Hess Georg , Herbrecht Raoul , Romaguera Jorge , Verhoef Gregor , Crump Michael , Gisselbrecht Christian , Laurell Anna , Offner Fritz , Strahs Andrew , Berkenblit Anna , Hanushevsky Orysia , Clancy Jill , Hewes Becker , Moore Laurence , Coiffier Bertrand 
Published: July 2009

Purpose Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease. Patients and Methods In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. Results Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. Conclusion Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
Patients With Merkel Cell Carcinoma Tumors ≤ 1.0 cm in Diameter Are Unlikely to Harbor Regional Lymph Node Metastasis
Authors: Stokes Jayme B. , Graw Katherine S. , Dengel Lynn T. , Swenson Brian R. , Bauer Todd W. , Slingluff Craig L. , Ledesma Elihu J. 
Published: July 2009

Purpose Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy. Current recommendations include offering regional lymph node evaluation by either sentinel lymph node biopsy (SLNB) or complete lymph node dissection (CLND) to all patients with MCC; however, we hypothesized a cohort of low-risk patients may exist for whom regional nodal metastasis would be unlikely. Methods A retrospective review of the Department of Veterans Affairs national health care database was performed. Patients undergoing resection of primary MCC were identified; and demographic, medical, and social history; tumor characteristics; nodal status; and recurrence events were recorded. Results Between 1995 and 2006, 346 patients were diagnosed with MCC. Of these, 213 underwent resection of the primary lesion and evaluation of the draining lymph node basin. Fifty-four patients (25%) had tumors ≤ 1.0 cm in diameter. Average tumor diameter was 0.7 cm, and 63% were located on the head or neck. Only two patients (4%) with tumors ≤ 1.0 cm had regional lymph node metastasis, compared with 51 (24%) of 213 patients with tumors more than 1.0 cm (P < .0001). Both patients had clinically evident nodal disease at presentation and underwent CLND. Both have remained recurrence-free for 40 months. Thirteen (25%) of 51 patients with nodal metastasis and tumors more than 1 cm had occult nodal metastasis. Conclusion In this series, patients with MCC ≤ 1.0 cm were unlikely to have regional lymph node metastasis, suggesting that regional nodal evaluation may reasonably be avoided in these patients. However, these data support SLNB for MCC more than 1 cm in diameter.
An in Vivo Study on Adjudin and Blood-Testis Barrier Dynamics
Authors: Kopera Ilona A. , Su Linlin , Bilińska Barbara , Cheng C. Yan , Mruk Dolores D. 
Published: July 2009

AbstractAdjudin is known to specifically affect Sertoli-germ cell adhesion, resulting in germ cell loss from the seminiferous epithelium and transient infertility. The apical ectoplasmic specialization (ES) was shown to be the primary target of adjudin because adhesion was unaffected in organs that lack this structure. Herein we expand previous findings by treating rat pups with adjudin, and we aimed to address two questions. First, can adjudin perturb germ cell adhesion in the seminiferous epithelium of testes in which the apical ES is not yet present? Second, can adjudin affect assembly of the blood-testis barrier (BTB) at 15–18 d of age? Interesting changes were noted when aged-matched testes from control and adjudin-treated rats were examined, including a delay in the appearance of developing germ cells as well as a delay in the formation of the tubule lumen. Immunoblotting using antibodies against BTB-constituent proteins indicated that formation of the BTB was affected in rat pups gavaged with adjudin. These results were corroborated by immunofluorescence microscopy, which showed profound changes in the cellular distribution of tight junction and basal ES proteins. Moreover, the BTB was shown to be compromised in 30-d-old rats when its integrity was assessed by a functional in vivo assay. By 45 d of age, however, the seminiferous epithelium of treated rats was indistinguishable from that of control rats. Collectively these results demonstrate that adjudin targets the apical ES as well as the basal ES and tight junction, which in turn delays assembly of the BTB.
Minireview: Epigenetic Changes in Ovarian Cancer
Authors: Balch Curt , Fang Fang , Matei Daniela E. , Huang Tim H.-M. , Nephew Kenneth P. 
Published: July 2009

Abstract
Epigenetic aberrations, including DNA methylation, histone modifications, and micro-RNA dysregulation, are now well established in the development and progression of ovarian cancer, and their gradual accumulation is associated with advancing disease stage and grade. Epigenetic aberrations are relatively stable, associated with distinct disease subtypes, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomarkers. In contrast to DNA mutations and deletions, aberrant gene-repressive epigenetic modifications are potentially reversible by epigenetic therapies, including inhibitors of DNA methylation or histone-modifying enzymes. Although epigenetic monotherapies have not shown activity against solid tumors, including ovarian cancer, preclinical studies suggest they will be effective when used in combination with one another or with conventional chemotherapeutics, and combinatorial epigenetic therapy regiments are being examined in cancer clinical trials. A greater understanding of the role of epigenetics in ovarian neoplasia will provide for improved interventions against this devastating malignancy.
Gonadotropin-Releasing Hormone-Mediated Phosphorylation of Estrogen Receptor-α Contributes to fosB Expression in Mouse Gonadotrophs
Authors: Chen Junling , An Beum-Soo , Cheng Linan , Hammond Geoffrey L. , Leung Peter C. K. 
Published: July 2009

AbstractEstrogen receptors (ERs) are activated by their ligands as well as signaling pathways that alter ER phosphorylation in response to peptide hormones and growth factors. In pituitary gonadotrophs, GnRHs act via the type I GnRH receptor (GnRHR). Both GnRH subtypes (GnRH-I and -II) activate an estrogen response element (ERE)-driven luciferase reporter gene in LβT2 mouse pituitary cells, and GnRH-I is most potent in this regard. Moreover, antide (a GnRH antagonist) and a GnRHR small interfering RNA (siRNA) abrogate this effect, whereas an ERα antagonist (ICI 182,780) does not. The ERα in LβT2 cells is phosphorylated at Ser118 in the nucleus and at Ser167 in both nucleus and cytoplasm after GnRH treatments and coincided with increased ERα binding to its coactivator, the p300/cAMP response element-binding protein-associated factor (PCAF). Moreover, siRNA-mediated knockdown of PCAF levels attenuated GnRH-induced ERE-luciferase transactivation in these cells. Most importantly, both GnRH subtypes robustly up-regulated expression of the immediate early response gene, fosB, whereas cotreatment with ERα siRNA or PCAF siRNA attenuated this effect. This appears to occur at the transcriptional level because corecruitment of ERα and PCAF to an ERE within the endogenous fosB promoter was increased by GnRH treatments, as shown by chromatin immunoprecipitation assays. These data demonstrate that GnRH-mediated phosphorylation of ERα in mouse LβT2 pituitary cells results in its rapid association with PCAF and the transcriptional activation of fosB, and we demonstrate that this in turn likely activates other genes in pituitary cells including the FSH β-subunit gene.
Unsteady behaviour of the tip clearance vortex in a rotor equivalent compressor cascade
Authors: Schrapp H , Stark U , Saathoff H 
Published: July 2009

From earlier experimental investigations in a single-stage axial-flow pump and different numerical calculations of the flow in single-stage axial-flow compressors, it is known that vortex breakdown of the tip clearance vortex can take place in turbomachines, although an experimental proof for subsonic compressors is lacking. Vortex breakdown, if existent, is a source of high instability in the sensitive tip region of axial-flow pumps and compressors and will also play an important role in the stall inception process. Therefore, the flow in a linear compressor cascade with a 3 per cent tip clearance to one side has been investigated at different flow angles from the design point up to the stability limit of the cascade. The cascade resembles the tip section of a single-stage, axial-flow, low-speed compressor that is also in use at the Technical University of Braunschweig. The measuring techniques used were (a) a commercial particle image velocimetry (PIV) system and (b) a pressure measuring system with several flush mounted high-response pressure transducers at selected locations where the vortex was expected. As the cascade approaches its stall limit, the analysis of the pressure signals in the frequency domain revealed a bump of increased amplitude at a certain non-dimensional frequency for some of the measuring positions. The measuring positions that exhibited the bump correlated very well with a paraboloid-shaped region of high standard deviation enveloping an area of very low momentum fluid. It is shown that the frequency of the striking bump corresponds to the rotational frequency of the vortex calculated from the PIV measurements.
Numerical investigation of the interaction between jet and bucket in a Pelton turbine
Authors: Santolin A , Cavazzini G , Ardizzon G , Pavesi G 
Published: July 2009

This article presents the numerical investigation of the interaction between the jet and the bucket in a Pelton turbine. Unsteady numerical analyses were carried out on a single jet Pelton turbine installed in the north of Italy. A two-phase inhomogeneous model was used. Two different jet configurations were analysed and compared. In the first configuration, the interaction between the runner and an axial-symmetric jet characterized by a given velocity jet profile was investigated, whereas in the second configuration the runner was coupled with the needle nozzle and the final part of the penstock and the interaction between the jet and the bucket was analysed. A detailed analysis of the torque highlighted the influence of the shape of the water jet on the turbine losses and the influence of the stator on the efficiency of this type of hydraulic machines was shown. The numerical results were compared with the experimental data derived from the installation test of the turbine in order to validate the numerical analysis.