bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors
Authors: Fouladi Maryam , Laningham Fred , Wu Jianrong , O'Shaughnessy Melinda A. , Molina Kristen , Broniscer Alberto , Spunt Sheri L. , Luckett Inga , Stewart Clinton F. , Houghton Peter J. , Gilbertson Richard J. , Furman Wayne L. 
Published: October 2007

PurposeTo determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors.Patients and MethodsEverolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients.ResultsThere were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL·h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs ≥ 200 ng/mL·h, equivalent to dosages of 3 to 5 mg/m2of everolimus. No objective tumor responses were observed.ConclusionContinuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.
Carbonic Anhydrase IX Is Not an Independent Predictor of Outcome for Patients With Clear Cell Renal Cell Carcinoma
Authors: Leibovich Bradley C. , Sheinin Yuri , Lohse Christine M. , Thompson R. Houston , Cheville John C. , Zavada Jan , Kwon Eugene D. 
Published: October 2007

Purpose Expression of carbonic anhydrase IX (CAIX) has been reported to be an independent predictor of outcome and is being investigated as a therapeutic target for patients with clear cell renal cell carcinoma (ccRCC). We attempted to validate the prognostic utility of CAIX expression using a large cohort of ccRCC patients with long-term follow-up. Patients and Methods We identified 730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999. Anti-CAIX monoclonal antibody (clone M75) was used, and tumor specimens were blindly scored for expression levels. Associations of CAIX expression with RCC death were evaluated using Cox proportional hazards regression models. Results There were 241 RCC deaths and a median of 9.4 years of follow-up for patients still under observation. CAIX was expressed in 708 (97.0%) of the specimens; 163 tumors (22.3%) exhibited low (≤ 85% tumor cells positive) expression, and 567 (77.7%) exhibited high (> 85% tumor cells positive) expression. Univariately, low CAIX expression was associated with increased risk of RCC death relative to high expression (risk ratio = 1.65; P < .001). However, low CAIX expression was not associated with RCC death after adjusting for nuclear grade or coagulative tumor necrosis. Additionally, we observed CAIX expression in a number of extrarenal organs. Conclusion CAIX is strongly expressed by ccRCC. Although CAIX is associated with outcome in patients with ccRCC, it is not an independent prognostic marker. Furthermore, CAIX expression is apparent in extrarenal organs. As such, exploitation of CAIX as a prognostic marker and therapeutic target merits additional consideration.
Phase II Trial of Sunitinib in Patients With Metastatic Colorectal Cancer After Failure of Standard Therapy
Authors: Saltz Leonard B. , Rosen Lee S. , Marshall John L. , Belt Robert J. , Hurwitz Herbert I. , Eckhardt S. Gail , Bergsland Emily K. , Haller Daniel G. , Lockhart A. Craig , Rocha Lima Caio M. , Huang Xin , DePrimo Samuel E. , Chow-Maneval Edna , Chao Richard C. , Lenz Heinz J. 
Published: October 2007

Purpose Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor receptor and multiple other growth factor receptors. We assessed the safety and efficacy of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. Patients and Methods Eighty-four patients were enrolled onto this two-stage phase II trial and were stratified by whether they had received prior bevacizumab (n = 43) or not (n = 41). Treatment comprised sunitinib 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. Results By Response Evaluation Criteria in Solid Tumors criteria, one patient, who was in the prior bevacizumab cohort, achieved a partial response, and 13 patients (two in the prior bevacizumab cohort and 11 in the no prior bevacizumab cohort) achieved stable disease lasting ≥ 22 weeks. Median time to progression in the prior bevacizumab and bevacizumab-naïve cohorts was 2.2 months (95% CI, 1.9 to 2.3 months) and 2.5 months (95% CI, 2.3 to 3.1 months), respectively, whereas median overall survival time was 7.1 months (95% CI, 4.9 to 10.6 months) and 10.2 months (95% CI, 8.2 to 15.3 months), respectively. The most common adverse events were fatigue, diarrhea, nausea, vomiting, and anorexia. Twenty-six patients (32%) required dose reduction to 37.5 mg/d, and one patient required dose reduction to 25 mg/d. Conclusion Sunitinib did not demonstrate a meaningful single-agent objective response rate in colorectal cancer refractory to standard chemotherapy. However, the mechanisms of action and acceptable safety profile of sunitinib warrant further study in combination with standard regimens for metastatic colorectal cancer.
SH2B1β (SH2-Bβ) Enhances Expression of a Subset of Nerve Growth Factor-Regulated Genes Important for Neuronal Differentiation Including Genes Encoding Urokinase Plasminogen Activator Receptor and Matrix Metalloproteinase 3/10
Authors: Chen Linyi , Maures Travis J. , Jin Hui , Huo Jeffrey S. , Rabbani Shafaat A. , Schwartz Jessica , Carter-Su Christin 
Published: October 2007

AbstractPrevious work showed that the adapter protein SH2B adapter protein 1β (SH2B1) (SH2-B) binds to the activated form of the nerve growth factor (NGF) receptor TrkA and is critical for both NGF-dependent neurite outgrowth and maintenance. To identify SH2B1β-regulated genes critical for neurite outgrowth, we performed microarray analysis of control PC12 cells and PC12 cells stably overexpressing SH2B1β (PC12-SH2B1β) or the dominant-negative SH2B1β(R555E) [PC12-SH2B1β(R555E)]. NGF-induced microarray expression of Plaur and Mmp10 genes was greatly enhanced in PC12-SH2B1β cells, whereas NGF-induced Plaur and Mmp3 expression was substantially depressed in PC12-SH2B1β(R555E) cells. Plaur, Mmp3, and Mmp10 are among the 12 genes most highly up-regulated after 6 h of NGF. Their protein products [urokinase plasminogen activator receptor (uPAR), matrix metalloproteinase 3 (MMP3), and MMP10] lie in the same pathway of extracellular matrix degradation; uPAR has been shown previously to be critical for NGF-induced neurite outgrowth. Quantitative real-time PCR analysis revealed SH2B1β enhancement of NGF induction of all three genes and the suppression of NGF induction of all three when endogenous SH2B1 was reduced using short hairpin RNA against SH2B1 and in PC12-SH2B1β(R555E) cells. NGF-induced levels of uPAR and MMP3/10 and neurite outgrowth through Matrigel (MMP3-dependent) were also increased in PC12-SH2B1β cells. These results suggest that SH2B1β stimulates NGF-induced neuronal differentiation at least in part by enhancing expression of a specific subset of NGF-sensitive genes, including Plaur, Mmp3, and/or Mmp10, required for neurite outgrowth.
Coordinated contractions effectively expel water from the aquiferous system of a freshwater sponge
Authors: Elliott Glen R. D. , Leys Sally P. 
Published: October 2007

SUMMARY
In response to mechanical stimuli the freshwater sponge Ephydatia muelleri (Demospongiae, Haplosclerida, Spongillidae) carries out a series of peristaltic-like contractions that is effective in expelling clumps of waste material from the aquiferous system. Rates of contraction depend on the region of tissue they are propagating through: 0.3–1 μm s–1 in the peripheral canals, 1–4 μm s–1 in central canals, and 6–122 μm s–1 in the osculum. Faster events include twitches of the entire sponge choanosome and contraction of the sheet-like apical pinacoderm that forms the outer surface of the animal. Contraction events are temporally and spatially coordinated. Constriction of the tip of the osculum leads to dilation of excurrent canals; fields of ostia in the apical pinacoderm close in unison just prior to contraction of the choanosome, apical pinacoderm and osculum. Relaxation returns the osculum, canals and the apical pinacoderm to their normal state, and three such coordinated `inflation–contraction'responses typically follow a single stimulus. Cells in the mesohyl arrest crawling as a wave of contraction passes, suggesting an extracellular signal may pass between cells. Bundles of actin filaments traverse endopinacocytes of the apical pinacoderm. Actin-dense plaques join actin bundles in adjacent pinacocytes to form continuous tracts spanning the whole sponge. The orchestrated and highly repeatable series of contractions illustrates that cellular sponges are capable of coordinated behavioural responses even in the absence of neurons and true muscle. Propagation of the events through the pinacocytes also illustrates the presence of a functional epithelium in cellular sponges. These results suggest that control over a hydrostatic skeleton evolved prior to the origin of nerves and true muscle.
Allometric scaling in centrarchid fish: origins of intra- and inter-specific variation in oxidative and glycolytic enzyme levels in muscle
Authors: Davies Rhiannon , Moyes Christopher D. 
Published: October 2007

SUMMARYThe influence of body size on metabolic rate, muscle enzyme activities and the underlying patterns of mRNA for these enzymes were explored in an effort to explain the genetic basis of allometric variation in metabolic enzymes. We studied two pairs of sister species of centrarchid fish: black bass(largemouth bass Micropterus salmoides and smallmouth bass Micropterus dolomieui) and sunfish (pumpkinseed Lepomis gibbosus and bluegill Lepomis macrochirus). Our goal was to assess the regulatory basis of both intraspecific and interspecific variation relative to body size, as well as to gain insights into the evolutionary constraints within lineages. Whole animal routine metabolic rate showed scaling coefficients not significantly different from 1, ranging from (+0.87 to +0.96). However, there were significant effects of body size on the specific activities of oxidative and glycolytic enzymes. Mass-specific activity of the oxidative enzyme citrate synthase (CS) scaled negatively with body size in each species, with scaling coefficients ranging from –0.15 to –0.19, whereas the glycolytic enzyme pyruvate kinase (PK) showed positive scaling, with scaling coefficients ranging from +0.08 to +0.23. The ratio of mass-specific enzyme activity in PK to CS increased with body size,whereas the ratio of mRNA transcripts of PK to CS was unaffected, suggesting the enzyme relationships were not due simply to transcriptional regulation of both genes. The mass-dependent differences in PK activities were best explained by transcriptional regulation of the muscle PK gene; PK mRNA was a good predictor of PK specific enzyme activity within species and between species. Conversely, CS mRNA did not correlate with CS specific enzyme activities, suggesting post-transcriptional mechanisms may explain the observed inter-specific and intraspecific differences in oxidative enzymes.
Drosophilaflies combine periodic heartbeat reversal with a circulation in the anterior body mediated by a newly discovered anterior pair of ostial valves and `venous' channels
Authors: Wasserthal Lutz T. 
Published: October 2007

SUMMARYHeartbeat activity in tethered adult drosophilids was recorded using a linear optosensor chip and an IR-light beam. Recording from two to five sensor elements within 250 μm along the anterior heart, it was possible to analyze periodic reversals. In intact Drosophila melanogaster and D. hydei, longer anterograde pulse periods with lower pulse rates generally alternated with shorter retrograde pulse periods having higher pulse rates. These differences are dependent on heart anatomy: a newly discovered first pair of ostia is connected to bilateral thoraco-abdominal hemolymph channels. These channels are part of a venous space separated from the abdominal hemocoel by a septum, consisting of a metanotal ridge and the pericardial diaphragm lined by a special form of fat body. The channels are sealed, and their lumen is possibly controlled by the metathoracic tergo-pleural muscle. During retrograde pulses, the heart chamber works like a suction pump,aspiring hemolymph through the first ostia from the venous channels and discharging it through a newly described caudal opening. During forward beating, the anterior chamber receives hemolymph via all inflow ostia from the entire heart and drives it like a pressure pump through the narrow aorta. Also, during forward pulses, a lateral circulation occurs in the thorax as a result of the venous supply. Inhibition of abdominal mobility leads to an irregular heart rate, with pulse-wise alternating heartbeat reversals. The possible involvement of slow abdominal movements in heartbeat periodicity is discussed. The heartbeat periods are superimposed with intermittent bouts of abdominal pumping movements.
An examination of the metabolic processes underpinning critical swimming in Atlantic cod (Gadus morhua L.) using in vivo31P-NMR spectroscopy
Authors: Lurman Glenn J. , Bock Christian H. , Pörtner Hans-O. 
Published: October 2007

SUMMARY
Traditionally, critical swimming speed has been defined as the speed when a fish can no longer propel itself forward, and is exhausted. To gain a better understanding of the metabolic processes at work during a Ucrit swim test, and that lead to fatigue, we developed a method using in vivo31P-NMR spectroscopy in combination with a Brett-type swim tunnel. Our data showed that a metabolic transition point is reached when the fish change from using steady state aerobic metabolism to non-steady state anaerobic metabolism, as indicated by a significant increase in inorganic phosphate levels from 0.3±0.3 to 9.5±3.4 mol g–1, and a drop in intracellular pH from 7.48±0.03 to 6.81±0.05 in muscle. This coincides with the point when the fish change gait from subcarangiform swimming to kick-and-glide bursts. As the number of kicks increased, so too did the Pi concentration, and the pHi dropped. Both changes were maximal at Ucrit. A significant drop in Gibbs free energy change of ATP hydrolysis from –55.6±1.4 to –49.8±0.7 kJ mol–1 is argued to have been involved in fatigue. This confirms earlier findings that the traditional definition of Ucrit, unlike other critical points that are typically marked by a transition from aerobic to anaerobic metabolism, is the point of complete exhaustion of both aerobic and anaerobic resources.
Experimental observations of an 8 m/s drop test of a metallic helicopter underfloor structure onto a hard surface: Part 1
Authors: Hughes K , Vignjevic R , Campbell J 
Published: October 2007

This is the first part of a two-part paper that describes the experimental observations for two similar sections of floor that were dropped onto both hard and water surfaces at 8 m/s, as a part of one experimental campaign. The current paper provides an assessment of a simple box-beam underfloor structure typically found in metallic helicopters and provides an overview of the failure modes and the collapse mechanism observed when dropped onto a hard surface. All findings are supported by quantitative measurements and extensive photographic evidence. The current paper identifies two limitations with the existing design, which are based upon the observations of the failure modes for different frame types and the performance of the intersection joints. In order to increase the level of crashworthiness currently offered, significant frame and joint redesign is required in order to provide a more progressive collapse. The simple buckling modes currently observed should be avoided, as the existing stroke is not fully utilized in the event of a crash, resulting in an inefficient structure. The current paper also discusses the sensitivity to impact angle, as slight variations from a normal impact may result in a detrimental response.
Experimental observations of an 8 m/s drop test of a metallic helicopter underfloor structure onto water: Part 2
Authors: Hughes K , Vignjevic R , Campbell J 
Published: October 2007

This is the second part of a two-part paper that describes the experimental observations for two similar sections of floor that were dropped onto both hard and water surfaces at 8 m/s, as part of one experimental campaign. The current paper provides an assessment of a simple box-beam under floor structure typically found in metallic helicopters and provides an overview of the failure modes and the collapse mechanism observed when dropped onto water at 8 m/s, as well as providing quantitative data for the skin deflections observed. The results demonstrate that the lack of frame and intersection joint collapse is a common feature, which is caused by the high failure strength of the existing construction, together with the inability of the skin to generate membrane loads that are sufficiently large to trigger progressive collapse within the structure. It is therefore recommended to reduce the collapse force of the structure through the use of geometry, material type, and inclusion of triggers. However, the caveat with this approach is that if the failure strength is optimized for a water impact, a poor crashworthy response may occur during a hard surface impact. The current paper discusses three main limitations with the design, which are heavily interrelated, as improvements in frame and joint collapse cannot be achieved without considering developing the ductile behaviour of the skin. However, maintaining skin integrity will be critical to maintain the floatation capabilities of the helicopter. The current paper recommends that a next generation design should encompass a passive dual role capability for both hard and soft surface impacts, by being able to degrade the localized strength depending upon the type of surface encountered. This will significantly improve the crashworthy response of a metallic under floor structure and have a significant impact on improving occupant survivability for an impact on water.
Computer-assisted hip resurfacing surgery using the Acrobot® Navigation System
Authors: Barrett A R W , Davies B L , Gomes M P S F , Harris S J , Henckel J , Jakopec M , Kannan V , Rodriguez y Baena F M , Cobb J P 
Published: October 2007

The authors have previously reported on the laboratory development of the Acrobot® Navigation System for accurate computer-assisted hip resurfacing surgery. This paper describes the findings of using the system in the clinical setting and including the improvements that have been made to expedite the procedure. The aim of the present system is to allow accurate planning of the procedure and precise placement of the prosthesis in accordance with the plan, with a zero intraoperative time penalty in comparison to the standard non-navigated technique. At present the navigation system is undergoing final clinical evaluation prior to a clinical study designed to demonstrate the accuracy of outcome compared with the conventional technique. While full results are not yet available, this paper describes the techniques that will be used to evaluate accuracy by comparing pre-operative computed tomography (CT)-based plans with post-operative CT scans. Example qualitative clinical results are included based on visual comparison of the plan with post-operative X-rays.
Comparative repeatability of guide-pin axis positioning in computer-assisted and manual femoral head resurfacing arthroplasty
Authors: Hodgson A , Helmy N , Masri B A , Greidanus N V , Inkpen K B , Duncan C P , Garbuz D S , Anglin C 
Published: October 2007

The orientation of the femoral component in hip resurfacing arthroplasty affects the likelihood of loosening and fracture. Computer-assisted surgery has been shown to improve significantly the surgeon's ability to achieve a desired position and orientation; nevertheless, both bias and variability in positioning remain and can potentially be improved. The authors recently developed a computer-assisted surgical (CAS) technique to guide the placement of the pin used in femoral head resurfacing arthroplasty and showed that it produced significantly less variation than a typical manual technique in varus/valgus placement relative to a pre-operatively determined surgical plan while taking a comparable amount of time. In the present study, the repeatability of both the CAS and manual techniques is evaluated in order to estimate the relative contributions to overall variability of surgical technique (CAS versus manual), surgeon experience (novice versus experienced), and other sources of variability (e.g. across specimens and across surgeons). This will enable further improvements in the accuracy of CAS techniques. Three residents/fellows new to femoral head resurfacing and three experienced hip arthroplasty surgeons performed 20-30 repetitions of each of the CAS and manual techniques on at least one of four cadaveric femur specimens. The CAS system had markedly better repeatability (1.2°) in varus/valgus placement relative to the manual technique (2.8°), slightly worse repeatability in version (4.4° versus 3.2°), markedly better repeatability in mid-neck placement (0.7 mm versus 2.5 mm), no significant dependence on surgeon skill level (in contrast to the manual technique), and took significantly less time (50 s versus 123 s). Proposed improvements to the version measurement process showed potential for reducing the standard deviation by almost two thirds. This study supports the use of CAS for femoral head resurfacing as it is quicker than the manual technique, independent of surgeon experience, and demonstrates improved repeatability.