bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective Study of Childhood Ganglioneuroma
Authors: De Bernardi Bruno , Gambini Claudio , Haupt Riccardo , Granata Claudio , Rizzo Antonino , Conte Massimo , Tonini Gian Paolo , Bianchi Maurizio , Giuliano Maria , Luksch Roberto , Prete Arcangelo , Viscardi Elisabetta , Garaventa Alberto , Sementa Angela Rita , Bruzzi Paolo , Angelini Paola 
Published: March 2008

Purpose To review a historical cohort of childhood ganglioneuroma (GN), the benign representative of the peripheral neuroblastic tumor (PNT) family. Patients and Methods Of 2,286 PNTs enrolled between 1979 and 2005, 146 (6.4%) were registered as GN. Histological revision was carried out on 76 tumors. Diagnosis was confirmed in 45, while 27 were reclassified as ganglioneuroblastoma intermixed (GNBI) and four were reclassified as other PNT subtypes. Results GNs differed from other PNTs for sex, age, tumor site, stage, tumor markers, and scintigraphic results. Characteristics of 76 reviewed and 70 nonreviewed patients were comparable. Reviewed GN and GNBI patients were comparable except for homovanillic acid excretion, metaiodobenzylguanidine scintigraphy, and DNA content. Seven patients were only biopsied and 139 underwent surgery. Twenty-two patients suffered surgery-related complications, of which two were fatal and seven were severe. Radical tumor resection and surgery-related complication rates were comparable for GN, GNBI, and nonreviewed instances. Six patients developed tumor progression but survived. Two patients developed a late malignancy but survived. None of the 146 patients received chemotherapy. Of 146 patients, two died of surgery-related complications and 144 survived. Conclusion Diagnosis was changed to GNBI for approximately one third of 76 reviewed tumors. Patients with confirmed GN, reclassified as GNBI, and nonreviewed histology presented with comparable clinical, biochemical, and biologic features. Surgical results, complication rate, number of progressions, and outcome were similar for the three groups. Surgery was associated with significant risk of complications. Survival was not influenced by extent of tumor resection. Aggressive surgical approach should not be recommended for childhood GN and GNBI.
Phase III Trial of Pemetrexed Plus Best Supportive Care Compared With Best Supportive Care in Previously Treated Patients With Advanced Malignant Pleural Mesothelioma
Authors: Jassem Jacek , Ramlau Rodryg , Santoro Armando , Schuette Wolfgang , Chemaissani Assad , Hong Shengyan , Blatter Johannes , Adachi Susumu , Hanauske Axel , Manegold Christian 
Published: March 2008

Purpose This multicenter, phase III study compared overall survival (OS) of second-line pemetrexed plus best supportive care (BSC) versus BSC alone in patients with advanced malignant pleural mesothelioma (MPM). Secondary end points included response rate, progression-free survival (PFS), time to tumor progression (TTP), time to treatment failure (TTF), and toxicity. Patients and Methods Patients with relapsed MPM after first-line chemotherapy were randomly assigned to receive pemetrexed 500 mg/m2 plus BSC (P+BSC) every 21 days or BSC alone. Results The study enrolled 243 patients (123 on P+BSC arm and 120 on BSC arm). Median OS time was not significantly different between the arms (8.4 months for P+BSC and 9.7 months for BSC; P = .74). Cox regression modeling suggested a trending survival benefit for patients who responded to first-line therapy. Time-to-event measures significantly favored P+BSC (median PFS, TTP, and TTF). Partial response was achieved in 18.7% and 1.7% of patients in P+BSC and BSC arms, respectively (P < .0001), and a disease control rate (partial response plus stable disease) was achieved in 59.3% and 19.2% of patients in P+BSC and BSC arms, respectively (P < .0001). Use of postdiscontinuation chemotherapy was significantly greater among BSC patients compared with P+BSC patients (51.7% v 28.5%, respectively; P = .0002), with more BSC patients receiving pemetrexed (18.3% v 3.3%, respectively; P = .0001). Postdiscontinuation therapy was initiated earlier for BSC than P+BSC patients (median time to initiation, 4.3 v 15.7 months, respectively; log-rank P < .0001). Chemotherapy was well tolerated, with expected modest (4% to 7%) grade 3 and 4 hematologic toxicities. Conclusion Second-line pemetrexed elicited significant tumor response and delayed disease progression compared with BSC alone in patients with advanced MPM. Improvement in OS was not seen in this study, possibly because of the significant imbalance in postdiscontinuation chemotherapy between the arms.
Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer
Authors: Kumar Amit , Petri Edward T. , Halmos Balazs , Boggon Titus J. 
Published: March 2008

Purpose To review the recent advances in the atomic-level understanding of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated. Methods The analysis was conducted on published crystal structures deposited in the Protein Data Bank ( www.pdb.org ) using the program O. Results In this review we emphasize how recent EGFR kinase domain crystal structures can explain the mechanisms of activation for L858R and other EGFR-TK mutations, and compare these distinct activating mechanisms with those recently described for the wild-type EGFR. We suggest an atomic-level mechanism for the poor efficacy of lapatinib against tumors with activating EGFR kinase domain point mutations compared with the efficacy of gefitinib and erlotinib, and demonstrate how structural insights help our understanding of acquired resistance to these agents. We also highlight how these new molecular-level structural data are expected to affect the development of EGFR-TK targeted small molecule kinase inhibitors. Conclusion There are now more crystal structures published for the EGFR-TK domain than for any other TK. This wealth of crystallographic information is beginning to describe the mechanisms by which proper regulation of EGFR-TK is lost in disease. These crystal structures are beginning to show how small molecules inhibit EGFR-TK activity and will aid development of EGFR-TK mutant targeted therapies.
Randomized Trial of Intravenous Iron Supplementation in Patients With Chemotherapy-Related Anemia Without Iron Deficiency Treated With Darbepoetin Alfa
Authors: Pedrazzoli Paolo , Farris Antonio , Del Prete Salvatore , Del Gaizo Filomena , Ferrari Daris , Bianchessi Clara , Colucci Giuseppe , Desogus Alberto , Gamucci Teresa , Pappalardo Alessandro , Fornarini Giuseppe , Pozzi Paola , Fabi Alessandra , Labianca Roberto , Di Costanzo Francesco , Secondino Simona , Crucitta Enrico , Apolloni Federica , Del Santo Antonio , Siena Salvatore 
Published: March 2008

Purpose Unresponsiveness to erythropoiesis-stimulating agents, occurring in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia. We have prospectively evaluated whether intravenous iron can increase the proportion of patients with chemotherapy-related anemia who respond to darbepoetin. Patients and Methods Between December 2004 and February 2006, 149 patients with lung, gynecologic, breast, and colorectal cancers and ≥ 12 weeks of planned chemotherapy were enrolled from 33 institutions. Patients were required to have hemoglobin ≤ 11 g/L and no absolute or functional iron deficiency. All patients received darbepoetin 150 μg subcutaneously once weekly for 12 weeks and were randomly assigned to sodium ferric gluconate 125 mg intravenously (IV) weekly for the first 6 weeks (n = 73) or no iron (n = 76). Primary end point of the study was the percentage of patients achieving hematopoietic response (hemoglobin ≥ 12 g/dL or ≥ 2 g/dL increase). Results Hematopoietic response by intention-to-treat analysis was 76.7% (95%CI, 65.4% to 85.8%) in the darbepoetin/iron group and 61.8% (95%CI, 50.0% to 72.7%) in the darbepoetin group (P = .0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5% (95% CI, 81.8% to 97.9%) and 70% (95% CI, 55.4% to 82.1%), respectively (P = .0033). Increase of hemoglobin during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on. The safety profile was comparable in the two arms. Conclusion In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.
Phase I Study of Bevacizumab Added to Fluorouracil- and Hydroxyurea-Based Concomitant Chemoradiotherapy for Poor-Prognosis Head and Neck Cancer
Authors: Seiwert Tanguy Y. , Haraf Daniel J. , Cohen Ezra E.W. , Stenson Kerstin , Witt Mary Ellyn , Dekker Allison , Kocherginsky Masha , Weichselbaum Ralph R. , Chen Helen X. , Vokes Everett E. 
Published: March 2008

Purpose We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients. Patients and Methods Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m2 (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded. Results Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m2, HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/2, HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5). Conclusion Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.
Estimating maximum performance: effects of intraindividual variation
Authors: Adolph Stephen C. , Pickering Trevor 
Published: March 2008

SUMMARYResearchers often estimate the performance capabilities of animals using a small number of trials per individual. This procedure inevitably underestimates maximum performance, but few studies have examined the magnitude of this effect. In this study we explored the effects of intraindividual variation and individual sample size on the estimation of locomotor performance parameters. We measured sprint speed of the lizard Sceloporus occidentalis at two temperatures (20°C and 35°C),obtaining 20 measurements per individual. Speed did not vary temporally,indicating no training or fatigue effects. About 50% of the overall variation in speed at each temperature was due to intraindividual variation. While speed was repeatable, repeatability decreased slightly with increasing separation between trials. Speeds at 20°C and 35°C were positively correlated,indicating repeatability across temperatures as well. We performed statistical sampling experiments in which we randomly drew a subset of each individual's full set of 20 trials. As expected, the sample's maximum speed increased with the number of trials per individual; for example, five trials yielded an estimate averaging 89% of the true maximum. The number of trials also influenced the sample correlation between mean speeds at 20°C and 35°C; for example, five trials yielded a correlation coefficient averaging 90% of the true correlation. Therefore, intraindividual variation caused underestimation of maximal speed and the correlation between speeds across temperatures. These biases declined as the number of trials per individual increased, and depended on the magnitude of intraindividual variation, as illustrated by running sampling experiments that used modified data sets.
A functional analysis of myotomal muscle-fibre reorientation in developing zebrafishDanio rerio
Authors: van Leeuwen Johan L. , van der Meulen Talitha , Schipper Henk , Kranenbarg Sander 
Published: March 2008

SUMMARYThe fast muscle fibres in the anterior trunk of teleost fish are primarily responsible for large amplitude undulatory swimming motions. Previous theoretical studies suggested that the near-helical arrangement of these fibres results in a (fairly) uniform distribution of fibre strain and work output during swimming. However, the underlying simplifications of these studies precluded unequivocal support for this hypothesis. We studied the fast muscle-fibre reorientation and the concomitant myotomal strain variance in a body segment near the anus during larval and juvenile development in the zebrafish. From 2 to 4 days post fertilization (d.p.f.), the measured angles between the muscle fibres and the longitudinal axis of the zebrafish were small. Yet, onset of a near-helical muscle-fibre arrangement was recognized. Juveniles of 51 d.p.f. have larger mean fibre angles and already possess the near-helical pattern of adult teleosts. We present a model that computes the distribution of the strain along the muscle fibres from measured muscle-fibre orientations, body curvature and prescribed tissue deformations. We selected the most extreme body curvatures, which only occur during fast starts and turning manoeuvres. Using the model, we identified the (non-linear) tissue deformations that yield the least variance in the muscle-fibre strain. We show that simple beam theory cannot reliably predict the strain distribution: it results in very small strains and negligible work output of the most medial fibres. In our model, we avoided these functional limitations by adding a shear deformation to the simple beam deformation. At 2 d.p.f., the predicted variance in the muscle-fibre strain for the shear deformation optimized for strain uniformity is fairly small, due to the small variation in the fibre distances to the medial plane that is caused by the relatively large spinal cord and notochord. The predicted minimal strain variance increases sharply from 2 d.p.f. to 3 d.p.f., remains relatively large at 4 d.p.f., but decreases again considerably at 15 and 39 d.p.f. The 51 d.p.f. stage exhibits the smallest variance in the fibre strains (for the identified optimal deformation), in spite of the widely varying muscle-fibre distances to the medial plane. The non-linear nature of the body deformations with the least strain variance implies an interesting optimization constraint: the juvenile muscle-fibre arrangement results in small predicted spatial strain variations at large-amplitude body curvatures, at the (modest) expense of a large coefficient of variation for small curvatures. We conclude that larval fish rapidly change their muscle-fibre orientations (probably in response to mechanical signals). Within the theoretically examined plausible range of deformations, the closest correspondence to a uniform strain field was found for the juvenile stage.
Mechanics of limb bone loading during terrestrial locomotion in river cooter turtles (Pseudemys concinna)
Authors: Butcher Michael T. , Blob Richard W. 
Published: March 2008

SUMMARYStudies of limb bone loading during terrestrial locomotion have focused primarily on birds and mammals. However, data from a broader functional and phylogenetic range of species are critical for understanding the evolution of limb bone function and design. Turtles are an interesting lineage in this context. Although their slow walking speeds and robust limb bones might lead to low locomotor forces and limb bone stresses similar to other non-avian reptiles, their highly sprawled posture could produce high bending loads,leading to high limb bone stresses similar to those of avian and mammalian species, as well as high torsion. To test between these possibilities, we evaluated stresses experienced by the femur of river cooter turtles(Pseudemys concinna) during terrestrial walking by synchronizing measurements of three-dimensional joint kinematics and ground reaction forces(GRFs) during isolated hindlimb footfalls. Further, we evaluated femoral safety factors for this species by comparing our locomotor stress calculations with the results of mechanical property tests. The net GRF magnitude at peak tensile bone stress averaged 0.35 BW (body weight) and was directed nearly vertically for the middle 40–65% of the contact interval, essentially orthogonal to the femur. Peak bending stresses experienced by the femur were low (tensile: 24.9±9.0 MPa; compressive: –31.1±9.1 MPa)and comparable to those in other reptiles, yet peak shear stresses were higher than those in other reptiles, averaging 13.7±4.2 MPa. Such high torsion is present despite cooters lacking a large tail, a feature that has been hypothesized to contribute to torsion in other reptiles in which the tail is dragged along the ground. Comparison of femoral stresses to measurements of limb bone mechanical properties in cooters indicates safety factors to yield of 13.9 in bending and 6.3 in torsion, considerably higher than values typical for birds and mammals, and closer to the elevated values calculated for other reptile species. Thus, not only do turtle limb bones seem considerably`over-designed' for resisting the loads that they encounter, but comparisons of bone loading across tetrapod lineages are consistent with the hypothesis that low limb bone loads, elevated torsion and high safety factors may be primitive features of limb bone design.
Task-dependent force sharing between muscle synergists during locomotion in turkeys
Authors: Nelson Frank E. , Roberts Thomas J. 
Published: March 2008

SUMMARYAt most joints, there is a redundancy of muscle function. For any given movement, there are a wide range of possible solutions to the problem of how force is shared among muscle synergists. A better understanding of how force is shared among muscle synergists can provide insight into the mechanics and control of movement. We examined force sharing in the gastrocnemius of wild turkeys (Meleagris gallopavo), using strain gauges bonded to bony tendons. Force was measured separately in the lateral (LG) and medial (MG)heads of the gastrocnemius, to evaluate force sharing. We also used inverse dynamics to determine the total force required during swing phase. To determine whether the pattern of force sharing varied depending on the mechanical task, we used running speed (1 to 3.5 m s–1) and limb loading (30 and 60 g added tarsometatarsal mass) to vary the force required at the intertarsal joint. We found that the distribution of force between these two heads varied depending on the phase of the stride cycle. During stance, force was shared in near equal amounts between the two heads and this distribution was unaffected by changes in running speed or limb load. During swing phase, however, there was no force sharing. Force was produced only in the lateral head, and this force was not significantly different from the total force required, as calculated from inverse dynamics. Thus, the LG produced all of the force required for limb extension during swing. This change in the pattern of force sharing between stance and swing supports the theory that force sharing between muscle synergists is task-dependent.
Heart rate regulation and extreme bradycardia in diving emperor penguins
Authors: Meir Jessica U. , Stockard Torre K. , Williams Cassondra L. , Ponganis Katherine V. , Ponganis Paul J. 
Published: March 2008

SUMMARYTo investigate the diving heart rate (fH) response of the emperor penguin (Aptenodytes forsteri), the consummate avian diver, birds diving at an isolated dive hole in McMurdo Sound, Antarctica were outfitted with digital electrocardiogram recorders, two-axis accelerometers and time depth recorders (TDRs). In contrast to any other freely diving bird,a true bradycardia (fH significantly&lt;fH at rest) occurred during diving [dive fH (total beats/duration)=57±2 beats min–1, fH at rest=73±2 beats min–1 (mean ± s.e.m.)]. For dives less than the aerobic dive limit (ADL; duration beyond which [blood lactate] increases above resting levels), dive fH=85±3 beats min–1, whereas fH in dives greater than the ADL was significantly lower (41±1 beats min–1). In dives greater than the ADL, fH reached extremely low values: fH during the last 5 mins of an 18 min dive was 6 beats min–1. Dive fH and minimum instantaneous fH during dives declined significantly with increasing dive duration. Dive fH was independent of swim stroke frequency. This suggests that progressive bradycardia and peripheral vasoconstriction (including isolation of muscle) are primary determinants of blood oxygen depletion in diving emperor penguins. Maximum instantaneous surface interval fH in this study is the highest ever recorded for emperor penguins (256 beats min–1), equivalent to fH at V̇O2 max.,presumably facilitating oxygen loading and post-dive metabolism. The classic Scholander–Irving dive response in these emperor penguins contrasts with the absence of true bradycardia in diving ducks, cormorants, and other penguin species.
A comparative analysis of putative oxygen-sensing cells in the fish gill
Authors: Coolidge Emily H. , Ciuhandu Cosima S. , Milsom William K. 
Published: March 2008

SUMMARYWe investigated the distribution of serotonin (5-HT)-containing neuroepithelial cells (NECs), the putative O2 sensing cells, in the gills of four species of fish: trout (Oncorhynchus mykiss), goldfish(Carassius auratus), trairão (Hoplias lacerdae) and traira (Hoplias malabaricus) using immunohistochemical markers for 5-HT, synaptic vesicles and neural innervation. We found that all fish had a cluster of innervated, serotonergic NECs at the filament tips, but there were species-specific distributions of serotonin-containing NECs within the primary gill filaments. Trout gill filaments had a greater number of serotonin-containing NECs than both trairão and traira, whereas goldfish primary filaments had none. Serotonin-containing NECs in the secondary lamellae were most numerous in goldfish, present in trairão and traira, but absent in trout. Those found in the primary filament were generally associated with the efferent filamental artery. Innervated,serotonin-containing cells (NECs or Merkel-like cells) were also found in the gill rakers of trout and goldfish although vesicular serotonin was only found in the gill rakers of goldfish. These differences in serotonergic NEC distribution appear to reflect paracrine versus chemoreceptive roles related to hypoxia tolerance in the different fish species.