bluuebunny/crossref_metadata_2025_split huggingface dataset:
CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy
Authors: Pardanani Animesh , Ketterling Rhett P. , Brockman Stephanie R. , Flynn Heather C. , Paternoster Sarah F. , Shearer Brandon M. , Reeder Terra L. , Li Chin-Yang , Cross Nicholas C. P. , Cools Jan , Gilliland D. Gary , Dewald Gordon W. , Tefferi Ayalew 
Published: July 2003

AbstractImatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl- or PDGFRβ- activating mutations. The drug is also active in a subset of patients with eosinophilic disorders and systemic mast cell disease (SMCD). Recently, a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 (FIP1L1) and PDGFRα (PDGFRA) genes has been identified as a therapeutic target for imatinib mesylate in hypereosinophilic syndrome (HES). We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion. CHIC2 deletion was observed in bone marrow cells for 3 of 5 patients with SMCD associated with eosinophilia. Deletion of this locus and expression of the FIP1L1–platelet-derived growth factor receptor α (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase–polymerase chain reaction (RT-PCR) for one patient. While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not. These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES. Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD.
Phase I/II Trial of Epratuzumab (Humanized Anti-CD22 Antibody) in Indolent Non-Hodgkin’s Lymphoma
Authors: Leonard John P. , Coleman Morton , Ketas Jamie C. , Chadburn Amy , Ely Scott , Furman Richard R. , Wegener William A. , Hansen Hans J. , Ziccardi Heather , Eschenberg Michael , Gayko Urte , Cesano Alessandra , Goldenberg David M. 
Published: July 2003

Purpose: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin’s lymphoma (NHL).Patients and Methods: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m2over 30 to 60 minutes weekly for four treatments.Results: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease (≥ 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m2dose group and 27% in the 480 mg/m2dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate.Conclusion: Epratuzumab was well tolerated at up to 1,000 mg/m2/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m2/wk indicates that this dose should be explored in additional studies.
Gemcitabine Plus Vinorelbine Compared With Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non–Small-Cell Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group
Authors: Gridelli Cesare , Gallo Ciro , Shepherd Frances A. , Illiano Alfonso , Piantedosi Francovito , Robbiati Sergio Federico , Manzione Luigi , Barbera Santi , Frontini Luciano , Veltri Enzo , Findlay Brian , Cigolari Silvio , Myers Robert , Ianniello Giovanni P. , Gebbia Vittorio , Gasparini Giampietro , Fava Sergio , Hirsh Vera , Bezjak Andrea , Seymour Lesley , Perrone Francesco 
Published: July 2003

Purpose: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non–small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient’s quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. Patients and Methods: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. Results: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. Conclusion: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.
Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non–Small-Cell Lung Cancer: The TAX 326 Study Group
Authors: Fossella Frank , Pereira Jose R. , von Pawel Joachim , Pluzanska Anna , Gorbounova Vera , Kaukel Eckhard , Mattson Karin V. , Ramlau Rodryg , Szczęsna Aleksandra , Fidias Panagiotis , Millward Michael , Belani Chandra P. 
Published: July 2003

Purpose: To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non–small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy. Patients and Methods: Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL • min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC). Results: Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P = .044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P = .029). Median survival (9.4 v 9.9 months [for VC]; P = .657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P < .01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL. Conclusion: DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.
Fasting Activates the Nonhuman Primate Hypocretin (Orexin) System and Its Postsynaptic Targets
Authors: Diano Sabrina , Horvath Balazs , Urbanski Henryk F. , Sotonyi Peter , Horvath Tamas L. 
Published: July 2003

Abstract
In rodents, hypocretin (HCRT, also called orexin) influences a variety of endocrine, autonomic, and metabolic functions. The present study was undertaken to determine whether the HCRT-producing circuit is involved in the hypothalamic regulation of homeostasis in primates as well. We studied female monkeys (Cercopithecus aethiops) that were either fed or fasted for 24 h. Immunocytochemistry revealed HCRT-producing perikarya exclusively in the lateral hypothalamus-perifornical region and dorsomedial hypothalamus of the monkey brain. HCRT axons and axon terminals were present in different parts of the hypothalamus and adjacent forebrain and thalamic nuclei. The 24-h fast resulted in an approximately 50% decline in circulating leptin levels and significantly elevated c-fos expression in the perifornical region; in the dorsomedial, ventromedial, and arcuate nuclei; and in the medial preoptic area. In the dorsomedial nucleus and perifornical region of fasted monkeys, three times more HCRT-neurons expressed nuclear c-fos than those of the normally fed controls. Neurons in different parts of the hypothalamus and basal forebrain that expressed c-fos, but did not contain HCRT, were targets of HCRT-immunopositive boutons establishing asymmetric synapses. In the arcuate nucleus, subsets of these HCRT-targeted c-fos-expressing cells contained neuropeptide Y. The present study provides the first experimental evidence to implicate HCRT in the hypothalamic regulation of homeostasis in primates. The fact that these lateral hypothalamic cells have leptin receptors and can be activated by a metabolic challenge and that they innervate diverse brain regions indicates that the HCRT system may be a key integrator of environmental cues in their regulation of diverse brain activity.
High Prevalence of Cardiac Valve Disease in Acromegaly: An Observational, Analytical, Case-Control Study
Authors: Colao Annamaria , Spinelli Letizia , Marzullo Paolo , Pivonello Rosario , Petretta Mario , Di Somma Carolina , Vitale Giovanni , Bonaduce Domenico , Lombardi Gaetano 
Published: July 2003

To characterize mitral and aortic valve abnormalities we performed M-mode, two-dimensional, and pulsed Doppler echocardiography in 42 patients with active acromegaly, 22 patients cured of acromegaly, and 64 controls pair-matched with the patients for sex and age. The overall prevalence of valve abnormalities was higher in both the active patients (86% vs. 24%; P &lt; 0.0001) and the cured patients (73% vs. 9%; P &lt; 0.0001) than in controls. Left ventricular hypertrophy was higher in active (81% vs. 29%; P &lt; 0.0001), but not in cured (41% vs. 14%; P = 0.09) patients than in controls. Cardiac valve abnormalities were associated with left ventricular hypertrophy in both patients and controls, without any difference between them. Conversely, among subjects without left ventricular hypertrophy, mitral and aortic abnormalities were only present in the patients (75% of active and 54% of cured), but not in controls (3% of active controls and 0% of cured controls).
In conclusion, patients with active acromegaly and those cured of the disease have a high prevalence of mitral and aortic abnormalities. The persistence of valve disease in patients with cured acromegaly is likely to be correlated with the persistence of left ventricular hypertrophy, which should be carefully and continuously monitored as an aspect of the risk of cardiac dysfunction in these patients.
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome: Time to Review Diagnostic Criteria?
Authors: Buzi F. , Badolato R. , Mazza C. , Giliani S. , Notarangelo Lucia D. , Radetti G. , Plebani A. , Notarangelo Luigi D. 
Published: July 2003

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive syndrome defined by two of the following conditions: chronic mucocutaneous candidiasis, hypoparathyroidism, or Addison’s disease. Other autoimmune conditions may be associated, such as hypothyroidism, hypogonadism, insulin-dependent diabetes mellitus, chronic active hepatitis, pernicious anemia, vitiligo, alopecia, biliary cirrhosis, and ectodermal dysplasia. APECED is caused by mutations in the autoimmune regulator gene, mapping to 21q22.3.
We report on three patients whose clinical and molecular features challenge the currently used diagnostic criteria for APECED. AR presented at 15 yr of age with a history of recurrent infections and mucocutaneous candidiasis. He is now 21 yr old, and no other signs or symptoms of APECED have appeared to date.
DR presented at 7 yr of age with hypocalcemia and a prolonged Q-T interval on the electrocardiogram. He also had minor facial dysmorphisms and mild mental retardation. Serum calcium levels were low, PTH levels were undetectable, and hypoparathyroidism was therefore diagnosed. All other biochemical, immunological, and endocrinological tests were normal. DR is now 8 yr old with no other signs or symptoms of APECED.
ST presented at 14 yr of age for alopecia aerata and pitted nail dystrophy and goiter. Thyroid function was normal in the presence of thyroid-specific antibodies. No other signs or symptoms of APECED have appeared to date.
Genetic analysis revealed a typical mutation (R257X) on a single allele in both AP and DR; in ST, heterozygosity for a novel mutation (V484M) involving one of the zinc fingers of the plant homeodomain of the protein was found. The finding of a typical APECED mutation in two patients presenting with one isolated major clinical APECED feature and of a novel mutation in a patient presenting with atypical features of APECED onset suggests that the time might have come for updating the diagnostic criteria of this syndrome.
Differential Regulation of Proopiomelanocortin and Pituitary-Restricted Transcription Factor (TPIT), a New Marker of Normal and Adenomatous Human Corticotrophs
Authors: Vallette-Kasic Sophie , Figarella-Branger Dominique , Grino Michel , Pulichino Anne-Marie , Dufour Henry , Grisoli François , Enjalbert Alain , Drouin Jacques , Brue Thierry 
Published: July 2003

Since the identification of the pituitary-restricted transcription factor Tpit, a novel T-box factor that is only present in mouse in the two pituitary proopiomelanocortin (POMC)-expressing lineages, no information was available on its pattern of expression in human pituitary. We investigated by immunohistochemistry and in situ hybridization the expression of TPIT in normal human anterior pituitary tissue and in several types of human pituitary adenomas (n = 52).
TPIT expression was restricted to the nucleus of normal or adenomatous human corticotroph cells. No specific TPIT immunostaining was detectable in all prolactin (PRL)-, GH-, or gonadotropin-secreting adenomas. In situ hybridization studies demonstrated that TPIT transcripts were coexpressed with POMC mRNA in both secreting and silent corticotroph adenomas, and in normal corticotrophs, whereas TPIT mRNA was not detectable in other types of pituitary adenomas. Unlike POMC, TPIT was not up-regulated by adrenalectomy in rats and did not seem down-regulated in the normal pituitary adjacent to human corticotroph microadenomas.
TPIT is the only currently known transcription factor selectively expressed in human normal and adenomatous corticotrophs. In human and experimental models, TPIT and its target gene POMC were thus differentially regulated by glucocorticoids. Moreover, TPIT represents a new marker of POMC-expressing pituitary cells.
Fibroblast Growth Factors Regulate Prolactin Transcription via an Atypical Rac-Dependent Signaling Pathway
Authors: Jackson Twila A. , Koterwas David M. , Morgan Melissa A. , Bradford Andrew P. 
Published: July 2003

AbstractFibroblast growth factors (FGFs) play a critical role in pituitary development and in pituitary tumor formation and progression. We have previously characterized FGF signal transduction and regulation of the tissue-specific rat prolactin (rPRL) promoter in GH4 pituitary cells. FGF induction of rPRL transcription is independent of Ras, but mediated by a protein kinase C-δ (PKCδ)-dependent activation of MAPK (ERK). Here we demonstrate a functional role for the Rho family monomeric G protein, Rac1, in FGF regulation of PRL gene expression via an atypical signaling pathway. Expression of dominant negative Rac, but not RhoA or Cdc42, selectively inhibited FGF-induced rPRL promoter activity. Moreover, expression of dominant negative Rac also attenuated FGF-2 and FGF-4 stimulation of MAPK (ERK). However, in contrast to other Rac-dependent signaling pathways, FGF activation of rPRL promoter activity was independent of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase/Akt cascades. FGFs failed to activate JNK1 or JNK2, and expression of dominant negative JNK or Akt constructs did not block FGF-induced PRL transcription. Consistent with the role of PKCδ in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase Cγ (PLCγ) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLCγ in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLCγ, PKCδ, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.
Adhesion measurements on the attachment devices of the jumping spiderEvarcha arcuata
Authors: Kesel A. B. , Martin A. , Seidl T. 
Published: July 2003

SUMMARYThe feet of the jumping spider Evarcha arcuata attach to rough substrates using tarsal claws. On smooth surfaces, however, attachment is achieved by means of a claw tuft, the scopula. All eight feet bear a tarsal scopula, which is equipped with setae, these again being covered by numerous setules. In E. arcuata, an estimated 624 000 setules, with a mean contact area of 1.7×105 nm2, are present. The spider's entire contact area thus totals 1.06×1011nm2. Adhesion to the substrate does not depend on the secretion of an adhesive fluid. Analysis via atomic force microscopy (AFM) shows that a single setule can produce an adhesive force (Fa) of 38.12 nN perpendicular to a surface. Consequently, at a total Fa of 2.38×10–2 N and a mean body mass of 15.1 mg, a safety factor (SF; Fa/Fm, where Fm is weight) of 160 is achieved. Tenacity (τn; Fa/A, where A is area of contact) amounts to 2.24×105 N m-2.
Initial mechanical efficiency of isolated cardiac muscle
Authors: Barclay C. J. , Widén C. , Mellors L. J. 
Published: July 2003

SUMMARYThe aim of this study was to determine whether the initial mechanical efficiency (ratio of work output to initial metabolic cost) of isolated cardiac muscle is over 60%, as has been reported previously, or whether it is approximately 30%, as suggested by an estimate based on the well-established net mechanical efficiency (ratio of work output to total, suprabasal energy cost) of 15%. Determination of initial efficiency required separation of the enthalpy output (i.e. heat + work) into initial and recovery components. The former corresponds to energy produced by reactions that use high-energy phosphates and the latter to energy produced in the regeneration of high-energy phosphates. The two components were separated mathematically. Experiments were performed in vitro (30°C) using preparations dissected from rat left ventricular papillary muscles (N=13). Muscle work output and heat production were measured during a series of 40 contractions using a contraction protocol designed to mimic in vivopapillary muscle activity. Net mechanical efficiency was 13.3±0.7%. The total enthalpy output was 2.16 times greater than the initial enthalpy output,so that initial mechanical efficiency was 28.1±1.2%.
Comparative studies of high performance swimming in sharks I. Red muscle morphometrics, vascularization and ultrastructure
Authors: Bernal D. , Sepulveda C. , Mathieu-Costello O. , Graham J. B. 
Published: July 2003

SUMMARYTunas (family Scombridae) and sharks in the family Lamnidae are highly convergent for features commonly related to efficient and high-performance(i.e. sustained, aerobic) swimming. High-performance swimming by fishes requires adaptations augmenting the delivery, transfer and utilization of O2 by the red myotomal muscle (RM), which powers continuous swimming. Tuna swimming performance is enhanced by a unique anterior and centrally positioned RM (i.e. closer to the vertebral column) and by structural features (relatively small fiber diameter, high capillary density and greater myoglobin concentration) increasing O2 flux from RM capillaries to the mitochondria. A study of the structural and biochemical features of the mako shark (Isurus oxyrinchus) RM was undertaken to enable performance-capacity comparisons of tuna and lamnid RM. Similar to tunas, mako RM is positioned centrally and more anterior in the body. Another lamnid, the salmon shark (Lamna ditropis), also has this RM distribution, as does the closely related common thresher shark (Alopias vulpinus; family Alopiidae). However, in both the leopard shark(Triakis semifasciata) and the blue shark (Prionace glauca),RM occupies the position where it is typically found in most fishes; more posterior and along the lateral edge of the body. Comparisons among sharks in this study revealed no differences in the total RM quantity (approximately 2–3% of body mass) and, irrespective of position within the body, RM scaling is isometric in all species. Sharks thus have less RM than do tunas(4–13% of body mass). Relative to published data on other shark species,mako RM appears to have a higher capillary density, a greater capillary-to-fiber ratio and a higher myoglobin concentration. However, mako RM fiber size does not differ from that reported for other shark species and the total volume of mitochondria in mako RM is similar to that reported for other sharks and for tunas. Lamnid RM properties thus suggest a higher O2 flux capacity than in other sharks; however, lamnid RM aerobic capacity appears to be less than that of tuna RM.