bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials
Authors: Rodeghiero Francesco , Stasi Roberto , Giagounidis Aristoteles , Viallard Jean‐François , Godeau Bertrand , Pabinger Ingrid , Cines Douglas , Liebman Howard , Wang Xuena , Woodard Paul 
Published: August 2013

AbstractBackground and objectivesThrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo‐controlled trials is available. We sought to determine the long‐term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events.MethodsData from 13 romiplostim clinical trials in which 653 patients with ITP received romiplostim for up to 5 yr (921.5 patient‐years) were pooled; subject incidence rates and exposure‐adjusted event rates (per 100 patient‐years) were calculated.ResultsThe rate of thrombotic events (6% of patients, 7.5 events per 100 patient‐years) did not appear to increase over time; 9 events were associated with platelet counts >400 × 109/L and 10 with romiplostim doses exceeding current recommendations. Serious and grade ≥3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient‐years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient‐years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient‐years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient‐years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient‐years, four events treatment‐related).ConclusionsRomiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long‐term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.
Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young β‐thalassemia intermedia patients
Authors: Elalfy Mohsen S. , Adly Amira A. M. , Ismail Eman A. , Elhenawy Yasmine I. , Elghamry Islam R. 
Published: August 2013

AbstractObjectiveTo assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in β‐thalassemia intermedia (TI) patients compared with single HU therapy.MethodsAn interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (≤18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study.ResultsTransfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion‐independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups.ConclusionsHU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events.
BCR‐ABL1 molecular remission after 90Y‐epratuzumab tetraxetan radioimmunotherapy in CD22+Ph+B‐ALL: proof of principle
Authors: Chevallier Patrice , Bodet‐Milin Caroline , Robillard Nelly , Eugene Thomas , Menard Audrey , Le Houerou Claire , Guillaume Thierry , Delaunay Jacques , Escoffre‐Barbe Martine , Wegener William A. , Goldenberg David M. , Kraeber‐Bodéré Francoise 
Published: August 2013

AbstractAlthough targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B‐acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome‐positive B‐ALL in third relapse who received RAIT with 90yttrium (90Y)‐labeled anti‐CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR‐ABL1 molecular remission documented by RT‐qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. 90Y‐Epratuzumab tetraxetan may be a promising therapeutic option for CD22+ B‐ALL patients.
Apoptotic signal molecules in skin biopsies of cutaneous lupus erythematosus: analysis using tissue microarray
Authors: Toberer Ferdinand , Sykora Jaromir , Göttel Daniel , Hartschuh Wolfgang , Werchau Siegfried , Enk Alexander , Joos Stefan , Krammer Peter H. , Kuhn Annegret 
Published: August 2013

AbstractCutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease. Different pathogenetic mechanisms, including the accumulation of apoptotic keratinocytes in CLE, have been reported. Therefore, we investigated whether CLE and other inflammatory skin diseases differ with regard to the epidermal expression of molecules that are crucial for the initiation and regulation of apoptosis. In this study, 241 skin biopsies from patients with CLE, psoriasis (PSO), lichen planus (LP) and healthy controls (HCs) were analysed immunohistochemically using the tissue microarray (TMA) technique. The TUNEL assay and anti‐activated caspase‐3 antibodies revealed a significant increase of apoptotic keratinocytes in CLE lesions compared with HCs. Furthermore, we detected a significant increase in the epidermal expression of CD95 in CLE specimens compared with PSO, LP and HCs. These data suggest that the accumulation of apoptotic keratinocytes in CLE might be due to the increased epidermal expression of CD95, resulting in increased activity of the extrinsic apoptotic pathway in the disease.
α‐Synuclein as an intrinsically disordered monomer – fact or artefact?
Authors: Coelho‐Cerqueira Eduardo , Carmo‐Gonçalves Phelippe , Sá Pinheiro Anderson , Cortines Juliana , Follmer Cristian 
Published: August 2013

Fibrillization of the protein α‐synuclein (α‐syn) is a hallmark of Parkinson's disease and other α‐synucleinopathies. The well‐established idea that α‐syn is a natively disordered monomer prone to forming fibrils was recently challenged by data showing that the protein mostly exists in vitro and in vivo as helically folded tetramers that are resistant to fibrillization. These apparently conflicting findings may be reconciled by the idea that α‐syn exists as a disordered monomer in equilibrium with variable amounts of dynamic oligomeric species. In this context, varying the approaches used for protein purification, such as the method used to lyse cells or the inclusion of denaturing agents, could dramatically perturb this equilibrium and hence alter the relative abundance of the disordered monomer. In the present study, we investigated how the current methods for α‐syn purification affect the structure and oligomeric state of the protein, and we discuss the main pitfalls associated with the production of recombinant α‐syn in Escherichia coli. We demonstrate that α‐syn was expressed in E. coli as a disordered monomer independent of both the cell lysis method and the use of heating/acidification for protein purification. In addition, we provide convincing evidence that the disordered monomer exists in equilibrium with a dynamic dimer, which is not an artefact of the cross‐linking protocol as previously suggested. Unlike the helically folded tetramer, α‐syn dimer is prone to fibrillate and thus it may be an interesting target for anti‐fibrillogenic molecules.Structured digital abstract

aplha-Syn and aplha-Syn bind by cross-linking study (View interaction)

aplha-Syn and aplha-Syn bind by detection by mass spectrometry (1, 2)

aplha-Syn and aplha-Syn bind by molecular sieving (View interaction)

aplha-Syn and aplha-Syn bind by circular dichroism (View interaction)
Identification of key amino acid residues in the catalytic mechanism of diaminopropionate ammonialyase from Salmonella typhimurium
Authors: Kalyani Josyula N. , Bisht Shveta , Lakshmikanth Mariyanna , Murthy Mathur R. N. , Savithri Handanahal S. 
Published: August 2013

Diaminopropionate ammonialyase (DAPAL), a fold‐type II pyridoxal 5′‐phosphate‐dependent enzyme, catalyzes the α,β‐elimination of diaminopropionate (DAP) to pyruvate and ammonia. DAPAL was able to utilize both d‐ and l‐DAP as substrates with almost equal efficiency. Mutational analysis of functionally important residues such as Thr385, Asp125 and Asp194 was carried out to understand the mechanism by which the isomers are hydrolyzed. Further, the putative residues involved in the formation of disulfide bond Cys271 and Cys299 were also mutated. T385S, T385D sDAPAL were as active with dl‐DAP as substrate as sDAPAL, whereas the later exhibited a threefold increase in catalytic efficiency with d‐Ser as substrate. Further analysis of these mutants suggested that DAPAL might follow an anti‐E2 mechanism of catalysis that does not involve the formation of a quinonoid intermediate. Of the two mutants of Asp125, D125E showed complete loss of activity with d‐DAP as substrate, whereas the reaction with l‐DAP was not affected significantly, demonstrating that Asp125 was essential for abstraction of protons from the d‐isomer. By contrast, mutational analysis of Asp194 showed that the residue may not be directly involved in proton abstraction from l‐DAP. sDAPAL does not form a disulfide bond in solution, although the position of Cys299 and Cys271 in the modeled structure of sDAPAL favored the formation of a disulfide bond. Further, unlike eDAPAL, sDAPAL could be activated by monovalent cations. Mutation of the cysteine residues showed that Cys271 may be involved in coordinating the monovalent cation, as observed in the case of other fold‐type II enzymes.
Differential effects of thapsigargin analogues on apoptosis of prostate cancer cells
Authors: Dubois Charlotte , Vanden Abeele Fabien , Sehgal Pankaj , Olesen Claus , Junker Steffen , Christensen Søren B. , Prevarskaya Natalia , Møller Jesper V. 
Published: August 2013

The inhibition of sarcoplasmic reticulum Ca2+‐ATPase (SERCA) by thapsigargin (Tg) and Tg‐type analogues is considered to trigger cell death by activation of apoptotic pathways. Some of these analogues may be useful as antineoplastic agents after appropriate targeting as peptide conjugated prodrugs to cancer cells. With this in mind, this study evaluates the effect on LNCaP androgen‐sensitive cancer cells of thapsigargin substituted with 12‐aminododecanoyl linkers and Leu (Leu‐8ADT), aspartate (Asp‐8ADT) or Boc‐8ADT. Our results show that both Leu‐8ADT and Asp‐8ADT result in rapid ER calcium depletion and an influx of calcium across the plasma membrane by activation of store‐operated calcium entry. By contrast, ER Ca2+ depletion by Boc‐8ADT is a very slow process that does not perceptibly increase cytosolic Ca2+ and activate store‐operated calcium entry, because the inhibition of SERCA with this compound is very slow. Nevertheless, we find that Boc‐8ADT is a more efficient inducer of apoptosis than both Tg and Leu‐8ADT. Compared with Tg and the other analogues, apoptosis induced by Asp‐8ADT is very modest, although this compound also activates store‐operated calcium entry and at high concentrations (1 μm) causes severe morphological changes, reflecting decreased cell viability. We conclude that many factors need to be considered for optimization of these compounds in antineoplastic drug design. Among these ER stress induced by Ca2+ endoplasmic reticulum mobilization seems particularly important, whereas the early cytosolic increase of Ca2+ concentration preceding the executive phase of apoptosis appears to be of no, or little, consequence for a subsequent apoptotic effect.
Fatigue performance and fatigue damage parameter estimation of spot welded joints of aluminium alloys 6111‐T4 and 5754
Authors: Shi Y. , Guo H. 
Published: August 2013

ABSTRACTIn the present study, fatigue behaviours of spot welded joints of aluminium alloys 6111‐T4 and 5754 have been experimentally investigated. Fatigue results indicate that fatigue strength of spot weld primarily depends on specimen loading type and gauge thickness. Effects of base material and load ratio on fatigue resistance of welded specimen are insignificant. An equivalent stress based fatigue damage parameter is derived to consolidate empirical data and develop predictive capabilities for automobile designers. The fatigue damage parameter defined in this study is proven effective in consolidating a large amount of fatigue data into a narrow band and is especially suitable for the comparative fatigue strength evaluation of components and specimens.
Vanishing bone disease of the mandible – a case report
Authors: Asha Mysore L. , Jose Anju Anu , Babshet Medha , Bajoria Atul Anand , Naveen Srinivas 
Published: August 2013

BackgroundMassive osteolysis (Gorham–Stout syndrome) is a rare condition of unknown etiology that is thought to result from a localized endothelial proliferation of lymphatic vessels resulting in destruction and absorption of bone. Osteolysis of the jaws has been reported in association with infection, cysts, neoplasia, and metabolic, endocrine, or hematologic abnormalities. Rare cases of idiopathic osteolysis have also been recorded. A detailed review from various peer reviewed journals has been discussed in this article.ObjectivesTo discuss the demographic distribution and possibilities of pathogenesis of Gorham–Stout syndrome.Materials and methodA case report of vanishing bone disease of the mandible in a 60 year old female patient has been discussed. A detail review of literature highlighting the demographic distribution and pathogenesis of vanishing bone disease has been made.ResultsThirty eight percentages of these lesions appear in older individuals with a slight male predilection. 68.6% of the oro‐facial massive osteolysis occurs in mandible has been reported. Variable etiopathogenesis such as vascular proliferation, increased levels of circulating cytokines and circulatory disturbances have been associated with this disease.ConclusionThe Gorham–Stout syndrome though rarely seen in the facial skeleton, it is important to consider it in the differential diagnosis of osteolytic lesions of the jaws.
Hyperplastic hepatocellular nodule with localized hemangiomatosis: A hither‐to unrecognized type of hypervascular hepatic lesion
Authors: Sasaki Motoko , Ikeda Tatsuru , Hatanaka Kanako C. , Nakanuma Yasuni 
Published: August 2013

AimThe differential diagnosis of hypervascular hepatocellular nodular lesion includes hepatocellular carcinoma and it is sometimes difficult to image. We report herein two patients with hyperplastic hepatocellular nodule associated with localized hemangiomatosis.MethodsA hypervascular hepatic nodule approximately 10 mm in diameter was incidentally detected in a 79‐year‐old woman and a 58‐year‐old man. Hepatocellular carcinoma was suspected and partial hepatectomy was performed.ResultsHepatitis viral markers and tumor markers were negative in both patients. On histology, the nodular lesions had an ill‐defined border and included hemangioma‐like vessels and sinusoidal dilatation showing immunoreactivity for CD34. There were no abnormal unpaired arteries or a central stellate scar suggesting focal nodular hyperplasia. Hepatic columns in the lesion were thickened to two to three cell layers and cellular density was mildly more increased than the background liver. Cellular atypia and diminished reticulin fibers around the hepatic column were not observed. A survey of the background livers of 13 patients with cavernous hemangioma disclosed similar hemangioma‐like vessels in hepatic parenchyma in six patients (46%), but similar nodular lesions were not detected in any patients.ConclusionTaken together, the hepatic lesions in these two patients may be hither‐to unrecognized types of hyperplastic hepatocellular lesion associated with localized hemangiomatous lesion that may cause irregular blood flow.
Effect of bismuth oxide on white mineral trioxide aggregate: chemical characterization and physical properties
Authors: Grazziotin‐Soares R. , Nekoofar M. H. , Davies T. E. , Bafail A. , Alhaddar E. , Hübler R. , Busato A. L. S. , Dummer P. M. H. 
Published: August 2013

AbstractAimTo assess the effect of bismuth oxide (Bi2O3) on the chemical characterization and physical properties of White mineral trioxide aggregate (MTA) Angelus.MethodologyCommercially available White MTA Angelus and White MTA Angelus without Bi2O3 provided by the manufacturer especially for this study were subjected to the following tests: Rietveld X‐ray diffraction analysis (XRD), energy‐dispersive X‐ray analysis (EDX), scanning electron microscopy (SEM), compressive strength, Vickers microhardness test and setting time. Chemical analysis data were reported descriptively, and physical properties were expressed as means and standard deviations. Data were analysed using Student's t‐test and Mann–Whitney U test (P = 0.05).ResultsCalcium silicate peaks were reduced in the diffractograms of both hydrated materials. Bismuth particles were found on the surface of White MTA Angelus, and a greater amount of particles characterized as calcium hydroxide was observed by visual examination on White MTA without Bi2O3. The material without Bi2O3 had the shortest final setting time (38.33 min, P = 0.002), the highest Vickers microhardness mean value (72.35 MPa, P = 0.000) and similar compressive strength results (P = 0.329) when compared with the commercially available White MTA Angelus containing Bi2O3.ConclusionThe lack of Bi2O3 was associated with an increase in Vickers microhardness, a reduction in final setting time, absence of Bi2O3 peaks in diffractograms, as well as a large amount of calcium and a morphology characteristic of calcium hydroxide in EDX/SEM analysis.
Scent‐marking in the Himalayan musk deer (Moschus chrysogaster)
Authors: Green Michael J. B. 
Published: August 2013

In view of its solitary behaviour and need for dense cover, the musk deer probably relies chiefly on olfaction for communication. The various forms of scent‐marking behaviour include defaecation at latrines by both sexes and, in the case of males, the secretion of musk and pasting with the caudal gland.The use of 120 latrines was monitored for periods of up to 27 months in the Kedarnath Sanctuary, North India. Latrines occurred throughout animals' ranges and were used most frequently during the autumn rut. There is limited evidence that in summer musk deer defaecated wherever they happened to be rather than at latrines, which were seldom used at this time of year. That latrines are regularly used for purposes of marking, rather than to orientate animals, is strongly supported by the musk deer's ability accurately to locate snow‐covered sites. Droppings were sometimes covered with debris, more often in autumn than in other seasons. The covering of droppings appears to be a characteristic of adults and probably helps to keep the pellets moist and smelly. It is suggested that some latrines were used exclusively by one animal whereas others were used by more than one animal. The extent to which latrines appear to have been shared corresponds with the degree of overlap between animals' ranges.There is some evidence that musk, which is synthesized before the rut, is conveyed in the urine of males. Snow stained with urine from males usually had a sweet scent and was pink or red, whereas that stained with urine from females never had a noticeable scent and was always amber in colour.Likely constraints influencing the spatial pattern of scent‐marking are considered. The paper concludes with a discussion of the role of scent‐marking in the musk deer.
Large Strain Response in 0.99(Bi0.5Na0.4K0.1)TiO3–0.01(KxNa1−x)NbO3 Lead‐Free Ceramics Induced by the Change of K/Na Ratio in (KxNa1−x)NbO3
Authors: Hao Jigong , Shen Bo , Zhai Jiwei , Liu Chunze , Li Xiaolong , Gao Xingyu 
Published: August 2013

Influence of K/Na ratio in (KxNa1−x)NbO3 on the ferroelectric stability and consequent changes in the electrical properties of 0.99(Bi0.5Na0.4K0.1)TiO3–0.01(KxNa1−x)NbO3 (BNKT–KxNN) ceramics were investigated. Results showed that change of K/Na ratio in KNN induces a phase transition from ferroelectric to ergodic relaxor phase with a significant disruption of the long‐range ferroelectric order, and correspondingly adjusts the ferroelectric–relaxor transition point TF−R to room temperature. Accordingly, giant strain of ~0.46% (corresponding to a large signal d33* of ~575 pm/V) which is comparable to that of Pb‐based antiferroelectrics is obtained at a K/Na ratio of ~1, and the emergence of large strain response induced by the change of K/Na ratio of KNN can be well explained by the correlation between the position of ferroelectric–ergodic relaxor phase boundary in the BNKT–KxNN system and the tolerance factor t of the end number (KxNN). In situ high‐energy X‐ray scattering experiments with external field reveals that the large strain response in the studied system is likely related to the electric field‐induced distortion from the pseudocubic structure.
On the Determination of the Concentration of Crystal Nuclei in Glasses by DSC
Authors: Cabral Aluisio A. , Ferreira Eduardo B. , Villas‐Boas Mariana O. C. , Zanotto Edgar D. 
Published: August 2013

An interesting technique was proposed by Ray et al. over a decade ago to determine the number density of nucleation sites, Nq, or the nucleation rate, I(T), in glasses that exhibit internal nucleation. Their approach is based on the measurement of the areas under the differential scanning calorimetry (DSC) crystallization peaks of partially crystallized glass samples. In this study, we review their method and test a modified equation recently proposed by some of us, which also takes into account the crystal morphology and impingement. We compare Nq obtained with both methods for a Li2O·2SiO2 glass. Small glass monoliths were treated at 620°C for different time periods for crystal growth, without any nucleation treatment, and subsequently analyzed by DSC up to 800°C. We thus estimated Nq from the area under the DSC crystallization peaks. The corrected approach resulted in Nq values which were not affected by the pair of growth times chosen, as expected, but the obtained values were two‐ to fivefold lower than those calculated with the Ray model. Taking into account previously reported nucleation rates and the corresponding induction periods as a function of temperature (for specimens of the same glass batch), we estimated the number of nuclei formed during the DSC heating/cooling steps, and also measured them by optical microscopy (OM). Finally, we compared the obtained values from OM with the Nq values determined by the DSC method. The Nq resulting from the original and new equations were approximately two orders of magnitude larger than those experimentally determined for the same glass using optical microscopy. This difference is attributed to the formation of new nuclei during the heating and cooling paths of the DSC runs and to surface crystallization, which are not taken into account in the DSC expressions.