bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonhydrolytic alkyl halide elimination reaction and its application in solution-processed zinc tin oxide thin film transistors
Authors: Yoo Young Bum , Park Jee Ho , Baik Hong Koo , Song Kie Moon
Published: March 2014

In this study, we fabricated zinc tin oxide (ZTO) thin-film transistors (TFTs) using a sol–gel solution at an annealing temperature of 350 °C. We used a precursor combination of alkoxide and metal chloride to utilize the alkyl halide elimination reaction. Compared with transistor using chloride-only precursors, the resulting ZTO transistor showed improved performance. Solution-processed ZTO-TFTs prepared at 350 °C using an alkoxide–chloride precursor combination showed a field-effect mobility of 4.17 cm2 V−1 s−1, whereas that prepared using a chloride-only solution showed a mobility of 0.98 cm2 V−1 s−1. Thermal analysis showed that the alkoxide–chloride precursor was decomposed well at a given annealing temperature and formed oxide with few residual impurities compared with chloride-only precursors.
Growth Mode Discrimination of Thin Films by Auger Electron Spectroscopy
Authors: Matsushita Yoshiaki , Yagi Katsumichi , Narusawa Tadashi , Honjo Goro
Published: March 2014

The growth mode of thin films is studied by Auger electron spectroscopy (AES) in comparison with the observations by electron microscope (EM). The simple criteria to discriminate by AES between the nucleation and growth (NG) and the monolayer overgrowth (MO) modes, which take account of the different trends of coverage of substrate surface by overgrown film, are shown to give consistent results with EM: Pd/MoS2, PbTe/MgO are NG and Pd/Au, Au/Pd, Ag/Au, Pd/Ag, GeTe/PbSe are MO. The case of GeTe/PbTe, which gives antinomic features in EM, is decided by AES to be MO. The values of escape depth for several Auger electrons are determined and compared with previous data. The problems of interdiffusion across the interface in MO are discussed.
Dose-Volume Factors to Select Patient-Specific Image-Guidance Action Thresholds in Prostate Cancer
Authors: Block A. M. , Lin J. , Hoggarth M. A. , Quinn M. , Garza R. , Mantz C. A. , Roeske J. C.
Published: March 2014

For radiation delivery tracking systems that monitor intrafraction prostate motion, generalized departmental threshold protocols may be used. The purpose of this study is to determine whether predefined action thresholds can be generally applied or if patient-specific action thresholds may be required. Software algorithms were developed in the MatLab (The Mathworks Inc., Natick, MA) software environment to simulate shifts of the patient structure set consisting of prostate, bladder, and rectum. These structures were shifted by +/- 10 mm in each direction in 1 mm increments to simulate displacements during treatment, without taking into consideration organ deformity. Dose-volume data at each shift were plotted and analyzed. A linear relationship was observed between planning dose-volume parameters and shifted dose-volume parameters. For a 5 mm anterior shift, it was observed that individual rectal V70 values increased by absolute magnitudes of 6–15%, dependent on the planning rectal V70 of each patient. Likewise, for a 5 mm inferior shift, individual bladder V70 values increased by 1–14%, dependent on planning bladder V70. This linear relationship was observed for all levels of shifts up to 10 mm. Since rectum and bladder dose-volume changes due to patient shifts are dependent on dose-volume parameters, this study suggests that patient-specific action thresholds may be necessary.
The Dosimetric and Delivery Advantages of a New 160-leaf MLC
Authors: Prah D. E. , Kainz K. , Peng C. , Li X. A.
Published: March 2014

The purpose of this study was to conduct a measurement and treatment planning study on the dosimetric and delivery advantages of a new 160-leaf multileaf collimator (MLC). Recently, a new 160-leaf multileaf collimator (Siemens 160 MLC™) was introduced. The 160-MLC is a single focused design that consists of 160-leafs (80 pairs), each 95 mm thick with a projected leaf width of 5 mm at the machine isocenter. Compared to its double focused predecessors, the 82-leaf MLC (Siemens OPTIVIEW™ MLC) and 58-leaf MLC (Siemens 3-D MLC™), the 160-MLC has leaf widths of half the size. The most notable difference is the new slanted leaf design that replaced the tongue and groove system and allows for complete interdigitation. A systematic study that compared the dosimetric and delivery differences among the 160-MLC, 58-MLC, and divergent Cerrobend blocks was performed. Dosimetric conformity for each collimator type was determined by conforming each to circular targets of various diameters. The effective penumbra for each collimator type was calculated by conforming each, at various collimator angles, to a square stationary target. The quality of 3D conformal radiotherapy treatment (3D-CRT) plans and the quality intensity modulated radiation treatment (IMRT) plans were respectively compared with each collimator type. The 160-MLC was found to have improved dosimetric conformity over the 58-MLC. The divergent Cerrobend block showed marginal dosimetric conformity improvement over the 160-LMC. Overall, the 160-MLC had a 45% and 29% reduction in the 20/80 and 30/90 effective penumbra over the 58-MLC, respectively, while exhibiting only a slightly larger effective penumbra over the divergent Cerrobend block. Comparing 3D-CRT plans generated for small lesions of the head and neck, the V100 for the PTV of the plans generated with the Cerrobend blocks, the 58-MLC, and the 160-MLC were 97.78%, 92.51%, and 99.18%, respectively, while with regards to the OARs, the three produced similar DVHs. IMRT plans generated with the 160-MLC were found to significantly reduce the total delivered monitor units by up to 14.7% and the number of segments by as much as 10.7% compared to the 58-MLC. The average delivery time for the direct aperture optimized (DAO) IMRT plans generated with the 160-MLC was approximately 5 minutes. Overall, compared to the 58-MLC, the new 160-MLC was found to improve dosimetric conformity and IMRT delivery efficiency.
Investigating the Clinical Aspects of Using CT vs. CT-MRI Images during Organ Delineation and Treatment Planning in Prostate Cancer Radiotherapy
Authors: Tzikas A. , Karaiskos P. , Papanikolaou N. , Sandilos P. , Koutsouveli E. , Lavdas E. , Scarleas C. , Dardoufas K. , Lind B. K. , Mavroidis P.
Published: March 2014

In order to apply highly conformal dose distributions, which are characterized by steep dose fall-offs, it is necessary to know the exact target location and extension. This study aims at evaluating the impact of using combined CT-MRI images in organ delineation compared to using CT images alone, on the clinical results. For 10 prostate cancer patients, the respective CT and MRI images at treatment position were acquired. The CTV was delineated using the CT and MRI images, separately, whereas bladder and rectum were delineated using the CT images alone. Based on the CT and MRI images, two CTVs were produced for each patient. The mutual information algorithm was used in the fusion of the two image sets. In this way, the structures drawn on the MRI images were transferred to the CT images in order to produce the treatment plans. For each set of structures of each patient, IMRT and 3D-CRT treatment plans were produced. The individual treatment plans were compared using the biologically effective uniform dose ([Formula: see text]) and the complication-free tumor control probability ( P+) concepts together with the DVHs of the targets and organs at risk and common dosimetric criteria. For the IMRT treatment, at the optimum dose level of the average CT and CT-MRI delineated CTV dose distributions, the P+ values are 74.7% in both cases for a [Formula: see text] of 91.5 Gy and 92.1 Gy, respectively. The respective average total control probabilities, PB are 90.0% and 90.2%, whereas the corresponding average total complication probabilities, PI are 15.3% and 15.4%. Similarly, for the 3D-CRT treatment, the average P+ values are 42.5% and 46.7%, respectively for a [Formula: see text] of 86.4 Gy and 86.7 Gy, respectively. The respective average PB values are 80.0% and 80.6%, whereas the corresponding average PI values are 37.4% and 33.8%, respectively. For both radiation modalities, the improvement mainly stems from the better sparing of rectum. According to these results, the expected clinical effectiveness of IMRT can be increased by a maximum Δ P+ of around 0.9%, whereas of 3D-CRT by about 4.2% when combined CT-MRI delineation is performed instead of using CT images alone. It is apparent that in both IMRT and 3D-CRT radiation modalities, the better knowledge of the CTV extension improved the produced dose distribution. It is shown that the CTV is irradiated more effectively, while the complication probabilities of bladder and rectum, which is the principal organs at risk, are lower in the CT-MRI based treatment plans.
Modeling Intracranial Second Tumor Risk and Estimates of Clinical Toxicity with Various Radiation Therapy Techniques for Patients with Pituitary Adenoma
Authors: Winkfield K. M. , Niemierko A. , Bussière M. R. , Crowley E. M. , Napolitano B. N. , Beaudette K. P. , Loeffler J. S. , Shih H. A.
Published: March 2014

This study was designed to estimate the risk of radiation-associated tumors and clinical toxicity in the brain following fractionated radiation treatment of pituitary adenoma. A standard case of a patient with a pituitary adenoma was planned using 8 different dosimetric techniques. Total dose was 50.4 Gy (GyE) at daily fractionation of 1.8 Gy (GyE). All methods utilized the same CT simulation scan with designated target and normal tissue volumes. The excess risk of radiation-associated second tumors in the brain was calculated using the corresponding dose-volume histograms for the whole brain and based on the data published by the United Nation Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and a risk model proposed by Schneider. The excess number of second tumor cases per 10,000 patients per year following radiation is 9.8 for 2-field photons, 18.4 with 3-field photons, 20.4 with photon intensity modulated radiation therapy (IMRT), and 25 with photon stereotactic radiotherapy (SRT). Proton radiation resulted in the following excess second tumor risks: 2-field = 5.1, 3-field = 12, 4-field = 15, 5-field = 16. Temporal lobe toxicity was highest for the 2-field photon plan. Proton radiation therapy achieves the best therapeutic ratio when evaluating plans for the treatment of pituitary adenoma. Temporal lobe toxicity can be reduced through the use of multiple fields but is achieved at the expense of exposing a larger volume of normal brain to radiation. Limiting the irradiated volume of normal brain by reducing the number of treatment fields is desirable to minimize excess risk of radiation-associated second tumors.
Clinical Observation of 73 Nasopharyngeal Carcinoma Patients Treated by Helical Tomotherapy: The China Experience
Authors: Ren G. , Du L. , Ma L. , Feng L-C. , Zhou G-X. , Qu B-L. , Xu S-P. , Xie C-B. , Ou G-M. , Li F. , Zhang X-X. , Yang J.
Published: March 2014

The preliminary short-term clinical outcome of 73 nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy at our cancer institute has been evaluated. Between September 2007 and September 2009, 73 newly diagnosed NPC patients were treated with helical tomotherapy. The distributions of clinical stages according to the UICC 2002 Staging System were: 6, 27, 24, and 16 for Stage I, IIa-b, III, and IVa-b, respectively. The prescription dose was 70–74 Gy/33F to planning gross tumor volume containing the primary tumor and positive lymph nodes, with 60–62.7 Gy/33F to high risk planning target volume, while delivering 52–56 Gy/33F to low risk planning target volume. Twenty-four patients were treated with radiation therapy as single modality, 25 with concurrent cisplatin-based chemotherapy with or without anti-EGFR monoclonal antibody therapy, and 24 with concurrent anti-EGFR monoclonal antibody therapy. Setup errors were analyzed. Side-effects were evaluated with the established RTOG/EORTC criteria. Average beam-on-time was 468.8 sec/F (396.7–696.1 sec). The setup errors in the lateral, longitudinal and vertical directions were 0.00 ± 1.79 mm, −0.55 ± 2.17 mm and 0.38 ± 1.43 mm, corresponding to 3.80 mm, 4.20 mm, and 2.46 mm as the CTV-PTV margin in these directions. The grade 0, 1, 2 and 3 acute skin toxicity was 2.7%, 76.7%, 13.8% and 6.8%; the grade 0, 1, 2 and 3 acute mucositis was 1.4%, 32.9%, 60.2% and 5.5%; and the grade 0, 1, 2 and 3 acute xerostomia was 4.0%, 45.3%, 50.7% and 0, respectively. Only 5 patients suffered from grade 3 or 4 leucopenia. Xerostomia resolved with passing of time and no grade 2 or more xerostomia was noted one year after radiation therapy. Concurrent chemotherapy significantly increased incidence of severe acute toxicities. One month after radiation therapy the remission rates of primary tumor and positive lymph nodes were 91.8% and 98.1%, respectively. The median follow-up was 14.8 months. The one-year relapse-free survival, distant metastasis-free survival and overall survival was 95.6%, 97.2% and 94.8%, respectively. In conclusion, the incidence of severe acute toxicities and late xerostomia was relatively infrequent for NPC patients treated with helical tomotherapy. The long-term clinical outcome for these patients is under investigation.
Percutaneous Vertebroplasty for Pain Management in Spinal Metastasis with Epidural Involvement
Authors: Sun Gang , Jin Peng , Li Min , Lu Yang , Liu Xunwei , Li Fandong , Xie Zhiyong , Ding Juan , Peng Zhaohui
Published: March 2014

Percutaneous vertebroplasty (PVP) has been widely used for the treatment of painful malignant lesions of the spine. Spinal metastasis with epidural involvement, with or without symptoms of neurologic compression, is regarded by some authors as a contraindication or relative contraindication to the procedure. To evaluate safety and effectiveness of PVP in pain management of spinal metastasis with epidural involvement, we retrospectively analyzed PVP in 32 patients with metastatic disease, who presented with at least one vertebral lesion with destruction of the posterior vertebral body wall or epidural extension of tumor. Among these patients, nine had signs of spinal cord or cauda equina compression. Procedural safety was evaluated by any post-procedure adverse events. The PVP analgesic efficacy was evaluated by follow-up neurological examination. Pain intensity was scored on a visual analog scale scored from 0 (no pain) to 10 (maximum pain intensity). The effective pain relief was defined as at least 50% improvement in pain score as compared with pre- procedure baseline. Follow-up assessments were performed at 1 day; 1 week; 1, 3, and 6 months after the procedure. Fifty-three vertebrae in 32 patients were treated in this group. Analgesic efficacy in survival patients was rated at 97% (31/32) at 1day and 1 week, 86.7% (26/30) at 1 month, 82.3% (24/29) at 3 months, and 76.9% (20/26) at 6 months after procedure. Leakage of PMMA was detected in 64% (33/53) treated vertebrae. No systemic complications were observed in all treated patients.
Organ-cocultures (COCs) for Long Term in vitro Studies of Lung Cancer Using 2-Photon Microscopy
Authors: Edelmann M. , Tufman A. , Huber R. M. , Bergner A.
Published: March 2014

Three-dimensional organ cultures allow performing research in vitro in a complex multi-cellular environment. We aimed at developing a long term coculture system (COC) for the study of lung cancer to repeatedly measure tumor volume. Organ cultures of bronchial mucosa with 1–2 mm diameter were embedded in agarose and bisected with a tissue slicer so that the organ culture within was cut into halves uncovering the connective tissue of the stroma of each half. A cell suspension of GFP-transfected EPLC 32M1 lung tumor cells was brought in contact with the connective tissue of the wounded surface. Adherent tumor cells grew invasively into the organ culture. Using 2-Photon microscopy, Z-stacks were recorded, reconstructed with appropriate analysis software, and the tumor volume was calcvulated. Tumor cells were identified by GFP-fluorescence. Repeated measurements of the same COC could be performed over up to 8 weeks. The tumor volume increased continually with the growth rate becoming slower towards the end of culture. A comparison of two clones of tumor cells which had shown different rates of proliferation in monolayer culture demonstrated that the clone with the higher rate of proliferation in monoculture produced tumors with more rapid growth in the COC model. In this study we present a coculture system for the study of lung cancer using 2-Photon microscopy. COCs are particularly appropriate for long term in vitro treatment studies.
Differential Sensitivities of Malignant and Normal Skin Cells to Nanosecond Pulsed Electric Fields
Authors: Yang W. , Wu Y-H. , Yin D. , Koeffler H. P. , Sawcer D. E. , Vernier P. T. , Gundersen M. A.
Published: March 2014

Pulsed electric fields with nanosecond duration and high amplitude have effects on biological subjects and bring new venue in disease diagnosis and therapy. To address this respect, we investigated the responses of paired tumor and normal human skin cells — a basal cell carcinoma (BCC) cell line, and its sister normal cell line (TE) — to nanosecond, megavoltper-meter pulses. When BCC (TE 354.T) and TE (TE 353.SK) cells, cultured under standard conditions, were exposed to 30 ns, 3 MV/m, 50 Hz pulses and tested for membrane permeabilization, viability, morphology, and caspase activation, we found that nanoelectropulse exposure: 1) increased cell membrane permeability in both cell lines but to a greater extent in BCC cells than in normal cells; 2) decreased cell viabilities with BCC cells affected more than normal cells; 3) induced morphological changes in both cell lines including condensed and fragmented chromatin with enlarged nuclei; 4) induced about twice as much caspase activation in BCC cells compared to normal cells. We concluded that in paired tumor and normal skin cell lines, the response of the tumor cells to nanoelectropulse exposure is stronger than the response of normal cells, indicating the potential for selectivity in therapeutic applications.
A Study of Diagnostic Value of Golgi Protein GP73 and its Genetic Assay in Primary Hepatic Carcinoma
Authors: Shi Y. , Chen J. , Li L. , Sun Z. , Zen L. , Xu S. , Zhang Y. , Zhang L.
Published: March 2014

This study aimed to investigate the diagnostic values of GP73 protein in patients' serum with primary hepatic carcinoma (PHC). Also GP73 mRNA expression level in peripheral blood mononuclear cells (PBMCs) and liver tissue between health controls and PHC patients was interrogated. Finally the role of combined detection of serum GP73 and alpha-fetoprotein (AFP) in high-risk population screening was evaluate, in an attempt to justify the new, sensitive, specific and rapid measure for the diagnosis and detection of PHC. Serum proteins of GP73 and AFP were examined in 73 patients with PHC, 13 patients with hepatic cirrhosis, 32 patients with hepatitis and 62 healthy subjects using enzyme-linked immunosorbent assay (ELISA). The relative expression levels of GP73 mRNA in PBMCs and liver tissues were examined by using SYBR Green quantitative reverse transcription polymerase chain reaction (RT-PCR) assay, calculated with the comparison of Cq value. In contrast to patients with cirrhosis and hepatitis, or healthy subjects, PHC patients had their serum GP73 and AFP significantly elevated (P < 0.05) while their PBMCs GP73 mRNA was not significantly different from those with cirrhosis and hepatitis, or healthy subjects (P > 0.05). The expression level of GP73 mRNA was significantly higher in PHC liver tissue than in normal liver tissue. The sensitivity for serum GP73 and AFP in PHC was 68.5% and 28.8%, respectively while that for the combined detection was up to 74%, justifying that the combined detection could prevent the false negative diagnosis by AFP alone and significantly improve the detection rate. As a new diagnostic biomarker of PHC, GP73 protein in serum was highly sensitive and specific. GP73 mRNA in PHC liver tissue specimens instead of whole blood could be used for the diagnosis of PHC as a tumor biomarker, whose detection was highly invasive, risky and afflicting otherwise. The combined detection of GP73 and AFP in serum effectively improved the diagnosis of PHC, in addition to the screening in high-risk population.
Late Pleistocene‐Holocene right slip rate and paleoseismology of the Nayband fault, western margin of the Lut block, Iran
Authors: Foroutan M. , Meyer B. , Sébrier M. , Nazari H. , Murray A. S. , Le Dortz K. , Shokri M. A. , Arnold M. , Aumaître G. , Bourlès D. , Keddadouche K. , Solaymani Azad S. , Bolourchi M. J.
Published: March 2014

The 290 km long Nayband right‐lateral fault cuts across a region seismically quiescent during the last few millennia. Chlorine‐36 and optically stimulated luminescence (OSL) dating of cumulative geomorphic offsets between 9 ± 1 m and 195 ± 15 m with ages from 6.8 ± 0.6 ka to ∼ 100 ka allow deriving a slip rate of 1.8 ± 0.7 mm yr‐1. The paleoseismic record retrieved from the first trench excavated across the fault combined with 18 OSL ages demonstrates the occurrence of at least four large (Mw∼ 7) earthquakes during the last 17.4 ± 1.3 ka and two older earthquakes (before ∼ 23 ka and 70 ± 5 ka). Sediments from the last ∼ 7 ka contain evidence of the three younger earthquakes. Penultimate and antepenultimate events occurred between 6.5 ± 0.4 ka and 6.7 ± 0.4 ka within at most 1 ka whereas the most recent earthquake occurred within the last millennium. Such an irregular earthquake occurrence may suggest seismic clustering. Therefore, the imminence of an earthquake along the fault cannot be discarded even if the most recent earthquake occurred within the last 800 years. This event went unnoticed in the historical records demonstrating the incompleteness of the historical seismic catalogs in Central Iran, challenging any assessment of seismic hazard without geologic information. Infrequent large earthquakes typify the slow‐slipping strike‐slip faults slicing Central and Eastern Iran. Also, the slip rates summed from the Iran Plateau up to the Afghan lowlands appear in fairly good agreement with the most recent GPS data.
How Awareness of Possible Evidence Induces Forthcoming Counter‐Interrogation Strategies
Authors: Luke Timothy J. , Dawson Evan , Hartwig Maria , Granhag Pär Anders
Published: March 2014

We propose that suspects' counter‐interrogation strategies vary as a function of their perception of the interrogator's knowledge about the events in question. The present study investigates the verbal behavior of guilty and innocent suspects when they are aware that there may be incriminating evidence against them. Participants (N = 143) took part in either a simulated act of terrorism or a benign task. They were then interviewed about their activities. Participants were randomly assigned to receive no additional information or to be informed that an investigative team may have collected evidence from surveillance cameras. Results suggest that when alerted to possible evidence against them, guilty suspects adopt either extremely withholding or extremely forthcoming verbal strategies. Theoretical implications of these results are discussed. Copyright © 2014 John Wiley & Sons, Ltd.
Proof‐of‐Concept Study of a Web‐Based Methotrexate Decision Aid for Patients With Rheumatoid Arthritis
Authors: Li Linda C. , Adam Paul M. , Backman Catherine L. , Lineker Sydney , Jones C. Allyson , Lacaille Diane , Townsend Anne F. , Yacyshyn Elaine , Yousefi Charlene , Tugwell Peter , Leese Jenny , Stacey Dawn
Published: March 2014

Objective

To assess the extent to which an online patient decision aid reduced decisional conflict and improved self‐management knowledge/skills in patients who were considering methotrexate for rheumatoid arthritis (RA).

Methods

We used a mixed‐methods pre‐post study design. Eligible participants had a diagnosis of RA, had been prescribed methotrexate but were unsure about starting it, and had access to the internet. Outcome included the Decisional Conflict Scale, the Methotrexate in RA Knowledge Test, and the Effective Consumer Scale. Paired t‐tests were used to assess changes before and after the intervention. Randomly selected participants were interviewed at the end of the study about their experiences with the decision aid.

Results

Of 30 participants, 23 were women. Mean ± SD age was 54.9 ± 14.9 years and the median disease duration was 1 year (interquartile range 0.3–5.0 years). Mean ± SD decisional conflict changed from 49.50 ± 23.17 preintervention to 21.83 ± 24.12 postintervention (change −27.67 [95% confidence interval −39.89, −15.44]; P < 0.001). Knowledge of methotrexate improved (mean ± SD 30.62 ± 9.26 preintervention and 41.67 ± 6.81 postintervention; P < 0.001), but there was no change in effective consumer attributes (mean ± SD 68.24 ± 12.46 preintervention and 72.94 ± 12.74 postintervention; P = 0.15). Three themes emerged from interviews of 11 participants: seeking confirmation of one's own knowledge of methotrexate, amplifying reluctance when they encountered information contradicting their own experiences, and clarifying thoughts about the next step during the process.

Conclusion

Patients' decisional conflict and knowledge improved after using the patient decision aid. Interview findings further highlighted the power of patients' prior knowledge and experiences with RA on how they approach the information presented in a decision aid.
Enantioselective Synthesis of Azaflavanones Using Organocatalytic 6‐endo Aza‐Michael Addition
Authors: Cheng Shuanghua , Zhao Lili , Yu Shouyun
Published: March 2014

A method to prepare highly enantioenriched azaflavanones using an organocatalytic 6‐endo aza‐Michael addition has been described. A variety of 2‐aryl‐, 2‐vinyl‐ and 2‐methylazaflavanones were prepared in good yields (53–84%) and excellent enantioselectivities (97.6:2.4 to 99.3:0.7 er).

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BCR/ABL level at 6 months identifies good risk CML subgroup after failing early molecular response at 3 months following imatinib therapy for CML in chronic phase
Authors: Kim Dennis (Dong Hwan) , Hamad Nada , Lee Hong Gi , Kamel‐Reid Suzanne , Lipton Jeffrey H.
Published: March 2014

It is unclear if patients with CML treated with imatinib who fail to achieve BCR/ABL transcript levels <10%IS at 3 months i.e. an early molecular response (EMR) have a better prognosis if they achieve a response by 6 months. We reviewed 320 patients with chronic myeloid leukemia (CML) in chronic phase receiving Imatinib therapy with 3 and 6 month BCR/ABL transcript levels available, and divided them into four groups. Group I (achieved an EMR at 3 months), Group II (did not achieve an EMR at 3 months, but achieved a transcript level of <1% at 6 months), Group III (did not achieve an EMR at 3 months, then at 6 months achieved a level between 1% and 10%) and Group IV (failed to achieve a response at 3 and 6 months). Compared to Group I, Group IV showed significantly worse freedom from treatment failure (FTF; 93.1% vs 69.0%, P < 0.001), progression free survival (97.7% vs 77.3%, P < 0.001) and overall survival (98.3% vs 78.9%, P < 0.001). While, group III showed inferior PFS (98.3% vs 90.4%, P = 0.013) and OS (97.7% vs 90.4%, P = 0.037), but no difference in FTF (93.1% vs 92.0%, P = 0.520). There were no significant differences between Groups I and II. A BCR/ABL transcript level at 6 months can identify a “good‐risk” subgroup among patients who fail to achieve an EMR on Imatinib therapy for CML.Am. J. Hematol. 89:626–632, 2014. © 2014 Wiley Periodicals, Inc.
Direct and Single‐Molecule Visualization of the Solution‐State Structures of G‐Hairpin and G‐Triplex Intermediates
Authors: Rajendran Arivazhagan , Endo Masayuki , Hidaka Kumi , Sugiyama Hiroshi
Published: March 2014

We present the direct and single‐molecule visualization of the in‐pathway intermediates of the G‐quadruplex folding that have been inaccessible by any experimental method employed to date. Using DNA origami as a novel tool for the structural control and high‐speed atomic force microscopy (HS‐AFM) for direct visualization, we captured images of the unprecedented solution‐state structures of a tetramolecular antiparallel and (3+1)‐type G‐quadruplex intermediates, such as G‐hairpin and G‐triplex, with nanometer precision. No such structural information was reported previously with any direct or indirect technique, solution or solid‐state, single‐molecule or bulk studies, and at any resolution. Based on our results, we proposed a folding mechanism of these G‐quadruplexes.
Steuerung der α‐Synuclein‐Aggregation durch Bindung einer β‐Haarnadel
Authors: Mirecka Ewa A. , Shaykhalishahi Hamed , Gauhar Aziz , Akgül Şerife , Lecher Justin , Willbold Dieter , Stoldt Matthias , Hoyer Wolfgang
Published: March 2014

Fehlfaltung, Aggregation und Amyloidfibrillenbildung des Proteins α‐Synuclein (α‐syn) sind an der Pathogenese der Parkinson‐Krankheit und weiterer Synucleinopathien beteiligt. Die Entwicklung der Amyloid‐Toxizität steht in Zusammenhang mit der Bildung partiell gefalteter Aggregationsintermediate. Hier beschreiben wir die Entwicklung einer Klasse gegen α‐syn gerichteter Bindeproteine, die wir als β‐Wrapine (β‐Wrap‐Proteine) bezeichnen. Die NMR‐Struktur eines α‐syn:β‐Wrapin‐Komplexes zeigt eine β‐Haarnadel‐Konformation von α‐syn im Sequenzbereich α‐syn(37–54). Substöchiometrische Mengen des Bindeproteins inhibieren die α‐syn‐Aggregation und ‐Toxizität, das β‐Wrapin greift folglich in die Bildung der Aggregationskeime ein.
DNA mit 3′‐5′‐Disulfid‐Verknüpfung – schnelle chemische Ligation durch isosteren Ersatz
Authors: Patzke Volker , McCaskill John S. , von Kiedrowski Günter
Published: March 2014

Die Bemühungen, die chemische Ligation von Oligonukleotiden ohne biochemische Enzyme zu etablieren, haben zu einer Vielzahl an synthetischen Analoga geführt und damit die Oligomer‐Ligation um neue Oligonukleotide, Peptide und Hybride, wie PNA, bereichert.1 Wichtigste Anforderungen an potenzielle PCR‐freie Diagnosewerkzeuge sind eine schnelle templatierte chemische DNA‐Ligation mit hoher Paarungsselektivität, sowie eine empfindliche Detektionsmethode. Hier berichten wir über eine Oligonukleotid‐Festphasensynthese von 5′‐ oder 3′‐Mercapto‐didesoxynukleotiden. Die chemische Ligation liefert 3′‐5′‐Disulfid‐Bindungen anstelle der 3′‐5′‐Phosphordiester‐Bindung. Unter Verwendung einer Fluoreszenzmethode beschreiben wir eine der schnellsten Ligationsreaktionen mit Halbwertszeiten in der Größenordnung von Sekunden. Durch die Wahl der DNA‐Modifikation und der 3′‐5′‐Orientierung der Aktivierung wird die nicht templatierte Ligation effektiv unterdrückt. Der Temperatureinfluss auf die templatierte Ligation wir aufgezeigt.
Ein niedermolekulares Ligand‐Wirkstoff‐Konjugat zur Behandlung von Carboanhydrase IX exprimierenden Tumoren
Authors: Krall Nikolaus , Pretto Francesca , Decurtins Willy , Bernardes Gonçalo J. L. , Supuran Claudiu T. , Neri Dario
Published: March 2014

Antikörper‐Wirkstoff‐Konjugate sind eine vielversprechende Klasse neuer Krebsmedikamente. Die Verwendung niedermolekularer Liganden für den zielgerichteten Transport zytotoxischer Substanzen in solide Tumoren ist dagegen weniger gut entwickelt. Hier beschreiben wir zum ersten Mal kleine Ligand‐Wirkstoff‐Konjugate zur Behandlung von Carboanhydrase IX exprimierenden Tumoren. Mit Ligand‐Fluoreszenzfarbstoff‐Konjugaten zeigen wir, dass solche Moleküle sich bevorzugt in Antigen exprimierenden Läsionen anreichern, schnell ihr Ziel erreichen und tief in den Tumor eindringen können. Ferner sind derartige Konstrukte durch Totalsynthese herstellbar. Ein über eine Disulfidbrücke verbundenes Wirkstoff‐Konjugat bestehend aus dem Maytansinoid DM1 als zytotoxischer Nutzlast und einem Derivat von Acetazolamid als Transportligand zeigte eine hohe Wirksamkeit gegen SKRC52‐Nierenkleinzellkarzinom in vivo. Die klinisch eingesetzten Standardtherapien Sunitinib und Sorafenib hatten dagegen keine Aktivität.
Rhodium(III)‐Catalyzed Alkenylation Reactions of 8‐Methylquinolines with Alkynes by C(sp3)H Activation
Authors: Liu Bingxian , Zhou Tao , Li Bin , Xu Shansheng , Song Haibin , Wang Baiquan
Published: March 2014

The alkenylation reactions of 8‐methylquinolines with alkynes, catalyzed by [{Cp*RhCl2}2], proceeds efficiently to give 8‐allylquinolines in good yields by C(sp3)H bond activation. These reactions are highly regio‐ and stereoselective. A catalytically competent five‐membered rhodacycle has been structurally characterized, thus revealing a key intermediate in the catalytic cycle.
Functionalizing Single Crystals: Incorporation of Nanoparticles Inside Gel‐Grown Calcite Crystals
Authors: Liu Yujing , Yuan Wentao , Shi Ye , Chen Xiaoqiang , Wang Yong , Chen Hongzheng , Li Hanying
Published: March 2014

Synthetic single crystals are usually homogeneous solids. Biogenic single crystals, however, can incorporate biomacromolecules and become inhomogeneous solids so that their properties are also extrinsically regulated by the incorporated materials. The discrepancy between the properties of synthetic and biogenic single crystals leads to the idea to modify the internal structure of synthetic crystals to achieve nonintrinsic properties by incorporation of foreign material. Intrinsically colorless and diamagnetic calcite single crystals are turned into colored and paramagnetic solids, through incorporation of Au and Fe3O4 nanoparticles without significantly disrupting the crystalline lattice of calcite. The crystals incorporate the nanoparticles and gel fibers when grown in agarose gel media containing the nanoparticles, whereas the solution‐grown crystals do not. As such, our work extends the long‐history gel method for crystallization into a platform to functionalize single‐crystalline materials.
Metal‐Triflate‐Catalyzed Synthesis of Polycyclic Tertiary Alcohols by Cyclization of γ‐Allenic Ketones
Authors: Diaf Ilhem , Lemière Gilles , Duñach Elisabet
Published: March 2014

It has been established that bismuth(III) triflate catalyzes the cyclization of γ‐allenic ketones under mild reaction conditions. This reaction allows the selective formation of polycyclic tertiary alcohols from cyclic ketone derivatives. The resulting dienols can engage in stereoselective cycloadditions to efficiently afford complex polycyclic systems.
Eine konvergente Totalsynthese des Telomerase‐Inhibitors (±)‐γ‐Rubromycin
Authors: Wilsdorf Michael , Reißig Hans‐Ulrich
Published: March 2014

Der Telomeraseinhibitor γ‐Rubromycin wurde in seiner racemischen Form in einer Gesamtausbeute von 3.8 % hergestellt. Der Schlüsselschritt der Synthesesequenz ist eine effiziente säurekatalysierte Spiroketalisierung unter Aufbau der zentralen Spiroketaleinheit. Die Synthese des erforderlichen, elektronisch ausbalancierten Spiroketalvorläufers erfolgte durch das konvergente Zusammenführen eines naphthylsubstituierten Aldehyds, eines α‐Methoxyallyl‐γ‐silyl‐substituierten Phosphonats als zentralem C3‐Baustein und eines hoch funktionalisierten Aryl‐Grignard‐Reagens. Ein weiteres Merkmal der Synthese ist eine späte Isocumarinbildung bei gleichzeitiger Protodesilylierung zu einem als Methylarylether geschützten γ‐Rubromycin‐Vorläufer.
Sequestration of a β‐Hairpin for Control of α‐Synuclein Aggregation
Authors: Mirecka Ewa A. , Shaykhalishahi Hamed , Gauhar Aziz , Akgül Şerife , Lecher Justin , Willbold Dieter , Stoldt Matthias , Hoyer Wolfgang
Published: March 2014

The misfolding and aggregation of the protein α‐synuclein (α‐syn), which results in the formation of amyloid fibrils, is involved in the pathogenesis of Parkinson’s disease and other synucleinopathies. The emergence of amyloid toxicity is associated with the formation of partially folded aggregation intermediates. Here, we engineered a class of binding proteins termed β‐wrapins (β‐wrap proteins) with affinity for α‐synuclein (α‐syn). The NMR structure of an α‐syn:β‐wrapin complex reveals a β‐hairpin of α‐syn comprising the sequence region α‐syn(37–54). The β‐wrapin inhibits α‐syn aggregation and toxicity at substoichiometric concentrations, demonstrating that it interferes with the nucleation of aggregation.
Disturbed B Cell Homeostasis in Newly Diagnosed Giant Cell Arteritis and Polymyalgia Rheumatica
Authors: van der Geest Kornelis S. M. , Abdulahad Wayel H. , Chalan Paulina , Rutgers Abraham , Horst Gerda , Huitema Minke G. , Roffel Mirjam P. , Roozendaal Caroline , Kluin Philip M. , Bos Nicolaas A. , Boots Annemieke M. H. , Brouwer Elisabeth
Published: March 2014

Objective

Several lines of evidence indicate that B cells may be involved in the immunopathology of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). This study was undertaken to examine the distribution of defined B cell subsets, including effector B (Beff) cells and regulatory B (Breg) cells, in patients with GCA and patients with PMR before and after corticosteroid treatment.

Methods

Circulating B cells were analyzed in 34 newly diagnosed, untreated patients with GCA or PMR, and in 44 followup samples from patients with GCA or PMR who received corticosteroids for 2 weeks or 3 months. For comparison, 40 age‐matched healthy controls and 11 rheumatoid arthritis (RA) patients were included. Serum BAFF levels were determined, and temporal arteries were studied by immunohistochemistry.

Results

Patients newly diagnosed as having GCA or PMR, but not patients with RA, had decreased numbers of circulating B cells compared to healthy controls. B cell numbers recovered rapidly in treated patients with GCA and PMR in remission. This recovery was not achieved by compensatory hyperproliferation or enhanced bone marrow production. B cell numbers inversely correlated with erythrocyte sedimentation rates, C‐reactive protein levels, and serum BAFF levels. Tumor necrosis factor α–positive Beff cells, but not interleukin‐10 (IL‐10)–positive Breg cells, were decreased in patients newly diagnosed as having GCA or PMR. Following treatment, circulating numbers of Beff cells normalized. The returning Beff cells demonstrated an enhanced capacity to produce IL‐6. Few B cells were found in temporal artery biopsy specimens from GCA patients.

Conclusion

We show for the first time that the distribution of B cells is highly disturbed in GCA and PMR and that B cells likely contribute to the enhanced IL‐6 response in both diseases.
Gold‐Catalyzed 6‐Exo‐Dig Cycloisomerization: A Versatile Approach to Functionalized Phenanthrenes
Authors: Shu Chao , Li Long , Chen Cheng‐Bin , Shen Hong‐Cheng , Ye Long‐Wu
Published: March 2014

A novel gold‐catalyzed 6‐exo‐dig cycloisomerization of o‐propargylbiaryls has been developed that provides ready access to functionalized phenanthrenes in largely good to excellent yields. Notable features of this method are readily available starting materials, mild reaction conditions, and broad substrate scope.
Electroencephalogram Coherence in Children With and Without Autism Spectrum Disorders: Decreased Interhemispheric Connectivity in Autism
Authors: Carson Audrey M. , Salowitz Nicole M. G. , Scheidt Robert A. , Dolan Bridget K. , Van Hecke Amy V.
Published: March 2014

Electroencephalogram coherence was measured in children with autism spectrum disorders (ASD) and control children at baseline and while watching videos of a familiar and unfamiliar person reading a story. Coherence was measured between the left and right hemispheres of the frontal, parietal, and temporal‐parietal lobes (interhemispheric) and between the frontal and parietal lobes in each hemisphere (intrahemispheric). A data‐reduction technique was employed to identify the frequency (alpha) that yielded significant differences in video conditions. Children with ASD displayed reduced coherence at the alpha frequency between the left and right temporal‐parietal lobes in all conditions and reduced coherence at the alpha frequency between left and right frontal lobes during baseline. No group differences in intrahemispheric coherence at the alpha frequency emerged at the chosen statistical threshold. Results suggest decreased interhemispheric connectivity in frontal and temporal‐parietal regions in children with ASD compared to controls. Autism Res 2014, 7: 334–343. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
A validated HPLC method for the determination of dimethyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylene dioxybiphenyl‐2,2′‐dicarboxylate (DDB) with fluorescence detection in raw material and pill form: application to an in vitro dissolution test and a content uniformity test
Authors: Walash Mohamed I. , Ibrahim Fawzia , El Abass Samah Abo
Published: March 2014

A simple, sensitive and rapid HPLC method with fluorescence detection for the determination of dimethyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylene dioxybiphenyl‐2,2′‐dicarboxylate (DDB) in the raw material and pill form was developed. Liquid chromatography was performed on a C18 column (250 × 4.6 mm i.d., 5 µm particle size), the mobile phase consisted of methanol and 0.05 M sodium dihydrogen phosphate buffer (80 : 20, v/v), and the apparent pH of the mobile phase was adjusted to 3. The fluorescence detector was operated at excitation/emission wavelengths of 275/400 nm. The proposed method allows the determination of DDB within concentration range 0.1–1.5 µg/mL with a limit of detection of 0.032 µg/mL, a limit of quantification of 0.097 µg/mL and a correlation coefficient of 0.9997. The proposed method has been successfully applied for the analysis of DDB in its pills with a percentage recovery of 98.45 ± 0.32. The method was fully validated according to ICH guidelines. Moreover, the high sensitivity of the method permits its use in an in vitro dissolution test for DDB under simulated intestinal conditions. In addition, the proposed method was extended to a content uniformity test according to USP guidelines. Copyright © 2014 John Wiley & Sons, Ltd.
Binding free energy calculations between bovine β‐lactoglobulin and four fatty acids using the MMGBSA method
Authors: Bello Martiniano
Published: March 2014

The bovine dairy protein β‐lactoglobulin (βlg) is a promiscuous protein that has the ability to bind several hydrophobic ligands. In this study, based on known experimental data, the dynamic interaction mechanism between bovine βlg and four fatty acids was investigated by a protocol combining molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MMGBSA) binding free energy calculations. Energetic analyses revealed binding free energy trends that corroborated known experimental findings; larger ligand size corresponded to greater binding affinity. Finally, binding free energy decomposition provided detailed information about the key residues stabilizing the complex. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 1010–1018, 2014.
A purge and trap technique to capture volatile compounds combined with comprehensive two‐dimensional gas chromatography/time‐of‐flight mass spectrometry to investigate the effect of sulfur‐fumigation on Radix Angelicae Dahuricae
Authors: Cao Gang , Li Qinglin , Zhang Jida , Cai Hao , Cai Baochang
Published: March 2014

Sulfur‐fumigation is known to reduce volatile compounds that are the main active components in herbs used in herbal medicine. We investigated changes in chemical composition between sun‐dried and sulfur‐fumigated Radix Angelicae Dahuricae using a purge and trap technique to capture volatile compounds, and two‐dimensional gas chromatography/time‐of‐flight mass spectrometry for identification. Using sun‐dried Radix Angelicae Dahuricae samples as a reference, the results showed that 73 volatile compounds, including 12 sulfide compounds, were found to be present only in sulfur‐fumigated samples. Furthermore, 32 volatile compounds that were found in sun‐dried Radix Angelicae Dahuricae samples disappeared after sulfur‐fumigation. The proposed method can be applied to accurately discriminate sulfur‐fumigated Radix Angelicae Dahuricae from different commercial sources. Copyright © 2014 John Wiley & Sons, Ltd.
Joint MS‐based platforms for comprehensive comparison of rat plasma and serum metabolic profiling
Authors: Lin Zhang , Zhang Zhimin , Lu Hongmei , Jin Yisu , Yi Lunzhao , Liang Yizeng
Published: March 2014

Metabolomics is a rapidly growing field in the comprehensive understanding of cellular and organism‐specific responses associated with perturbations induced by medicines, chemicals and environment. Blood matrices are frequently used in clinical and biological studies. In this study, we compared metabolic profiling between rat plasma and serum using complementary platforms of gas chromatography–mass spectrometry (GC‐MS) and liquid chromatography–quadruple time‐of‐flight–mass spectrometry (LC‐QTOF‐MS). The sample types that were tested included plasma prepared with K2EDTA and serum collected using venous blood collection protocols. The results of peak area variation for each detected metabolite/feature in the quality control samples showed a good reproducibility in LC‐QTOF‐MS and better reproducibility in GC‐MS. In GC‐MS analysis: (a) 25.8% of the defined metabolites differed serum from plasma profiling (t‐test, p < 0.05); and (b) serum possessed higher sensitivity than plasma for its generally higher peak intensity in the metabolic profiling. In LC‐QTOF‐MS analysis, 13 (in positive ion mode) and seven (in negative ion mode) important metabolites were identified as mainly contributing to the separation between serum and plasma. Copyright © 2014 John Wiley & Sons, Ltd.
Development and validation of an HPLC method for tetracycline‐related USP monographs
Authors: Hussien Emad M.
Published: March 2014

A novel reversed‐phase HPLC method was developed and validated for the assay of tetracycline hydrochloride and the limit of 4‐epianhydrotetracycline hydrochloride impurity in tetracycline hydrochloride commercial bulk and pharmaceutical products. The method employed L1 (3 µm, 150 × 4.6 mm) columns, a mobile phase of 0.1% phosphoric acid and acetonitrile at a flow rate of 1.0 mL/min, and detection at 280 nm. The separation was performed in HPLC gradient mode. Forced degradation studies showed that tetracycline eluted as a spectrally pure peak and was well resolved from its degradation products. The fast degradation of tetracycline hydrochloride and 4‐epianhydrotetracycline hydrochloride in solution was retarded by controlling the autosampler temperature at 4 °C and using 0.1% H3PO4 as diluent. The robustness of the method was tested starting with the maximum variations allowed in the US Pharmacopeia (USP) general chapter Chromatography <621>. The method was linear over the range 80–120% of the assay concentration (0.1 mg/mL) for tetracycline hydrochloride and 50–150% of the acceptance criteria specified in the individual USP monographs for 4‐epianhydrotetracycline hydrochloride. The limit of quantification for 4‐epianhydrotetracycline hydrochloride was 0.1 µg/mL, 20 times lower than the acceptance criteria. The method was specific, precise, accurate and robust. Copyright © 2014 John Wiley & Sons, Ltd.