bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers
Authors: Jeong Eun Goo , Kim Min Sung , Nam Hyo Kyung , Min Chang Ki , Lee Seok , Chung Yeun Jun , Yoo Nam Jin , Lee Sug Hyung 
Published: June 2008

Abstract
Purpose: The aim of this study was to see whether JAK1, JAK3, and TYK2 genes are altered in human cancers.
Experimental Design: We analyzed 494 tissues from 186 acute adulthood leukemias, 30 multiple myelomas, and 278 common solid cancers, including 90 breast, 47 gastric, 47 colon, 47 lung, and 47 hepatocellular carcinomas by single-strand conformation polymorphism analysis.
Results: Overall, we found six JAK1 mutations (four in acute leukemias, one in a lung carcinoma, and one in a breast carcinoma) and three JAK3 mutations (two in breast carcinomas and one in a gastric carcinoma). Of note, three JAK1 mutations were an identical p.V658F mutation, which is homologous to JAK2 p.V617F mutation. We also found two other JAK1 mutations that occurred at very close sites (p.T782M and p.L783F). We found three of the four leukemias with JAK1 mutations expressed mutated JAK1 at the mRNA level. For JAK3 mutations, one of them was JAK3 p.V715I that is homologous to the JAK1 p.L783F. These recurrent mutations in identical and homologous sites suggest a possibility that alterations of these amino acids might be important for tumor pathogenesis. With respect to the cancer types, T-acute lymphoblastic leukemia (T-ALL) showed the highest incidence of the mutations (3 of 11; 27.3%).
Conclusion: Our data indicate that both JAK1 and JAK3 mutations occur in common human cancers and that JAK1 mutation in T-ALL is a frequent event. The data suggest that some of the JAK1 and JAK3 mutations may to be functional and contributes to cancer development, especially to T-ALL development.
Improved Prediction of Disease Relapse after Radical Prostatectomy through a Panel of Preoperative Blood-Based Biomarkers
Authors: Shariat Shahrokh F. , Karam Jose A. , Walz Jochen , Roehrborn Claus G. , Montorsi Francesco , Margulis Vitaly , Saad Fred , Slawin Kevin M. , Karakiewicz Pierre I. 
Published: June 2008

AbstractPurpose: The preoperative blood levels of biomarkers may allow accurate identification of patients who are likely to fail radical prostatectomy as a first-line therapy for localized prostate cancer, thereby allowing more efficient delivery of neoadjuvant and adjuvant therapy. The aim of this study was to determine the added value of biomarkers relative to established predictors of biochemical recurrence, such as clinical stage, biopsy Gleason sum, and preoperative prostate-specific antigen.Experimental Design: The preoperative plasma levels of transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), endoglin, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor were measured with the use of commercially available enzyme immunoassays in 423 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer. Multivariable models were used to explore the gain in the predictive accuracy of the models. This predictive accuracy was quantified by the concordance index statistic and was validated with 200 bootstrap resamples.Results: In standard multivariable analyses, TGF-β1 (P &lt; 0.001), sIL-6R (P &lt; 0.001), IL-6 (P &lt; 0.001), VCAM-1 (P &lt; 0.001), VEGF (P = 0.008), endoglin (P = 0.002), and uPA (P &lt; 0.001) were associated with biochemical recurrence. The multivariable model containing standard clinical variables alone had an accuracy of 71.6%. The addition of TGF-β1, sIL-6R, IL-6, VCAM-1, VEGF, endoglin, and uPA increased the predictive accuracy by 15% to 86.6% (P &lt; 0.001) and showed excellent calibration.Conclusions: A nomogram based on these biomarkers improves the accuracy of standard predictive models and could help counsel patients about their risk of biochemical recurrence following radical prostatectomy.
Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cβ inhibitor, in non-small cell lung cancer cells
Authors: Morgillo Floriana , Martinelli Erika , Troiani Teresa , Laus Gianluca , Pepe Stefano , Gridelli Cesare , Ciardiello Fortunato 
Published: June 2008

Abstract
Enzastaurin, an acyclic bisindolymaleimide, is a potent and selective competitive inhibitor of protein kinase Cβ, which has been shown to inhibit cancer cell proliferation and angiogenesis in human cancer cell lines. Gemcitabine and pemetrexed are two cytotoxic drugs that are currently used in non-small cell lung cancer (NSCLC) therapy. In this study, we have investigated whether the addition of enzastaurin to gemcitabine or to pemetrexed is able to increase their antitumor activity to establish an effective schedule of combined treatment. The effects on cancer cell proliferation, cell cycle distribution, intracellular mitogenic and antiapoptotic signaling pathways, and induction of apoptosis were evaluated in three different combination sequences (concomitant treatment, sequential treatment with the cytotoxic drug followed by enzastaurin, or sequential treatment with enzastaurin followed by the cytotoxic drug) in a panel of human NSCLC cell lines. The combination of enzastaurin with either gemcitabine or pemetrexed caused different antiproliferative and proapoptotic effects depending on the treatment schedule. A synergistic antiproliferative and proapoptotic activity was only obtained when chemotherapy was followed by treatment with enzastaurin. These effects were accompanied by the arrest of the surviving cancer cells in the S phase, thus limiting their ability to proceed through the cell cycle, and by a maximum inhibition in the activated, phosphorylated forms of Akt and mitogen-activated protein kinase. In contrast, the concomitant treatments or the sequential treatments, in which enzastaurin was given before chemotherapy, resulted in significant antagonistic effects. [Mol Cancer Ther 2008;7(6):1698–707]
Targeting IL-13Rα2-positive cancer with a novel recombinant immunotoxin composed of a single-chain antibody and mutated Pseudomonas exotoxin
Authors: Kioi Mitomu , Seetharam Saraswathy , Puri Raj K. 
Published: June 2008

Abstract
We have shown previously that high-affinity receptors for interleukin-13 (IL-13Rα2) are overexpressed on a variety of solid cancer cells, diseased fibroblasts, and other cells, and a chimeric fusion protein composed of human IL-13 and mutated Pseudomonas exotoxin (IL-13-PE38) is highly and specifically cytotoxic to these cells in vitro and in vivo. To improve the specificity for the target, we isolated specific antibodies against IL-13Rα2 from human single-chain Fv (scFv) antibody phage library and developed immunotoxin by selecting two high-affinity clones of scFv and fused to PE. The fusion chimeric gene was expressed in Escherichia coli, and highly purified IL-13R-specific immunotoxin, termed anti-IL-13Rα2(scFv)-PE38, was tested for its cytotoxicity. This molecule was highly cytotoxic to U251 glioma and PM-RCC renal cell carcinoma cell lines in vitro. The cytotoxic activity was neutralized by purified extracellular domain of IL-13Rα2 but not by IL-13, indicating that cytotoxic activity is specific. Anti-IL-13Rα2(scFv)-PE38 showed significant antitumor activity in immunodeficient mice with s.c. glioma tumors. Both i.p. and i.t. routes of administration showed antitumor activity in a dose-dependent manner. The maximum tolerated dose of anti-IL-13Rα2(scFv)-PE38 was 200 μg/kg i.p. twice daily for 5 days. These results indicate that anti-IL-13Rα2(scFv)-PE38 is a highly selective therapeutic agent for cancer therapy and should be further tested in animal models of human cancer. [Mol Cancer Ther 2008;7(6):1579–87]
ISG15 as a novel tumor biomarker for drug sensitivity
Authors: Desai Shyamal D. , Wood Laurence M. , Tsai Yu-Chen , Hsieh Tao-Shih , Marks Jeffrey R. , Scott Georgia L. , Giovanella Beppino C. , Liu Leroy F. 
Published: June 2008

AbstractTumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity. [Mol Cancer Ther 2008;7(6):1430–9]
Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies
Authors: Garcia Jorge A. , Danielpour David 
Published: June 2008

Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth, and apoptosis. Recently, there has been an enormous increase in our understanding on molecular mechanisms underlying the therapeutics of rapamycin in cancer. Alterations in the pathway regulating mTOR occur in many solid malignancies including prostate, bladder, and kidney cancer; in vitro and in vivo models of prostate and bladder cancer have established the importance of the mTOR pathway in control of cancer progression and metastasis. Temsirolimus (Torisel) and everolimus (RAD-001), two ester analogues of rapamycin, as well as rapamycin itself have clear antitumor activity in in vitro and in vivo models and are under clinical trial investigations for prostate and bladder cancer. Phase II and III trials have already established the clinical efficacy of temsirolimus in renal cancer, and current renal trials are evaluating the combined effects of vascular endothelial growth factor and mTOR inhibition. Ongoing studies in prostate and bladder cancer will soon define the activity and safety profiles of everolimus and temsirolimus. Recent molecular advances have uncovered a startling complexity in the macromolecular function of mTOR complexes, with the identification of new mTOR partners (raptor, rictor, FKBP38, PRAS40, and mSIN1), putative cancer therapeutic/prognostic targets for future clinical trials. [Mol Cancer Ther 2008;7(6):1347–54]
Apoptosis-inducing effect of erlotinib is potentiated by 3,3′-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer
Authors: Ali Shadan , Banerjee Sanjeev , Ahmad Aamir , El-Rayes Bassel F. , Philip Philip A. , Sarkar Fazlul H. 
Published: June 2008

Abstract
Blockade of epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective antitumor activity because of independently activated survival pathways. A multitargeted approach may therefore improve the outcome of anti-EGFR therapies. In the present study, we determined the effects of 3,3′-diindolylmethane (Bioresponse BR-DIM referred to as B-DIM), a formulated DIM with greater bioavailability on cell viability and apoptosis with erlotinib in vitro and in vivo using an orthotopic animal tumor model. BxPC-3 and MIAPaCa cells with varying levels of EGFR and nuclear factor-κB (NF-κB) DNA-binding activity were treated with B-DIM (20 μmol/L), erlotinib (2 μmol/L), and the combination. Cell survival and apoptosis was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and histone-DNA ELISA. Electrophoretic mobility shift assay was used to evaluate NF-κB DNA-binding activity. We found significant reduction in cell viability by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays, induction of apoptosis, down-regulation of EGFR phosphorylation, NF-κB DNA-binding activity, and expression of antiapoptotic genes in BxPC-3 cells when treated with the combination of erlotinib and B-DIM compared with either agent alone. In contrast, no such effect was observed in MIAPaCa cells by similar treatment. Most importantly, these in vitro results were recapitulated in animal model showing that B-DIM in combination with erlotinib was much more effective as an antitumor agent compared with either agent alone. These results suggest that the utilization of B-DIM could be a useful strategy for achieving better treatment outcome in patients with activated status of EGFR and NF-κB in their tumors. [Mol Cancer Ther 2008;7(6):1708–19]
To Bet or Not to Bet? The Error Negativity or Error-related Negativity Associated with Risk-taking Choices
Authors: Yu Rongjun , Zhou Xiaolin 
Published: June 2008

Abstract
The functional significance of error-related negativity (Ne/ERN), which occurs at approximately the same time as erroneous responses, has been investigated extensively using reaction time (RT) tasks. The error detection theory assumes that the Ne/ERN reflects the mismatch detected by comparing representations of the intended and the actually performed actions. The conflict monitoring theory asserts that the Ne/ERN reflects the detection of response conflict between intended and actually performed actions during response selection. In this study, we employed a gambling task in which participants were required to choose whether they would take part in betting in each trial and they were presented with gain or loss feedback in both the “to bet” and the “not to bet” trials. The response-locked ERP magnitudes were more negative for “to bet” than for “not to bet” choices for both large and small stakes and were more negative for choices involving large rather than small stakes. Dipole source analysis localized the ERP responses to the anterior cingulate cortex (ACC). These findings suggest that the ACC signals the riskiness of choices and may function as an early warning system that alerts the brain to prepare for the potential negative consequence associated with a risky action.
Electrophysiological Indices of Target and Distractor Processing in Visual Search
Authors: Hickey Clayton , Di Lollo Vincent , McDonald John J. 
Published: June 2008

Abstract
Attentional selection of a target presented among distractors can be indexed with an event-related potential (ERP) component known as the N2pc. Theoretical interpretation of the N2pc has suggested that it reflects a fundamental mechanism of attention that shelters the cortical representation of targets by suppressing neural activity stemming from distractors. Results from fields other than human electrophysiology, however, suggest that attention does not act solely through distractor suppression; rather, it modulates the processing of both target and distractors. We conducted four ERP experiments designed to investigate whether the N2pc reflects multiple attentional mechanisms. Our goal was to reconcile ostensibly conflicting outcomes obtained in electrophysiological studies of attention with those obtained using other methodologies. Participants viewed visual search arrays containing one target and one distractor. In Experiments 1 through 3, the distractor was isoluminant with the background, and therefore, did not elicit early lateralized ERP activity. This work revealed a novel contralateral ERP component that appears to reflect direct suppression of the cortical representation of the distractor. We accordingly name this component the distractor positivity (PD). In Experiment 4, an ERP component associated with target processing was additionally isolated. We refer to this component as the target negativity (NT). We believe that the N2pc reflects the summation of the PD and NT, and that these discrete components may have been confounded in earlier electrophysiological studies. Overall, this study demonstrates that attention acts on both target and distractor representations, and that this can be indexed in the visual ERP.
Retrieval Processes Supporting Judgments of Recency
Authors: Grove Kerrie L. , Wilding Edward L. 
Published: June 2008

AbstractThe circumstances under which different retrieval processes can support judgments about how long ago events occurred remain a matter of debate, as do the ways in which retrieved information can be employed in support of such judgments. In order to contribute to an understanding of the nature and number of distinct retrieval processes that support time judgments, event-related potentials (ERPs) were acquired during a continuous verbal memory task, where the lag between presentation and re-presentation of words was varied. Participants made judgments of recency (JORs), indicating the number of words that had intervened between presentation and re-presentation. Two spatially and temporally separable ERP effects predicted JORs, and the two effects bore correspondences with ERP modulations that have been linked to the processes of recollection and familiarity, suggesting that both of these processes contributed to JORs. The two effects predicting recency judgments also did so in the same way, with larger effects uniformly predicting shorter lag judgments. In so far as the sizes of the effects index memory strength, these findings are consistent with theoretical accounts of JORs where strength is employed heuristically: The more information recovered, the more recently the event occurred.
On the Analysis of Mean Downward Velocities around the Antarctic Polar Vortex
Authors: Miyazaki Kazuyuki , Iwasaki Toshiki 
Published: June 2008

Abstract
The Lagrangian characteristics of vertical motions around the Antarctic polar vortex are investigated using a general circulation model (GCM) and various analysis methods. A trace analysis that estimated the vertical velocity from the vertical displacement of tracer isopleths confirmed that using zonal means at geographical latitudes gives a Lagrangian mean circulation around the Antarctic polar vortex similar to that computed using equivalent latitudes. In the mass-weighted isentropic zonal means, the mean vertical velocity dynamically estimated from the meridional velocity shows strong downward motion outside the Antarctic polar vortex around 45°–55°S in the lower stratosphere, which is consistent with the thermodynamically estimated values from the diabatic heating rate. In comparison, the transformed Eulerian mean analysis tends to overestimate the downward velocity outside the Antarctic polar vortex and underestimate it inside the Antarctic polar vortex. Trace analysis produces a good approximation of the dynamical estimate inside the Antarctic polar vortex, but it does not capture the strong downward velocity outside the vortex because of active horizontal mixing. If eddy mixing effects are included in the mean-meridional transport equation, the trace analysis agrees well with the dynamical estimate. The mean downward motion outside the Antarctic polar vortex causes adiabatic heating and contributes to the formation of the polar night jet stream from the lower to middle stratosphere through the thermal wind balance. Analysis of the mean vertical velocities in reanalysis products (assimilations) is very noisy compared to that from free running models because of dynamical inconsistencies caused by the assimilation process.
GRACE-Based Estimates of Terrestrial Freshwater Discharge from Basin to Continental Scales
Authors: Syed Tajdarul H. , Famiglietti James S. , Chambers Don P. 
Published: June 2008

Abstract
In this study, new estimates of monthly freshwater discharge from continents, drainage regions, and global land for the period of 2003–05 are presented. The method uses observed terrestrial water storage change estimates from the Gravity Recovery and Climate Experiment (GRACE) and reanalysis-based atmospheric moisture divergence and precipitable water tendency in a coupled land–atmosphere water mass balance. The estimates of freshwater discharge are analyzed within the context of global climate and compared with previously published estimates. Annual cycles of observed streamflow exhibit stronger correlations with the computed discharge compared to those with precipitation minus evapotranspiration (P − E) in several of the world’s largest river basins. The estimate presented herein of the mean monthly discharge from South America (∼846 km3 month−1) is the highest among the continents and that flowing into the Atlantic Ocean (∼1382 km3 month−1) is the highest among the drainage regions. The volume of global freshwater discharge estimated here is 30 354 ± 1212 km3 yr−1. Monthly variations of global freshwater discharge peak between August and September and reach a minimum in February. Global freshwater discharge is also computed using a global ocean–atmosphere mass balance in order to validate the land–atmosphere water balance estimates and as a measure of global water budget closure. Results show close proximity between the two estimates of global discharge at monthly (RMSE = 329 km3 month−1) and annual time scales (358 km3 yr−1). Results and comparisons to observations indicate that the method shows important potential for global-scale monitoring of combined surface water and submarine groundwater discharge at near-real time, as well as for contributing to contemporary global water balance studies and for constraining global hydrologic model simulations.
Efficacy of venlafaxine compared with tricyclic antidepressants in depressive disorder: a meta-analysis
Authors: van den Broek WW , Mulder PGH , van Os E , Birkenhäger TK , Pluijms E , Bruijn JA 
Published: June 2008

Abstract With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect ( P = 0.38). The odds ratios were not homogenous across studies ( P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.