bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloproliferative Defects following Targeting of the Drf1 Gene Encoding the Mammalian Diaphanous–Related Formin mDia1
Authors: Peng Jun , Kitchen Susan M. , West Richard A. , Sigler Robert , Eisenmann Kathryn M. , Alberts Arthur S. 
Published: August 2007

Abstract
Rho GTPase-effector mammalian diaphanous (mDia)–related formins assemble nonbranched actin filaments as part of cellular processes, including cell division, filopodia assembly, and intracellular trafficking. Whereas recent efforts have led to thorough characterization of formins in cytoskeletal remodeling and actin assembly in vitro, little is known about the role of mDia proteins in vivo. To fill this knowledge gap, the Drf1 gene, which encodes the canonical formin mDia1, was targeted by homologous recombination. Upon birth, Drf1+/− and Drf1−/− mice were developmentally and morphologically indistinguishable from their wild-type littermates. However, both Drf1+/− and Drf1−/− developed age-dependent myeloproliferative defects. The phenotype included splenomegaly, fibrotic and hypercellular bone marrow, extramedullary hematopoiesis in both spleen and liver, and the presence of immature myeloid progenitor cells with high nucleus-to-cytoplasm ratios. Analysis of cell surface markers showed an age-dependent increase in the percentage of CD11b+-activated and CD14+-activated monocytes/macrophages in both spleen and bone marrow in Drf1+/− and Drf1−/− animals. Analysis of the erythroid compartment showed a significant increase in the proportion of splenic cells in S phase and an expansion of erythroid precursors (TER-119+ and CD71+) in Drf1-targeted mice. Overall, knocking out mDia1 expression in mice leads to a phenotype similar to human myeloproliferative syndrome (MPS) and myelodysplastic syndromes (MDS). These observations suggest that defective DRF1 expression or mDia1 function may contribute to myeloid malignancies and point to mDia1 as an attractive therapeutic target in MDS and MPS. [Cancer Res 2007;67(16):7565–71]
Comparison of Ductal Lavage and Random Periareolar Fine Needle Aspiration as Tissue Acquisition Methods in Early Breast Cancer Prevention Trials
Authors: Arun Banu , Valero Vicente , Logan Catherine , Broglio Kristine , Rivera Edgardo , Brewster Abenaa , Yin Guosheng , Green Marjorie , Kuerer Henry , Gong Yun , Browne Doris , Hortobagyi Gabriel N. , Sneige Nour 
Published: August 2007

Abstract
Purpose: Short-term phase I and phase II breast cancer prevention trials require tissue acquisition at baseline and after intervention to evaluate modulation of potential biomarkers. Currently used tissue acquisition methods include ductal lavage (DL), random periareolar fine needle aspiration (RPFNA), and core needle biopsy. The optimum method to retrieve adequate samples and the most accepted method by study participants is not known.
Experimental Design: We compared RPFNA and DL as breast tissue acquisition methods for short-term breast cancer prevention trials by evaluating sample adequacy and tolerability in subjects who participated in two prospective phase II breast cancer prevention trials. Eighty-six women at increased risk for breast cancer were included in this study and underwent baseline DL and RPFNA. High risk was defined as having a 5-year Gail score of &gt;1.67% or a history of atypical hyperplasia (AH), lobular carcinoma, or breast cancer.
Results: Median age was 54.5 years (range, 39-75 years); 75% of the women were postmenopausal. About 51% of the women yielded nipple aspiration fluid, and breast fluid samples via DL were retrieved in 73% of these subjects. Of these samples, 71% were adequate samples (greater than 10 epithelial cells). However, when the entire cohort was considered, only 31% of the subjects had adequate samples. RPFNA was also attempted in all subjects, and sample retrieval rate was 100%. Out of these, 96% of the subjects had adequate samples. In DL samples, AH rate was 3.7% was and hyperplasia (H) rate was 11.1%. In RPFNA samples, AH rate was 12.9%, and H rate was 24.7%. Cytology findings in RPFNA samples correlated with age, menopausal status, and breast cancer risk category (previous history of lobular carcinoma in situ). Both procedures were well tolerated, and no complications occurred among participants.
Conclusions: Considering that the main end point for short-term prevention trials is the modulation of biomarkers, it is important to optimize adequate sample acquisition; therefore, RPFNA is a more practical option for future phase I and II breast cancer prevention trials compared with DL.
Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells
Authors: Meyers John A. , Taverna Josephine , Chaves Jorge , Makkinje Anthony , Lerner Adam 
Published: August 2007

AbstractType 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up-regulate glucocorticoid receptor (GRα) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GRα transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRα mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRα transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid-mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR up-regulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GRα transcript levels in a dose-related manner, cotreatment with rolipram maintained GRα transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor–mediated up-regulation of GRα expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.
Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors
Authors: Duran Ignacio , Hotté Sebastien J. , Hirte Holger , Chen Eric X. , MacLean Martha , Turner Sandra , Duan Lixia , Pond Gregory R. , Lathia Chetan , Walsh Scott , Wright John J. , Dancey Janet , Siu Lillian L. 
Published: August 2007

Abstract
Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities.
Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed.
Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response.
Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species–mediated damage
Authors: Oh Se-Yeong , Sohn Young-Woo , Park Jong-Whi , Park Hyo-Jung , Jeon Hye-Min , Kim Tae-Kyung , Lee Joong-Seob , Jung Ji-Eun , Jin Xun , Chung Yong Gu , Choi Young-Ki , You Seungkwon , Lee Jang-Bo , Kim Hyunggee 
Published: August 2007

Abstract
We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf−/− murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf−/− astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]
A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-κB, COX-1, and COX-2
Authors: Yeoh Ann S.J. , Gibson Rachel J. , Yeoh Eric E.K. , Bowen Joanne M. , Stringer Andrea M. , Giam Kar A. , Keefe Dorothy M.K. 
Published: August 2007

Abstract
Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-κB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-κB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti–mucotoxic-targeted therapies. [Mol Cancer Ther 2007;6(8):2319–27]
213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe
Authors: Seidl Christof , Port Matthias , Gilbertz Klaus-Peter , Morgenstern Alfred , Bruchertseifer Frank , Schwaiger Markus , Röper Barbara , Senekowitsch-Schmidtke Reingard , Abend Michael 
Published: August 2007

Abstract
Tumor cells are efficiently killed after incubation with α-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of α-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the α-emitter 213Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by α-emitters in tumor cells could help to improve strategies of α-emitter radioimmunotherapy. For that purpose, gene expression of 213Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that 213Bi-induced cell death was initiated by G2 arrest; up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that 213Bi activates death cascades different from apoptosis. Furthermore, 213Bi-triggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen. [Mol Cancer Ther 2007;6(8):2346–59]
A bifunctional colchicinoid that binds to the androgen receptor
Authors: Sharifi Nima , Hamel Ernest , Lill Markus A. , Risbood Prabhakar , Kane Charles T. , Hossain Md Tafazzal , Jones Amanda , Dalton James T. , Farrar William L. 
Published: August 2007

Abstract
Castrate-resistant prostate cancer (CRPC) continues to be dependent on the androgen receptor (AR) for disease progression. We have synthesized and evaluated a novel compound that is a conjugate of colchicine and an AR antagonist (cyanonilutamide) designed to inhibit AR function in CRPC. A problem in multifunctional AR-binding compounds is steric hindrance of binding to the embedded hydrophobic AR ligand-binding pocket. Despite the bulky side chain projecting off of the AR-binding moiety, this novel conjugate of colchicine and cyanonilutamide binds to AR with a Ki of 449 nmol/L. Structural modeling of this compound in the AR ligand-binding domain using a combination of rational docking, molecular dynamics, and steered molecular dynamics simulations reveals a basis for how this compound, which has a rigid alkyne linker, is able to bind to AR. Surprisingly, we found that this compound also binds to tubulin and inhibits tubulin function to a greater degree than colchicine itself. The tubulin-inhibiting activity of this compound increases cytoplasmic AR levels in prostate cancer cells. Finally, we found that this compound has greater toxicity against androgen-independent prostate cancer cells than the combination of colchicine and nilutamide. Together, these data point to several ways of inhibiting AR function in CRPC. [Mol Cancer Ther 2007;6(8):2328–36]
Comparison of 11C-choline-PET/CT and whole body-MRI for staging of prostate cancer
Authors: Pfannenberg A. C. , Rieger A. , Aschoff P. , Müller M. , Paulsen F. , Anastasiadis A. , Claussen C. D. , Bares R. , Schlemmer H. P. , Eschmann S. M. 
Published: August 2007

SummaryAim of this study was to compare the diagnostic accuracy of positron emission tomography and computed tomography with 11C-Choline (Cho-PET/CT) and whole body magnetic resonance imaging (WB-MRI) for diagnostic work-up of prostate cancer. Patients, methods: We evaluated retrospectively 42 patients with untreated prostate cancer (n = 17), or increasing levels of prostate-specific antigen (PSA) after curative therapy (n = 25) who had been investigated by both Cho-PET/CT and WB-MRI. MRI, CT, and PET images were separately analyzed by experienced radiologists or nuclear medicine experts, followed by consensus reading. Validation was established by histology, follow-up, or consensus reading. Results: 88/103 detected lesions were considered as malignant: 44 bone metastases, 22 local tumor, 15 lymph node metastases, 3 lung, and 3 brain metastases. One further lesion was located in the adrenal gland, which was a second tumor. Overall sensitivity, specificity and accuracy for Cho-PET/CT were 96.6%, 76.5%, and 93.3%, resp., and for WB-MRI 78.4%, 94.1%, and 81.0%, resp. 3 vertebral metastases had initially been missed by Cho-PET/CT and were found retrospectively. MRI identified 2 bone metastases and 1 lymph node metastasis after being informed about the results of Cho-PET/CT. Conclusions: Cho-PET/CT and WB-MRI both presented high accuracy in the detection of bone and lymph node metastases. The strength of MRI is excellent image quality providing detailed anatomical information whereas the advantage of Cho-PET/CT is high image contrast of pathological foci.
Procedure guideline for iodine-131 whole-body scintigraphy for differentiated thyroid cancer (version 3)
Authors: Dressler J. , Eschner W. , Grünwald F. , Lassmann M. , Leisner B. , Luster M. , Reiners C. , Schicha H. , Schober O. , Dietlein M. 
Published: August 2007

SummaryVersion 3 of the procedure guideline for 131I whole-body scintigraphy (WBS) is the counterpart to the procedure guideline for radioiodine therapy (version 3) and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. 131I WBS 3–6 months after 131I ablation remains a standard procedure in an endemic area for thyroid nodules and the high frequency of subtotal surgical procedures. Follow-up without 131I WBS is only justified if the following preconditions are fulfilled: low-risk group pT1–2, pN0 M0 with histopathologically confirmed pN0, 131I uptake <2%, 131I WBS during ablation without any suspicious lesion, stimulated thyroglobulin (Tg)-level 3–6 months after ablation <2 ng/mL, and absence of anti-thyroglobulin- antibodies with normal recovery-testing. If patients from the low-risk group show normal 131I WBS 3–6 months after ablation and stimulated Tg is of <2 ng/mL, there will be no need for additional routine 131I WBS. If patients from the high-risk group show normal 131I WBS and stimulated Tg-level of <2 ng/mL 3–6 months after ablation, the follow- up care should include repeated stimulated Tgmeasurements. If the Tg-level remains below 2 ng/mL, an additional 131I WBS will be not necessary. The recommended intervals for stimulated Tg-testing are adapted to the prior intervals for 131I WBS-testing in the high-risk group. Increased anti-thyroglobulin-antibodies or incomplete recovery-testing make an individual strategy of follow- up care necessary, which include 131I WBS.
A Physics-Based Parameterization of Air–Sea Momentum Flux at High Wind Speeds and Its Impact on Hurricane Intensity Predictions
Authors: Moon Il-Ju , Ginis Isaac , Hara Tetsu , Thomas Biju 
Published: August 2007

Abstract
A new bulk parameterization of the air–sea momentum flux at high wind speeds is proposed based on coupled wave–wind model simulations for 10 tropical cyclones that occurred in the Atlantic Ocean during 1998–2003. The new parameterization describes how the roughness length increases linearly with wind speed and the neutral drag coefficient tends to level off at high wind speeds. The proposed parameterization is then tested on real hurricanes using the operational Geophysical Fluid Dynamics Laboratory (GFDL) coupled hurricane–ocean prediction model. The impact of the new parameterization on the hurricane prediction is mainly found in increased maximum surface wind speeds, while it does not appreciably affect the hurricane central pressure prediction. This helps to improve the GFDL model–predicted wind–pressure relationship in strong hurricanes. Attempts are made to provide physical explanations as to why the reduced drag coefficient affects surface wind speeds but not the central pressure in hurricanes.
The Diurnal and Seasonal Variation of the Northern Australian Dryline
Authors: Arnup Sarah J. , Reeder Michael J. 
Published: August 2007

Abstract
The diurnal and seasonal variations of the northern Australian dryline are examined by constructing climatologies of low-level dynamic and thermodynamic variables taken from the high-resolution Australian Bureau of Meteorology’s Limited Area Prediction Scheme (LAPS) forecasts from 2000 to 2003. The development of the dryline is analyzed within the framework of the frontogenesis function applied to the mixing ratio and the airstream diagnostics of Cohen and Schultz. A case study of 12–13 October 2002 illustrating the airmass boundaries over the Australian region is also examined. Daytime surface heating produces sea-breeze circulations around the coast and a large inland heat trough that extends east–west along northern Australia. At night, air parcels accelerate toward low pressure, increasing convergence and deformation within the heat trough. This sharpens the moisture gradient across the tropical and continental airmass boundary into a dryline. This is different than the dryline of the Great Plains in the United States, which generally weakens overnight. The Australian dryline is strongest in spring just poleward of the Gulf of Carpentaria, where the moisture gradient across the heat trough is enhanced by the coast, and the axis of dilatation is closely aligned with mixing ratio isopleths. The dryline is weakest in winter, when the heat trough is weak. The LAPS 3-h forecasts are in good agreement with observations obtained from the Automatic Weather Station network. The 3-h forecasts capture the observed diurnal and seasonal cycle of the airmass boundaries. However, the sea-breeze circulation and ageostrophic flow into the surface heat trough is limited by the model resolution. The LAPS 3-h forecasts may therefore underestimate the nocturnal intensification of the dryline, especially since the inland moisture content is overestimated.