bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 21 Days Every 28 Days in Pediatric Patients with Solid Tumors
Authors: Fox Elizabeth , Maris John M. , Widemann Brigitte C. , Goodspeed Wendy , Goodwin Anne , Kromplewski Marie , Fouts Molly E. , Medina Diane , Cohn Susan L. , Krivoshik Andrew , Hagey Anne E. , Adamson Peter C. , Balis Frank M. 
Published: February 2008

Abstract
Purpose: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population.
Experimental Design: Patients who were ≤18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m2/d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m2/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle.
Results: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m2/d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor.
Conclusion: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m2/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule.
Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non–Hodgkin's Lymphoma
Authors: Ansell Stephen M. , Witzig Thomas E. , Inwards David J. , Porrata Luis F. , Ythier Arnaud , Ferrande Lee , Nestorov Ivan , DeVries Todd , Dillon Stacey R. , Hausman Diana , Novak Anne J. 
Published: February 2008

Abstract
Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies.
Experimental Design: A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done. Atacicept was given s.c. weekly for 5 weeks to sequential patient cohorts at doses of 2, 4, 7, or 10 mg/kg. Patients responding or with stable disease were eligible for treatment on an extension study for up to 24 weeks or until disease progression.
Results: All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received a stem cell transplant. Four patients were treated at the 2, 4, or 7 mg/kg dose levels, and three patients received 10 mg/kg of atacicept. Atacicept was well tolerated at all doses. Three adverse events with grade 3 severity were reported for one patient, including jaw pain, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Pharmacokinetic results were nonlinear, and treatment with atacicept resulted in dose-dependent decreases in immunoglobulin concentrations. Two patients had stable disease at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns.
Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin concentrations, although tumor responses were not observed.
Calcitrol (1α,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells
Authors: Kaeding Jenny , Bélanger Julie , Caron Patrick , Verreault Mélanie , Bélanger Alain , Barbier Olivier 
Published: February 2008

AbstractCalcitriol (1α,25-dihydroxyvitamin D3), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3α-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15- and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells. [Mol Cancer Ther 2008;7(2):380–90]
Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines
Authors: Cavazzoni Andrea , Alfieri Roberta R. , Carmi Caterina , Zuliani Valentina , Galetti Maricla , Fumarola Claudia , Frazzi Raffaele , Bonelli Mara , Bordi Fabrizio , Lodola Alessio , Mor Marco , Petronini Pier Giorgio 
Published: February 2008

AbstractIn this study, we examined the mechanism of action of the novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor 5-benzylidene-hydantoin UPR1024, whose structure was designed to interact at the ATP-binding site of EGFR. The compound had antiproliferative and proapoptotic effects when tested on the non–small cell lung cancer cell line A549. The growth inhibitory effect was associated with an accumulation of the cells in the S phase of the cell cycle. Moreover, UPR1024 induced significant level of DNA strand breaks associated with increased expression of p53 and p21WAF1 proteins, suggesting an additive mechanism of action. The presence of wild-type p53 improved the drug efficacy, although the effect was also detectable in p53 null cells. We also noted apoptotic cell death after treatment with UPR1024 at concentrations above 10 μmol/L for &gt;24 h, with involvement of both the extrinsic and intrinsic pathways. The present data show that UPR1024 may be considered a combi-molecule capable of both blocking EGFR tyrosine kinase activity and inducing genomic DNA damage. UPR1024 or its derivatives might serve as a basis for development of drugs for the treatment of lung cancer in patients resistant to classic tyrosine kinase inhibitors. [Mol Cancer Ther 2008;7(2):361–70]
DNAzyme technology and cancer therapy: cleave and let die
Authors: Dass Crispin R. , Choong Peter F.M. , Khachigian Levon M. 
Published: February 2008

Abstract
Novel molecules are constantly being discovered and developed to find better means of managing debilitating and fatal diseases, which include cancer in its multiple forms. Among these molecules, and as a direct consequence of a better understanding of the molecular basis of diseases, are those falling within the class of gene therapeutics. Among these players, deoxyribozymes (DNAzymes) have come a long way from being just another analytic tool available to molecular biologists. Recent studies have shown the potential DNAzymes to serve as drugs both in cell-based assays and preclinical models of cancer. It is anticipated that with the development of smart delivery systems for DNAzymes, better pharmacokinetics and pharmacodynamics will be possible, expediting DNAzyme march toward the clinic. Also, the ability of DNAzymes to yield to such phenomena as light-induced activation may be exploited for targeted therapy. This review documents the rise of DNAzymes in the fight against cancer and serves as a forecast for this promising biotechnology in this context. [Mol Cancer Ther 2008;7(2):243–51]
Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers
Authors: Wang Jianbo , Day Ryan , Dong Yiyu , Weintraub Steven J. , Michel Loren 
Published: February 2008

Abstract
The cell surface protein Trop-2 is highly expressed in a wide variety of epithelial cancers. In contrast, there is little or no expression of Trop-2 in adult somatic tissue. Because it is a cell surface protein that is selectively expressed in tumor cells, Trop-2 is a potential therapeutic target. However, whether Trop-2 is actively involved in tumorigenesis and whether its targeting for treatment would be effective have not been examined. Here, we show that Trop-2 expression is necessary for tumorigenesis and invasiveness of colon cancer cells, as both are inhibited when Trop-2 expression is suppressed by RNA interference. Conversely, ectopic expression of Trop-2 in colon cancer cells enhances their capacity for anchorage-independent growth and ectopic expression of Trop-2 in NIH3T3 cells is sufficient to promote both anchorage-independent growth and tumorigenesis. Importantly, we show that an antibody against the extracellular domain of Trop-2 reduces tumor cell invasiveness. Therefore, we have identified Trop-2 as an oncogene that has potential as a therapeutic target. Given the restricted expression of Trop-2 in normal tissue, anti–Trop-2 therapeutics would be predicted to have limited toxicity. [Mol Cancer Ther 2008;7(2):280–5]
Defective p53 signaling in p53 wild-type tumors attenuates p21waf1 induction and cyclin B repression rendering them sensitive to Chk1 inhibitors that abrogate DNA damage-induced S and G2 arrest
Authors: Levesque Aime A. , Fanous Andrew A. , Poh Alissa , Eastman Alan 
Published: February 2008

Abstract
DNA damage induces cell cycle arrest to provide time for repair and enhance cell survival. The Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) can overcome both S and G2 arrest and drive cells through a lethal mitosis. S-phase arrest induced by the topoisomerase I inhibitor SN38 results from activation of Chk1 and degradation of Cdc25A phosphatase that occurs independent of p53 status. However, p53-mediated induction of p21waf1 and repression of cyclin B prevent abrogation of S and G2 arrest, respectively. Surprisingly, incubation of MCF10A immortalized breast cells with UCN-01 fails to elevate Cdc25A protein due to p53-mediated inhibition of Cdc25A transcription. Suppression of p21waf1 in MCF10A cells overcame this transcriptional inhibition, and the S-phase-arrested cells became sensitive to UCN-01, although they now arrested in G2 as cyclin B expression remained suppressed. We also compared the response of p53 wild-type tumors to the combination of SN38 and UCN-01. In CAKI-1, U87MG, and SUM102, SN38 induced p21waf1 and the cells were resistant to UCN-01. In contrast, HCT116 and MCF7 cells had markedly attenuated induction of p21waf1 and failed to repress cyclin B. Accordingly, these cells were susceptible to UCN-01-mediated abrogation of both S and G2 arrest. SN38 induced expression of another p53-inducible gene, 14-3-3σ, suggesting selective dysregulation of p53 response genes. In summary, several cell lines commonly considered wild-type for p53 appear to have defects in expression of selected p53 response genes following DNA damage, and this makes them sensitive to the combination of DNA damage plus Chk1 inhibitor. [Mol Cancer Ther 2008;7(2):252–62]
Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells
Authors: Yacoub Adly , Park Margaret A. , Gupta Pankaj , Rahmani Mohammed , Zhang Guo , Hamed Hossein , Hanna David , Sarkar Devanand , Lebedeva Irina V. , Emdad Luni , Sauane Moira , Vozhilla Nicollaq , Spiegel Sarah , Koumenis Costas , Graf Martin , Curiel David T. , Grant Steven , Fisher Paul B. , Dent Paul 
Published: February 2008

Abstract
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R–like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK−/− cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B–dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival. [Mol Cancer Ther 2008;7(2):297–313]
Kinetics of Cloud Drop Formation and Its Parameterization for Cloud and Climate Models
Authors: Khvorostyanov Vitaly I. , Curry Judith A. 
Published: February 2008

Abstract
To study the kinetics of drop nucleation in clouds, the integro–differential equation for integral water supersaturation in cloud is derived and analyzed. Solving the supersaturation equation with an algebraic form of the cloud condensation nuclei (CCN) activity spectrum, analytical expressions are obtained for the time tm of CCN activation process, the maximum supersaturation sm, and droplet concentration Ndr(sm), limited by the total aerosol concentration at high supersaturations. All three quantities are expressed as functions of vertical velocity and characteristics of the CCN size spectra: mean geometric radius, dispersion, and parameters of solubility. A generalized power law for the drop activation, Ndr(sm) = C(sm)sk(sm)m, is formulated that is similar in form to the Twomey power law, but both the coefficient C(sm) and index k(sm) are functions of supersaturation expressed analytically in terms of vertical velocities and CCN microphysical parameters.
A simple and economical numerical solution was developed that describes all of these characteristics without conducting numerous simulations using parcel models. An extended series of numerical experiments was performed, in which the dependencies of tm, sm, Ndr(sm), C(sm), k(sm), and several other important characteristics of activation process were studied as functions of vertical velocity and physicochemical properties of the aerosol. In particular, it is shown that a decrease in the condensation coefficient αc leads to slower CCN activation and higher maximum supersaturation and droplet concentration. Uncertainties in αc may prevent correct estimates of the direct and indirect aerosol effects on climate. The solutions and expressions for the parameters presented here can be used for parameterization of the drop activation process in cloud and climate models.
Persistent Nature of Secondary Diurnal Modes of Precipitation over Oceanic and Continental Regimes
Authors: Yang Song , Kuo Kwo-Sen , Smith Eric A. 
Published: February 2008

Abstract
This investigation seeks a better understanding of the assorted mechanisms controlling the global distribution of diurnal precipitation variability based on the use of the Tropical Rainfall Measuring Mission (TRMM) microwave radiometer and radar data. The horizontal distributions of precipitation’s diurnal cycle are derived from 8 yr of TRMM Microwave Imager (TMI) and Precipitation Radar (PR) measurements involving three TRMM standard rain retrieval algorithms; the resultant distributions are analyzed at various spatiotemporal scales. The results reveal both the prominent and expected late-evening (LE) to early-morning (EM) precipitation maxima over oceans and the counterpart prominent and expected mid- to late-afternoon (MLA) maxima over continents. Moreover, and not generally recognized, the results reveal a widespread distribution of secondary maxima, which generally mirror their counterpart regime’s behavior, occurring over both oceans and continents. That is, many ocean regions exhibit clear-cut secondary MLA precipitation maxima, while many continental regions exhibit just as evident secondary LE–EM maxima. This investigation is the first comprehensive study of these globally prevalent secondary maxima and their widespread nature, a type of study only made possible when the analysis procedure is applied to a high-quality global-scale precipitation dataset.
The characteristics of the secondary maxima are mapped and described on global grids using an innovative clock-face format, while a current study that is to be published at a later date provides physically based explanations of the seasonal regional distributions of the secondary maxima. In addition to a primary “explicit” maxima identification scheme, a secondary “Fourier decomposition” maxima identification scheme is used as a cross-check to examine the amplitude and phase properties of the multimodal maxima. Accordingly, the advantages and ambiguities resulting from the use of a Fourier harmonic analysis are investigated.
Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours
Authors: Lunt Sarah Jane , Kalliomaki Tuula MK , Brown Allison , Yang Victor X , Milosevic Michael , Hill Richard P 
Published: February 2008

Abstract

Background
High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread.

Methods
KHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging.

Results
Tumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2–42 mmHg, s/c: 1–14 mmHg, ME180: i/m 5–68 mmHg, cervix 4–21 mmHg, SiHa: i/m 20–56 mmHg, cervix 2–26 mmHg, MMTV-PyMT: i/m: 13–45 mmHg, spontaneous 2–20 mmHg and transplanted 2–22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown i/m versus orthotopically despite differences in IFP.

Conclusion
Our studies across a range of different tumour models showed substantial heterogeneity in tumour IFP, suggesting differences in the vascular development and interstitial fluid dynamics in the individual tumours. The results demonstrate a strong stochastic aspect to tumour IFP development, notably the variation apparent between different tumours within the same animal and the lack of correlation between donor and recipient tumours.
Nurse-led implementation of an insulin-infusion protocol in a general intensive care unit: improved glycaemic control with increased costs and risk of hypoglycaemia signals need for algorithm revision
Authors: Alm-Kruse Kristin , Bull Eva M , Laake Jon H 
Published: February 2008

Abstract

Background
Strict glycaemic control (SGC) has become a contentious issue in modern intensive care. Physicians and nurses are concerned about the increased workload due to SGC as well as causing harm through hypoglycaemia. The objective of our study was to evaluate our existing degree of glycaemic control, and to implement SGC safely in our ICU through a nurse-led implementation of an algorithm for intensive insulin-therapy.

Methods
The study took place in the adult general intensive care unit (11 beds) of a 44-bed department of intensive care at a tertiary care university hospital. All patients admitted during the 32 months of the study were enrolled. We retrospectively analysed all arterial blood glucose (BG) results from samples that were obtained over a period of 20 months prior to the implementation of SGC. We then introduced an algorithm for intensive insulin therapy; aiming for arterial blood-glucose at 4.4 – 6.1 mmol/L. Doctors and nurses were trained in the principles and potential benefits and risks of SGC. Consecutive statistical analyses of blood samples over a period of 12 months were used to assess performance, provide feedback and uncover incidences of hypoglycaemia.

Results
Median BG level was 6.6 mmol/L (interquartile range 5.6 to 7.7 mmol/L) during the period prior to implementation of SGC (494 patients), and fell to 5.9 (IQR 5.1 to 7.0) mmol/L following introduction of the new algorithm (448 patients). The percentage of BG samples > 8 mmol/L was reduced from 19.2 % to 13.1 %. Before implementation of SGC, 33 % of samples were between 4.4 to 6.1 mmol/L and 12 patients (2.4 %) had one or more episodes of severe hypoglycaemia (< 2.2 mmol/L). Following implementation of SGC, 45.8 % of samples were between 4.4 to 6.1 mmol/L and 40 patients (8.9 %) had one or more episodes of severe hypoglycaemia. Of theses, ten patients died while still hospitalised (all causes).

Conclusion
The retrospective part of the study indicated ample room for improvement. Through the implementation of SGC the fraction of samples within the new target range increased from 33% to 45.8%. There was also a significant increase in severe hypoglycaemic episodes. There continues to be potential for improved glycaemic control within our ICU. This might be achieved through an improved algorithm and continued efforts to increase nurses' confidence and skills in achieving SGC.