bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternate Endpoints for Screening Phase II Studies
Authors: Dhani Neesha , Tu Dongsheng , Sargent Daniel J. , Seymour Lesley , Moore Malcolm J. 
Published: March 2009

Abstract
Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development and those for which further evaluation should be halted. Although definitive phase III trials use progression-free or overall survival to confirm clinical benefit, earlier endpoints are preferable for phase II trials. Traditionally, tumor shrinkage of a predetermined degree (response) has been used as a surrogate of eventual survival benefit based on the observation that high response rates (RR), and particularly complete responses, in the phase II setting resulted in survival benefit in subsequent phase III trials. Recently, some molecularly targeted agents have shown survival and clinical benefit despite very modest RRs in early clinical trials. These observations provide a major conundrum, with concerns of inappropriate termination of development for active agents with low RRs being balanced by concerns of inactive agents being taken to late-phase development with resultant increases in the failure rate of phase III trials. Numerous alternate or complementary endpoints have been explored, incorporating multinomial endpoints (including progression and response), progression-free survival, biomarkers, and, more recently, evaluation of tumor size as a continuous variable. In this review, we discuss the current status of phase II endpoints and present retrospective analyses of two international gastrointestinal cancer studies showing the potential utility of one novel approach. Alternate endpoints, although promising, require additional evaluation and prospective validation before their use as a primary endpoint for phase II trials.
Fluorescence In situ Hybridization Analysis of Circulating Tumor Cells in Metastatic Prostate Cancer
Authors: Leversha Margaret A. , Han Jialian , Asgari Zahra , Danila Daniel C. , Lin Oscar , Gonzalez-Espinoza Rita , Anand Aseem , Lilja Hans , Heller Glenn , Fleisher Martin , Scher Howard I. 
Published: March 2009

Abstract
Purpose: To assess the feasibility of characterizing gene copy number alteration by fluorescence in situ hybridization (FISH) of circulating tumor cells (CTC) isolated using the CellSearch system in patients with progressive castration-resistant metastatic prostate cancer.
Experimental Design: We used probe combinations that included the androgen receptor (AR) and MYC genes for FISH analysis of CTC samples collected from 77 men with castration-resistant metastatic prostate cancer.
Results: High-level chromosomal amplification of AR was detected in 38% and relative gain of MYC in 56% of samples analyzed. No such abnormalities were detected in samples with CTC counts of &lt;10, reflecting ascertainment difficulty in these lower count samples.
Conclusion: The CTC isolated from our patient cohort present a very similar molecular cytogenetic profile to that reported for late-stage tumors and show that FISH analysis of CTC can be a valuable, noninvasive surrogate for routine tumor profiling. That as many as 50% of these patients have substantial amplification of the AR locus indicates that androgen signaling continues to play an important role in late-stage prostate cancer.
Expression of Immunosuppresive B7-H3 Ligand by Hormone-Treated Prostate Cancer Tumors and Metastases
Authors: Chavin Grant , Sheinin Yuri , Crispen Paul L. , Boorjian Stephen A. , Roth Timothy J. , Rangel Laureano , Blute Michael L. , Sebo Thomas J. , Tindall Don J. , Kwon Eugene D. , Karnes R. Jeffrey 
Published: March 2009

AbstractPurpose: Prostate cancer cells uniformly express the immune cell inhibitory B7-H3 ligand. Enhanced B7-H3 expression correlates with increased disease progression and cancer-specific death after radical prostatectomy (RP).Experimental Design: To further assess whether B7-H3 expression is hormone regulated and persists as a viable target during (or after) androgen-ablative therapy, we examined B7-H3 ligand expression within primary and metastatic cancer lesions in response to neoadjuvant hormone therapy (NHT) or palliative hormone deprivation. Tumor B7-H3 in RP specimens from men treated with ≥3 months of NHT was compared with B7-H3 in tumors from matched patients who received no therapy before RP. Hormone-treated and untreated metastatic lesions involving bone were also compared for levels of B7-H3 expression.Results: Of 165 consecutive RP specimens in each cohort studied, sufficient tissues were available for 148 patients (89.7%) treated with NHT versus 127 patients (77.0%) treated with surgery alone. B7-H3 was expressed in 142 (95.9%) tumors from NHT patients compared with 122 (96.0%) tumors from patients treated with surgery alone (P = 0.91). B7-H3 expression intensity in RP specimens was not affected by NHT (P = 0.12). Bone metastases from 11 (32.4%) untreated and 23 (67.6%) androgen-ablated patients revealed that B7-H3 expression increased in response to hormone therapy (P = 0.04) relative to untreated lesions.Conclusions: Taken together, B7-H3 expression seems to remain stable (or may even increase) in response to hormone therapy. As such, B7-H3 may represent an attractive target to improve treatment of men with high-risk hormone-treated or refractory prostate cancer.
CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model
Authors: Ma Xinrong , Norsworthy Kelly , Kundu Namita , Rodgers William H. , Gimotty Phyllis A. , Goloubeva Olga , Lipsky Michael , Li Yanchun , Holt Dawn , Fulton Amy 
Published: March 2009

Abstract
Breast tumor cells express the chemokine receptor CXCR3, which binds the ligands CXCL9, CXCL10, and CXCL11. CXCR3 and other chemokine receptors may mediate tumor metastasis by supporting migration of tumor cells to sites of ligand expression including the lymph nodes, lungs, and bone marrow. We examined the relationship of CXCR3 expression to clinical outcome in 75 women diagnosed with early-stage breast cancer. We detected CXCR3 in malignant epithelium from all tumors. Twelve percent were weakly positive and 64% had moderate levels of CXCR3. Strong CXCR3-positive staining was observed in 24% of tumors. Kaplan-Meier survival curves showed that high CXCR3 expression was associated with poorer overall survival; the unadjusted hazard ratio was 1.56 and it was marginally significant (P = 0.07). When interactions between lymph node status and CXCR3 were considered, the adjusted hazard ratio for CXCR3 was 2.62 (P = 0.02) for women with node-negative disease at diagnosis, whereas the hazard ratio for CXCR3 was not significant for those with node-positive disease. CXCR3 gene silencing inhibited lung colonization and spontaneous lung metastasis from mammary gland–implanted tumors in a murine model. The size or growth rate of the locally growing tumors was not affected. The antimetastatic effect of CXCR3 gene silencing was compromised in mice depleted of Natural Killer cells or with mutations in IFN-γ, suggesting that the role of CXCR3 is not simply to mediate tumor cell trafficking. These studies support the continued examination of CXCR3 as a potential therapeutic target in patients with breast cancer. [Mol Cancer Ther 2009;8(3):490–8]
Potent induction of B- and T-cell immunity against human carcinoembryonic antigen-expressing tumors in human carcinoembryonic antigen transgenic mice mediated by direct lentivector injection
Authors: Loisel-Meyer Severine , Felizardo Tania , Mariotti Jacopo , Mossoba Miriam E. , Foley Jason E. , Kammerer Robert , Mizue Nobuo , Keefe Robert , McCart J. Andrea , Zimmermann Wolfgang , Dropulic Boro , Fowler Daniel H. , Medin Jeffrey A. 
Published: March 2009

AbstractThe applicability of immunotherapy would be dramatically broadened to a greater number of recipients if direct “off-the-shelf” products could be engineered to engender functionally potent immune responses against true “self”-tumor antigens. This would obviate the need for ex vivo culture of dendritic cells or T cells on a patient-by-patient basis, for example. The carcinoembryonic antigen (CEA) is a glycoprotein expressed in normal gut epithelium that is up-regulated in the majority of colon cancers, non-small cell lung cancers, and half of all breast cancers. Such properties make CEA an excellent and important target for cancer immunotherapy. In this study, we show stabilization of 14-day established s.c. mGC4CEA tumors in human CEA (huCEA) transgenic mice following two direct low-dose injections of 0.15 × 106 transducing units of a lentiviral vector (LV) that directs expression of huCEA (LV-huCEA). This stabilization result was reproducible and detailed analyses including antibody assays, multiplex cytokine analyses on unstimulated splenocytes, lymph node cell characterizations, tetramer staining, and immunofluorescence staining of tumor sections showed that this outcome correlated with both a cellular and humoral immune response. Similar tumor outcomes were not seen when mice were vaccinated with a control LV that engineered expression of enGFP only. The long-term potency of this vaccination strategy was also studied and revealed the requirement for maintenance of tumor antigen-specific immunity for efficient tumor control. These data support the use of direct injections of low doses of LV-huCEA for enhancement of tumor immunotherapy directed against CEA. [Mol Cancer Ther 2009;8(3):OF692–11]
Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer
Authors: McGovern Ursula B. , Francis Richard E. , Peck Barrie , Guest Stephanie K. , Wang Jun , Myatt Stephen S. , Krol Janna , Kwok Jimmy M-M. , Polychronis Andreas , Coombes R. Charles , Lam Eric W-F. 
Published: March 2009

Abstract
Gefitinib (Iressa) is a specific and effective epidermal growth factor receptor inhibitor. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-epidermal growth factor receptor therapies and provide information for overcoming gefitinib resistance. In this study, we investigated the role and regulation of FOXM1 in response to gefitinib treatment in breast cancer. Using the gefitinib-sensitive breast carcinoma cell lines BT474 and SKBR3 as well as the resistant lines MCF-7, MDA-MB-231, and MDA-MB-453, we showed that gefitinib represses the expression of the transcription factor FOXM1 in sensitive, but not resistant, cells. FOXM1 repression by gefitinib is associated with FOXO3a activation and is mediated at the transcriptional level and gene promoter level. These results were verified by immunohistochemical staining of biopsy samples from primary breast cancer patients obtained from a gefitinib neoadjuvant study. We also showed that ectopic expression of an active FOXO3a represses FOXM1 expression, whereas knockdown of FOXO3a expression using small interfering RNA can up-regulate FOXM1 and its downstream targets polo-like kinase, cyclin B1, and CDC25B and rescue sensitive BT474 cells from gefitinib-induced cell proliferative arrest. These results suggest that gefitinib represses FOXM1 expression via FOXO3a in breast cancer. We further showed that overexpression of a wild-type FOXM1 or a constitutively active FOXM1, ΔN-FOXM1, abrogates the cell death induced by gefitinib, indicating that FOXM1 has a functional role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. In summary, our study defined FOXM1 as a cellular target and marker of gefitinib activity in breast cancer. [Mol Cancer Ther 2009;8(3):582–91]
p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption
Authors: Yun Miyong , Han Young-Hoon , Yoon Sun Hee , Kim Hee Young , Kim Bu-Yeo , Ju Yeun-Jin , Kang Chang-Mo , Jang Su Hwa , Chung Hee-Yong , Lee Su-Jae , Cho Myung-Haing , Yoon Gyesoon , Park Gil Hong , Kim Sang Hoon , Lee Kee-Ho 
Published: March 2009

Abstract
Functional suppression of spindle checkpoint protein activity results in apoptotic cell death arising from mitotic failure, including defective spindle formation, chromosome missegregation, and premature mitotic exit. The recently identified p31comet protein acts as a spindle checkpoint silencer via communication with the transient Mad2 complex. In the present study, we found that p31comet overexpression led to two distinct phenotypic changes, cellular apoptosis and senescence. Because of a paucity of direct molecular link of spindle checkpoint to cellular senescence, however, the present report focuses on the relationship between abnormal spindle checkpoint formation and p31comet-induced senescence by using susceptible tumor cell lines. p31comet-induced senescence was accompanied by mitotic catastrophe with massive nuclear and chromosomal abnormalities. The progression of the senescence was completely inhibited by the depletion of p21Waf1/Cip1 and partly inhibited by the depletion of the tumor suppressor protein p53. Notably, p21Waf1/Cip1 depletion caused a dramatic phenotypic conversion of p31comet-induced senescence into cell death through mitotic catastrophe, indicating that p21Waf1/Cip1 is a major mediator of p31comet-induced cellular senescence. In contrast to wild-type p31comet, overexpression of a p31 mutant lacking the Mad2 binding region did not cause senescence. Moreover, depletion of Mad2 by small interfering RNA induced senescence. Here, we show that p31comet induces tumor cell senescence by mediating p21Waf1/Cip1 accumulation and Mad2 disruption and that these effects are dependent on a direct interaction of p31comet with Mad2. Our results could be used to control tumor growth. (Mol Cancer Res 2009;7(3):371–82)
Improving Global Model Precipitation Forecasts over India Using Downscaling and the FSU Superensemble. Part II: Seasonal Climate
Authors: Chakraborty Arindam , Krishnamurti T. N. 
Published: March 2009

AbstractThis study addresses seasonal forecasts of rains over India using the following components: high-resolution rain gauge–based rainfall data covering the years 1987–2001, rain-rate initialization, four global atmosphere–ocean coupled models, a regional downscaling of the multimodel forecasts, and a multimodel superensemble that includes a training and a forecast phase at the high resolution over the internal India domain. The results of monthly and seasonal forecasts of rains for the member models and for the superensemble are presented here. The main findings, assessed via the use of RMS error, anomaly correlation, equitable threat score, and ranked probability skill score, are (i) high forecast skills for the downscaled superensemble-based seasonal forecasts compared to the forecasts from the direct use of large-scale model forecasts were possible; (ii) very high scores for rainfall forecasts have been noted separately for dry and wet years, for different regions over India and especially for heavier rains in excess of 15 mm day−1; and (iii) the superensemble forecast skills exceed that of the benchmark observed climatology. The availability of reliable measures of high-resolution rain gauge–based rainfall was central for this study. Overall, the proposed algorithms, added together, show very promising results for the prediction of monsoon rains on the seasonal time scale.
Copy number abnormalities, MYC activity, and the genetic fingerprint of normal B cells mechanistically define the microRNA profile of diffuse large B-cell lymphoma
Authors: Li Cheng , Kim Sang-Woo , Rai Deepak , Bolla Aswani R. , Adhvaryu Siddharth , Kinney Marsha C. , Robetorye Ryan S. , Aguiar Ricardo C. T. 
Published: March 2009

AbstractMicroRNA (miRNA) deregulation contributes to cancer pathogenesis. However, analysis of miRNAs in diffuse large B-cell lymphoma (DLBCL) has been hindered by a focus on cell lines, limited number of miRNAs examined, and lack of copy number data. To address these restrictions, we investigated genomewide miRNA expression and copy number data in 86 DLBCLs. Permutation analysis showed that 63 miRNAs were recurrently disrupted in DLBCL, including highly expressed oncomirs not previously linked to chromosomal abnormalities. Further, using training and validation tumor groups, we defined a collection of miRNAs that robustly segregates DLBCLs into 3 subsets, which are independent of the cell-of-origin classification, extent of T-cell infiltrate, and tumor site. Instead, these unique miRNA-driven DLBCL subgroups showed markedly different MYC transcriptional activity, which explained the dominance of miRNAs regulated by MYC in their expression signatures. In addition, analysis of miRNA expression patterns of normal B cells and integration of copy number and expression data showed that genomic abnormalities and the genetic fingerprint of nonmalignant cells also contribute to the miRNA profile of DLBCL. In conclusion, we created a comprehensive map of the miRNA genome in DLBCL and, in the process, have uncovered and mechanistically elucidated the basis for additional molecular heterogeneity in this tumor.
Lung ventilation scintigraphy in the assessment of obstructive lung diseases
Authors: Fazzi P. , Albertelli R. , Grana M. , Paggiaro P.L. 
Published: March 2009

Educational aimsTo describe more recent techniques used to study the regional distribution of ventilation.To learn the most frequent abnormal patterns of lung ventilation scintigraphy (LVS) in obstructive lung diseases.To compare the information obtained by this technique with that obtained by traditional lung function tests.To understand that LVS may provide further information on lung pathophysiology.SummaryLVS is a well known technique that is used to study the distribution of ventilation in pulmonary diseases. However, its application in current practice has been poorly developed, mainly because of methodological problems. Redistribution of convective ventilation is the leading disorder in patients with chronic obstructive pulmonary disease (COPD) and is the target of most treatments, either by drugs or mechanical ventilation. The current availability of a new delivery inhaler (FAI; Medical Products Research, Legnano, Italy) with fine particles allows: 1) fast aerosol administration; 2) high-quality early images; 3) improved visualisation of pulmonary periphery; and 4) wider physiological distribution of the radioaerosol. Several patterns of distribution of pulmonary ventilation can be described in different airway disorders (asthma and COPD). These abnormalities are often too subtle to be picked up by traditional lung function tests, both in the baseline evaluation and after different interventions. Wider use of this technique may increase the knowledge and the management of obstructive lung diseases.
Characterization of the hupSL promoter activity in Nostoc punctiformeATCC 29133
Authors: Holmqvist Marie , Stensjö Karin , Oliveira Paulo , Lindberg Pia , Lindblad Peter 
Published: March 2009

Abstract

Background
In cyanobacteria three enzymes are directly involved in the hydrogen metabolism; a nitrogenase that produces molecular hydrogen, H2, as a by-product of nitrogen fixation, an uptake hydrogenase that recaptures H2 and oxidize it, and a bidirectional hydrogenase that can both oxidize and produce H2.Nostoc punctiforme ATCC 29133 is a filamentous dinitrogen fixing cyanobacterium containing a nitrogenase and an uptake hydrogenase but no bidirectional hydrogenase. Generally, little is known about the transcriptional regulation of the cyanobacterial uptake hydrogenases. In this study gel shift assays showed that NtcA has a specific affinity to a region of the hupSL promoter containing a predicted NtcA binding site. The predicted NtcA binding site is centred at 258.5 bp upstream the transcription start point (tsp). To further investigate the hupSL promoter, truncated versions of the hupSL promoter were fused to either gfp or luxAB, encoding the reporter proteins Green Fluorescent Protein and Luciferase, respectively.

Results
Interestingly, all hupsSL promoter deletion constructs showed heterocyst specific expression. Unexpectedly the shortest promoter fragment, a fragment covering 57 bp upstream and 258 bp downstream the tsp, exhibited the highest promoter activity. Deletion of the NtcA binding site neither affected the expression to any larger extent nor the heterocyst specificity.

Conclusion
Obtained data suggest that the hupSL promoter in N. punctiforme is not strictly dependent on the upstream NtcA cis element and that the shortest promoter fragment (-57 to tsp) is enough for a high and heterocyst specific expression of hupSL. This is highly interesting because it indicates that the information that determines heterocyst specific gene expression might be confined to this short sequence or in the downstream untranslated leader sequence.
In vitromodel for the analysis of synovial fibroblast-mediated degradation of intact cartilage
Authors: Pretzel David , Pohlers Dirk , Weinert Sönke , Kinne Raimund W 
Published: March 2009

Abstract
Introduction
Activated synovial fibroblasts are thought to play a major role in the destruction of cartilage in chronic, inflammatory rheumatoid arthritis (RA). However, profound insight into the pathogenic mechanisms and the impact of synovial fibroblasts in the initial early stages of cartilage destruction is limited. Hence, the present study sought to establish a standardised in vitro model for early cartilage destruction with native, intact cartilage in order to analyse the matrix-degrading capacity of synovial fibroblasts and their influence on cartilage metabolism.

Methods
A standardised model was established by co-culturing bovine cartilage discs with early-passage human synovial fibroblasts for 14 days under continuous stimulation with TNF-α, IL-1β or a combination of TNF-α/IL-1β. To assess cartilage destruction, the co-cultures were analysed by histology, immunohistochemistry, electron microscopy and laser scanning microscopy. In addition, content and/or neosynthesis of the matrix molecules cartilage oligomeric matrix protein (COMP) and collagen II was quantified. Finally, gene and protein expression of matrix-degrading enzymes and pro-inflammatory cytokines were profiled in both synovial fibroblasts and cartilage.

Results
Histological and immunohistological analyses revealed that non-stimulated synovial fibroblasts are capable of demasking/degrading cartilage matrix components (proteoglycans, COMP, collagen) and stimulated synovial fibroblasts clearly augment chondrocyte-mediated, cytokine-induced cartilage destruction. Cytokine stimulation led to an upregulation of tissue-degrading enzymes (aggrecanases I/II, matrix-metalloproteinase (MMP) 1, MMP-3) and pro-inflammatory cytokines (IL-6 and IL-8) in both cartilage and synovial fibroblasts. In general, the activity of tissue-degrading enzymes was consistently higher in co-cultures with synovial fibroblasts than in cartilage monocultures. In addition, stimulated synovial fibroblasts suppressed the synthesis of collagen type II mRNA in cartilage.

Conclusions
The results demonstrate for the first time the capacity of synovial fibroblasts to degrade intact cartilage matrix by disturbing the homeostasis of cartilage via the production of catabolic enzymes/pro-inflammatory cytokines and suppression of anabolic matrix synthesis (i.e., collagen type II). This new in vitro model may closely reflect the complex process of early stage in vivo destruction in RA and help to elucidate the role of synovial fibroblasts and other synovial cells in this process, and the molecular mechanisms involved in cartilage degradation.