bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary Acute Lymphoblastic Leukemia Cells Use a Novel Promoter and 5′Noncoding Exon for the Human Reduced Folate Carrier That Encodes a Modified Carrier Translated from an Upstream Translational Start
Authors: Flatley Robin M. , Payton Scott G. , Taub Jeffrey W. , Matherly Larry H. 
Published: September 2005

Abstract
The human reduced folate carrier (hRFC) is reported to be regulated by up to seven alternatively spliced noncoding exons (A1, A2, A, B, C, D, and E). Noncoding exon and promoter usage was analyzed in RNAs from 27 childhood acute lymphoblastic leukemia (ALL) specimens by real-time PCR and/or 5′ rapid amplification of cDNA ends (5′ RACE) assay. By real-time PCR, total hRFC transcripts in ALL spanned a 289-fold range. Over 90% of hRFC transcripts were transcribed with A1, A2, and B 5′ untranslated regions (UTRs). Analysis of 5′ RACE clones showed that the A1 + A2 5′UTRs contained A1 sequence alone or a fusion of A1 and A2, implying the existence of a single, alternatively spliced 1021-bp A1/A2 noncoding region. High frequency sequence polymorphisms (AGG deletion, C/T transition) identified in the A1/A2 region by 5′RACE were confirmed in normal DNAs. By reporter assays in HepG2 hepatoma and Jurkat leukemia cells, A1/A2 promoter activity was localized to a 134-bp minimal region. Translation from an upstream AUG in the A1/A2 noncoding region in-frame with the normal translation start resulted in synthesis of a larger (∼7 kDa) hRFC protein with transport properties altered from those for wild-type hRFC. Although there was no effect on transcript or protein stabilities, in vitro translation from A1/A2 transcripts was decreased compared with those with the B 5′UTR. Our results document the importance of the hRFC A1/A2 upstream region in childhood ALL and an intricate transcriptional and posttranscriptional regulation of hRFC-A1/A2 mRNAs. Furthermore, they suggest that use of the A1/A2 5′UTR may confer a transport phenotype distinct from the other 5′UTRs due to altered translation efficiency and transport properties.
Prognostic Analysis of Early Lymphocyte Recovery in Patients with Advanced Breast Cancer Receiving High-Dose Chemotherapy with an Autologous Hematopoietic Progenitor Cell Transplant
Authors: Nieto Yago , Shpall Elizabeth J. , McNiece Ian K. , Nawaz Samia , Beaudet Julie , Rosinski Steve , Pellom Julie , Slat-Vasquez Victoria , McSweeney Peter A. , Bearman Scott I. , Murphy James , Jones Roy B. 
Published: September 2005

Abstract
Purpose: The purpose of this study was to evaluate the prognostic effect of early posttransplant lymphocyte recovery in patients with advanced breast cancer receiving high-dose chemotherapy with autologous hematopoietic progenitor cell transplantation.
Experimental Design: We analyzed the effect of the absolute lymphocyte count on day +15 posttransplant on freedom from relapse and overall survival in patients with high-risk primary breast cancer or metastatic breast cancer, enrolled between 1990 and 2001 in prospective high-dose chemotherapy trials, using a uniform regimen of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea.
Results: Four hundred and seventy-six patients (264 high-risk primary breast cancer and 212 metastatic breast cancer patients) were evaluated at median follow-up of 8 years (range, 1.5–11 years). The disease-free survival and overall survival rates in the high-risk primary breast cancer group were 67% and 70%, respectively. Patients with metastatic breast cancer patients had 21.8% disease-free survival and 31.5% overall survival rates. Day +15 absolute lymphocyte count correlated with freedom from relapse (P = 0.007) and overall survival (P = 0.04) in the metastatic breast cancer group, but not in the high-risk primary breast cancer group (P = 0.5 and 0.8, respectively). The prognostic effect of absolute lymphocyte count in metastatic breast cancer was restricted to those patients receiving unmanipulated peripheral blood progenitor cells (P = 0.04). In contrast, absolute lymphocyte count had no significant effect in those metastatic breast cancer patients receiving bone marrow or a CD34-selected product. In multivariate analyses, the prognostic effect of day +15 absolute lymphocyte count in metastatic breast cancer was independent of other predictors, such as disease status, pre-high-dose chemotherapy treatment, number of tumor sites, or HER2.
Conclusions: Early lymphocyte recovery is an independent outcome predictor in metastatic breast cancer patients receiving high-dose chemotherapy and an autologous peripheral blood progenitor cell transplant. These observations suggest that immune strategies targeting minimal posttransplant residual disease may prove worthwhile.
Antitumor Activity of Systemically Delivered Ribozymes Targeting Murine Telomerase RNA
Authors: Nosrati Mehdi , Li Shang , Bagheri Sepideh , Ginzinger David , Blackburn Elizabeth H. , Debs Robert J. , Kashani-Sabet Mohammed 
Published: September 2005

Abstract
Purpose: To test ribozymes targeting mouse telomerase RNA (mTER) for suppression of the progression of B16-F10 murine melanoma metastases in vivo.
Experimental Design: Hammerhead ribozymes were designed to target mTER. The ribozyme sequences were cloned into a plasmid expression vector containing EBV genomic elements that substantially prolong expression of genes delivered in vivo. The activity of various antitelomerase ribozymes or control constructs was examined after i.v. injection of cationic liposome:DNA complexes containing control or ribozyme constructs. Expression of ribozymes and mTER at various time points were evaluated by quantitative real-time PCR. Telomerase activity was examined using the telomeric repeat amplification protocol.
Results: Systemic administration of cationic liposome:DNA complexes containing a plasmid-expressed ribozyme specifically targeting a cleavage site at mTER nucleotide 180 significantly reduced the metastatic progression of B16-F10 murine melanoma. The antitumor activity of the anti-TER 180 ribozyme in mice was abolished by a single inactivating base mutation in the ribozyme catalytic core. The EBV-based expression plasmid produced sustained levels of ribozyme expression for the full duration of the antitumor studies. In addition to antitumor activity, cationic liposome:DNA complex-based ribozyme treatment also produced reductions in both TER levels and telomerase enzymatic activity in tumor-bearing mice.
Conclusions: Systemic, plasmid-based ribozymes specifically targeting TER can reduce both telomerase activity and metastatic progression in tumor-bearing hosts. The work reported here demonstrates the potential utility of plasmid-based anti-TER ribozymes in the therapy of melanoma metastasis.
Elevated S-Phase Kinase-Associated Protein 2 Protein Expression in Acute Myelogenous Leukemia
Authors: Min Yoo Hong , Cheong June-Won , Lee Mark Hong , Kim Ji Yeon , Lee Seung Tae , Hahn Jee Sook , Ko Yun Woong 
Published: September 2005

Abstract
Purpose: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S phase transition by controlling the stability of several G1 regulators, such as p27Kip1. However, the clinical significance of Skp2 in patients with acute myelogenous leukemia (AML) remains unknown.
Experimental Design: We examined the clinical and biological significance of Skp2 expression in AML and evaluated the relationship between Skp2 and p27Kip1 expression and phosphatase and tensin homologue (PTEN) phosphorylation.
Results: Western blot analysis showed that high Skp2 expression was observed in 57 (57.6%) cases and significantly correlated with unfavorable cytogenetics (P = 0.035) but not with age, white blood cell count, serum lactic dehydrogenase level, and the French-American-British subtype. An inverse correlation was not observed between Skp2 and p27Kip1 expression. However, p27Kip1 protein was preferentially localized to cytoplasm in the high-Skp2-expression group. The cytoplasmic to nuclear ratio of p27Kip1 expression was significantly correlated with the levels of Skp2 expression (P &lt; 0.001). The frequency of PTEN phosphorylation was significantly higher in the high-Skp2-expression group compared with the low- Skp2-expression group (P = 0.035). The Skp2 overexpression was significantly associated with shorter disease-free survival and overall survival (P = 0.0386 and P = 0.0369, respectively). Multivariate analysis showed that Skp2 expression was an independent prognostic factor both in the disease-free survival and overall survival.
Conclusion: These findings suggest that Skp2 expression is an independent marker for a poor prognosis in AML. The presence of a positive correlation between Skp2 and phosphorylated PTEN suggests that an aberration in the PTEN/Skp2 signaling pathway might be operating in AML.
Cytochrome P450 and Glutathione Transferase Expression in Squamous Cell Cancer
Authors: Ali Shadan , El-Rayes Basil F. , Heilbrun Lance K. , Sarkar Fazlul H. , Ensley John F. , Kucuk Omar , Philip Philip A. 
Published: September 2005

Abstract
Purpose: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems modulate the carcinogenic effects of tobacco. Therefore, the expression of these enzymes may be in part responsible for the observed interindividual and inter-racial differences in the risk of development of squamous cell carcinoma of the head and neck (SCCHN). The first aim of this study was to evaluate the feasibility of measuring the expression of the CYP and GST in target tissue from the head and neck. The second aim was to compare the expression of CYPs 1A1, 2E1, and 3A4 in squamous epithelium from African-American and Caucasian pediatric patients. The third aim was to compare the expression of CYPs 1A1, 2E1, 3A4, and GST-π on the p16 expression in patients with SCCHN.
Experimental Design: The expression of CYP 1A1, 2E1, 3A4, GST-π, and p16 was quantified by immunoblotting. Expression of CYPs 1A1, 2E1, and 3A4 was quantified in tissue from 160 pediatric patients undergoing tonsillectomy. Expression of CYPs 1A1, 2E1, 3A4, GST-π, and p16 was determined in 46 resected SCCHN patients.
Results: Large interindividual variability in the expression of these enzymes was observed in the pediatric and adult populations. No significant difference was observed in CYP 1A1, 2E1, and 3A4 expression of Caucasian and African-American patients. There was no correlation between p16 and enzyme expression in patients with SCCHN.
Conclusion: Evaluation of CYP expression in the target tissue of interest is feasible. The clinical significance of CYPs and GST-π alterations in the risk of developing SCCHN will need to be investigated in larger trials.
Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas
Authors: Heymach John V. , Desai Jayesh , Manola Judith , Davis Darren W. , McConkey David J. , Harmon David , Ryan David P. , Goss Geraldine , Quigley Travis , Van den Abbeele Annick D. , Silverman Stuart G. , Connors Susan , Folkman Judah , Fletcher Christopher D. M. , Demetri George D. 
Published: September 2005

Abstract
Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas.
Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m2 twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment.
Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting &gt;36 months.
Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.
Spontaneous Tumor-Specific Humoral and Cellular Immune Responses to NY-ESO-1 in Hepatocellular Carcinoma
Authors: Korangy Firouzeh , Ormandy Lars A. , Bleck Jörg S. , Klempnauer Jürgen , Wilkens Ludwig , Manns Michael P. , Greten Tim F. 
Published: September 2005

AbstractPurpose: Hepatocellular carcinoma (HCC) is the fifth most common cancer around the world. Although several therapeutic approaches for treatment of HCC are available, survival rates for HCC patients are still very poor because of inefficient treatment options. For HCC, as well as other tumors, antigen-specific immunotherapy remains a viable approach that is dependent on the definition of tumor-associated antigens. NY-ESO-1, a member of the cancer testis antigen family, is one possible candidate for a tumor-specific antigen in HCC. The aim of this study was to show the relevance of NY-ESO-1 in hepatocellular carcinoma.Experimental Design: Sera samples from 189 HCC patients were analyzed for NY-ESO-1-specific antibodies. Forty-nine HCC patients were screened for NY-ESO-1 mRNA expression in HCC tissue. Selected patients were followed for up to 3 years to correlate their immune response with their clinical course of events. NY-ESO-1-specific CD4+ and CD8+ T-cell responses from NY-ESO-1 seropositive patients were analyzed and a NY-ESO-1+ specific cytotoxic T-cell line was generated.Results: Twelve of 49 analyzed tumor samples expressed NY-ESO-1 mRNA and 23 of 189 patients showed NY-ESO-1-specific antibody responses. These humoral immune responses were accompanied by NY-ESO-1-specific functional CD4+ and CD8+ T-cell responses. Finally, NY-ESO-1 humoral responses were dependent on the presence of NY-ESO-1-expressing tumors.Conclusions: This is the first report of a spontaneous immune response in HCC patients to a known tumor-specific antigen, NY-ESO-1 protein. Our data favor the possibility of immunotherapeutic strategies for the treatment of HCC.
Gefitinib (ZD1839) Monotherapy as a Salvage Regimen for Previously Treated Advanced Non-Small Cell Lung Cancer
Authors: Park Jinny , Park Byung Bae , Kim Jee Youn , Lee Se-Hoon , Lee Soon Il , Kim Ho Young , Kim Jung Han , Park Se Hoon , Lee Kyung-Eun , Park Joon Oh , Kim Kihyun , Jung Chul Won , Park Young Suk , Im Young-Hyuck , Kang Won Ki , Lee Mark H. , Park Keunchil 
Published: September 2005

Abstract
Purpose: A worldwide compassionate-use program has enabled &gt;42,000 patients with advanced non-small cell lung cancer (NSCLC) to receive gefitinib treatment. Here we report the outcome of gefitinib therapy in patients who enrolled in the “Iressa” Expanded Access Program at the Samsung Medical Center.
Experimental Design: Patients with advanced or metastatic NSCLC who had progressed after prior systemic chemotherapy and for whom no other treatment option was available were eligible to receive gefitinib treatment as part of the Expanded Access Program. A post hoc assessment of potential prognostic factors for response and survival was performed by multivariate analysis.
Results: All 111 evaluable patients had stage IV disease; most patients had a baseline performance status of 2 [n = 52 (47%)] or 3 [n = 18 (16%)] and had received ≥2 prior chemotherapy regimens (56%). The objective response rate was 26%, the disease control rate (measured over ≥8 weeks) was 40%, and the 1-year survival rate was 44%. Adenocarcinoma histology was associated with better response and disease control rates, and a performance status of 0–2 was also associated with a better disease control rate. Both of these factors, as well as female gender, were significantly associated with longer survival. Gefitinib was well tolerated; the most common adverse event was grade 1 skin rash.
Conclusions: Gefitinib demonstrated significant antitumor activity and a favorable tolerability profile in this series of NSCLC patients with poor prognosis.
Phospho-Serine-118 Estrogen Receptor-α Expression Is Associated with Better Disease Outcome in Women Treated with Tamoxifen
Authors: Murphy Leigh C. , Niu Yulian , Snell Linda , Watson Peter 
Published: September 2005

Abstract
Purpose: The purpose of this research was to determine whether estrogen receptor α specifically phosphorylated at Ser118 is associated with clinical outcome in primary breast tumors from estrogen receptor-positive and node-negative breast cancer patients.
Experimental Design: Estrogen receptor α specifically phosphorylated at Ser118 was determined by immunohistochemistry in 117 primary breast tumors from node-negative patients who were subsequently treated with adjuvant tamoxifen. The relationship of estrogen receptor α specifically phosphorylated at Ser118 expression to disease-free survival and overall survival was determined.
Results: Estrogen receptor α specifically phosphorylated at Ser118 was limited to estrogen receptor α ligand binding assay-positive tumors and among this subset was expressed in 70 (62%) of these tumors. Estrogen receptor α specifically phosphorylated at Ser118 expression was more frequently observed in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors (χ2 test, P = 0.012, n = 113). A significant correlation was also seen between estrogen receptor α specifically phosphorylated at Ser118 and progesterone receptor levels (Spearman r = 0.236, P = 0.0118, n = 113). Kaplan-Meier outcome analysis showed that patients whose primary tumors expressed estrogen receptor α specifically phosphorylated at Ser118 had a longer disease-free survival (P = 0.0018, n = 113) and a trend toward better overall survival, but this was not statistically significant. Among the subset of progesterone receptor-positive tumors, progesterone receptor-positive/estrogen receptor α specifically phosphorylated at Ser118-positive patients had a significantly longer disease-free survival that progesterone receptor-positive/estrogen receptor α specifically phosphorylated at Ser118-negative patients (P = 0.0041).
Conclusions: Our data suggest that estrogen receptor α specifically phosphorylated at Ser118 is a marker of a functional, intact ligand-dependent estrogen receptor signaling pathway in breast cancer and that estrogen receptor α specifically phosphorylated at Ser118 status has the potential to provide a more precise biomarker of responsiveness to endocrine therapy in conjunction with estrogen receptor α and progesterone receptor status.
Loss of Fhit Expression in Head and Neck Squamous Cell Carcinoma and Its Potential Clinical Implication
Authors: Tai Shyh-Kuan , Lee Janet I. , Ang K. Kian , El-Naggar Adel K. , Hassan Khaled A. , Liu Diane , Lee J. Jack , Ren Hening , Hong Waun K. , Mao Li 
Published: September 2005

Abstract
Purpose: Abnormalities of FHIT, a candidate tumor suppressor gene, have frequently been found in multiple malignancies, including head and neck squamous cell carcinoma (HNSCC). To define its role in HNSCC treated with surgery and postoperative radiotherapy (PORT), the Fhit protein expression status was investigated in 80 patients enrolled in a prospective Phase III clinical trial addressing the dose and fractionation regimen of PORT.
Experimental Design: Immunohistochemical staining of HNSCC tissue sections for Fhit expression was performed. The Fhit expression status was correlated with the clinicopathological characteristics and clinical course. The median follow-up duration was 4.9 years.
Results: Loss of Fhit expression was found in 52 of the 80 study patients (65%). There was not a significant association between Fhit expression and clinical characteristics. Patients whose tumor exhibited negative Fhit expression had a significantly worse 5-year overall survival duration [hazard ratio = 0.49; 95% confidence interval, 0.23–1.03; P = 0.05 (log-rank test)] than did those whose tumor exhibited positive Fhit expression. One third of the patients with a Fhit-negative tumor had distant metastasis during the follow-up period. Paradoxically, patients classified as high risk who had a Fhit-negative tumor experienced locoregional recurrence less often (18%) than did high-risk patients who had a Fhit-positive tumor (33%).
Conclusions: Loss of Fhit expression is a poor prognostic indicator in patients with HNSCC. However, tumors lacking Fhit expression may be more sensitive to PORT and therefore more susceptible to locoregional control.
Superior Activity of the Combination of Histone Deacetylase Inhibitor LAQ824 and the FLT-3 Kinase Inhibitor PKC412 against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3
Authors: Bali Purva , George Prince , Cohen Pamela , Tao Jianguo , Guo Fei , Sigua Celia , Vishvanath Anasuya , Scuto Anna , Annavarapu Srinivas , Fiskus Warren , Moscinski Lynn , Atadja Peter , Bhalla Kapil 
Published: September 2005

Abstract
Purpose: Mutant FLT-3 receptor tyrosine kinase is a client protein of the molecular chaperone heat shock protein 90 and is commonly present and contributes to the leukemia phenotype in acute myelogenous leukemia (AML). LAQ824, a cinnamyl hydroxamate histone deacetylase inhibitor, is known to induce acetylation and inhibition of heat shock protein 90. Here, we determined the effects of LAQ824 and/or PKC412 (a FLT-3 kinase inhibitor) on the levels of mutant FLT-3 and its downstream signaling, as well as growth arrest and cell-death of cultured and primary human AML cells.
Experimental Design: The effect of LAQ824 and/or PKC412 treatment was determined on the levels of FLT-3 and phosphorylated (p)-FLT-3, on downstream pro-growth and pro-survival effectors, e.g., p-STAT5, p-AKT, and p-extracellular signal-regulated kinase (ERK) 1/2, and on the cell cycle status and apoptosis in the cultured MV4–11 and primary AML cells with mutant FLT-3.
Results: Treatment with LAQ824 promoted proteasomal degradation and attenuation of the levels of FLT-3 and p-FLT-3, associated with cell cycle G1-phase accumulation and apoptosis of MV4–11 cells. This was accompanied by attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels. STAT-5 DNA-binding activity and the levels of c-Myc and oncostatin M were also down-regulated. Cotreatment with LAQ824 and PKC412 synergistically induced apoptosis of MV4–11 cells and induced more apoptosis of the primary AML cells expressing mutant FLT-3. This was also associated with more attenuation of p-FLT-3, p-AKT, p-ERK1/2, and p-STAT5.
Conclusions: The combination of LAQ824 and PKC412 is highly active against human AML cells with mutant FLT-3, which merits in vivo studies of the combination against human AML.