bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic Silencing of the Candidate Tumor Suppressor Gene Per1 in Non–Small Cell Lung Cancer
Authors: Gery Sigal , Komatsu Naoki , Kawamata Norihiko , Miller Carl W. , Desmond Julian , Virk Renu K. , Marchevsky Alberto , Mckenna Robert , Taguchi Hirokuni , Koeffler H. Phillip 
Published: March 2007

Abstract
Purpose: Epigenetic events are a critical factor contributing to cancer development. The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non–small cell lung cancer (NSCLC).
Experimental Design: We used microarray analysis to screen for tumor suppressor genes.
Results: We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1 levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1 in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1 expression NSCLC.
Conclusions: These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.
Tumor Growth Inhibition with Cetuximab and Chemotherapy in Non–Small Cell Lung Cancer Xenografts Expressing Wild-type and Mutated Epidermal Growth Factor Receptor
Authors: Steiner Philipp , Joynes Christopher , Bassi Rajiv , Wang Su , Tonra James R. , Hadari Yaron R. , Hicklin Daniel J. 
Published: March 2007

AbstractPurpose: Targeting the epidermal growth factor receptor (EGFR) is a validated approach to treat cancer. In non–small cell lung cancer (NSCLC), EGFR contains somatic mutations in 10% of patients, which correlates with increased response rates to small molecule inhibitors of EGFR. We analyzed the effects of the monoclonal IgG1 antibody Erbitux (cetuximab) in NSCLC xenografts with wild-type (wt) or mutated EGFR.Experimental Design: NSCLC cell lines were grown s.c. in nude mice. Dose-dependent efficacy was established for cetuximab. To determine whether combination therapy produces tumor regressions, cetuximab was dosed at half-maximal efficacy with chemotherapy used at maximum tolerated dose.Results: Cetuximab showed antitumor activity in wt (A549, NCI-H358, NCI-H292) and mutated [HCC-827 (delE746-A750), NCI-H1975 (L858R, T790M)] EGFR-expressing xenografts. In the H292 model, cetuximab and docetaxel combination therapy was more potent to inhibit tumor growth than cetuximab or docetaxel alone. Cisplatin augmented efficacy of cetuximab to produce 6 of 10 regressions, whereas 1 of 10 regressions was found with cetuximab and no regression was found with cisplatin. Using H1975 xenografts, gemcitabine increased efficacy of cetuximab resulting in 12 of 12 regressions. Docetaxel with cetuximab was more efficacious with seven of nine regressions compared with single treatments. Cetuximab inhibited autophosphorylation of EGFR in both H292 and H1975 tumor lysates. Exploring the underlying mechanism for combination effects in the H1975 xenograft model, docetaxel in combination with cetuximab added to the antiproliferative effects of cetuximab but was the main component in this drug combination to induce apoptosis.Conclusions: Cetuximab showed antitumor activity in NSCLC models expressing wt and mutated EGFR. Combination treatments increased the efficacy of cetuximab, which may be important for the management of patients with chemorefractory NSCLC.
Longitudinal Assessment of Genetic and Epigenetic Markers in Oligodendrogliomas
Authors: Lavon Iris , Zrihan Daniel , Zelikovitch Bracha , Fellig Yakov , Fuchs Dana , Soffer Dov , Siegal Tali 
Published: March 2007

Abstract
Purpose: Because little is known about the evolution of genetic and epigenetic changes that occur during tumor progression in oligodendrogliomas, we evaluated these changes in paired early and progressive oligodendrogliomas.
Experimental Design: 1p36, 19q13, 10q22-26, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were assessed in 46 paired early and progressive oligodendrogliomas from 23 patients.
Results: In early tumors, 60.8% were of low grade compared with only 17% low-grade tumors at recurrence. Of 17 early tumors described as pure oligodendrogliomas, 76.5% remained in this lineage, regardless of their grade, whereas others changed to astrocytic tumors. Oligoastrocytic tumors had a significantly higher tendency to transform to astrocytic tumors. All pure oligodendrogliomas with 1p/19q codeletions remained phenotypically unchanged, unlike mixed tumors with codeletions, of which 83% changed their cell lineage. Of tumors with early 1p deletion, 80% remained oligodendroglial at progression, whereas 75% of tumors with an intact 1p changed to astrocytic phenotype. 10q loss was uncommon in both early and progressive tumors. The proportional gain in methylation at progression was 31% for tumors with early 1p deletion, unlike tumors with an intact 1p, which had an 87.5% gain of methylation at progression.
Conclusions: Pure oligodendrogliomas with 1p/19q deletion tend to retain their cell phenotype and genetic profile unlike tumors with no deletions or mixed histology. MGMT promoter methylation is more pronounced at tumor progression, particularly in tumors with an intact 1p. These observations suggest that MGMT promoter methylation is a late event in progressive oligodendrogliomas, and therefore, their chemosensitivity is not necessarily related to MGMT methylation status.
Retropharyngeal Lymph Node Metastasis in Nasopharyngeal Carcinoma: Prognostic Value and Staging Categories
Authors: Ma Jun , Liu Lizhi , Tang Linglong , Zong Jingfeng , Lin Aihua , Lu Taixiang , Cui Nianji , Cui Chunyan , Li Li 
Published: March 2007

Abstract
Purpose: To investigate the incidence, prognostic value, and staging categories of retropharyngeal lymph node (RLN) metastasis in nasopharyngeal carcinoma (NPC).
Experimental Design: We did a retrospective review of the data from 749 biopsy-proved nonmetastatic NPC patients. All patients had undergone contrast-enhanced computed tomography and had radiotherapy as their primary treatment.
Results: The incidence of RLN metastasis was 51.5%. After adjusting for tumor (T) and node (N) classifications, a borderline significant difference of distant metastasis-free survival (DMFS) rates was observed between patients with or without RLN metastasis. In N0 disease, the presence of RLN metastasis was a significant independent predictor for overall survival (OS), loco-regional relapse-free survival, and DMFS in multivariate Cox modeling analysis. No significant difference was observed in all end points between patients with unilateral and bilateral RLN metastasis. The hazard ratios of death and distant failure for N0 with RLN metastasis were similar to N1. The survival curve of OS and DMFS for N0 disease with RLN metastasis had approximated that of N1 disease. The survival curve of OS for T1 disease with RLN metastasis was approximately the same as T2 disease. However, the survival curve of DMFS for T1 disease with RLN metastasis was approximately the same as in T3 disease.
Conclusions: RLN metastasis has a tendency to affect the DMFS rates of patients with NPC. Retropharyngeal node involvement has a negative effect on the prognosis of N0 disease. RLN metastasis should be classified as N1.
High Macrophage Infiltration along the Tumor Front Correlates with Improved Survival in Colon Cancer
Authors: Forssell Johan , Öberg Åke , Henriksson Maria L. , Stenling Roger , Jung Andreas , Palmqvist Richard 
Published: March 2007

AbstractPurpose: The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development.Experimental Design: Four hundred forty-six colorectal cancer specimens were stained with the pan-monocyte/macrophage marker CD68, and average infiltration along the tumor front was semiquantitatively evaluated using a four-grade scale. Each section was similarly scored for the presence of CD68 hotspots. Some aspects of macrophage-tumor cell interactions were also studied using in vitro coculture systems.Results: Including all patients, regardless of surgical outcome and localization, survival increased incrementally with CD68TFMean infiltration grade (P = 0.0001) but not in curatively resected colon cancers (P = 0.28). CD68 hotspot score (CD68TFHotspot) was divided into high and low. A high hotspot score conferred a highly significant survival advantage also in curatively resected colon cancer cases (n = 199, P = 0.0002) but not in rectal cancers. CD68TFHotspot high turned out as an independent prognostic marker for colon cancer in multivariate analyses including gender, age, localization, grade, stage, tumor type, and lymphocytes at the tumor front, conferring a relative risk of 0.49 (P = 0.007). In vitro coculture experiments, using phorbol 12-myristate 13-acetate–activated U937 cells as macrophage model, revealed that a high ratio of macrophages to colon cancer cells inhibited cancer cell growth. This was partially dependent on cell-to-cell contact, whereas Boyden chamber cocultivation without cell-to-cell contact promoted cancer cell spread.Conclusions: In conclusion, our data indicate that a dense macrophage infiltration at the tumor front positively influences prognosis in colon cancer and that the degree of cell-to-cell contact may influence the balance between protumorigenic and antitumorigenic properties of macrophages.
A Phase 1 Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients with Refractory Leukemia: a Children's Oncology Group Study
Authors: Horton Terzah M. , Pati Debananda , Plon Sharon E. , Thompson Patrick A. , Bomgaars Lisa R. , Adamson Peter C. , Ingle Ashish M. , Wright John , Brockman Adam H. , Paton Martin , Blaney Susan M. 
Published: March 2007

Abstract
Purpose: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia.
Experimental Design: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m2 dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor κB (NF-κB) binding activity were evaluated during the first treatment cycle.
Results: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m2 dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m2 revealed a clearance of 11 mL/h/m2, a central volume of distribution of 6.7 L/m2, and a terminal half-life of 12.6 h. NF-κB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses.
Conclusions: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m2/dose. Although bortezomib treatment inhibited NF-κB activity, bortezomib had little activity as a single agent in this population.
Insulin-like Growth Factor Binding Proteins IGFBP3, IGFBP4, and IGFBP5 Predict Endocrine Responsiveness in Patients with Ovarian Cancer
Authors: Walker Graeme , MacLeod Kenneth , Williams Alistair R.W. , Cameron David A. , Smyth John F. , Langdon Simon P. 
Published: March 2007

Abstract
Purpose: This study sought to explore the predictive value of the insulin-like growth factor (IGF) binding proteins (IGFBP) as markers of response in ovarian cancer patients treated with the aromatase inhibitor letrozole.
Experimental Design: IGFBP mRNA expression in cell lines was measured by quantitative reverse transcription-PCR and IGFBP protein expression measured in sections from primary tumors of patients treated with letrozole by semiquantitative immunohistochemistry.
Results: Quantitative reverse transcription-PCR analysis showed that IGFBP3 and IGFBP5 were down-regulated and IGFBP4 was up-regulated by 17β-estradiol (E2) in an estrogen receptor (ER)–positive ovarian cancer cell line. Expressions of IGFBP1, IGFBP2, and IGFBP6 were unaffected by E2. The E2 modulation of these genes was reversed by tamoxifen. Using ERα-specific (propyl pyrazole triol) and ERβ-specific (diarylpropionitrile) agonists, the gene expression modulations produced by E2 could be replicated by propyl pyrazole triol but not by diarylpropionitrile.
For ovarian cancer patients being treated with letrozole, we tested the predictive value of the IGFBPs in paraffin-fixed sections from their primary tumors by semiquantitative immunohistochemistry. Using serum CA125 as an indicator of progression/response, significant differences in expression levels of IGFBPs were observed between tumors from CA125 responding/stable patients compared with tumors from progressing patients. Mean immunoscores for IGFBP3 and IGFBP5 were significantly lower, and mean expression of IGFBP4 was significantly higher in tumors from patients demonstrating CA125 response or stabilization compared with CA125 progression.
Conclusion: These results indicate that expression levels of certain IGFBP family members in ovarian cancers are estrogen regulated and can, thus, help identify patients who could benefit from endocrine therapy.
Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology
Authors: Ratnam Kapila , Low Jennifer A. 
Published: March 2007

Abstract
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents.
Cancer Cachexia Signaling Pathways Continue to Emerge Yet Much Still Points to the Proteasome
Authors: Acharyya Swarnali , Guttridge Denis C. 
Published: March 2007

AbstractCachexia is a life-threatening consequence of cancer that diminishes both quality of life and survival. It is a syndrome that is characterized by extreme weight loss resulting mainly from the depletion of skeletal muscle. Research from the past decades investigating the mechanisms of tumor-induced muscle wasting has identified several key cachectic factors that act through the ubiquitin-dependent proteasome system. Signaling pathways that mediate the effects of these cachectic factors have also subsequently emerged. Here, we review some of these pathways specific to myostatin, nuclear factor κB, and the newly elucidated dystrophin glycoprotein complex. Although these molecules are likely to employ distinct modes of action, results suggest that they nevertheless maintain a link to the proteasome pathway. Therefore, although the proteasome remains a preferred choice for therapy, the continually emerging upstream signaling molecules serve as additional promising therapeutic targets for the treatment of tumor-induced muscle wasting.
Sperm-Associated Antigen 9, a Novel Cancer Testis Antigen, Is a Potential Target for Immunotherapy in Epithelial Ovarian Cancer
Authors: Garg Manoj , Chaurasiya Dipak , Rana Ritu , Jagadish Nirmala , Kanojia Deepika , Dudha Namrata , Kamran Neha , Salhan Sudha , Bhatnagar Amar , Suri Sushma , Gupta Anju , Suri Anil 
Published: March 2007

Abstract
Purpose: Cancer testis antigens are a group of tumor antigens with gene expression restricted to male germ cells in the testis and in various cancerous tissues. Recently, we reported a novel testis-specific sperm-associated antigen 9 (SPAG9) gene, a new member of the c-Jun NH2-terminal kinase–interacting protein family, having functional role in sperm-egg fusion and mitogen-activated protein kinase signaling pathway. National Center for Biotechnology Information Blast searches revealed SPAG9 nucleotide sequence similarities with expressed sequence tags of various cancerous tissues. In an effort to examine the clinical utility of SPAG9, we investigated the SPAG9 mRNA and protein expression in epithelial ovarian cancer (EOC). Humoral immune response to SPAG9 was also evaluated in EOC patients.
Experimental Design: We determined the expression profile of SPAG9 transcript by reverse transcription-PCR and RNA in situ hybridization and SPAG9 protein expression by immunohistochemistry in EOC specimens and human ovarian cancer cell lines. Using ELISA and Western blotting, we analyzed specific antibodies for SPAG9 in sera from patients with EOC.
Results: SPAG9 mRNA and protein expression was detected in 90% of EOC tissues and in all three human ovarian cancer cell lines. Specific SPAG9 antibodies were detected in 67% of EOC patients and not in sera from healthy individuals.
Conclusions: Our findings indicate that SPAG9 is highly expressed in EOC and immunogenic in patients. Humoral immune response against SPAG9 in early stages of EOC suggests its important role in early diagnostics. These results collectively suggest that SPAG9, a novel member of cancer testis antigen family, could be a potential target for the development of diagnostic and therapeutic methods in EOC.
Plasma and Cerebrospinal Fluid Pharmacokinetics of Erlotinib and Its Active Metabolite OSI-420
Authors: Broniscer Alberto , Panetta John C. , O'Shaughnessy Melinda , Fraga Charles , Bai Feng , Krasin Matthew J. , Gajjar Amar , Stewart Clinton F. 
Published: March 2007

AbstractPurpose: To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420.Experimental Design: Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC0-24).Results: This patient was assigned to receive erlotinib at a dose level of 70 mg/m2, but the actual daily dose was 75 mg (78 mg/m2). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC0-24 in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC0-24 in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and ∼9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was ∼130 ng/mL (325 nmol/L).Conclusions: The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.
Transcriptomic versus Chromosomal Prognostic Markers and Clinical Outcome in Uveal Melanoma
Authors: Worley Lori A. , Onken Michael D. , Person Erica , Robirds Diane , Branson Julie , Char Devron H. , Perry Arie , Harbour J. William 
Published: March 2007

Abstract
Purpose: To compare a gene expression–based classifier versus the standard genetic prognostic marker, monosomy 3, for predicting metastasis in uveal melanoma.
Experimental Design: Gene expression profiling, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) were done on 67 primary uveal melanomas. Clinical and pathologic prognostic factors were also assessed. Variables were analyzed by Cox proportional hazards, Kaplan-Meier analysis, sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios.
Results: The gene expression–based molecular classifier assigned 27 tumors to class 1 (low risk) and 25 tumors to class 2 (high risk). By Cox univariate proportional hazards, class 2 signature (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were the only variables significantly associated with metastasis. Only the class 2 signature was needed to optimize predictive accuracy in a Cox multivariate model. A less significant association with metastasis was observed for monosomy 3 detected by aCGH (P = 0.076) and FISH (P = 0.127). The sensitivity and specificity for the molecular classifier (84.6% and 92.9%, respectively) were superior to monosomy 3 detected by aCGH (58.3% and 85.7%, respectively) and FISH (50.0% and 72.7%, respectively). Positive and negative predictive values (91.7% and 86.7%, respectively) and positive and negative likelihood ratios (11.9 and 0.2, respectively) for the molecular classifier were also superior to those for monosomy 3.
Conclusions: Molecular classification based on gene expression profiling of the primary tumor was superior to monosomy 3 and clinicopathologic prognostic factors for predicting metastasis in uveal melanoma.
Impaired Executive Control Is Associated with a Variation in the Promoter Region of the Tryptophan Hydroxylase 2 Gene
Authors: Reuter Martin , Ott Ulrich , Vaitl Dieter , Hennig Jürgen 
Published: March 2007

Abstract
Current models of attention describe attention not as a homogenous entity but as a set of neural networks whose measurement yields a set of three endophenotypes—alerting, orienting, and executive control. Previous findings revealed different neuroanatomical regions for these subsystems, and data from twin studies indicate differences in their heritability. The present study investigated the molecular genetic basis of attention in a sample of 100 healthy subjects. Attention performance was assessed with the attention network test that distinguishes alerting, orienting, and executive control (conflict) using a simple reaction time paradigm with different cues and congruent and incongruent flankers. Two gene loci on candidate genes for cognitive functioning, the functional catechol-O-methyltransferase (COMT) VAL158MET and the tryptophan hydroxylase 2 (TPH2) −703 G/T promoter polymorphism, were tested for possible associations with attention. COMT is involved in the catabolism of dopamine, and TPH is the rate-limiting enzyme for serotonin synthesis. Results showed no effect of the COMT polymorphism on attention performance. However, the TT genotype of TPH2 −03 G/T was significantly associated with more errors (a possible indicator of impaired impulse control; p = .001) and with decreased performance in executive control (p = .001). This single-nucleotide polymorphism on the TPH2 gene explained more than 10% of the variance in both indicators of attention stressing the role of the serotonergic system for cognitive functions.