bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Prostate Carcinoma Binding Peptide (DUP-1) for Tumor Imaging and Therapy
Authors: Zitzmann Sabine , Mier Walter , Schad Arno , Kinscherf Ralf , Askoxylakis Vasileios , Krämer Susanne , Altmann Annette , Eisenhut Michael , Haberkorn Uwe 
Published: June 2022

Abstract
Purpose: Prostate carcinomas belong to the most widespread tumors, and their number is increasing. Imaging modalities used for diagnosis, such as ultrasound, computed tomography, and positron emission tomography, often produce poor results. Radiolabeled peptides with high sensitivity and specificity for prostate cancer would be a desirable tool for tumor diagnosis and treatment.
Experimental Design: We used phage display and the prostate-specific membrane antigen–negative cell line DU-145 to identify a peptide. The isolated DUP-1 was tested invitro for its binding specificity, kinetics, and affinity. Internalization of the peptide was evaluated with confocal microscopy. The tumor accumulation in a nude mouse model was analyzed with 131I-labeled DUP-1 in PC-3 and DU-145 prostate tumors as well as in the rat prostate tumor model AT-1.
Results: The synthesized peptide showed rapid binding kinetics peaking at 10 minutes. It shows specific binding to prostate carcinoma cells but low binding affinity to nontumor cells. Peptide binding is competed with unlabeled DUP-1, and a time-dependent internalization into DU-145 cells was shown. Biodistribution studies of DUP-1 in nude mice with s.c. transplanted DU-145 and PC-3 tumors showed a tumor accumulation of 5% and 7% injected dose per gram, and bound peptide could not be removed by perfusion. The rat prostate tumor model showed an increase of radioactivity in the prostate tumor up to 300% in comparison with normal prostate tissue.
Conclusions: DUP-1 holds promise as a lead peptide structure applicable in the development of new diagnostic tracers or anticancer agents that specifically target prostate carcinoma.
Prognostic Significance of Metastasis-Associated Protein S100A4 (Mts1) in Prostate Cancer Progression and Chemoprevention Regimens in an Autochthonous Mouse Model
Authors: Saleem Mohammad , Adhami Vaqar Mustafa , Ahmad Nihal , Gupta Sanjay , Mukhtar Hasan 
Published: June 2022

Abstract
Purpose: We recently showed that metastasis-promoting Mts1 gene (S100A4) and protein is overexpressed during progression of prostate cancer in humans. The purpose of this study was to assess the expression of S100A4 during autochthonous prostate cancer progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Because oral consumption of green tea polyphenols (GTP) has been shown to inhibit metastasis and prostate cancer in TRAMP, we further assessed the significance of S100A4 during chemoprevention regimen.
Experimental Design: Male TRAMP mice 8 weeks of age were equally divided into two groups. A freshly prepared 0.1% GTP solution in tap water was supplied thrice a week to experimental animals as the sole source of drinking fluid for 24 weeks, whereas the control group of animals received the same tap water throughout the experiment. The animals were sacrificed at 0, 8, 16, and 24 weeks of GTP feeding and were analyzed for S100A4 and E-cadherin. Additional untreated and treated nontransgenic controls were also included in the study.
Results: With the progression of age and prostate cancer growth in TRAMP mice, an increase in the expression of S100A4 at mRNA and protein level in dorsolateral prostate, but not in nontransgenic mice, occurred. GTP feeding to TRAMP mice resulted in marked inhibition of prostate cancer progression, which was associated with reduction of S100A4 and restoration of E-cadherin.
Conclusions: S100A4 represents a promising marker for prostate cancer progression and could be employed as a biomarker in chemoprevention regimens.
Expression of Receptor Activator of Nuclear Factor-κB Ligand Is Inversely Correlated with Metastatic Phenotype in Breast Carcinoma
Authors: Bhatia Pardeep , Sanders M. Melinda , Hansen Marc F. 
Published: June 2022

Abstract
During normal bone remodeling, the receptor activator of nuclear factor-κB (RANK) interacts with its ligand RANKL, which is present on pre-osteoclasts, resulting in bone resorption and initiation of new bone formation. When breast cancer metastasizes to bone, normal bone remodeling is disturbed by invasion of tumor cells, resulting in osteolytic lesions. We have studied the expression of both RANK and RANKL in 10 nonneoplastic breast samples, 58 infiltrating ductal carcinoma (IDC), and 43 breast cancer bony metastases (BTM). RANK seemed to be present in all samples tested. However, whereas RANKL expression was observed in 90% of nonneoplastic breast, RANKL expression was only observed in 62% of nonmetastatic IDC, 31% of metastatic IDC, and 2% of osteolytic BTM lesions. This decreased or absent expression of RANKL in the tumor cells may allow RANK, which is normally expressed as a receptor on the cell surface, to target RANKL present on the cell surface of normal osteoblasts and stromal cells of the bone. Stimulation of the normal osteoblasts and stromal cells by the tumor cells may then lead to secondary osteoclastogenesis, resulting in the osteolytic phenotype common to breast metastases.
Promoter Hypermethylation in Benign Breast Epithelium in Relation to Predicted Breast Cancer Risk
Authors: Lewis Cheryl M. , Cler Leslie R. , Bu Da-Wei , Zöchbauer-Müller Sabine , Milchgrub Sara , Naftalis Elizabeth Z. , Leitch A. Marilyn , Minna John D. , Euhus David M. 
Published: June 2022

Abstract
Introduction: The tumor suppressor genes RASSF1A, APC, H-cadherin, RARβ2, and cyclin D2 are methylated more frequently in breast cancer than in adjacent benign tissue. However, it is unclear whether promoter methylation of tumor suppressor genes in benign breast tissue is associated with an increased risk for breast cancer.
Methods: Promoter hypermethylation was measured in benign and malignant breast samples obtained by fine needle aspiration biopsy from 27 breast cancer patients and 55 unaffected women whose risk of breast cancer had been defined using the Gail, Claus, and BRCAPRO models.
Results: Cyclin D2 methylation occurred in 57% of tumor samples but not in corresponding benign breast samples and in only one sample from an unaffected patient (P &lt; 0.0001). RARβ2 methylation occurred in 32% of benign breast samples from cancer patients but only 9% of similar samples from unaffected women (P = 0.002). Promoter methylation of RASSF1A and APC occurred more frequently (70% and 56%, respectively) in unaffected women at high-risk for breast cancer as defined by the Gail model than in low/intermediate risk women (29% and 20%, P = 0.04 and P = 0.03). Of the Gail model risk factors, only number of prior breast biopsies was highly correlated with APC and RASSF1A methylation (P = 0.0001 and 0.02, respectively).
Conclusions: Since cyclin D2 promoter methylation occurs almost exclusively in tumors, it may be possible to exploit it for the early detection of breast cancer. Promoter methylation of APC, RARβ2, and RASSF1A in benign breast epithelium is associated with epidemiologic markers of increased breast cancer risk.
ATBF1-A Messenger RNA Expression Is Correlated with Better Prognosis in Breast Cancer
Authors: Zhang Zhenhuan , Yamashita Hiroko , Toyama Tatsuya , Sugiura Hiroshi , Ando Yoshiaki , Mita Keiko , Hamaguchi Maho , Kawaguchi Makoto , Miura Yutaka , Iwase Hirotaka 
Published: June 2022

Abstract
Purpose: The AT motif-binding factor 1 (ATBF1) gene was first identified as a suppressor of the α-fetoprotein (AFP) gene through its binding to an AT-rich enhancer element of this gene. The gene is located at chromosome 16q22.3-q23.1 where loss of heterozygosity has been observed in various malignant tumors, especially in breast cancer. It was also found that in highly malignant AFP-producing gastric cancer cells the expression of AFP is inhibited by ATBF1-A. This led us to hypothesize that there was a link between levels of ATBF1 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients.
Experimental Design: In the present study, the level of ATBF1-A mRNA expression was analyzed using quantitative real-time reverse transcriptase-PCR, in 153 female patients with invasive carcinoma of the breast. ATBF1-A protein expression was also determined by immunohistochemistry from available 90 cases of paired tissues. An association was sought between ATBF1-A expression and various clinicopathologic factors.
Results: ATBF1-A mRNA was expressed at significantly higher levels in breast cancer patients with no axillary lymph node involvement, with small tumors measuring &lt;2 cm and in estrogen receptor-α–positive tumors. By contrast, no relationship was found between ATBF1-A mRNA expression and ATBF1-A protein expression, and also no relationship was found between ATBF1-A protein expression and any of the other clinicopathologic factors. Patients expressing high levels of ATBF1-A mRNA tended to have a better prognosis than those expressing low levels. Univariate and multivariate prognostic analyses showed that ATBF1-A mRNA expression is an independent prognostic factor for disease-free survival.
Conclusions: In breast cancer, levels of ATBF1-A mRNA may serve as a predictive indicator of lymph node metastasis. The results of this study also imply that ATBF1-A gene expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator for breast cancer progression.
Overexpression of h-prune in Breast Cancer is Correlated with Advanced Disease Status
Authors: Zollo Massimo , Andrè Alessandra , Cossu Antonio , Sini Maria C. , D'Angelo Anna , Marino Natascia , Budroni Mario , Tanda Francesco , Arrigoni Gianluigi , Palmieri Giuseppe 
Published: June 2022

Abstract
Purpose: The h-prune gene is involved in cellular motility and metastasis formation in breast cancer through interacting with the nm23-H1 protein. The aim of this study was to better define the clinical and pathologic role of h-prune in breast cancer patients.
Experimental Design: Using immunohistochemistry, we assessed h-prune and nm23-H1 protein expression in two series of breast cancer patients: (i) in 2,109 cases with pathologic reports on primary tumors and (ii) in 412 cases with detailed clinical information. To assess the role of DNA amplification in gene activation, the h-prune copy number was evaluated by fluorescence in situ hybridization analysis in 1,016 breast cancer cases.
Results: In the patients tested (n = 2,463), 1,340 (54%) had an increased level of h-prune expression; a positive immunostaining for nm23-H1 was observed in 615 of 2,061 (30%) cases. Overexpression of h-prune was associated with multiple gene copy number at chromosome 1q21.3 in a very limited fraction of cases (68 of 1,016; 6.7%), strongly indicating that alternative pathways induce h-prune activation in breast cancer. Multivariate Cox regression analysis showed that neither h-prune overexpression nor decreased nm23-H1 immunostaining is independent prognostic factors. However, a significant association of h-prune overexpression with either advanced lymph node status (P = 0.017) or presence of distant metastases (P = 0.029) was observed.
Conclusions: Although not significantly correlated with overall survival, positive h-prune immunostaining identifies subsets of breast cancer patients with higher tumor aggressiveness. Further investigations using larger collections of advanced breast cancer patients are required for assessing the predictive role of h-prune in breast cancer.
A Robust Assay for Alternative Lengthening of Telomeres in Tumors Shows the Significance of Alternative Lengthening of Telomeres in Sarcomas and Astrocytomas
Authors: Henson Jeremy D. , Hannay Jonathan A. , McCarthy Stanley W. , Royds Janice A. , Yeager Thomas R. , Robinson Robert A. , Wharton Stephen B. , Jellinek David A. , Arbuckle Susan M. , Yoo Jinyoung , Robinson Bruce G. , Learoyd Diana L. , Stalley Paul D. , Bonar S. Fiona , Yu Dihua , Pollock Raphael E. , Reddel Roger R. 
Published: June 2022

Abstract
Purpose and Experimental Design: Telomeres of tumor cells may be maintained by telomerase or by alternative lengthening of telomeres (ALT). The standard ALT assay requires Southern analysis of high molecular weight genomic DNA. We aimed to establish and validate an ALT assay suitable for archived paraffin-embedded tumors and to use it to examine the prevalence and clinical significance of ALT in various types of tumors that are often telomerase negative.
Results: To assay for ALT, we detected ALT-associated promyelocytic leukemia (PML) bodies (APBs) by combined PML immunofluorescence and telomere fluorescence in situ hybridization. APBs are PML nuclear domains containing telomeric DNA and are a known hallmark of ALT in cell lines. The APB assay concurred with the standard ALT assay in 62 of 62 tumors and showed that 35% of 101 soft tissue sarcomas (STS), 47% of 58 osteosarcomas (especially younger patients), 34% of 50 astrocytomas, and 0% of 17 papillary thyroid carcinomas were ALT positive (ALT+). The prevalence of ALT varied greatly among different STS subtypes: malignant fibrous histiocytomas, 77%; leiomyosarcomas, 62%; liposarcomas, 33%; synovial sarcomas, 9%; and rhabdomyosarcomas, 6%. ALT correlated with survival in glioblastoma multiforme and occurred more often in lower-grade astrocytomas, but ALT+ and ALT− sarcomas were equally aggressive in terms of grade and clinical outcome.
Conclusion: The APB assay for ALT is suitable for paraffin-embedded tumors. It showed that a substantial proportion of STS, osteosarcomas, and astrocytomas, but not papillary thyroid carcinomas use ALT. APB positivity correlated strongly with survival of patients with astrocytomas.
Cyclin D3 Immunoreactivity Is an Independent Predictor of Survival in Laryngeal Squamous Cell Carcinoma
Authors: Pruneri Giancarlo , Pignataro Lorenzo , Valentini Stefano , Fabris Sonia , Maisonneuve Patrick , Carboni Nadia , Pece Salvatore , Capra Maria , Del Curto Barbara , Neri Antonino , Viale Giuseppe 
Published: June 2022

Abstract
Purpose: To analyze the prevalence and clinical relevance of cyclin D3 abnormalities in laryngeal squamous cell carcinoma (LSCC).
Experimental Design: Cyclin D3 immunoreactivity was evaluated in 223 formalin-fixed and paraffin-embedded samples of LSCC patients with a mean follow-up of 62.8 ± 43.2 months. The occurrence of cyclin D3 extra signals was analyzed by fluorescence in situ hybridization in 47 randomly selected cases collected in a tissue microarray. Cyclin D1 immunoreactivity had been previously investigated in 133 cases.
Results: Cyclin D3 immunoreactivity and gene extra signals were found in 39.5% and 42.6% of the cases, respectively, and the concordance between immunohistochemical and fluorescence in situ hybridization results was 70.2% (P = 0.0085). Cyclin D3 immunoreactivity was significantly associated with a high risk of death. Multivariate analysis showed that high tumor grade, exophytic/ulcerating tumor type, low performance status, and cyclin D3 immunoreactivity were the only independent predictors of poor overall survival. In the 133 cases analyzed for both cyclin D1 and cyclin D3, patients with cyclin D1+/cyclin D3+ tumors experienced the worst prognosis, patients with cyclin D1−/cyclin D3− exhibited the most prolonged survival, and with cyclin D1−/cyclin D3+ or cyclin D1+/cyclin D3− tumors an intermediate course was associated.
Conclusions: Our data suggest that cyclin D3 immunoreactivity, possibly due to the occurrence of gene extra copies, may represent an adjunct in LSCC patients' prognostication and contribute to identify D-type cyclins as potential targets of newly developed therapies.
Small Molecule Inhibitors of IκB Kinase Are Selectively Toxic for Subgroups of Diffuse Large B-Cell Lymphoma Defined by Gene Expression Profiling
Authors: Lam Lloyd T. , Davis R. Eric , Pierce Jackie , Hepperle Michael , Xu Yajun , Hottelet Maria , Nong Yuhua , Wen Danyi , Adams Julian , Dang Lenny , Staudt Louis M. 
Published: June 2022

Abstract
Constitutive activation of the NF-κB pathway is required for survival of the activated B cell–like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IκB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell–like DLBCL. Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-κB, confirming the effectiveness and specificity of this compound. Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle. To test further the specificity of this toxicity, an inducible form of NF-κB was created by fusing the p65 NF-κB subunit with the ligand-binding domain of the estrogen receptor (p65-ERD). In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-κB target genes. Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-κB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-κB target genes. These studies validate the NF-κB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-κB for survival and proliferation.
Addition of Histamine to Interleukin 2 Treatment Augments Type 1 T-Cell Responses in Patients with Melanoma In vivo: Immunologic Results from a Randomized Clinical Trial of Interleukin 2 with or without Histamine (MP 104)
Authors: Asemissen Anne Marie , Scheibenbogen Carmen , Letsch Anne , Hellstrand Kristoffer , Thorén Fredrik , Gehlsen Kurt , Schmittel Alexander , Thiel Eckhard , Keilholz Ulrich 
Published: June 2022

Abstract
Purpose: Preclinical investigations suggest that histamine dihydrochloride (HDC) protects T cells and natural killer cells from inhibition by monocyte-derived reactive oxygen metabolites and synergizes with interleukin (IL) 2 in inducing T-cell activation. Here, we investigate whether this mechanism is operational in patients with melanoma treated with HDC as an adjunct to IL-2.
Experimental Design: Melanoma patients having liver metastases were treated with IL-2 with or without HDC within a randomized, multicenter, phase III trial. The effect of HDC on type 1 and type 2 T-cell cytokine production was investigated in peripheral blood samples from 19 patients with the use of intracellular cytokine flow cytometry. Melanoma-specific T-cell responses were analyzed in eight HLA-A2–positive patients.
Results: Frequencies of CD3+ T cells producing IFN-γ (type 1 T cells) in response to phorbol myristate acetate/ionomycin increased (median, 1.8-fold) in patients receiving IL-2 plus HDC but not in those receiving IL-2 alone (P &lt; 0.01 for comparison between arms). In contrast, the number of IL-13-producing type 2 T cells that increased in patients after treatment with IL-2 was not modulated by HDC. Melanoma- and tyrosinase-specific IFN-γ and IL-13-producing T cells were detected in two of four HLA-A2–positive patients with melanoma following treatment with HDC + IL-2.
Conclusions: Treatment of patients with stage IV melanoma with HDC in combination with IL-2 increases type 1 T-cell responses and may promote induction of melanoma-specific T cells. These effects are of relevance for tumor immunotherapy and provide a potential mechanism for the clinical efficacy of HDC added to IL-2.
Class III β-Tubulin Overexpression Is a Prominent Mechanism of Paclitaxel Resistance in Ovarian Cancer Patients
Authors: Mozzetti Simona , Ferlini Cristiano , Concolino Paola , Filippetti Flavia , Raspaglio Giuseppina , Prislei Silvia , Gallo Daniela , Martinelli Enrica , Ranelletti Franco Oreste , Ferrandina Gabriella , Scambia Giovanni 
Published: June 2022

Abstract
The vast majority of women with advanced ovarian cancer will ultimately relapse and develop a drug-resistant disease with an overall 5-year survival of &lt;50%. Unfortunately, the mechanisms of drug resistance actually operating in patients are still unknown. To address this issue, in 41 patients affected by advanced ovarian cancer the three main mechanisms of paclitaxel resistance were investigated: overexpression of MDR-1 gene, point mutations at prominently expressed α-tubulin and β-tubulin genes and selective alterations in the expression of β-tubulin isotypes. MDR-1 and the β-tubulin isotypes expression were evaluated by semiquantitative and real-time PCR. On the same specimens, quantitative immunohistochemistry was also done in the tumor area. No statistically significant changes of MDR-1 expression were noticed between the sensitive and resistant patients either at the mRNA or protein level. The tubulin mutations for the ubiquitous α-tubulin and β-tubulin genes were evaluated by automated DNA sequencing, and in all patients, no mutations were detected in both resistant and sensitive cases. With regard to the expression of tubulin isoforms, a statistically significant up-regulation of class III β-tubulin was found in the resistant subset. It is worth noting that this statistically significant increase of the expression of class III β-tubulin was detectable at the mRNA and protein level. By a direct comparison of the three main known mechanisms of paclitaxel resistance, this study indicates that overexpression of class III β-tubulin is the most prominent mechanism of paclitaxel resistance in ovarian cancer.
TAS-108, a Novel Oral Steroidal Antiestrogenic Agent, Is a Pure Antagonist on Estrogen Receptor α and a Partial Agonist on Estrogen Receptor β with Low Uterotrophic Effect
Authors: Yamamoto Yasuji , Shibata Jiro , Yonekura Kazuhiko , Sato Kouji , Hashimoto Akihiro , Aoyagi Yoshimi , Wierzba Konstanty , Yano Shingo , Asao Tetsuji , Buzdar Aman U. , Terada Tadafumi 
Published: June 2022

Abstract
Purpose: Investigators are currently conducting phase II trials on TAS-108, a novel oral steroidal antiestrogenic agent. The purpose of this study is to investigate the molecular and pharmacologic properties of TAS-108 comparedwith other antiestrogenic agents such as tamoxifen,raloxifene, and fulvestrant.
Experimental Design: The antagonistic or agonistic activities of these agents against both estrogen receptors (ER) α and β were compared in the reporter assay systems. Their effects on the uterus were evaluated in ovariectomized rat models. The antitumor activity of TAS-108 given p.o. was evaluated in both dimethylbenzanthracene-induced mammary tumor model and human breast cancer MCF-7 cell line xenografts.
Results: TAS-108 inhibited the transactivation of ERα under the presence of 17β-estradiol (E2) and did not induce the transactivation of ERα in the absence of E2, unlike the agonistic activity of tamoxifen. On the other hand, it exhibited the most agonistic activity on ERβ among the antiestrogenic agents tested. When given p.o. in the ovariectomized rat, TAS-108 showed a much weaker estrogenic effect on utterine weight compared to tamoxifen, or with similar levels of raloxifene, a selective estrogen receptor modulator. Also, TAS-108 strongly inhibited tumor growth in dimethylbenzanthracene-induced mammary carcinomain the rat, the endogenous E2 model, at a dosage of 1 to 3 mg/kg/day. It also inhibited high exogenous E2, inducing tumor growth against MCF-7 xenografts at a dosage of 1 mg/kg/day without any toxic manifestation.
Conclusions: Taken together, p.o. treatment with TAS-108 has a novel mode of action on ERs and inhibits E2-dependent tumor growth with little uterotrophic effect.