bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Micrometastatic Prostate Cancer Cell Spread in Animal Models By 213Bilabeled Multiple Targeted α Radioimmunoconjugates
Authors: Li Yong , Song Emma , Abbas Rizvi Syed M. , Power Carl A. , Beretov Julia , Raja Chand , Cozzi Paul J. , Morgenstern Alfred , Apostolidis Christos , Allen Barry J. , Russell Pamela J. 
Published: February 2009

Abstract
Purpose: To investigate the therapeutic potential of 213Bilabeled multiple targeted α-radioimmunoconjugates for treating prostate cancer (CaP) micrometastases in mouse models.
Experimental Design: PC-3 CaP cells were implanted s.c., in the prostate, and intratibially in NODSCID mice. The expression of multiple tumor–associated antigens on tumor xenografts and micrometastases was detected by immunohistochemistry. Targeting vectors were two monoclonal antibodies, and a plasminogen activator inhibitor type 2 that binds to cell surface urokinase plasminogen activator, labeled with 213Bi using standard methodology. In vivo efficacy of multiple α conjugates (MTAT) at different activities was evaluated in these mouse models. Tumor growth was monitored during observations and local regional lymph node metastases were assessed at the end of experiments.
Results: The take rate of PC-3 cells was 100% for each route of injection. The tumor-associated antigens (MUC1, urokinase plasminogen activator, and BLCA-38) were heterogeneously expressed on primary tumors and metastatic cancer clusters at transit. A single i.p. injection of MTAT (test) at high and low doses caused regression of the growth of primary tumors and prevented local lymph node metastases in a concentration-dependent fashion; it also caused cancer cells to undergo necrosis and apoptosis.
Conclusions: Our results suggest that MTAT can impede primary PC-3 CaP growth at three different sites in vivo through induction of apoptosis, and can prevent the spread of cancer cells and target lymph node micrometastases in a concentration-dependent manner. MTAT, by targeting multiple antigens, can overcome heterogeneous antigen expression to kill small CaP cell clusters, thus providing a potent therapy for micrometastases.
Genetic Variants in TAP Are Associated with High-Grade Cervical Neoplasia
Authors: Einstein Mark H. , Leanza Suzanne , Chiu Lydia G. , Schlecht Nicolas F. , Goldberg Gary L. , Steinberg Bettie M. , Burk Robert D. 
Published: February 2009

Abstract
Purpose: The transporter associated with antigen processing (TAP) is essential in assembling MHC-I proteins. Human papillomavirus (HPV) evades immune recognition by decreasing class I MHC cell surface expression through down-regulation of TAP1 levels. Consistent with heterogeneity in MHC expression is the individual variability in clearing detectable HPV infections. Genetic polymorphisms in TAP genes may affect protein structure, function, and the ability to clear HPV infection.
Experimental Design: Case-control study of women with cervical intraepithelial neoplasia (CIN) II or III (n = 114) and women without high-grade CIN (n = 366). Five nonsynonymous single nucleotide polymorphisms (SNP) in TAP1 and TAP2 were genotyped using DNA collected in cervicovaginal lavage samples using microsphere array technology (Luminex xMAP). HPV typing was done using a PCR-based system with MY09/MY11 primers. TAP1 and TAP2 SNPs were validated by direct sequencing.
Results: Differences in allele distribution between women with high-grade cervical neoplasia and women without was seen for TAP1 I333V (P = 0.02) and TAP1 D637G (P = 0.01). The odds ratios (OR) for CIN III were significantly lower among carriers of the TAP1 I333V polymorphism (OR, 0.28; 95% confidence interval, 0.1-0.8), and TAP1 D637G polymorphism (OR, 0.27; 95% confidence interval, 0.1-0.7). These associations remained significant even after restricting the evaluation to women who were positive for high-risk HPV types.
Conclusions: In addition to the down-regulation of MHC-1 by oncogenic HPV, HPV pathogenesis might be facilitated by polymorphisms in the TAP proteins. Identifying TAP polymorphisms may potentially be used to identify women less susceptible to progression to high-grade CIN and cervical cancer.
Polymerase η mRNA Expression Predicts Survival of Non–Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy
Authors: Ceppi Paolo , Novello Silvia , Cambieri Alberto , Longo Marina , Monica Valentina , Lo Iacono Marco , Giaj-Levra Matteo , Saviozzi Silvia , Volante Marco , Papotti Mauro , Scagliotti Giorgio 
Published: February 2009

Abstract
Purpose: The effect of translesion DNA synthesis system in conferring cellular tolerance to DNA-damaging agents has been recently described. DNA polymerase η (Pol η) is part of this machinery and in vitro models showed that it can overcome DNA damages caused by cisplatin and UV rays. The aim of the present study was to investigate the role of Pol η mRNA expression levels in non–small cell lung cancer (NSCLC).
Experimental Design: Pol η mRNA expression levels were evaluated by real-time PCR in (a) formalin-fixed paraffin-embedded biopsies of 72 NSCLC patients treated with platinum-based chemotherapy, (b) fresh snap-frozen surgical specimens of tumor and corresponding normal lung tissue from 50 consecutive patients not treated with perioperative or postoperative chemotherapy, and (c) five NSCLC cell lines.
Results: High Pol η expression levels were strongly associated with shorter survival at both univariate (6.9 versus 21.1 months; P = 0.003) and multivariate (hazard ratio, 3.18; 95% confidence interval, 1.73-5.84; P = 0.008) analysis in the group of platinum-treated patients. By contrast, Pol η expression was not significantly correlated with the prognosis in surgically resected patients (P = 0.54) and mRNA levels did not significantly differ in tumor versus normal lung (P = 0.82). Moreover, endogenous Pol η mRNA expression was found to be inducible by cisplatin in three of five cell lines and significantly associated with in vitro sensitivity (P = 0.01).
Conclusions: Taken together, these data indicate Pol η as a predictive rather than prognostic marker worth of further investigation in NSCLC patients candidate to platinum-based chemotherapy.
Diffusion-Weighted Magnetic Resonance Imaging for Predicting and Detecting Early Response to Chemoradiation Therapy of Squamous Cell Carcinomas of the Head and Neck
Authors: Kim Sungheon , Loevner Laurie , Quon Harry , Sherman Eric , Weinstein Gregory , Kilger Alex , Poptani Harish 
Published: February 2009

Abstract
Purpose: The aim of this study was to investigate the utility of apparent diffusion coefficient (ADC) for prediction and early detection of treatment response in head and neck squamous cell carcinomas (HNSCC).
Experimental Design: Diffusion-weighted magnetic resonance imaging studies were performed on 40 patients with newly diagnosed HNSCC before, during, and after the end of chemoradiation therapy. Analysis was done on data from 33 patients after exclusion of 7 patients that had incomplete data.
Results: Pretreatment ADC value of complete responders (1.04 ± 0.19 × 10−3 mm2/s) was significantly lower (P &lt; 0.05) than that from partial responders (1.35 ± 0.30 × 10−3 mm2/s). A significant increase in ADC was observed in complete responders within 1 week of treatment (P &lt; 0.01), which remained high until the end of the treatment. The complete responders also showed significantly higher increase in ADC than the partial responders by the first week of chemoradiation (P &lt; 0.01). When pretreatment ADC value was used for predicting treatment response, the area under the receiver operating characteristic curve was 0.80 with a sensitivity of 65% and a specificity of 86%. However, change in ADC within the first week of chemoradiation therapy resulted in an area under the receiver operating characteristic curve of 0.88 with 86% sensitivity and 83% specificity for prediction of treatment response.
Conclusions: These results suggest that ADC can be used as a marker for prediction and early detection of response to concurrent chemoradiation therapy in HNSCC.
Increased Intratumoral FOXP3-positive Regulatory Immune Cells during Interleukin-2 Treatment in Metastatic Renal Cell Carcinoma
Authors: Jensen Hanne Krogh , Donskov Frede , Nordsmark Marianne , Marcussen Niels , von der Maase Hans 
Published: February 2009

Abstract
Purpose: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2–based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown.
Experimental Design: Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2–based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival.
Results: A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P &lt; 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P &lt; 0.05 in all comparisons). All patients achieving high numbers (&gt;180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (&lt;180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells.
Conclusion: Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2–based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.
Nuclear versus Cytoplasmic Localization of Filamin A in Prostate Cancer: Immunohistochemical Correlation with Metastases
Authors: Bedolla Roble G. , Wang Yu , Asuncion Alfredo , Chamie Karim , Siddiqui Salma , Mudryj Maria M. , Prihoda Thomas J. , Siddiqui Javed , Chinnaiyan Arul M. , Mehra Rohit , de Vere White Ralph W. , Ghosh Paramita M. 
Published: February 2009

Abstract
Purpose: We previously showed that nuclear localization of the actin-binding protein, filamin A (FlnA), corresponded to hormone-dependence in prostate cancer. Intact FlnA (280 kDa, cytoplasmic) cleaved to a 90 kDa fragment which translocated to the nucleus in hormone-naïve cells, whereas in hormone-refractory cells, FlnA was phosphorylated, preventing its cleavage and nuclear translocation. We have examined whether FlnA localization determines a propensity to metastasis in advanced androgen-independent prostate cancer.
Experimental Design: We examined, by immunohistochemistry, FlnA localization in paraffin-embedded human prostate tissue representing different stages of progression. Results were correlated with in vitro studies in a cell model of prostate cancer.
Results: Nuclear FlnA was significantly higher in benign prostate (0.6612 ± 0.5888), prostatic intraepithelial neoplasia (PIN; 0.6024 ± 0.4620), and clinically localized cancers (0.69134 ± 0.5686) compared with metastatic prostate cancers (0.3719 ± 0.4992, P = 0.0007). Cytoplasmic FlnA increased from benign prostate (0.0833 ± 0.2677), PIN (0.1409 ± 0.2293), localized cancers (0.3008 ± 0.3762, P = 0.0150), to metastases (0.7632 ± 0.4414, P &lt; 0.00001). Logistic regression of metastatic versus nonmetastatic tissue yielded the area under the receiver operating curve as 0.67 for nuclear-FlnA, 0.79 for cytoplasmic-FlnA, and 0.82 for both, indicating that metastasis correlates with cytoplasmic to nuclear translocation. In vitro studies showed that cytoplasmic localization of FlnA induced cell invasion whereas nuclear translocation of the protein inhibited it. FlnA dephosphorylation with the protein kinase A inhibitor H-89 facilitated FlnA nuclear translocation, resulting in decreased invasiveness and AR transcriptional activity, and induced sensitivity to androgen withdrawal in hormone-refractory cells.
Conclusions: The data presented in this study indicate that in prostate cancer, metastasis correlates with cytoplasmic localization of FlnA and may be prevented by cleavage and subsequent nuclear translocation of this protein.
CAT-8015: A Second-GenerationPseudomonasExotoxin A–Based Immunotherapy Targeting CD22-Expressing Hematologic Malignancies
Authors: Alderson Ralph F. , Kreitman Robert J. , Chen Tianling , Yeung Peter , Herbst Ronald , Fox Judy A. , Pastan Ira 
Published: February 2009

AbstractPurpose: To compare the in vitro and in vivo efficacy of CAT-8015, a second-generation recombinant immunotoxin composed of disulfide-linked affinity matured VH and VL chains of the mouse anti-CD22 monoclonal antibody RFB4 fused to PE38, to the parental compound CAT-3888.Experimental Design: The biological activity of CAT-8015 was examined in vitro using B-cell tumor lines and in vivo in a JD38-based s.c. tumor model in NCr athymic mice. Pharmacokinetics and interspecies scaling of CAT-8015 were evaluated in mice, rats, and cynomolgus monkeys. The potential toxicity of CAT-8015 was assessed in monkeys in a toxicologic study and compared with CAT-3888.Results: The IC50 values of CAT-8015 in vitro using the EHEB, MEC1, Daudi, CA46, and JD38 cell lines ranged from 0.3 to 8.6 ng/mL. Pharmacokinetic studies with CAT-8015 were conducted in mouse, rat, and cynomolgus monkey. The t1/2 was calculated to be 0.42, 0.61, and 0.79 hours and the Vss was 1.37, 5.57, and 140.3 mL in mouse, rat, and monkey, respectively. In vivo, when JD38 tumor-bearing animals were treated with CAT-8015 at doses ≥75 μg/kg at 48-hour intervals for a total of three doses, a rapid reduction in tumor volume and in some cases complete remission in tumor growth was observed. The comparative toxicologic study showed comparable clinical and anatomic pathology changes for CAT-8015 and CAT-3888.Conclusions: CAT-8015 is a CD22-targeting immunotoxin that, in preclinical studies, has greatly improved efficacy compared with CAT-3888.
Targeted Photothermal Ablation of Murine Melanomas with Melanocyte-Stimulating Hormone Analog–Conjugated Hollow Gold Nanospheres
Authors: Lu Wei , Xiong Chiyi , Zhang Guodong , Huang Qian , Zhang Rui , Zhang Jin Z. , Li Chun 
Published: February 2009

AbstractPurpose: To develop melanoma-targeted hollow gold nanospheres (HAuNS) and evaluate their potential utility for selective photothermal ablation in melanoma.Experimental Design: A new class of photothermal coupling agents based on HAuNS was synthesized. HAuNS were stabilized with polyethylene glycol (PEG) coating and attached with α–melanocyte-stimulating hormone (MSH) analog, [Nle4,D-Phe7]α-MSH (NDP-MSH), which is a potent agonist of melanocortin type-1 receptor overexpressed in melanoma. The intracellular uptake of the NDP-MSH–conjugated PEGylated HAuNS (NDP-MSH-PEG-HAuNS) and the distribution of β-arrestin were examined in murine B16/F10 melanoma cells. The biodistribution of NDP-MSH-PEG-HAuNS was assessed at 4 hours post i.v. injection in tumor-bearing nude mice. Photothermal ablation effect of the nanoparticles was evaluated both histologically using excised tissue and functionally by [18F]fluorodeoxyglucose positron emission tomography.Results: NDP-MSH-PEG-HAuNS consist only of a thin gold wall with hollow interior (outer diameter, 43.5 ± 2.3 nm; shell thickness, 3-4 nm), which displays strong and tunable resonance absorption in near-IR region (peak, 808 nm). The nanoparticles were specifically taken up by melanoma cells, which initiated the recruitment of β-arrestins, the adapters to link the activated G-protein–coupled receptors to clathrin, indicating the involvement of receptor-mediated endocytosis. This resulted in enhanced extravasation of NDP-MSH-PEG-HAuNS from tumor blood vessels and their dispersion into tumor matrix compared with nonspecific PEGylated HAuNS. Successful selective photothermal ablation of B16/F10 melanoma with targeted HAuNS was confirmed by histologic and [18F]fluorodeoxyglucose positron emission tomography evaluation at 24 hours post near IR–region laser irradiation at a low-dose energy of 30 J/cm2.Conclusion: NDP-MSH-PEG-HAuNS have the potentials to mediate targeted photothermal ablation of melanoma.
Clinical Significance of Cytokeratin 20-Positive Circulating Tumor Cells Detected by a Refined Immunomagnetic Enrichment Assay in Colorectal Cancer Patients
Authors: Wong Sze Chuen Cesar , Chan Charles Ming Lok , Ma Brigette Buig Yue , Hui Edwin Pun , Ng Simon Siu Man , Lai Paul Bo San , Cheung Moon Tong , Lo Elena Siu Fong , Chan Amanda Kit Ching , Lam Money Yan Yee , Au Thomas Chi Chuen , Chan Anthony Tak Cheung 
Published: February 2009

Abstract
Purpose: Current immunomagnetic enrichment method can only detect general epithelial antigens of circulating tumor cells (CTC). Further characterization of the CTCs to provide specific information on the tumor type is not possible. We attempted to overcome this drawback by developing the methodology for using a gastrointestinal-specific anti-cytokeratin (CK) 20 antibody to detect CTCs in colorectal cancer patients' blood.
Experimental Design: The protocol was validated using a colorectal cancer SW480 cell line. The clinical significance of findings in colorectal cancer was investigated by detecting CK20-positive CTCs (pCTC) in patients with colorectal cancer, other common cancers, colorectal adenoma, benign colorectal diseases, and normal subjects. Moreover, the malignant nature of CK20 pCTCs was examined by comparing chromosome 17 aberration patterns with those from the corresponding primary tumors.
Results: The assay successfully showed CK20-positive SW480 cells. When applied in patient samples, the detection rates were 62% (132 colorectal cancer patients; median number = 11 CTCs), 0% (120 patients with other common cancers), 6% (50 colorectal adenoma patients), 0% (120 patients with benign colorectal diseases), and 0% (40 normal subjects). Furthermore, statistical analysis showed that CK20 pCTC numbers were associated with tumor-node-metastasis stage and lymph node status. Using the median CK20 pCTC numbers as the cutoff points, stratified groups of colorectal cancer patients had significant differences in their recurrence, metastasis, and survival. Finally, chromosome 17 aneusomy in 90% of colorectal cancer patients with CK20 pCTCs matched with those from the primary tumors.
Conclusions: Detection of CK20 pCTCs using the new protocol could generate clinically important information for colorectal cancer patients.
Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma
Authors: Gao Qiang , Wang Xiao-Ying , Qiu Shuang-Jian , Yamato Ichiro , Sho Masayuki , Nakajima Yoshiyuki , Zhou Jian , Li Bai-Zhou , Shi Ying-Hong , Xiao Yong-Sheng , Xu Yang , Fan Jia 
Published: February 2009

AbstractPurpose: The aberrant expression of programmed cell death 1 ligands 1 and 2 (PD-Ls) on tumor cells dampens antitumor immunity, resulting in tumor immune evasion. In this study, we investigated the expression of PD-Ls in human hepatocellular carcinoma (HCC) to define their prognostic significance after curative surgery.Experimental Design: Immunohistochemistry was used to investigate PD-Ls expression as well as granzyme B+ cytotoxic and FoxP3+ regulatory T cell infiltration on tissue microarrays containing 240 randomly selected HCC patients who underwent surgery. The results were further verified in an independent cohort of 125 HCC patients. PD-Ls expression on HCC cell lines was detected by Western blot assay.Results: Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-L2 also had a poorer survival, the difference in recurrence was not statistically significant. Multivariate analysis identified tumor expression of PD-L1 as an independent predictor for postoperative recurrence. No correlation was found between PD-Ls expression and granzyme B+ lymphocyte infiltration, whereas a significant positive correlation was detected between PD-Ls expression and FoxP3+ lymphocyte infiltration. In addition, tumor-infiltrating cytotoxic and regulatory T cells were also independent prognosticators for both survival and recurrence. The prognostic value of PD-L1 expression was validated in the independent data set.Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of recurrence for HCC patients and provide the rationale for developing a novel therapy of targeting the PD-L1/PD-1 pathway against this fatal malignancy.
The Prognostic Value of TP53 Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and Chemorefractoriness
Authors: Rossi Davide , Cerri Michaela , Deambrogi Clara , Sozzi Elisa , Cresta Stefania , Rasi Silvia , De Paoli Lorenzo , Spina Valeria , Gattei Valter , Capello Daniela , Forconi Francesco , Lauria Francesco , Gaidano Gianluca 
Published: February 2009

Abstract
Purpose: Del17p13 predicts poor outcome and chemorefractoriness in chronic lymphocytic leukemia (CLL). Conversely, it is unknown whether TP53 mutations carry any prognostic value independent of del17p13. We tested the independent prognostic value of TP53 mutations in CLL.
Experimental Design: The study was based on a consecutive series of 308 CLL. DNA sequencing of TP53 exons 2 to 10 and del17p13 interphase fluorescence in situ hybridization were done at CLL diagnosis. Study end points were survival and chemorefractoriness.
Results: At diagnosis, TP53 mutations (n = 32) occurred in 31 of 308 (10.0%) patients. Of all CLL showing TP53 disruption by either mutation and/or deletion (n = 44), 10 cases (22.7%) showed TP53 mutations in the absence of del17p13. Multivariate analysis selected TP53 mutations (hazard ratio, 3.20; P = 0.002) as an independent predictor of overall survival after adjustment for del17p13. Also, multivariate analysis selected TP53 mutations (hazard ratio, 3.97; P &lt; 0.001) as an independent predictor of chemorefractoriness after adjustment for del17p13. Compared with cases without TP53 alterations, CLL harboring any type of TP53 disruption (mutation only, del17p13 only, or both mutation and del17p13) uniformly displayed a high prevalence of unfavorable prognosticators and poor outcome. Analysis of sequential CLL samples showed the acquisition of new or additional TP53 alterations at the time of chemorefractoriness.
Conclusions: These data show that (a) TP53 mutations are an independent predictor of short survival and chemorefractoriness, and (b) that CLL presenting with TP53 mutations without del17p13 fare as poorly as CLL carrying del17p13. Because CLL harboring TP53 mutations without del17p13 are currently not recognized by conventional diagnostic strategies, these results may be relevant for a comprehensive prognostic characterization of CLL.