bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical Characterization of SGN-70, a Humanized Antibody Directed against CD70
Authors: McEarchern Julie A. , Smith Leia M. , McDonagh Charlotte F. , Klussman Kerry , Gordon Kristine A. , Morris-Tilden Carol A. , Duniho Steven , Ryan Maureen , Boursalian Tamar E. , Carter Paul J. , Grewal Iqbal S. , Law Che-Leung
Published: December 2008

Purpose: CD70 (CD27L) is a member of the tumor necrosis factor family aberrantly expressed on a number of hematologic malignancies and some carcinomas. CD70 expression on malignant cells coupled with its highly restricted expression on normal cells makes CD70 an attractive target for monoclonal antibody (mAb)–based therapies. We developed a humanized anti-CD70 antibody, SGN-70, and herein describe the antitumor activities of this mAb.

Experimental Design: CD70 expression on primary tumors was evaluated by immunohistochemical staining of Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and renal cell carcinoma tissue microarrays. The CD70-binding and cytotoxic activities of SGN-70 were tested in vitro using a number of cell-based assays. The in vivo antitumor properties of SGN-70 were tested in severe combined immunodeficient mice bearing disseminated lymphoma and multiple myeloma xenografts. Mechanism-of-action studies were conducted using SGN-70v, a variant mAb with equivalent target-binding activity but impaired Fcγ receptor binding compared with SGN-70.

Results: Immunohistochemical analysis identified CD70 expression on ∼40% of multiple myeloma isolates and confirmed CD70 expression on a high percentage of Hodgkin lymphoma Reed-Sternberg cells, non-Hodgkin lymphoma, and renal cell carcinoma tumors. SGN-70 lysed CD70+ tumor cells via Fc-dependent functions, including antibody-dependent cellular cytotoxicity and phagocytosis and complement fixation. In vivo, SGN-70 treatment significantly decreased tumor burden and prolonged survival of tumor-bearing mice.

Conclusions: SGN-70 is a novel humanized IgG1 mAb undergoing clinical development for the treatment of CD70+ cancers. SGN-70 possesses Fc-dependent antibody effector functions and mediates antitumor activity in vivo.
Analysis of Gene Expression in Early-Stage Ovarian Cancer
Authors: Marchini Sergio , Mariani Pietro , Chiorino Giovanna , Marrazzo Eleonora , Bonomi Riccardo , Fruscio Robert , Clivio Luca , Garbi Annalisa , Torri Valter , Cinquini Michela , Dell'Anna Tiziana , Apolone Giovanni , Broggini Massimo , D'Incalci Maurizio
Published: December 2008

Purpose: Gene expression profile was analyzed in 68 stage I and 15 borderline ovarian cancers to determine if different clinical features of stage I ovarian cancer such as histotype, grade, and survival are related to differential gene expression.

Experimental Design: Tumors were obtained directly at surgery and immediately frozen in liquid nitrogen until analysis. Glass arrays containing 16,000 genes were used in a dual-color assay labeling protocol.

Results: Unsupervised analysis identified eight major patient partitions, one of which was statistically associated to overall survival, grading, and histotype and another with grading and histotype. Supervised analysis allowed detection of gene profiles clearly associated to histotype or to degree of differentiation. No difference was found between borderline and grade 1 tumors. As to recurrence, a subset of genes able to differentiate relapsers from nonrelapsers was identified. Among these, cyclin E and minichromosome maintenance protein 5 were found particularly relevant, as their expression was inversely correlated to progression-free survival (P = 0.00033 and 0.017, respectively).

Conclusions: Specific molecular signatures define different histotypes and prognosis of stage I ovarian cancer. Mucinous and clear cells histotypes can be distinguished from the others regardless of tumor grade. Cyclin E and minichromosome maintenance protein 5, whose expression was found previously to be related to a bad prognosis of advanced ovarian cancer, appear to be potential prognostic markers in stage I ovarian cancer too, independent of other pathologic and clinical variables.
Elevated Phospho-S6 Expression Is Associated with Metastasis in Adenocarcinoma of the Lung
Authors: McDonald J. Matthew , Pelloski Christopher E. , Ledoux Alicia , Sun Menghong , Raso Gabriela , Komaki Ritsuko , Wistuba Ignacio I. , Bekele B. Nebiyou , Aldape Ken
Published: December 2008

Purpose: The primary objective of this study was to determine whether markers of differentiation and activation of the Akt pathway are associated with metastasis in adenocarcinoma of the lung.

Experimental Design: Paired primary and metastatic tumor samples were obtained from 41 patients who had undergone resection of both primary lung adenocarcinoma and brain metastatic lesions. Paired samples were compared for relative expression of thyroid transcription factor 1 (TTF-1) and E-cadherin as potential markers of differentiation. Activation of the Akt pathway was assessed by expression of p-Akt and p-S6. Biomarkers that showed relative discordance in expression between the matched pairs were then assessed in a cohort of 77 primary lung adenocarcinomas. Validation was done in an independent cohort of 82 primary lung adenocarcinomas.

Results: Among the 41 matched pairs, E-cadherin (23 discordant pairs) and TTF-1 (18 discordant pairs) were overexpressed in primary tumors (20 of 23 and 15 of 18, respectively). In contrast, p-S6 overexpression was significantly associated with metastatic tumors (20 of 21 discordant pairs). The expression of E-cadherin, p-S6, and TTF-1 was evaluated in 77 primary lung adenocarcinomas, in which high p-S6 expression was associated with shorter time to metastasis. The association of p-S6 with metastasis was then validated in an independent set of 82 tumors. In multivariable analysis, p-S6 expression was a negative independent predictor of metastasis-free survival after adjustment for tumor stage.

Conclusions: The biomarker p-S6 is overexpressed in metastatic tumors. In primary tumors, higher p-S6 expression is associated with shorter metastatic-free survival. This biomarker has the potential for risk stratification in future clinical trials.
Cooperation of the Agonistic DR5 Antibody Apomab with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival
Authors: Jin Hongkui , Yang Renhui , Ross Jed , Fong Sharon , Carano Richard , Totpal Klara , Lawrence David , Zheng Zhong , Koeppen Hartmut , Stern Howard , Schwall Ralph , Ashkenazi Avi
Published: December 2008

Purpose: Apomab is a fully human monoclonal antibody that induces programmed cell death through the proapoptotic receptor DR5 in various cancer cells but not in normal cells. Several lung cancer cell lines express DR5 and exhibit apoptosis in response to apomab in vitro.

Experimental Design: We investigated the efficacy of apomab and its interaction with chemotherapy in xenograft models based on human NCI-H460 non–small-cell lung carcinoma cells. In an established model of s.c. tumor xenografts, apomab or Taxol plus carboplatin chemotherapy delayed tumor progression, whereas combined treatment caused tumor regression and a substantially longer growth delay. To test apomab activity in a setting that may more closely mimic lung cancer pathology in patients, we developed a lung orthotopic model.

Results: In this model, microcomputed tomography imaging showed that apomab, chemotherapy, or combination treatment significantly inhibited tumor growth compared with vehicle, whereas the combination caused greater inhibition in tumor growth relative to chemotherapy or apomab. Similarly, histologic analysis revealed that apomab, chemotherapy, or the combination significantly reduced tumor size compared with vehicle, whereas the combination induced significantly greater reduction in tumor size than did chemotherapy or apomab. Furthermore, combined treatment improved 105-day survival relative to vehicle (P = 0.0023) as well as to apomab (P = 0.0445) or chemotherapy (P = 0.0415).

Conclusion: These results show a positive interaction of apomab with chemotherapy, evidenced by significant inhibition of tumor growth as well as improved survival, thus supporting further investigation of this therapeutic approach in lung cancer patients.
Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors
Authors: Ricart Alejandro D. , Berlin Jordan D. , Papadopoulos Kyriakos P. , Syed Samira , Drolet Daniel W. , Quaratino-Baker Charlotte , Horan Julie , Chick Jon , Vermeulen Wendy , Tolcher Anthony W. , Rowinsky Eric K. , Rothenberg Mace L.
Published: December 2008

Purpose: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors.

Experimental Design: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated.

Results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity.

Conclusions: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.
High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer
Authors: Hayashi Mikiko , Inokuchi Mikito , Takagi Yoko , Yamada Hiroyuki , Kojima Kazuyuki , Kumagai Jiro , Kawano Tatsuyuki , Sugihara Kenichi
Published: December 2008

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers.

Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival.

Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048).

Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.
Single Nucleotide Polymorphisms of microRNA Machinery Genes Modify the Risk of Renal Cell Carcinoma
Authors: Horikawa Yohei , Wood Christopher G. , Yang Hushan , Zhao Hua , Ye Yuanqing , Gu Jian , Lin Jie , Habuchi Tomonori , Wu Xifeng
Published: December 2008

Purpose: MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of basic cellular functions through posttranscriptional regulations on their target genes. Compelling evidence has shown that miRNAs are involved in cancer initiation and progression. We hypothesized that genetic variations of the miRNA machinery genes could be associated with the risk of renal cell carcinoma.

Experimental Design: We genotyped 40 single nucleotide polymorphisms (SNP) from 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes in 279 Caucasian patients with renal cell carcinoma and 278 matched controls.

Results: We found that two SNPs in the GEMIN4 gene were significantly associated with altered renal cell carcinoma risks. The variant-containing genotypes of Asn929Asp and Cys1033Arg exhibited significantly reduced risks, with odds ratios (OR) of 0.67 [95% confidence interval (95% CI), 0.47-0.96] and 0.68 (95% CI, 0.47-0.98), respectively. Haplotype analysis showed that a common haplotype of GEMIN4 was associated with a significant reduction in the risk of renal cell carcinoma (OR, 0.66; 95% CI, 0.45-0.97). We also conducted a combined unfavorable genotype analysis including five promising SNPs showing at least a borderline significant risk association. Compared with the low-risk reference group with one unfavorable genotype, the median-risk and high-risk groups exhibited a 1.55-fold (95% CI, 0.96-2.50) and a 2.49-fold (95% CI, 1.58-3.91) increased risk of renal cell carcinoma, respectively (P for trend < 0.001).

Conclusions: Our results suggested that genetic polymorphisms of the miRNA-machinery genes may affect renal cell carcinoma susceptibility individually and jointly.
Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors
Authors: Plummer Ruth , Jones Christopher , Middleton Mark , Wilson Richard , Evans Jeffrey , Olsen Anna , Curtin Nicola , Boddy Alan , McHugh Peter , Newell David , Harris Adrian , Johnson Patrick , Steinfeldt Heidi , Dewji Raz , Wang Diane , Robson Lesley , Calvert Hilary
Published: December 2008

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.

Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.

Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.

Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.
Heat Shock Protein 90 Overexpression Independently Predicts Inferior Disease-Free Survival with Differential Expression of the α and β Isoforms in Gastrointestinal Stromal Tumors
Authors: Li Chien-Feng , Huang Wen-Wei , Wu Jing-Mei , Yu Shih-Chen , Hu Tsung-Hui , Uen Yih-Huei , Tian Yu-Fang , Lin Ching-Nan , Lu David , Fang Fu-Min , Huang Hsuan-Ying
Published: December 2008

Purpose: Most gastrointestinal stromal tumors harbor a mutated KIT or PDGFRA receptor tyrosine kinase (RTK). Heat shock protein 90 (Hsp90) is a chaperone mediating the folding and stabilization of many oncoproteins, including KIT. An Hsp90 inhibitor, 17-AAG, can attenuate KIT activation and proliferation of gastrointestinal stromal tumor cell lines. We further evaluated Hsp90 immunoexpression and the difference between α and β isoforms in gastrointestinal stromal tumor specimens.

Experimental Design: Hsp90 immunostain was assessable in 306 cases on tissue microarrays of primary gastrointestinal stromal tumors and correlated with various variables and disease-free survival (DFS). RTK mutation variants, confirmed in 142 cases by sequencing with or without precedent denaturing high pressure liquid chromatography screening, were dichotomized into two prognostically different groups. Differential expression of transcript and protein isoforms was measured by real-time reverse transcription-PCR and Western blotting in 16 and 6 cases, respectively.

Results: Hsp90 overexpression (55%) significantly correlated with larger size, nongastric location, higher mitotic count and NIH risk level, Ki-67 overexpression (all P ≤ 0.001), and unfavorable RTK genotypes (P = 0.020). It strongly portended inferior DFS univariately (P < 0.0001) and remained independent in multivariate analysis (P = 0.031; risk ratio, 2.44), along with high-risk category, Ki-67 overexpression, and old age. For both mRNA and protein, Hsp90β was more abundant than Hsp90α, whereas the latter was significantly higher in high-risk cases.

Conclusions: Hsp90 overexpression represents a poor prognosticator that correlates with several adverse parameters, highlighting its role in disease progression and alternative therapy for high-risk, imatinib-resistant gastrointestinal stromal tumors. Hsp90α seems more relevant to the intrinsic aggressiveness of gastrointestinal stromal tumors, albeit less abundant than Hsp90β.
Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients
Authors: Fleischmann Achim , Schlomm Thorsten , Huland Hartwig , Köllermann Jens , Simon Philipp , Mirlacher Martina , Salomon Georg , Chun Felix H.K. , Steuber Thomas , Simon Ronald , Sauter Guido , Graefen Markus , Erbersdobler Andreas
Published: December 2008

Purpose: Neutral endopeptidase (CD10), an ectopeptidase bound to the cell surface, is thought to be a potential prognostic marker for prostate cancer.

Experimental Design: Prostate cancer patients (N = 3,261) treated by radical prostatectomy at a single institution were evaluated by using tissue microarray. Follow-up data were available for 2,385 patients. The cellular domain (membranous, membranous-cytoplasmatic, and cytoplasmatic only) of CD10 expression was analyzed immunohistochemically and correlated with various clinical and histopathologic features of the tumors.

Results: CD10 expression was detected in 62.2% of cancer samples and occurred preferentially in higher Gleason pattern (P < 0.0001). CD10 expression positively correlated with adverse tumor features such as elevated preoperative prostate-specific antigen (PSA), higher Gleason score, and advanced stage (P < 0.0001 each). Survival analyses showed that PSA recurrence was significantly associated with the staining pattern of CD10 expression. Outcome significantly declined from negative over membranous, membranous-cytoplasmatic, to exclusively cytoplasmatic CD10 expression (P < 0.0001). In multivariate analysis, CD10 expression was an independent predictor for PSA failure (P = 0.0343).

Conclusions: CD10 expression is an unfavorable independent risk factor in prostate cancer. The subcellular location of CD10 protein is associated with specific clinical courses, suggesting an effect on different important biological properties of prostate cancer cells. The frequent expression of CD10 in prostate cancer and the strong association of CD10 with unfavorable tumor features may qualify this biomarker for targeted therapies.
Ascites Specific Inhibition of CD1d-Mediated Activation of Natural Killer T Cells
Authors: Webb Tonya J. , Giuntoli Robert L. , Rogers Ophelia , Schneck Jonathan , Oelke Mathias
Published: December 2008

Purpose: Natural killer T (NKT) cells recognize lipid antigen presented by CD1 molecules. NKT cells can both directly, through cytotoxicity, and indirectly, through activation of other effector cells, mediate antitumor immunity. It has been shown, however, that tumor-associated lipids are frequently shed into the tumor microenvironment, which can mediate immunosuppressive activity. Given that ovarian cancer–associated ascites has been reported to have increased levels of gangliosides, we examined the effect of tumor-associated and other ascites on CD1d-mediated antigen presentation to NKT cells.

Experimental Design: To investigate the effects of ascites on NKT cell activation, we pretreated CD1d-expressing cells with the ascites and measured their ability to stimulate cytokine production in NKT cells. To determine whether antigen processing or editing was necessary, CD1d-immunoglobulin–based artificial antigen presenting cells (aAPC) were also incubated with ascites. In addition, to examine specificity, we analyzed whether ascites fluid could influence the activation of classic CD8+ T cells.

Results: Pretreatment of CD1d-expressing cells with ascites from the majority of patients inhibited the ability of the cells to stimulate/activate NKT cells in a dose-dependent manner. Ascites treatment also partially blocked the ability of α-galactosylceramide–loaded CD1d-immunoglobulin–based aAPC to activate NKT cells. In addition, our data show that treatment with ascites does not inhibit HLA-A2–mediated activation of classic CD8+ T cells.

Conclusions: Together, these data suggest that ovarian and other cancers may have developed immune evasion mechanisms specifically targeting the CD1/NKT cell system.
Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development
Authors: Sahin Ugur , Koslowski Michael , Dhaene Karl , Usener Dirk , Brandenburg Gunda , Seitz Gerhard , Huber Christoph , Türeci Özlem
Published: December 2008

Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer.

Experimental Design: We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage–specific cell surface molecules and to validate them as therapeutic antibody targets.

Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP–responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells.

Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.
Perilobar Nephrogenic Rests Are Nonobligate Molecular Genetic Precursor Lesions of Insulin-Like Growth Factor-II-Associated Wilms Tumors
Authors: Vuononvirta Raisa , Sebire Neil J. , Dallosso Anthony R. , Reis-Filho Jorge S. , Williams Richard D. , Mackay Alan , Fenwick Kerry , Grigoriadis Anita , Ashworth Alan , Pritchard-Jones Kathy , Brown Keith W. , Vujanic Gordan M. , Jones Chris
Published: December 2008

Purpose: Perilobar nephrogenic rests (PLNRs) are abnormally persistent foci of embryonal immature blastema that have been associated with dysregulation at the 11p15 locus by genetic/epigenetic means and are thought to be precursor lesions of Wilms tumor. The precise genomic events are, however, largely unknown.

Experimental Design: We used array comparative genomic hybridization to analyze a series of 50 PLNRs and 25 corresponding Wilms tumors characterized for 11p15 genetic/epigenetic alterations and insulin-like growth factor-II expression.

Results: The genomic profiles of PLNRs could be subdivided into three categories: those with no copy number changes (22 of 50, 44%); those with single, whole chromosome alterations (8 of 50, 16%); and those with multiple gains/losses (20 of 50, 40%). The most frequent aberrations included 1p- (7 of 50, 14%) +18 (6 of 50, 12%), +13 (5 of 50, 10%), and +12 (3 of 50, 6%). For the majority (19 of 25, 76%) of cases, the rest harbored a subset of the copy number changes in the associated Wilms tumor. We identified a temporal order of genomic changes, which occur during the insulin-like growth factor-II/PLNR pathway of Wilms tumorigenesis, with large-scale chromosomal alterations such as 1p-, +12, +13, and +18 regarded as “early” events. In some of the cases (24%), the PLNRs harbored large-scale copy number changes not observed in the concurrent Wilms tumor, including +10p, +14q, and +18.

Conclusions: These data suggest that although the evidence for PLNRs as precursors is compelling, not all lesions must necessarily undergo malignant transformation.
Chemokine Markers Predict Biochemical Recurrence of Prostate Cancer following Prostatectomy
Authors: Blum David L. , Koyama Tatsuki , M'Koma Amosy E. , Iturregui Juan M. , Martinez-Ferrer Magaly , Uwamariya Consolate , Smith Joseph A. , Clark Peter E. , Bhowmick Neil A.
Published: December 2008

Purpose: Stratifying patients who have a high risk of prostate cancer recurrence following prostatectomy can potentiate the use of adjuvant therapy at an early stage. Inflammation has emerged as a mediator of prostate cancer metastatic progression. We hypothesized that chemokines can be biomarkers for distinguishing patients with high risk for biochemical recurrence of prostate cancer.

Experimental Design: In a nested case-control study, 82 subjects developed biochemical recurrence within 5 years of prostatectomy. Prostate tissues from 98 age-matched subjects who were recurrence-free following prostatectomy in the same period were the controls. A high-throughput lectin-based enrichment of prostate tissue enabled multiplex ELISA to identify the expression of three chemokines to discriminate the two patient populations.

Results: The expression of CX3CL1 and IL-15 in prostate tissue was associated with 5-year biochemical recurrence-free survival following prostatectomy. However, the expression of chemokine ligand 4 (CCL4) was associated with biochemical recurrence. Multivariable logistic regression model combining preoperative prostate-specific antigen, Gleason score, surgical margin, and seminal vesicle status with the three chemokines doubled the specificity of prediction at 90% sensitivity compared with use of the clinicopathologic variables alone (P < 0.0001). Survival analysis yielded a nomogram that supported the use of CX3CL1, IL-15, and CCL4 in predicting 1-, 3-, and 5-year recurrence-free survival after prostatectomy.

Conclusions: Each of the three chemokines can serve as independent predictors of biochemical recurrence. However, the combination of chemokine biomarkers plus clinicopathologic variables discriminated prostatectomy subjects for the probability of biochemical recurrence significantly better than clinicopathologic variables alone.
Role of Intestinal Mucins in Innate Host Defense Mechanisms against Pathogens
Authors: Dharmani Poonam , Srivastava Vikas , Kissoon-Singh Vanessa , Chadee Kris
Published: December 2008

Gastrointestinal mucins produced by goblet cells comprise the main structural components of the mucus layer. Mucins play a critical role in the maintenance of mucosal homeostasis and are responsible for the differential effector and regulatory responses against a plethora of microorganisms, including commensals and pathogens. In this review, we present a comprehensive overview on mucin biology, its properties, classification and gene assembly. We also consider the structure of the mucin gene, its proteins and its role in innate host defenses. We compare the various mucin secretagogues and the differential regulatory pathways involved in mucin biosynthesis and secretion during normal and diverse pathogenic conditions. Finally, we summarize the putative uncharted aspects of mucin-derived innate host defenses, whose exploration will help drug developers to identify factors that can strengthen mucosal integrity and will facilitate basic science research into curative treatments for gastrointestinal diseases.
Engaging the Public on Biobanks: Outcomes of the BC Biobank Deliberation
Authors: O’Doherty K.C. , Burgess M.M.
Published: December 2008

In April 2007, a research team led by M. Burgess conducted a public engagement, the BC Biobank Deliberation, focused on the issue of biobanks. The project was motivated by an observation that current policy approaches to social and ethical issues surrounding biobanks manifest certain democratic deficits. The public engagement was informed by political theory on deliberative democracy with the aim of informing biobanking policies, in particular in British Columbia (BC), Canada. The purpose of this paper is to provide a comprehensive outline of the conclusions reached by the deliberants (both recommendations based on consensus and issues that emerged as persistent disagreements). However, the process whereby the specific conclusions to be delivered to policy makers are identified is not a self-evident process. We thus provide a critical analysis of how the results of a public engagement such as the BC Biobank Deliberation can be conceptualized given the context of a large qualitative data set and an imperative to provide useful information to policy makers, while honoring the mandate under which deliberants were recruited. In particular, we make the case for distinguishing between deliberative outputs of public engagement and analytical outputs that are the product of social scientific analyses of such engagements.
Gene Expression Profiles in Murine Influenza Pneumonia
Authors: Dessing Mark C. , van der Sluijs Koenraad F. , Spek C. Arnold , van der Poll Tom
Published: December 2008

Background: Many in vitro studies have focused on gene expression in influenza-infected leukocytes, lung tissue or cell lines. However, knowledge of in vivo gene expression in these compartments is limited. Methods: To obtain insight into gene expression profiles during influenza infection, we determined the expression of multiple genes by using a newly developed mouse-specific multiplex ligation-dependent probe amplification assay. Results: The genes involved in inflammation, Toll-like receptor signaling, coagulation, fibrinolysis, cell adhesion, tissue repair and homeostasis were measured in lung tissue, leukocytes in bronchoalveolar lavage fluid and tracheal epithelial cells in mice, before and after intranasal infection with influenza A. Most of the genes investigated were differentially expressed during the course of infection and returned to baseline levels when mice had recovered from the infection. However, expression of several genes remained altered even though mice had completely cleared the virus. Conclusion: These data provide the first information on compartmentalized gene expression profiles in the respiratory tract during influenza.
Host Defence Peptide LL-37 Induces IL-6 Expression in Human Bronchial Epithelial Cells by Activation of the NF-κB Signaling Pathway
Authors: Pistolic Jelena , Cosseau Celine , Li Yuexin , Yu Jie (Jessie) , Filewod Niall C.J. , Gellatly Shaan , Rehaume Linda M. , Bowdish Dawn M.E. , Hancock Robert E.W.
Published: December 2008

LL-37, the only member of the cathelicidin family of cationic host defence peptides in humans, has been shown to mediate multiple immunomodulatory effects and as such is thought to be an important component of innate immune responses. A growing body of evidence indicates that LL-37 affects lung mucosal responses to pathogens through altered regulation of cell migration, proliferation, wound healing and cell apoptosis. These functions are consistent with LL-37 playing a role in regulating lung epithelial inflammatory responses; however, that role has not been clearly defined. In this report we have demonstrated that host defence peptide LL-37 induced cytokine (IL-6) and chemokine (CXCL-1/GRO-α and CXCL-8/IL-8) release from human bronchial epithelial cells. It was demonstrated that LL-37-mediated IL-6 release was time and dose dependent and that LL-37 up-regulated this pleiotropic cytokine at the transcriptional level. Using specific inhibitors it was shown that NF-κB signaling led to the LL-37-stimulated production of IL-6. LL-37 stimulation of airway epithelial cells activated NF-κB signaling, as demonstrated by the phosphorylation and degradation of Iκ-Bα, and consequent nuclear translocation of p65 and p50 NF-κB subunits. Furthermore this host defence peptide augmented flagellin-mediated cytokine production, indicating that LL-37 likely modulates Toll-like receptor 5-mediated responses.
Alfons Maria Jakob (1884–1931), Neuropathologist par Excellence
Authors: Triarhou Lazaros C.
Published: December 2008

The study briefly reviews the life and work of Alfons Maria Jakob (1884–1931), a notable representative of pre-war German neuropathology. Today Jakob is mainly remembered by neurologists for the spongiform encephalopathy with progressive dementia and spasticity that he, and Kiel neuropathologist Hans Gerhard Creutzfeldt (1885–1964), described independently. However, Jakob has left additional contributions to neuroanatomy, neuropathology and neuropsychiatry in the form of original articles and valuable monographs.
Deep Brain Stimulation of Two Unconventional Targets in Refractory Non-Resectable Epilepsy
Authors: Franzini Angelo , Messina Giuseppe , Marras Carlo , Villani Flavio , Cordella Roberto , Broggi Giovanni
Published: December 2008

Introduction: Several deep brain targets have been assessed for the treatment of unresectable refractory epileptic conditions. Adrian Upton in 1985 proposed deep brain stimulation (DBS) of the anterior nucleus of the thalamus for the treatment of seizures and psychosis [Cooper I.S., Upton A.R.: Biol Psychiatry 1985;20:811–813]. Francisco Velasco, in 1987, introduced DBS of the thalamic centromedian nucleus, proposing its employment for Lennox-Gastaut syndrome and for multifocal epilepsy. Other proposed targets are the subthalamic nucleus, caudate nucleus, Forel fields and mammillothalamic tract. We employed DBS for stimulating 2 ‘unconventional targets’, the posterior hypothalamus (pHyp) and caudal zona incerta (CZi), for the treatment of 2 patients with multifocal epilepsy and behavioural comorbidity, and 2 patients with sensorimotor focal seizures, respectively. Such patients did not meet criteria for resective surgery. Material and Methods: In our institution, between January 2003 and May 2004, we started DBS in 2 epileptic patients The former patient was affected by multifocal epilepsy, and the second one by refractory partial motor and secondary generalized seizures. The chosen targets were the pHyp in the former case and the CZi in the latter. The encouraging results obtained led us to replicate such a favourable experience in 2 more patients, 1 with focal motor epilepsy once again (resulting in status epilepticus) and the other with behavioural comorbidity and multifocal epilepsy. Results: A significant reduction in seizure frequency was observed, and the 2 patients with behavioural comorbidity also showed a dramatic improvement in their disruptive behaviour. The patient with motor focal seizures showed a 70% reduction in seizure frequency, and in the last patient remission from status epilepticus was obtained. Conclusion: Our data confirm DBSof deep brain structures modulates the functional activity of the cerebral cortex as suggested by Adrian Upton in 1985. In the reported series, deep-brain stimulation of 2 unconventional targets belonging to the reticulo-cortical system (the brainstem-diencephalon functional system including structures that act as remote controls in modulating cortical excitability) was found to be effective in controlling otherwise refractory multifocal (pHyp) and focal sensorimotor (CZi) epilepsy when resective surgery was not feasible.
Ciliated Hepatic Foregut Cyst with Obstructive Jaundice
Authors: Kiyochi Hidenori , Okada Kenzo , Iwakawa Kazuhide , Nakanishi Mamoru , Satoh Hajime , Iimori Shunsuke , Miyoshi Maiko , Yamamoto Koji , Kotegawa Hiroshi , Takai Akihiro , Kajiwara Shinsuke
Published: December 2008

Ciliated hepatic foregut cysts (CHFCs) are rare congenital cystic lesion that are most often solitary, unilocular, and located in the subcapsular region of the medial segment of the left hepatic lobe. The mucoid fluid contents affect imaging studies and often make definitive diagnosis difficult. CHFCs are usually asymptomatic and found incidentally. We report a 69-year-old female patient with a CHFC causing obstructive jaundice, which was difficult to differentiate from a biliary cystic neoplasm. A well-defined cystic lesion measuring 25 mm in diameter was located in the porta hepatis region. The lesion was densely adherent to the left and right hepatic ducts, riding on the bifurcation, and the common hepatic duct was extrinsically compressed. An extended left hepatectomy was performed. A diagnosis of CHFC was made on the basis of typical histological findings. CHFC should be included in the differential diagnosis for cystic lesions of the liver.
Geographical Clustering of Amyotrophic Lateral Sclerosis in South-East England: A Population Study
Authors: Scott Kirsten M. , Abhinav Kumar , Stanton Biba R. , Johnston Clare , Turner Martin R. , Ampong Mary-Ann , Sakel Mohamed , Orrell Richard W. , Howard Robin , Shaw Christopher E. , Leigh P. Nigel , Al-Chalabi Ammar
Published: December 2008

Background: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that causes progressive paralysis and eventually results in death from respiratory failure. Environmental factors that trigger ALS might result in a pattern of geographical clustering of cases. We tested this hypothesis using the South-East England ALS population register, which covers south-east London, Kent and parts of neighbouring counties. Methods: The register’s catchment area was divided into postcode districts and sectors. The expected rates of ALS (adjusted for age and sex) were compared with the observed rates using a standardised residuals method and the SaTScan programme. Results: There were 406 cases of ALS identified in the catchment area during the study period. Four of the 126 postcode districts, all in Greater London, had residuals >2.5 SDs from the mean. Similarly, there were 15 postcode sectors (out of 420) that had residuals >1.96 SDs from the mean. Nine of these were in Greater London. SaTScan identified an area that had a 5.61-km radius in which the relative risk of ALS was 1.70 (p = 0.012). This area overlapped with the postcode districts and some of the sectors identified using the residuals method. Conclusions: These findings suggest an excess of ALS cases in some postcode districts in south-east England.
The Prevalence of Hereditary Spastic Paraplegia and the Occurrence of SPG4 Mutations in Estonia
Authors: Braschinsky Mark , Lüüs Siiri-Merike , Gross-Paju Katrin , Haldre Sulev
Published: December 2008

Background: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder, with a variable reported prevalence ranging from 0.5 to 12 per 100,000. The aim of this retrospective study was to evaluate the prevalence of HSP and estimate the percentage of SPG4 mutations in the Estonian population. Methods: A simple model with multiple data sources was selected to enable as many patients as possible to be detected. All relevant case histories from Estonian regional neurological centers for the last 20 years were reviewed; all neurologists and general practitioners were contacted. Results: A total of 737 case records were captured for secondary evaluation. Among these cases, 88 potential HSP-affected subjects were identified. During this study 59 patients with HSP were identified, giving a crude prevalence rate of 4.4 per 100,000. Eleven persons (21.6% of all studied Estonian HSP patients) with HSP were found to have mutations in the spastin gene (SPG4). Conclusions: Our epidemiological data are comparable with the results from epidemiological studies performed elsewhere, indicating that the clinical diagnostic management of HSP patients in Estonia is adequate and the chosen methodological approach for data collection was reliable.
Prevalence of Dementia in the Rural Island Town of Ama-cho, Japan
Authors: Wada-Isoe Kenji , Uemura Yusuke , Suto Yutaka , Doi Koji , Imamura Keiko , Hayashi Ai , Kitayama Michio , Watanabe Yasuhiro , Adachi Yoshiki , Nakashima Kenji
Published: December 2008

Background: With the striking increase in the number of elderly people in Japan, dementia has not only become a medical but also a social issue. Methods: We studied the prevalence of dementing disorders in a rural island town of Japan (Ama-cho), using a door-to-door 2-phase design. Results: Of the 120 persons screened as having cognitive impairment, 104 people were diagnosed as having dementia. The prevalence (cases/100 persons aged 65 years and older) was 11.0 for all types of dementia, 7.0 for Alzheimer’s disease, 1.7 for vascular dementia, 0.53 for dementia with Lewy bodies, 0.74 for Parkinson’s disease dementia, 0.21 for progressive supranuclear palsy, 0.11 for frontotemporal lobar degeneration and 0.74 for other dementia. The overall prevalence was higher in women for Alzheimer’s disease and Parkinson’s disease dementia, and in men, for vascular dementia and dementia with Lewy bodies. Conclusion: We confirmed the overall prevalence of dementia in the elderly population aged 65 years and older to be 11.0. This finding is higher compared with previous reports in Japan.
Can Comprehensive Stroke Centers Erase the ‘Weekend Effect’?
Authors: Albright Karen C. , Raman Rema , Ernstrom Karin , Hallevi Hen , Martin-Schild Sheryl , Meyer Brett C. , Meyer Dawn M. , Morales Miriam M. , Grotta James C. , Lyden Patrick D. , Savitz Sean I.
Published: December 2008

Background: Prior epidemiological work has shown higher mortality in ischemic stroke patients admitted on weekends, which has been termed the ‘weekend effect’. Our aim was to assess stroke patient outcomes in order to determine the significance of the ‘weekend effect’ at 2 comprehensive stroke centers. Methods: Consecutive stroke patients were identified using prospective databases. Patients were categorized into 4 groups: intracerebral hemorrhage (ICH group), ischemic strokes not treated with IV t-PA (intravenous tissue plasminogen activator; IS group), acute ischemic strokes treated with IV t-PA (AIS-TPA group), and transient ischemic attack (TIA group). Weekend admission was defined as the period from Friday, 17:01, to Monday, 08:59. Patients treated beyond the 3-hour window, receiving intra-arterial therapy, or enrolled in nonobservational clinical trials were excluded. Patient demographics, NIHSS scores, and admission glucose levels were examined. Adverse events, poor functional outcome (modified Rankin scale, mRS, 3–6), and mortality were compared. Results: A total of 2,211 patients were included (1,407 site 1, 804 site 2). Thirty-six percent (800/2,211) arrived on a weekend. No significant differences were found in the ICH, IS, AIS-TPA, or TIA groups with respect to the rate of symptomatic ICH, mRS on discharge, discharge disposition, 90-day mRS, or 90-day mortality when comparing weekend and weekday groups. Using multivariate logistic regression to adjust for site, age, admission NIHSS, and blood glucose, weekend admission was not a significant independent predictive factor for in-hospital mortality in all strokes (OR = 1.10, 95% CI 0.74–1.63, p = 0.631). Conclusions: Our results suggest that comprehensive stroke centers (CSC) may ameliorate the ‘weekend effect’ in stroke patients. These results may be due to 24/7 availability of stroke specialists, advanced neuroimaging, or ongoing training and surveillance of specialized nursing care available at CSC. While encouraging, these results require confirmation in prospective studies.
Antithrombotic Therapy Influences Location, Enlargement, and Mortality from Intracerebral Hemorrhage
Authors: Toyoda Kazunori , Yasaka Masahiro , Nagata Ken , Nagao Takehiko , Gotoh Jun , Sakamoto Tomohiro , Uchiyama Shinichiro , Minematsu Kazuo
Published: December 2008

Background: To determine whether the use of oral antithrombotic agents before the onset of intracerebral hemorrhage (ICH) affects hematoma features and early patient outcome. Methods: A retrospective, multicenter study involving 1,006 consecutive Japanese patients (607 men, 67 ± 12 years of age) hospitalized within 24 h after the onset of nontraumatic ICH was conducted. Results: One hundred and eighty patients were taking oral antiplatelet agents (17.9%, AP group), 67 were taking warfarin (6.7%, W group), and 21 were taking both (2.1%, W + AP group). After adjustment for age, sex, and known confounders, the taking of each kind of antithrombotic therapy was independently related to cerebellar hemorrhage; the odds ratios (OR) and 95% CI, with patients taking no antithrombotic agents as the reference group, were 2.31 (1.23–4.32) for the AP group, 2.90 (1.26–6.63) for the W group, and 3.43 (1.02–11.59) for the W + AP group. Similarly, the taking of each kind of antithrombotic therapy was independently related to hematoma enlargement within the initial 24 h (OR and 95% CI: AP group, 1.92, 1.10–3.34; W group, 4.80, 2.12–10.87; W + AP group, 4.94, 1.31–18.61) and mortality at 3 weeks post-ICH (OR and 95% CI: AP group, 2.70, 1.56–4.68; W group, 2.50, 1.05–5.96; W + AP group, 9.41, 2.78–31.88). Conclusions: Prior medication with antiplatelet agents, warfarin, or both was predictive of cerebellar hemorrhage, hematoma enlargement, and early death in Japanese ICH patients.