bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-time Study of E-Cadherin and Membrane Dynamics in Living Animals: Implications for Disease Modeling and Drug Development
Authors: Serrels Alan , Timpson Paul , Canel Marta , Schwarz Juliane P. , Carragher Neil O. , Frame Margaret C. , Brunton Valerie G. , Anderson Kurt I.
Published: March 2009

The ability of tumor cells to invade and metastasize requires deregulation of interactions with adjacent cells and the extracellular matrix. A major challenge of cancer biology is to observe the dynamics of the proteins involved in this process in their functional and physiologic context. Here, for the first time, we have used photobleaching and photoactivation to compare the mobility of cell adhesion and plasma membrane probes in vitro and in tumors grown in mice (in vivo). We find differences between in vitro and in vivo recovery dynamics of two key molecules, the tumor suppressor E-cadherin and the membrane-targeting sequence of H-Ras. Our data show that E-cadherin dynamics are significantly faster in vivo compared with cultured cells, that the ratio of E-cadherin stabilized in cell-cell junctions is significantly higher in vivo, and that E-cadherin mobility correlates with cell migration. Moreover, quantitative imaging has allowed us to assess the effects of therapeutic intervention on E-cadherin dynamics using dasatinib, a clinically approved Src inhibitor, and show clear differences in the efficacy of drug treatment in vivo. Our results show for the first time the utility of photobleaching and photoactivation in the analysis of dynamic biomarkers in living animals. Furthermore, this work highlights critical differences in molecular dynamics in vitro and in vivo, which have important implications for the use of cultured disease models as surrogates for living tissue. [Cancer Res 2009;69(7):2714–9]
Urinary Levels of Tobacco-Specific Nitrosamine Metabolites in Relation to Lung Cancer Development in Two Prospective Cohorts of Cigarette Smokers
Authors: Yuan Jian-Min , Koh Woon-Puay , Murphy Sharon E. , Fan Yunhua , Wang Renwei , Carmella Steven G. , Han Shaomei , Wickham Katie , Gao Yu-Tang , Yu Mimi C. , Hecht Stephen S.
Published: March 2009

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL can induce lung cancer in laboratory animals but human data are limited. The association between prediagnostic levels of urinary total NNAL and risk of lung cancer development was evaluated in two prospective cohorts of Chinese cigarette smokers. We conducted a nested case-control study involving 246 cases of incident lung cancer and 245 cohort controls who were individually matched to the index cases by age, gender, neighborhood of residence at cohort enrollment, and date of urine collection. Urinary levels of total NNAL were significantly associated with risk of lung cancer in a dose-dependent manner. Relative to the lowest tertile, risks associated with the second and third tertiles of total NNAL were 1.43 [95% confidence interval (95% CI), 0.86–2.37] and 2.11 (95% CI, 1.25–3.54), respectively (P for trend = 0.005) after adjustment for self-reported smoking history and urinary total cotinine. Smokers in the highest tertiles of urinary total NNAL and total cotinine exhibited a 8.5-fold (95% CI, 3.7–19.5) increased risk for lung cancer relative to smokers with comparable smoking history but possessing the lowest tertiles of urinary total NNAL and total cotinine. Findings of the present study directly link NNK exposure to lung cancer development in humans. [Cancer Res 2009;69(7):2990–5]
Potential Stages for Prostate Cancer Prevention with Selenium: Implications for Cancer Survivors
Authors: Facompre Nicole , El-Bayoumy Karam
Published: March 2009

The lack of treatment for “worried well” patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an ample opportunity to intervene with mechanistically based chemopreventive agents at various stages of disease progression. Our rationale for selenium intervention is based on current mechanistic knowledge derived solely from preclinical investigations. Clearly, there is sufficient scientific support for its entry into current clinical trials, the outcome of which will be highly valuable in assessing whether selenium can be recommended for cancer survivors. [Cancer Res 2009;69(7):2699–703]
Clock-Cancer Connection in Non–Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2
Authors: Hoffman Aaron E. , Zheng Tongzhang , Stevens Richard G. , Ba Yue , Zhang Yawei , Leaderer Derek , Yi Chunhui , Holford Theodore R. , Zhu Yong
Published: March 2009

Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non–Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging single nucleotide polymorphisms (SNP) in CRY2 and NHL risk using DNA samples from a population-based case-control study (n = 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes [dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR, 2.34 (1.28–4.27), P = 0.006; rs7123390, OR, 2.40 (1.39–4.13), P = 0.002; and rs1401417, OR, 2.97 (1.57–5.63, P = 0.001)]. Each of these associations remained significant when restricting the analysis to B-cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional effect of CRY2, we silenced the gene in vitro and performed a whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response and hematologic system development. In addition, these genes were predicted to have significant effects on several disease processes, including cancer (B-H P = 3.75E−9) and hematologic disease (B-H P = 8.01E−8). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development. [Cancer Res 2009;69(8):3605–13]
Cdc7 Kinase Is a Predictor of Survival and a Novel Therapeutic Target in Epithelial Ovarian Carcinoma
Authors: Kulkarni Anjana A. , Kingsbury Sarah R. , Tudzarova Slavica , Hong Hye-Kyung , Loddo Marco , Rashid Mohammed , Rodriguez-Acebes Sara , Prevost Andrew T. , Ledermann Jonathan A. , Stoeber Kai , Williams Gareth H.
Published: March 2009

Purpose: There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma.

Experimental Design: A total of 143 cases of ovarian cancer and 5 cases of normal ovary were analyzed for Cdc7 protein expression dynamics and clinicopathologic features. To assess the therapeutic potential of Cdc7, expression was down-regulated by RNA interference in SKOV-3 and Caov-3 ovarian cancer cells.

Results: Increased Cdc7 protein levels were significantly associated with arrested tumor differentiation (P = 0.004), advanced clinical stage (P = 0.01), genomic instability (P < 0.001), and accelerated cell cycle progression. Multivariate analysis shows that Cdc7 predicts disease-free survival independent of patient age, tumor grade and stage (hazard ratio, 2.03; confidence interval, 1.53-2.68; P < 0.001), with the hazard ratio for relapse increasing to 10.90 (confidence interval, 4.07-29.17) for the stages 3 to 4/upper Cdc7 tertile group relative to stages 1 to 2/lower Cdc7 tertile tumors. In SKOV-3 and Caov-3 cells, Cdc7 siRNA knockdown triggered high levels of apoptosis, whereas untransformed cells arrest in G1 phase and remain viable.

Conclusions: Our findings show that Cdc7 kinase predicts survival and is a potent anticancer target in epithelial ovarian carcinoma, highlighting its potential as a predictor of susceptibility to small molecule kinase inhibitors currently in development.
Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer
Authors: Eder Joseph Paul , Vande Woude George F. , Boerner Scott A. , LoRusso Patricia M.
Published: March 2009

A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas of the breast, liver, lung, ovary, kidney, and thyroid. Notably, activating mutations in c-Met have been positively identified in patients with a particular hereditary form of papillary renal cancer, directly implicating c-Met in human tumorigenesis. Aberrant signaling of the c-Met signaling pathway due to dysregulation of the c-Met receptor or overexpression of its ligand, hepatocyte growth factor (HGF), has been associated with an aggressive phenotype. Extensive evidence that c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met and HGF as major targets in cancer drug development. This has led to the development of a variety of c-Met pathway antagonists with potential clinical applications. The three main approaches of pathway-selective anticancer drug development have included antagonism of ligand/receptor interaction, inhibition of the tyrosine kinase catalytic activity, and blockade of the receptor/effector interaction. Several c-Met antagonists are now under clinical investigation. Preliminary clinical results of several of these agents, including both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have been encouraging. Several multitargeted therapies have also been under investigation in the clinic and have demonstrated promise, particularly with regard to tyrosine kinase inhibition.
Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers
Authors: Natrajan Rachael , Lambros Maryou B. , Rodríguez-Pinilla Socorro María , Moreno-Bueno Gema , Tan David S.P. , Marchió Caterina , Vatcheva Radost , Rayter Sydonia , Mahler-Araujo Betania , Fulford Laura G. , Hungermann Daniela , Mackay Alan , Grigoriadis Anita , Fenwick Kerry , Tamber Narinder , Hardisson David , Tutt Andrew , Palacios Jose , Lord Christopher J. , Buerger Horst , Ashworth Alan , Reis-Filho Jorge S.
Published: March 2009

Purpose: To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes.

Experimental Design: Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs.

Results: We show that basal-like and HER-2 tumors are characterized by “sawtooth” and “firestorm” genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification.

Conclusions: Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.
Cytosine Deaminase-Uracil Phosphoribosyltransferase and Interleukin (IL)-12 and IL-18: A Multimodal Anticancer Interface Marked by Specific Modulation in Serum Cytokines
Authors: Khatri Aparajita , Husaini Yasmin , Ow Kim , Chapman Jane , Russell Pamela J.
Published: March 2009

Purpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)–mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival.

Experimental Design: Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11 serum cytokines using Luminex technology.

Results: Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus individual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase in Th1 cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment.

Conclusion: Locoregional application of CDUPRT-GDEPT and IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor burden and, hence, host response to therapy.
Mathematical Modeling of Herpes Simplex Virus Distribution in Solid Tumors: Implications for Cancer Gene Therapy
Authors: Mok Wilson , Stylianopoulos Triantafyllos , Boucher Yves , Jain Rakesh K.
Published: March 2009

Purpose: Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site.

Experimental Design: The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus.

Results: This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains.

Conclusions: This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy.
Triple-Negative Breast Cancer: Distinguishing between Basal and Nonbasal Subtypes
Authors: Rakha Emad A. , Elsheikh Somaia E. , Aleskandarany Muhammed A. , Habashi Hany O. , Green Andrew R. , Powe Desmond G. , El-Sayed Maysa E. , Benhasouna Ahmed , Brunet Jean-Sébastien , Akslen Lars A. , Evans Andy J. , Blamey Roger , Reis-Filho Jorge S. , Foulkes William D. , Ellis Ian O.
Published: March 2009

Purpose: Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers.

Experimental Design: We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE−).

Results: Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE- tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE- tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival.

Conclusion: TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (in TN tumors) to define BLBC.
High Tumor Metabolic Activity as Measured by Fluorodeoxyglucose Positron Emission Tomography Is Associated with Poor Prognosis in Limited and Extensive Stage Small-Cell Lung Cancer
Authors: Lee Young Joo , Cho Arthur , Cho Byoung Chul , Yun Mijin , Kim Se Kyu , Chang Joon , Moon Jin Wook , Park In Kyu , Choi Hye Jin , Kim Joo-Hang
Published: March 2009

Purpose: We investigated the prognostic effect of incorporating metabolic assessment by 18F-fluoro-2-deoxyglucose uptake on positron emission tomography/computed tomography (18F-FDG-PET/CT) into a conventional staging system in small-cell lung cancer (SCLC).

Experimental Design: Seventy-six consecutive patients with pathologically proven SCLC were enrolled. All patients underwent standard treatment after pretreatment 18F-FDG-PET/CT scanning. The mean values of maximal standardized uptake values (meanSUVmax) of the malignant lesions upon 18F-FDG-PET/CT were calculated. The Cox proportional hazards model was used with performance status, lactate dehydrogenase, stage, and meanSUVmax.

Results: Patients with high meanSUVmax were significantly related with the established poor prognostic factors, such as higher lactate dehydrogenase (P = 0.04) and extensive disease (ED; P = 0.01). Furthermore, in multivariate analysis, patients with high meanSUVmax were associated with poor survival outcomes compared with patients with low meanSUVmax [adjusted hazard ratio, 3.74; 95% confidence interval (95% CI), 1.67-8.37; P = 0.001, for death and adjusted hazard ratio, 2.25; 95% CI, 1.21-4.17; P = 0.01 for recurrence/progression]. In subgroup analysis, limited disease (LD) with high meanSUVmax showed significantly shorter overall survival than LD with low meanSUVmax [high versus low meanSUVmax, 20.1 months (95% CI, 7.9-23.2) versus 35.3 months (95% CI, 27.6-42.9); P = 0.02]. ED with high meanSUVmax had significantly shorter overall survival than ED with low meanSUVmax [high versus low meanSUVmax, 9.5 months (95% CI, 4.9-13.9) versus 17.7 months (95% CI, 12.0-20.1); P = 0.007]. These findings were replicated in progression-free survival analysis.

Conclusions: In SCLC, tumor metabolic activity as assessed by FDG-PET is a significant prognostic factor and identifies subgroups of patients at higher risk of death in both LD and ED SCLC.
Tumor-Localized Ligation of CD3 and CD28 with Systemic Regulatory T-Cell Depletion Induces Potent Innate and Adaptive Antitumor Responses
Authors: Lee Chien-Hsin , Chiang Yi-Hsuan , Chang Shih-En , Chong Chin-Liew , Cheng Bing-Mae , Roffler Steve R.
Published: March 2009

Purpose: Tumor-localized activation of immune cells by membrane-tethered anti-CD3 antibodies (CD3L) is under investigation to treat poorly immunogenic tumors. Here we sought to elucidate the mechanism of antitumor immunity elicited by CD3L.

Experimental Design: CD3L and CD86 were expressed on poorly immunogenic B16 melanoma cells (B16/3L86 cells) and the effect of various lymphocytes, including CD4+ and CD8+ T cells, natural killer T (NKT) cells, and regulatory T cells, on antitumor activity was investigated.

Results: B16/3L86 cells activated naïve T cells; suppressed tumor growth in subcutaneous, peritoneal, and metastasis models; and protected mice from rechallenge with B16 melanoma cells. However, in vivo antitumor activity against primary B16/3L86 tumors unexpectedly depended on NKT cells rather than CD4+ or CD8+ T cells. Treatment of mice with low-dose cyclophosphamide or anti-CD25 antibody to deplete regulatory T cells unmasked latent T-cell antitumor activity; the number of activated CD8+ T cells in tumors increased and B16/3L86 tumors were completely rejected in a CD8+ and CD4+ T-cell–dependent fashion. Furthermore, fibroblasts expressing CD3L and CD86 suppressed the growth of neighboring B16 cancer cells in vivo, and direct intratumoral injection of adenoviral vectors expressing CD3L and CD86 or CD3L and a membrane-tethered anti-CD28 antibody significantly suppressed the growth of subcutaneous tumors.

Conclusions: Tumor-located ligation of CD3 and CD28 can activate both innate (NKT cells) and adaptive (CD4+ and CD8+ T cells) responses to create a tumor-destructive environment to control tumor growth, but modulation of regulatory T cells is necessary to unmask local adaptive antitumor responses.
Melan-A–specific Cytotoxic T Cells Are Associated with Tumor Regression and Autoimmunity Following Treatment with Anti-CTLA-4
Authors: Klein Oliver , Ebert Lisa M. , Nicholaou Theo , Browning Judy , Russell Sarah E. , Zuber Marina , Jackson Heather M. , Dimopoulos Nektaria , Tan Bee Shin , Hoos Axel , Luescher Immanuel F. , Davis Ian D. , Chen Weisan , Cebon Jonathan
Published: March 2009

Purpose: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known.

Experimental Design: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated.

Results: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A–specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A–specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A–expressing tumor cells.

Conclusions: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.
Phosphorylation of the src Epithelial Substrate Trask Is Tightly Regulated in Normal Epithelia but Widespread in Many Human Epithelial Cancers
Authors: Wong Ching Hang , Baehner Frederick L. , Spassov Danislav S. , Ahuja Deepika , Wang Donghui , Hann Byron , Blair Jimmy , Shokat Kevan , Welm Alana L. , Moasser Mark M.
Published: March 2009

Purpose: The frequently elevated activities of the c-src and c-yes products in human epithelial tumors suggest that these activated tyrosine kinases have tumorigenic functions analogous to the v-src and v-yes oncogene products. Studies of v-src–transformed fibroblasts have identified many of the effectors of this potent oncogene; however, because c-src and c-yes lack the mutational and promiscuous activities of their retroviral oncogene homologues, their presumptive tumorigenic functions in human epithelial tumors are more subtle, less well-defined, and await identification of possible effectors more directly relevant to epithelial cells.

Experimental Design: We recently identified a transmembrane glycoprotein named Trask that is expressed in epithelial tissues but not fibroblasts and is phosphorylated by SRC kinases in mitotic epithelial cells. In this study, we have surveyed the expression and phosphorylation of Trask in many human epithelial cancer cell lines and surgical tissues and tumors.

Results: Trask is widely expressed in human epithelial tissues, but its phosphorylation is tightly regulated and restricted to detached mitotic cells or cells undergoing physiologic shedding. However, abberant Trask phosphorylation is seen in many epithelial tumors from all stages including preinvasive, invasive, and metastatic tumors. Trask phosphorylation requires SRC kinases, and is also aberrantly hyperphosphorylated in the SRC-activated PyMT mouse epithelial tumors and dephosphorylated by the SRC inhibitor treatment of these tumors.

Conclusions: The widespread phosphorylation of Trask in many human epithlelial cancers identifies a new potential effector of SRC kinases in human epithelial tumorigenesis.
CCL22 Recruits CD4-positive CD25-positive Regulatory T Cells into Malignant Pleural Effusion
Authors: Qin Xue-Jun , Shi Huan-Zhong , Deng Jing-Min , Liang Qiu-Li , Jiang Jing , Ye Zhi-Jian
Published: March 2009

Purpose: The aim of this study was to explore the presence of the chemokines CCL22 and CCL17 in malignant pleural effusion, and the chemoattractant activity of these chemokines on CD4-positive CD25-positive Foxp3-positive regulatory T cells infiltrating into the pleural space.

Experimental Design: The concentrations of CCL22 and CCL17 in both pleural effusions and sera from 33 patients with lung cancer were determined. Flow cytometry was done to determine T lymphocyte subsets in cell pellets of pleural effusion. Pleural cells were analyzed for the expression of CCL22 and CCL17. The chemoattractant activity of CCL22 for regulatory T cells in vitro and in vivo was also observed.

Results: The concentration of CCL22 in malignant pleural effusion was significantly higher than that in the corresponding serum. Pleural fluid from lung cancer patients was chemotactic for regulatory T cells, and this activity was partly blocked by an anti-CCL22, but not by an anti-CCL17 antibody. Intrapleural administration of CCL22 of patients produced a marked progressive influx of regulatory T cells into pleural space.

Conclusions: Compared with serum, CCL22 seemed to be increased in malignant pleural effusion, and could directly induce regulatory T cell infiltration into the pleural space in patients with malignant effusion.
Association of MDM2 SNP309, Age of Onset, and Gender in Cutaneous Melanoma
Authors: Firoz Elnaz F. , Warycha Melanie , Zakrzewski Jan , Pollens Danuta , Wang Guimin , Shapiro Richard , Berman Russell , Pavlick Anna , Manga Prashiela , Ostrer Harry , Celebi Julide Tok , Kamino Hideko , Darvishian Farbod , Rolnitzky Linda , Goldberg Judith D. , Osman Iman , Polsky David
Published: March 2009

Purpose: In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among MDM2 SNP309, age at diagnosis, and gender among melanoma patients.

Experimental Design: Prospectively enrolled melanoma patients (N = 227) were evaluated for MDM2 SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples, and genotypes were analyzed by PCR-restriction fragment length polymorphism. Associations among MDM2 SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed.

Results: The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared with women with TG+TT genotypes (59 years; P = 0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages <50 years compared with women ≥50 years, but not when the comparison was made between women <60 and ≥60 years. At ages <50 years, women with a GG genotype had a 3.89 times greater chance of being diagnosed compared with women with TG+TT genotypes (P = 0.01). Similar observations were not seen among men.

Conclusions: Our data suggest that MDM2 may play an important role in the development of melanoma in women. The MDM2 SNP309 genotype may help identify women at risk of developing melanoma at a young age.
Characterization of the Class I-Restricted gp100 Melanoma Peptide-stimulated Primary Immune Response in Tumor-Free Vaccine-draining Lymph Nodes and Peripheral Blood
Authors: Walker Edwin B. , Miller William , Haley Daniel , Floyd Kevin , Curti Brendan , Urba Walter J.
Published: March 2009

Purpose: The aim of this study was to characterize the primary gp100209-2M-specific T-cell response in vaccine-draining, metastases-free lymph nodes and peripheral blood of peptide-vaccinated stage I to III melanoma patients.

Experimental Design: After two or three gp100209-2M vaccinations, sentinel lymph nodes that drained both the primary tumor and adjacent vaccine sites were excised concomitant with wide excision of the tumor. Comparative 7-color flow cytometry phenotype analysis was done on gp100 tetramer-positive CD8+ T cells from sentinel lymph nodes, closely proximate time-related peripheral blood mononuclear cells (PBMC) collected 2 to 4 weeks after sentinel lymph node excision, and on PBMC collected 6 months later after 7 or 11 more immunizations. Lymph node and peripheral blood T cells were tested for proliferative response, functional avidity, and tumor cell–induced CD107 mobilization.

Results: The frequencies of gp100-specific CD8+ T cells from time-related PBMC and sentinel lymph nodes were comparable and were similar to those reported for virus-specific memory T cells. Their respective in vitro proliferation responses were also equivalent but statistically higher than proliferation responses of peripheral blood T cells collected after completion of the entire vaccine regimen. By contrast, functional avidity and CD107 responses were significantly higher in circulating T cells. Sentinel lymph node–derived, gp100-specific CD8+ T cells predominantly expressed central and effector memory phenotype signatures, whereas there were higher frequencies of effector T cells in the peripheral blood.

Conclusion: Priming immunization with gp100209-2M without coadministration of CD4+ helper T cell–restricted antigens induced the effective expansion of peptide-specific central and effector memory CD8+ T cells with high proliferation potential in vaccine-draining lymph nodes of stage I to III melanoma patients. Lymph node memory T cells gave rise to circulating gp100-specific effector T cells exhibiting increased functional maturation.
Understanding the Dialogue: the Microbial–Host Interaction
Authors: Fasano Alessio
Published: March 2009

The mammalian gastrointestinal tract is much more complex than previously appreciated. A single layer of epithelial cells covers the entire gastrointestinal tract, so providing the largest interface with the environment. The gut epithelium is a sensor of the luminal environment, not only controlling digestive, absorptive, and secretory functions, but also relaying information to the mucosal immune, vascular and nervous systems. These functions involve a complex array of pattern recognition receptors (PRRs) and cell types that elaborate growth factors, cytokines, and extracellular matrix proteins. Moreover, enteric microbes may hijack PRR-activated pathways as part of their pathogenic arsenal through ‘host mimicry’. Understanding the cross-talk between enteric microbiota and the host under both physiological and pathological circumstances may provide key information on the pathogenesis of local as well as systemic diseases. This knowledge may potentially lead to the identification of novel therapeutic strategies for the treatment of these disorders.
The Role of Microbiota in Inflammatory Bowel Disease
Authors: Chermesh Irit , Shamir Raanan
Published: March 2009

Crohn’s disease and ulcerative colitis are inflammatory diseases of the gastrointestinal tract that together comprise a spectrum of diseases entitled inflammatory bowel disease (IBD). The human intestine is colonized with commensal microbiota in concentrations that exceed the number of cells in the human body. Under normal physiologic conditions there is an interplay between these bacteria and the human host in a process that maintains the integrity of the immune system in health and disease. Gut microbiota play an important role in IBD. Commensal and pathologic bacteria comprise part of the etiology of IBD, and the gut microbiota in patients with IBD is different from that in healthy controls. Their influence is probably brought about in initiation of disease as well as in flare-ups, and it is logical to assume that manipulation of the gut microbiota could be a preventive measure in IBD evolution and may play a therapeutic role in disease exacerbation. This review will briefly discuss issues related to studying gut microbiota, the interplay of these microbiota with the immunologic system in IBD, and focus on the role of microbiota in the etiology, flare-ups and treatment of IBD.
Tratamientos de la colestasis crónica en niños
Authors: Álvarez Fernando
Published: March 2009

Se dispone de pocos tratamientos específicos para los niños con colestasis crónica. La mayoría de las estrategias terapéuticas alivian la retención de componentes de la bilis o aminoran algunas de las consecuencias de la colestasis crónica. El ácido ursodesoxicólico es el fármaco que con más frecuencia se utiliza en niños con colestasis crónica. Este ácido biliar se administra a la dosis de 10 a 30 mg/kg/día en pacientes con fibrosis quística, errores congénitos del metabolismo de los ácidos biliares, colestasis intrahepática familiar progresiva, colangitis esclerosante, atresia biliar, síndrome de Alagille o a aquéllos tratados con nutrición parenteral total. El ácido ursodesoxicólico incrementa principalmente el flujo de bilis y posee un efecto estabilizador de la membrana reduciendo la toxicidad de los ácidos biliares más hidrofóbicos. La rifampicina, un antibiótico, a una dosis entre 10 y 20 mg/kg/día, es muy eficaz en el alivio del prurito. Se obtienen efectos similares utilizando resinas intercambiadoras de iones no absorbibles. Además, estas moléculas disminuyen los niveles séricos de colesterol contribuyendo a reducir los xantomas. La sustitución de algunas carencias generadas por la nutrición parenteral total mediante la administración de ácidos grasos esenciales o cisteína puede evitar los trastornos hepáticos asociados o contribuir a mejorarlos. En algunas enfermedades colestáticas, las intervenciones quirúrgicas pueden ayudar a aliviar el obstáculo frente al flujo de bilis, como es el caso de la portoenterostomía en pacientes con atresia biliar. En casos de colestasis interhepática, puede registrarse una mejoría clínica y bioquímica tras una derivación de la bilis u otra intervención (exclusión del íleon), que limita la absorción de ácidos biliares en el intestino. En el futuro, la asociación de estos diferentes agentes farmacológicos, que incrementan el flujo de bilis, protegen las membranas celulares o restablecen las carencias nutricionales, podría contribuir a mejorar la calidad de vida en niños con colestasis crónica y retrasar en última instancia la necesidad de un tratamiento más drástico como el trasplante hepático. También podrían ser de gran ayuda los progresos en la terapia génica y el trasplante de hepatocitos; no obstante, todavía son necesarios muchos años de investigación intensiva antes de que pueda considerarse incluso un estudio piloto que utilice uno de estos tratamientos en hepatopatías inductoras de colestasis crónica.
Erhaltung der Fertilität bei Tumorerkrankungen
Authors: De Geyter C. , De Geyter M. , Wight E.
Published: March 2009

Die Erfolge bei der Therapie bösartiger Erkrankungen haben eine Zunahme des Interesses an der Sicherstellung der Lebensqualität der behandelten Patientinnen und Patienten hervorgerufen. Zum erfüllten Lebensinhalt und zur Selbstverwirklichung gehört auch die Möglichkeit zur Fortpflanzung. Sehr oft jedoch vernichten die modernen Behandlungsmethoden eines bösartigen Tumorleidens die Bildung von Samenzellen und die Reifung der Eizellen. Wie ansonsten keine andere medizinische Disziplin verfügt die Reproduktionsmedizin durch ihre Erfahrung mit der Kryokonservierung von Samenzellen, Eizellen und Embryonen über die technische Voraussetzung für die Erhaltung der Fertilität. Während die Anlage einer Zeugungsreserve bei Männern mit einem bösartigen Tumorleiden heute zu einem Standardverfahren geworden ist, sind die Möglichkeiten bei der Frau noch begrenzt. Die Kryokonservierung von unbefruchteten Eizellen oder von Eizellen im Vorkernstadium ist zwar etabliert, jedoch sind die Erfolgschancen pro Eizelle sehr gering, und die Zeit zwischen der Diagnose des Tumorleidens und dem Beginn der Chemotherapie ist oft zu kurz, um sie für diese Indikation sinnvoll einzusetzen. Die Kryokonservierung von Ovarialgewebe und dessen spätere Retransplantation nach erfolgter Heilung vom Tumorleiden haben mittlerweile zu ersten Erfolgen geführt, sodass jetzt der Beweis der Machbarkeit dieses Vorgehens vorliegt. Ihre weitere Verbreitung hängt nun von der Bildung von Netzwerken ab, in denen Reproduktionsmediziner, Spezialisten der Kryokonservierung von Ovarialgewebe und Onkologen eingebunden sein müssen.
Lessons from 52 Patients with Leydig Cell Tumor of the Testis: The GUONE (North-Eastern Uro-Oncological Group, Italy) Experience
Authors: Di Tonno Fulvio , Tavolini Ivan Matteo , Belmonte Piero , Bertoldin Roberto , Cossaro Enrico , Curti Paolo , D’Incà Giulio , Fandella Andrea , Guaitoli Paolo , Guazzieri Stefano , Mazzariol Chiara
Published: March 2009

Introduction: The goal of the study was to define treatment rules for the uncommon, rarely (10%) malignant and chemorefractory Leydig cell tumors (LCT) of the testis. Methods: The main clinical data of patients treated in centers affiliated to the GUONE (North-Eastern Uro-Oncological Group, Italy) were reviewed. We considered 52 patients (54 tumors, 2 bilateral) whose ages ranged from 13 to 70 years (mean 36). Of the treatments performed, 52 were orchiectomies and 2 were enucleations (unfavorable pathology in only 2 tumors). There were 5 lymphadenectomies (retroperitoneal lymph node dissections): 2 for suspected stage II disease and 1 each for unfavorable pathology, bilateral disease and associated Sertoli tumor (pathology: pN0 in all cases). The length of follow-up ranged from 15 to 249 months (mean 81). Results: There was no relapse in 51 patients and 1 died as a result of metastatic disease (orchiectomy at the age of 70; unremarkable pathology). Conclusions: Malignant LCT seems to be, in our experience, less frequent than previously reported. Age and pathology are useful prognostic factors, but their predictive value should never be considered absolute. Enucleation seems justified in young patients with favorable pathology. In clinical stage I LCT, retroperitoneal lymph node dissection should be offered to older patients and/or to patients with unfavorable pathology. A prolonged follow-up is mandatory.
Decrease of Renal Function due to Warm Ischemia after Laparoscopic Partial Nephrectomy: Evaluation Using 99mTc-DMSA Renal Scintigraphy
Authors: Tachikake Toshihiro , Shigeta Masanobu , Mita Koji , Marukawa Kazushi , Usui Tsuguru , Ito Katsuhide
Published: March 2009

Introduction: The purpose of this study is, using technetium-99m-dimercaptosuccinic acid (99mTc-DMSA), to evaluate the decrease of renal function caused by warm ischemia. Patients and Methods: The 99mTc-DMSA scan was performed before and 1, 3 and 6 months after the operation for 19 consecutive patients. The patients were divided into three groups by warm ischemic time (group A: ≤40 min, B: >40 min ∩ ≤60 min, C: >60 min). Renal function of the unresected part was defined as the uptake to unresected part relative to the uptake to the contralateral kidney. The reduction of renal function was expressed as a ratio of the function after the surgery divided by function before the surgery and was compared between the three groups. Results: The reduction in group C after 1 and 3 months tended to be greater than that in group A or B, although not reaching statistical significance (one-way ANOVA test, 1 month: p = 0.15 and 3 months: p = 0.13). There was a significant difference in reduction of renal function between the three groups after 6 months (one-way ANOVA test, p = 0.02). The Scheffé test showed a statistical significance between groups A and C (p < 0.05). Conclusion: Renal function calculated by 99mTc-DMSA shows that prolonged ischemic time causes significant damage to the kidney.
Adjunctive Medical Therapy with an α-1A-Specific Blocker after Shock Wave Lithotripsy of Lower Ureteral Stones
Authors: Wang Chung-Jing , Huang Shi-Wei , Chang Chien-Hsing
Published: March 2009

Introduction: We assessed the efficacy of using an α-1A-specific blocker for improving the success rate in shock wave lithotripsy (SWL) for lower ureteral stones. Materials and Methods: This prospective study was conducted from June 2005 to December 2006 and involved 107 patients. All the patients underwent SWL with the PCK Stonelith. The patients were randomly divided into 3 groups: group 1 (34 patients) received tamsulosin, group 2 (35 patients) received terazosin, and group 3 (38 patients) received placebo. All patients were diagnosed by kidney-ureter-bladder X-ray, abdominal ultrasonography and intravenous urography. The number of colic episodes, lower urinary tract symptoms, analgesic dosage and days for spontaneous passage of the stones through the ureter were recorded by diary. Statistical analyses were performed using ANOVA, the χ2 test, Fisher’s exact test and the non-parametric Wilcoxon 2-sample t test. Results: There were no differences between the groups regarding age, stone size, expulsion time and expulsion rate. The number of colic episodes and the analgesic dosage were significantly lower in group 1 compared with groups 2 and 3. A statistically significant difference was observed in lower urinary tract symptoms: lower urinary tract symptoms were observed in 4 of 34 patients in group 1 (12%), in 8 of 35 in group 2 (23%), and in 13 of 38 in group 3 (34%). Adverse effects were noted in 5 of 32 patients in group 2 (16%), which was significantly different in comparison with group 3. Conclusions: Administration of an α-1A-specific blocker reduced analgesic dosage and colic episodes after SWL of lower ureteral stones. There was no benefit with regard to increasing stone expulsion rate or decreasing expulsion time.
Vasectomy Reversal: A Seven-Year Experience
Authors: Busato, Jr. Wilson F.S.
Published: March 2009

Introduction: Since the demand for vasectomy reversal is increasing and many populations in Brazil and other countries show distinct characteristics, this study was carried out as an effort to determine factors and characteristics associated with the success rate of reversal in a population in Southern Brazil. Patients and Methods: We reviewed 29 cases of vasectomy reversal performed over a 7-year period using the single-layer technique under microscopic magnification. Results: Mean patency, pregnancy, and birth rates were 75, 41.7 and 29%, respectively. The patency and pregnancy rates were 92.3 and 38.5%, respectively, for time intervals since vasectomy <10 years and 63.6 and 45.4%, respectively, for intervals >10 years. Patency and pregnancy rates were 87.5 and 50%, respectively, for patients who had their vasectomy performed by a urologist, and 50 and 25%, respectively, for those who had their vasectomy performed by a generalist surgeon (p < 0.05). Conclusions: High patency and pregnancy rates are associated with time intervals since vasectomy of <10 years and vasectomies performed by urologists. There was no significant difference in the anastomosis time between the first 12 procedures and the next 12 procedures.
Penile Vascular Impairment in Erectile Dysfunction Patients with Metabolic Syndrome: Penile Doppler Ultrasound Findings
Authors: Demir Omer , Demir Tevfik , Kefi Aykut , Secil Mustafa , Comlekci Abdurrahman , Yesil Sena , Esen Ahmet Adil
Published: March 2009

Background: The constellation of truncal obesity, glucose intolerance, dyslipidemia (high triglycerides, low HDL cholesterol), and hypertension has been recognized as metabolic syndrome. However, the pathophysiological association between metabolic syndrome and erectile dysfunction (ED) has not yet been clearly determined. This study aimed to evaluate the penile Doppler ultrasound (PDU) findings of ED patients with metabolic syndrome. Patients and Methods: Sixty-one age-matched ED patients with or without metabolic syndrome were included in the study. Patients were investigated by grouping according to risk factors of metabolic syndrome with PDU parameters (5th, 10th and 20th minute peak systolic velocity and end-diastolic velocity). PDU parameters of patients with and without metabolic syndrome were compared. Results: The mean age of the patients were 54.9 ± 8.3 and 54.9 ± 7.6 years for the groups of with (n = 27) and without (n = 34) metabolic syndrome, respectively. When the mean peak flow velocities were compared with presence of metabolic syndrome, we observed differences between at the 5th, 10th and 20th minute peak systolic velocities (p = 0.083, p = 0.022 and p = 0.080, respectively). Conclusion: Metabolic syndrome seems to be the potential risk factor for ED, which may exert its effect by decreased arterial inflow due to endothelial dysfunction.