bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscle Synergy Organization Is Robust Across a Variety of Postural Perturbations
Authors: Torres-Oviedo Gelsy , Macpherson Jane M. , Ting Lena H.
Published: June 2006

We recently showed that four muscle synergies can reproduce multiple muscle activation patterns in cats during postural responses to support surface translations. We now test the robustness of functional muscle synergies, which specify muscle groupings and the active force vectors produced during postural responses under several biomechanically distinct conditions. We aimed to determine whether such synergies represent a generalized control strategy for postural control or if they are merely specific to each postural task. Postural responses to multidirectional translations at different fore-hind paw distances and to multidirectional rotations at the preferred stance distance were analyzed. Five synergies were required to adequately reconstruct responses to translation at the preferred stance distance—four were similar to our previous analysis of translation, whereas the fifth accounted for the newly added background activity during quiet stance. These five control synergies could account for >80% total variability or r2> 0.6 of the electromyographic and force tuning curves for all other experimental conditions. Forces were successfully reconstructed but only when they were referenced to a coordinate system that rotated with the limb axis as stance distance changed. Finally, most of the functional muscle synergies were similar across all of the six cats in terms of muscle synergy number, synergy activation patterns, and synergy force vectors. The robustness of synergy organization across perturbation types, postures, and animals suggests that muscle synergies controlling task-variables are a general construct used by the CNS for balance control.
Analysis of LFP Phase Predicts Sensory Response of Barrel Cortex
Authors: Haslinger R. , Ulbert I. , Moore C. I. , Brown E. N. , Devor A.
Published: June 2006

Several previous studies have shown the existence of Up and Down states and have linked their magnitude (e.g., depolarization level) to the size of sensory-evoked responses. Here, we studied how the temporal dynamics of such states influence the sensory-evoked response to vibrissa deflection. Under α-chloralose anesthesia, barrel cortex exhibits strong quasi-periodic ∼1-Hz local field potential (LFP) oscillations generated by the synchronized fluctuation of large populations of neurons between depolarized (Up) and hyperpolarized (Down) states. Using a linear depth electrode array, we recorded the LFP and multiunit activity (MUA) simultaneously across multiple layers of the barrel column and used the LFP to approximate the subthreshold Up–Down fluctuations. Our central finding is that the MUA response is a strong function of the LFP oscillation’s phase. When only ongoing LFP magnitude was considered, the response was largest in the Down state, in agreement with previous studies. However, consideration of the LFP phase revealed that the MUA response varied smoothly as a function of LFP phase in a manner that was not monotonically dependent on LFP magnitude. The LFP phase is therefore a better predictor of the MUA response than the LFP magnitude is. Our results suggest that, in the presence of ongoing oscillations, there can be a continuum of response properties and that each phase may, at times, need to be considered a distinct cortical state.
Oncogenic Function of a Novel WD-Domain Protein, STRAP, in Human Carcinogenesis
Authors: Halder Sunil K. , Anumanthan Govindaraj , Maddula Ramakoti , Mann Jason , Chytil Anna , Gonzalez Adriana L. , Washington M. Key , Moses Harold L. , Beauchamp R. Daniel , Datta Pran K.
Published: June 2006

The development and progression of malignancies is a complex multistage process that involves the contribution of a number of genes giving growth advantage to cells when transformed. The role of transforming growth factor-β (TGF-β) in carcinogenesis is complex with tumor-suppressor or prooncogenic activities depending on the cell type and the stage of the disease. We have previously reported the identification of a novel WD-domain protein, STRAP, that associates with both TGF-β receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-β–induced transcription. Here, we show that STRAP is ubiquitously expressed and is localized in both cytoplasm and nucleus. STRAP is up-regulated in 60% colon and in 78% lung carcinomas. Stable expression of STRAP results in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and in down-regulation of the cyclin-dependent kinase inhibitor p21Cip1, which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-β–mediated transcription, and growth inhibition are induced in STRAP-knockout mouse embryonic fibroblasts compared with wild-type cells. Ectopic expression of STRAP in A549 lung adenocarcinoma cell line inhibits TGF-β–induced growth inhibition and enhances anchorage-independent growth of these cells. Moreover, overexpression of STRAP increases tumorigenicity in athymic nude mice. Knockdown of endogenous STRAP by small interfering RNA increases TGF-β signaling, reduces ERK activity, increases p21Cip1 expression, and decreases tumorigenicity. Taken together, these results suggest that up-regulation of STRAP in human cancers may provide growth advantage to tumor cells via TGF-β–dependent and TGF-β–independent mechanisms, thus demonstrating the oncogenic function of STRAP. (Cancer Res 2006; 66(12): 6156-66)
Notch3Gene Amplification in Ovarian Cancer
Authors: Park Joon T. , Li Mei , Nakayama Kentaro , Mao Tsui-Lien , Davidson Ben , Zhang Zhen , Kurman Robert J. , Eberhart Charles G. , Shih Ie-Ming , Wang Tian-Li
Published: June 2006

Gene amplification is one of the common mechanisms that activate oncogenes. In this study, we used single nucleotide polymorphism array to analyze genome-wide DNA copy number alterations in 31 high-grade ovarian serous carcinomas, the most lethal gynecologic neoplastic disease in women. We identified an amplicon at 19p13.12 in 6 of 31 (19.5%) ovarian high-grade serous carcinomas. This amplification was validated by digital karyotyping, quantitative real-time PCR, and dual-color fluorescence in situ hybridization (FISH) analysis. Comprehensive mRNA expression analysis of all 34 genes within the minimal amplicon identified Notch3 as the gene that showed most significant overexpression in amplified tumors compared with nonamplified tumors. Furthermore, Notch3 DNA copy number is positively correlated with Notch3 protein expression based on parallel immunohistochemistry and FISH studies in 111 high-grade tumors. Inactivation of Notch3 by both γ-secretase inhibitor and Notch3-specific small interfering RNA suppressed cell proliferation and induced apoptosis in the cell lines that overexpressed Notch3 but not in those with minimal amount of Notch3 expression. These results indicate that Notch3 is required for proliferation and survival of Notch3-amplified tumors and inactivation of Notch3 can be a potential therapeutic approach for ovarian carcinomas. (Cancer Res 2006; 66(12): 6312-8)
Mitogen-Activated Protein Kinase Phosphatase 2: A Novel Transcription Target of p53 in Apoptosis
Authors: Shen Wen Hong , Wang Jianli , Wu Jingjing , Zhurkin Victor B. , Yin Yuxin
Published: June 2006

The p53 tumor suppressor plays critical roles in diverse cellular responses such as cell cycle arrest, senescence, and apoptosis through transcriptional control of its target genes. Identification and characterization of new p53 target genes will advance our understanding of how p53 exerts its multiple regulatory functions. In this article, we show that mitogen-activated protein kinase phosphatase 2 (MKP2) is a novel transcription target of p53 in mediating apoptosis. Moreover, we identify a 10-bp perfect palindrome motif (CTGGCGCCAG) in the MKP2 promoter as a new binding site for p53 to activate the MKP2 gene. This GC-rich palindrome is completely different from the consensus p53 binding sequence. Induction of MKP2 is highly responsive to oxidative stress in a p53-dependent manner. Interestingly, the p53-dependent induction of MKP2 is prominent only in the cellular response to stimuli leading to apoptosis but not to cell cycle arrest. In response to oxidative stress, MKP2 is not only required for p53-mediated apoptosis, but ectopic MKP2 expression can also enhance apoptotic responses even independent of p53. These data suggest that p53 regulates distinct genes via different binding mechanisms and that MKP2 is an essential target of p53 in signaling apoptosis. (Cancer Res 2006; 66(12): 6033-9)
Influence of Antibiotic Treatment on Breast Carcinoma Development in Proto-neu Transgenic Mice
Authors: Rossini Anna , Rumio Cristiano , Sfondrini Lucia , Tagliabue Elda , Morelli Daniele , Miceli Rosalba , Mariani Luigi , Palazzo Marco , Ménard Sylvie , Balsari Andrea
Published: June 2006

The effect of prolonged antibiotic treatments on tumor development was evaluated in proto-neu transgenic mice, which spontaneously develop mammary carcinomas. Virgin transgenic mice were treated with metronidazole/ciprofloxacin or gentamicin through the drinking water. The hazard ratio [HR; 95% confidence interval (95% CI)] of breast cancer occurrence in metronidazole/ciprofloxacin-treated mice was more than triple that for controls [3.11 (1.13-8.53); P = 0.028], whereas only a slight increase in HR (95% CI) was observed in gentamicin-treated mice [1.39 (0.56-3.47); P = 0.481]. Tumor growth rate in gentamicin-treated mice was significantly faster than in untreated control mice (P = 0.043). Moreover, mammary glands from mice treated with either antibiotic regimen showed increased lobulization, with more numerous and more developed terminal ductal lobular units than in controls. These results indicate that prolonged exposure to relevant doses of antibiotics affects the mammary glands in this particular model of HER-2/neu transgenic mice; further studies to understand the precise mechanism by which antibiotic treatments influence mammary gland differentiation are critical. (Cancer Res 2006; (12): 6219-24)
Fatty Acid Synthase and Cancer: New Application of an Old Pathway
Authors: Kuhajda Francis P.
Published: June 2006

Fatty acid synthase (FAS), the sole mammalian enzyme capable of de novo fatty acid synthesis, is highly expressed in most human carcinomas. FAS is associated with poor prognosis in breast and prostate cancer, is elaborated into the blood of cancer patients, and its inhibition is selectively cytotoxic to human cancer cells. Thus, FAS and fatty acid metabolism in cancer has become a focus for the potential diagnosis and treatment of cancer. (Cancer Res 2006; 66(12): 5977-80)
The Receptor-Type Protein Tyrosine Phosphatase J Antagonizes the Biochemical and Biological Effects of RET-Derived Oncoproteins
Authors: Iervolino Angela , Iuliano Rodolfo , Trapasso Francesco , Viglietto Giuseppe , Melillo Rosa Marina , Carlomagno Francesca , Santoro Massimo , Fusco Alfredo
Published: June 2006

Thyroid cancer is frequently associated with the oncogenic conversion of the RET receptor tyrosine kinase. RET gene rearrangements, which lead to the generation of chimeric RET/papillary thyroid carcinoma (PTC) oncogenes, occur in PTC, whereas RET point mutations occur in familial multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinomas (MTC). We showed previously that the expression of the receptor-type protein tyrosine phosphatase J (PTPRJ) is suppressed in neoplastically transformed follicular thyroid cells. We now report that PTPRJ coimmunoprecipitates with wild-type RET and with the MEN2A-associated RET(C634R) oncoprotein but not with the RET/PTC1 and RET-MEN2B isoforms. Using mutated forms of PTPRJ and RET-MEN2A, we show that the integrity of the respective catalytic domains is required for the PTPRJ/RET-MEN2A interaction. PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels. In line with this finding, adoptive PTPRJ expression reduced the oncogenic activity of RET(C634R) in an in vitro focus formation assay of NIH3T3 cells. As expected from the coimmunoprecipitation results, the RET(M918T) oncoprotein, which is associated to MEN2B and sporadic MTC, was resistant to the dephosphorylating activity of PTPRJ. Taken together, these findings identify RET as a novel substrate of PTPRJ and suggest that PTPRJ expression levels may affect tumor phenotype associated with RET/PTC1 and RET(C634R) mutants. On the other hand, resistance to PTPRJ may be part of the mechanism of RET oncogenic conversion secondary to the M918T mutation. (Cancer Res 2006; 66(12): 6280-7)
Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression
Authors: Souazé Frédérique , Dupouy Sandra , Viardot-Foucault Véronique , Bruyneel Erik , Attoub Samir , Gespach Christian , Gompel Anne , Forgez Patricia
Published: June 2006

Emerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the high-affinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients. (Cancer Res 2006; 66(12): 6243-9)
Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma
Authors: Piekarz Richard L. , Frye A. Robin , Wright John J. , Steinberg Seth M. , Liewehr David J. , Rosing Douglas R. , Sachdev Vandana , Fojo Tito , Bates Susan E.
Published: June 2006

Purpose: The histone deacetylase inhibitor depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial.

Patients and Methods: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, ST segment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage.

Results: Cardiac studies from 282 cycles and 736 doses of depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for ≥6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate–corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects.

Conclusion: The data obtained in this study show that the administration of depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate–corrected QT interval prolongation remains under study.
Dose-Finding Phase I Clinical and Pharmacokinetic Study of Orally Administered Irinotecan in Patients with Advanced Solid Tumors
Authors: Kuppens Isa E.L.M. , Dansin Eric , Boot Henk , Feger Celine , Assadourian Sylvia , Bonneterre Maria-Edith , Beijnen Jos H. , Schellens Jan H.M. , Bonneterre Jacques
Published: June 2006

Purpose: The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study.

Experimental Design: Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m2 once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m2/d.

Results: The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m2/d for irinotecan single agent and 30/1,600 mg/m2/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively.

Conclusions: In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m2/d administered daily for 14 days every 3 weeks.
Expression of p53R2 Is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma
Authors: Okumura Hiroshi , Natsugoe Shoji , Yokomakura Naoya , Kita Yoshiaki , Matsumoto Masataka , Uchikado Yasuto , Setoyama Tetsuro , Owaki Tetsuhiro , Ishigami Sumiya , Aikou Takashi
Published: June 2006

Purpose: The p53 gene and its family are important factors for carcinogenesis, prognosis, and chemoresistance in esophageal squamous cell carcinoma. A recently identified ribonucleotide reductase, p53R2, is regulated by p53 for supplying nucleotides to repair damaged DNA. In the present study, we analyzed the expression and clinicopathologic significance of p53 and p53R2 in esophageal squamous cell carcinoma.

Experimental Design: We immunohistochemically investigated the relationship between p53 and p53R2 expressions in surgical specimens of primary tumors in 222 patients with esophageal squamous cell carcinoma.

Results: The positive expression rate of p53 was 47.1% and that of p53R2 was 61.7%. Positive p53R2 expression was significantly correlated with depth of invasion, lymph node metastasis, stage, and poor prognosis. In the p53-negative group, the 5-year survival rate was better in patients with negative p53R2 expression than in those with positive p53R2 expression. Multivariate analysis indicated that the negative expression of both p53 and p53R2 was an independent prognostic factor along with tumor depth nodal metastasis and stage.

Conclusions: We showed that positive p53R2 expression was related to tumor development and that alteration of p53R2 expression in p53-negative tumors was closely related to prognosis. Evaluation of the expressions of p53 and p53R2 proteins should be useful for determining the tumor properties, including prognosis, in patients with esophageal squamous cell carcinoma.
Distinct Effects of Ionizing Radiation on In vivo Murine Kidney and Brain Normal Tissue Gene Expression
Authors: Zhao Weiling , Chuang Eric Y. , Mishra Mark , Awwad Rania , Bisht Kheem , Sun Lunching , Nguyen Phuongmai , Pennington J. Daniel , Wang Tony Jau Cheng , Bradbury C. Matthew , Huang Lei , Chen Zhijun , Bar-Sela Gil , Robbins Michael E.C. , Gius David
Published: June 2006

Purpose: There is a growing awareness that radiation-induced normal tissue injury in late-responding organs, such as the brain, kidney, and lung, involves complex and dynamic responses between multiple cell types that not only lead to targeted cell death but also acute and chronic alterations in cell function. The specific genes involved in the acute and chronic responses of these late-responding normal tissues remain ill defined; understanding these changes is critical to understanding the mechanism of organ damage. As such, the aim of the present study was to identify candidate genes involved in the development of radiation injury in the murine kidney and brain using microarray analysis.

Experimental Design: A multimodality experimental approach combined with a comprehensive expression analysis was done to determine changes in normal murine tissue gene expression at 8 and 24 hours after irradiation.

Results: A comparison of the gene expression patterns in normal mouse kidney and brain was strikingly different. This observation was surprising because it has been long assumed that the changes in irradiation-induced gene expression in normal tissues are preprogrammed genetic changes that are not affected by tissue-specific origin.

Conclusions: This study shows the potential of microarray analysis to identify gene expression changes in irradiated normal tissue cells and suggests how normal cells respond to the damaging effects of ionizing radiation is complex and markedly different in cells of differing origin.
Lack of Methylthioadenosine Phosphorylase Expression in Mantle Cell Lymphoma Is Associated with Shorter Survival: Implications for a Potential Targeted Therapy
Authors: Marcé Silvia , Balagué Olga , Colomo Luis , Martinez Antonio , Höller Sylvia , Villamor Neus , Bosch Francesc , Ott German , Rosenwald Andreas , Leoni Lorenzo , Esteller Manel , Fraga Mario F. , Montserrat Emili , Colomer Dolors , Campo Elias
Published: June 2006

Purpose: To determine the methylthioadenosine phosphorylase (MTAP) gene alterations in mantle cell lymphoma (MCL) and to investigate whether the targeted inactivation of the alternative de novo AMP synthesis pathway may be a useful therapeutic strategy in tumors with inactivation of this enzyme.

Experimental Design: MTAP gene deletion and protein expression were studied in 64 and 52 primary MCL, respectively, and the results were correlated with clinical behavior. Five MCL cell lines were analyzed for MTAP expression and for the in vitro sensitivity to l-alanosine, an inhibitor of adenylosuccinate synthetase, and hence de novo AMP synthesis.

Results: No protein expression was detected in 8 of 52 (15%) tumors and one cell line (Granta 519). Six of these MTAP negative tumors and Granta 519 cell line had a codeletion of MTAP and p16 genes; one case showed a deletion of MTAP, but not p16, and one tumor had no deletions in neither of these genes. Patients with MTAP deletions had a significant shorter overall survival (mean, 16.1 months) than patients with wild-type MTAP (mean, 63.6 months; P < 0.0001). l-Alanosine induced cytotoxicity and activation of the intrinsic mitochondrial-dependent apoptotic pathway in MCL cells. 9-β-d-Erythrofuranosyladenine, an analogue of 5′-methylthioadenosine, selectively rescued MTAP-positive cells from l-alanosine toxicity.

Conclusions: MTAP gene deletion and lack of protein expression are associated with poor prognosis in MCL and might identify patients who might benefit from treatment with de novo AMP synthesis pathway–targeted therapies.
Aberrant Expression of Collagen Triple Helix Repeat Containing 1 in Human Solid Cancers
Authors: Tang Liren , Dai Derek L. , Su Mingwan , Martinka Magdalena , Li Gang , Zhou Youwen
Published: June 2006

Purpose: The collagen triple helix repeat containing 1 (CTHRC1) is a promigratory protein first found to be expressed during rat tissue repair process. Recent preliminary results revealed CTHRC1 mRNA in melanoma and breast cancer. However, the full significance of CTHRC1 to human carcinogenesis remains unclear. This study is to further characterize the clinical and functional relevance of CTHRC1 in melanoma and other human solid cancers.

Experimental Design: First, semiquantitative immunohistochemistry analysis was done on 304 clinically annotated, paraffin-embedded biopsies representing different stages of melanoma progression. Then, short interfering RNA was used to inhibit expression of CTHRC1 protein for migration analysis on cultured melanoma cells. Finally, the CTHRC1 expression was surveyed in 310 samples representing 19 types of human solid cancers.

Results: In benign nevi and noninvasive melanoma biopsies, there was little CTHRC1 protein expression. In contrast, in invasive primary melanomas, there was a significant increase of CTHRC1 protein (P < 0.01, χ2 test). There was a further increase of CTHRC1 protein in metastatic melanoma specimens compared with nonmetastatic lesions (P < 0.01, χ2 test). In addition, inhibition of CTHRC1 expression resulted in decreased cell migration in vitro. Finally, transcription survey in 19 types of human solid cancers revealed aberrant CTHRC1 expression in 16 cancer types, especially cancers of the gastrointestinal tract, lung, breast, thyroid, ovarian, cervix, liver, and the pancreas.

Conclusions: Aberrant expression of CTHRC1 is widely present in human solid cancers and seems to be associated with cancer tissue invasion and metastasis. It potentially plays important functional roles in cancer progression, perhaps by increasing cancer cell migration.
PIK3CA Mutations in Intraductal Papillary Mucinous Neoplasm/Carcinoma of the Pancreas
Authors: Schönleben Frank , Qiu Wanglong , Ciau Nancy T. , Ho Daniel J. , Li Xiaojun , Allendorf John D. , Remotti Helen E. , Su Gloria H.
Published: June 2006

Purpose: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic-α (PIK3CA) gene in various human solid tumors. More than 75% of those somatic mutations are clustered in the helical (exon 9) and kinase domains (exon 20). The three hot-spot mutations, E542K, E545K, and H1047R, have been proven to elevate the lipid kinase activity of PIK3CA and activate the Akt signaling pathway. The mutational status of PIK3CA in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) has not been evaluated previously.

Experimental Design: To evaluate a possible role for PIK3CA in the tumorigenesis of IPMN and IPMC, exons 1, 4, 5, 6, 7, 9, 12, 18, and 20 were analyzed in 36 IPMN/IPMC and two mucinous cystadenoma specimens by direct genomic DNA sequencing.

Results: We identified four missense mutations in the nine screened exons of PIK3CA from 36 IPMN/IPMC specimens (11%). One of the four mutations, H1047R, has been previously reported as a hot-spot mutation. The remaining three mutations, T324I, W551G, and S1015F, were novel and somatic.

Conclusion: This is the first report of PIK3CA mutation in pancreatic cancer. Our data provide evidence that the oncogenic properties of PIK3CA contribute to the tumorigenesis of IPMN/IPMC.
Application of Intraoperative Ultrasound to Nonsentinel Node Assessment in Primary Breast Cancer
Authors: Hsu Giu-Cheng , Ku Chih-Hung , Yu Jyh-Cherng , Hsieh Chung-Bo , Yu Cheng-Pin , Chao Tsu-Yi
Published: June 2006

Purpose: To evaluate whether intraoperative ultrasonography can help surgeons to identify patients with breast cancer and metastases confined to the sentinel node.

Experimental Design: We used blue dye to identify sentinel node during 512 procedures done on 509 patients with breast cancers of <3 cm. After sentinel node biopsy, we used intraoperative ultrasonography to explore the whole axilla followed by at least level II axillary dissection. All sentinel nodes were evaluated histologically and immunohistochemically using anti-cytokeratin antibody. All nonsentinel nodes were examined by routine histology. Multiple logistic regression was used to assess the associations of interest and to adjust for potential confounders. Receiver operating characteristic curves were used to calculate the areas under the curves of interest and for comparisons.

Results: Sentinel nodes were identified in 506 of 512 (98.8%) procedures and sentinel node metastases were found in 161 of these (31.8%). Subsequent axillary dissection revealed tumor involvement in nonsentinel nodes in 93 of 161 (57.8%) procedures. Multivariate analysis showed that tumor size, number of positive sentinel nodes, and metastatic size in sentinel nodes were independent factors predicting the presence of tumor-positive nonsentinel nodes. The validity of using either node size or cortical thickness ascertained by intraoperative ultrasound to predict nonsentinel node metastases was highly significant (P < 0.0001). Intraoperative ultrasound not only detected metastatic nonsentinel nodes in 89 of 93 (95.7%) cases but also detected metastatic nonsentinel nodes in patients with false-negative sentinel node mapping.

Conclusion: Sentinel node biopsy combined with intraoperative ultrasonography can help breast surgeons decide whether to perform a subsequent nonsentinel node dissection after identification of a positive sentinel node.
Interplay between Epidermal Growth Factor Receptor and Janus Kinase 3 Regulates Polychlorinated Biphenyl–Induced Matrix Metalloproteinase-3 Expression and Transendothelial Migration of Tumor Cells
Authors: Eum Sung Yong , Lee Yong Woo , Hennig Bernhard , Toborek Michal
Published: June 2006

We hypothesize that environmental toxicants, such as polychlorinated biphenyl congeners, can activate vascular endothelial cells and thus increase formation of blood-borne metastases. This study indicates that exposure of human microvascular endothelial cells to 2,2′,4,6,6′-pentachlorobiphenyl can stimulate transendothelial migration of tumor cells through up-regulation of matrix metalloproteinase (MMP)-3. In a series of experiments with specific small interfering RNA and pharmacologic inhibitors, we provide evidence that 2,2′,4,6,6′-pentachlorobiphenyl can activate epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3) in a closely coordinated and cross-dependent fashion. Activated EGFR and JAK3 stimulate in concert c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 1/2 as well as increase DNA-binding activity of transcription factors activator protein-1 and polyomavirus enhancer activator protein 3, leading to transcriptional up-regulation of MMP-3 expression. These results indicate that the interplay among EGFR, JAK3, and mitogen-activated protein kinases, such as c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 1/2, is critical for polychlorinated biphenyl–induced MMP-3 expression and accelerated transendothelial migration of tumor cells. (Mol Cancer Res 2006;4(6):361–70)
Regulation of Vascular Endothelial Growth Factor Expression by EMMPRIN via the PI3K-Akt Signaling Pathway
Authors: Tang Yi , Nakada Marian T. , Rafferty Patricia , Laraio Jenny , McCabe Francis L. , Millar Hillary , Cunningham Mark , Snyder Linda A. , Bugelski Peter , Yan Li
Published: June 2006

Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) is a cell surface glycoprotein overexpressed in many solid tumors. In addition to its ability to stimulate stromal MMP expression, tumor-associated EMMPRIN also induces vascular endothelial growth factor (VEGF) expression. To explore the underlying signaling pathways used by EMMPRIN, we studied the involvement of phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), JUN, and p38 kinases in EMMPRIN-mediated VEGF regulation. Overexpression of EMMPRIN in MDA-MB-231 breast cancer cells stimulated the phosphorylation of only Akt and MAPKs but not that of JUN and p38 kinases. Conversely, inhibition of EMMPRIN expression resulted in suppressed Akt and MAPK phosphorylation. Furthermore, the PI3K-specific inhibitor LY294002 inhibited VEGF production by EMMPRIN-overexpressing cells in a dose- and time-dependent manner. On the other hand, the MAPK inhibitor U0126 did not affect VEGF production. In vivo, EMMPRIN-overexpressing tumors with elevated VEGF expression had a high level of phosphorylation of Akt and MAPK. Finally, when fibroblast cells were treated with recombinant EMMPRIN, Akt kinase but not MAPK was phosphorylated concomitant with an increase in VEGF production. Both the activation of Akt kinase and the induction of VEGF were specifically inhibited with a neutralizing antibody to EMMPRIN. Our results show that in both tumor and fibroblast cells EMMPRIN regulates VEGF production via the PI3K-Akt pathway but not via the MAPK, JUN, or p38 kinase pathways. (Mol Cancer Res 2006;4(6):371–8)
The Effects of Boundary Turbulence on Canyon Flows Forced by Periodic Along-Shelf Currents
Authors: Boyer Don L. , Sommeria Joel , Mitrovic Andjelka Srdic , Pakala V. K. Chaitanya , Smirnov Sergey A. , Etling Dieter
Published: June 2006

Previous laboratory experiments and associated numerical models of laminar flows forced by oscillatory, along-shelf background currents are extended to include some of the effects of boundary-generated turbulence. The experiments are conducted in the 13-m-diameter rotating-flow facility in Grenoble, France. Two pairs of case studies, one at a large forcing velocity (designated as FAST) for which the boundary layers are fully turbulent during part of the flow cycle and one at relatively smaller forcing (SLOW) for which transitional boundary layers are operative at the higher speeds of the background flow, are conducted. Smooth and artificially roughened boundaries are considered, respectively, for each of these pairs. Phase-averaged and time-mean velocity, vertical vorticity, and horizontal divergence fields are found to be qualitatively similar to those of previous laminar experiments. The similarities in the time-mean fields are that (i) within the canyon they are dominated by cyclonic vorticity with maxima centered near the shelf break; (ii) within and in the vicinity of the canyon the general circulation pattern includes a net transport into the canyon through its mouth, a net upwelling in the canyon interior, a transport away from the canyon over the shelf break along both sides of the canyon, and, by inference, a return flow to the deep ocean; and (iii) the interior time-mean flow is characterized by a well-defined coastal current whose axis follows the shelf in the vicinity of the shelf break, with the coast on the right. It is found that the measurements of the characteristic speed of the residual or time-mean flow within the canyon for the transitional and fully turbulent experiments do not follow the scaling law derived earlier for laminar experiments. An alternative scaling analysis for large-Reynolds-number flows is thus derived. Although sufficient numbers of experiments are not available to test the hypothesis fully, the measurements available for the fully turbulent flows are consistent with the theory advanced.
Upstream Internal Hydraulic Jumps
Authors: Cummins Patrick F. , Armi Laurence , Vagle Svein
Published: June 2006

In stratified tidal flow over a sill, the character of the upstream response is determined by a Froude number Fs based on the stratification near the surface. This is distinguished from the Froude number governing the response in the neighborhood of the sill crest, which is based on the weak density step associated with a flow bifurcation. For moderate values of Fs, the upstream response consists of nonlinear waves or a weak undular bore. For larger values of Fs, a strong, quasi-stationary, internal hydraulic jump dominates the upstream response. At sufficiently large values of Fs, the upstream bore is swept downstream and lost. Acoustic backscatter and velocity data are presented for the case of a strong internal bore or gravity current in a tidally modulated sill flow. Numerical simulations with varying near-surface stratification are presented to illustrate the upstream responses at different values of Fs. The theory of two-layer hydraulic flows is invoked to account for the development of the upstream jump.
What Fraction of a Kelvin Wave Incident on a Narrow Strait Is Transmitted?
Authors: Johnson Helen L. , Garrett Chris
Published: June 2006

Parameters governing the fraction of a Kelvin wave transmitted through a narrow gap or channel include time dependence, nonlinearity, friction, and strait geometry, yet only limited regions of this parameter space have been explored. Linear inviscid models (which neglect advective and frictional terms in the momentum equations) predict that 100% of the volume flux of a low-frequency Kelvin wave or steady boundary current incident on a narrow strait is transmitted, even when the strait width becomes infinitesimally small. Here the nonlinear, inviscid, flat bottom problem is considered, and it is shown that, provided the geometry varies slowly, the quasi-steady solution can be found in the rotating-hydraulics literature. In the narrow channel limit the fraction transmitted can be approximated by a simple prediction based on nonrotating hydraulics. Unless an incoming Kelvin wave has a large amplitude in comparison with the background layer depth, the strait width must be considerably smaller than the deformation radius before it limits the volume flux passing through. Results also show that a Kelvin wave of given volume flux will squeeze through a narrower gap if it is pushed rather than pulled.
Toward a Unified Scaling Relation for Interfacial Fluxes
Authors: Lorke Andreas , Peeters Frank
Published: June 2006

Interfacial fluxes, that is, gas exchange at the water–atmosphere interface and benthic fluxes at the sediment–water interface, are often parameterized in terms of wind speed or turbulent friction velocity, with numerous empirical relationships obtained from individual experiments. The present study attempts to combine the general outcome of such experiments at both interfaces into a universal scaling relation for the thicknesses of the viscous and diffusive sublayers in terms of the Kolmogorov and Batchelor length scales, respectively. Transfer velocities can then be described in terms of the Schmidt number of the respective tracer and in terms of the turbulence dissipation rate. Applying law-of-the-wall scaling to convert dissipation rates into an appropriate friction velocity estimate results in a mechanistic description of the transfer velocity, which is comparable to common empirical parameterizations. It is hypothesized, however, that the dissipation rate and hence the directly estimated level of turbulence provide a more appropriate variable for the parameterization of interfacial fluxes than wind speed or turbulent friction velocity inferred from law-of-the-wall scaling.
Generalizing Nigrescence Profiles
Authors: Worrell Frank C. , Vandiver Beverly J. , Schaefer Barbara A. , Cross William E. , Fhagen-Smith Peony E.
Published: June 2006

The two studies in this article examine the interpretability and generalizability of nigrescence profiles based on Cross Racial Identity Scale scores across different educational contexts. Study 1 participants ( N = 333) came from a predominantly White institution (PWI) and were grouped into six clusters labeled Afrocentric, multiculturalist, assimilated, immersion, low race salience, and miseducated variant. The two samples in Study 2 consisted of students from PWIs ( N = 314) and from historically Black colleges and universities (HBCUs; N = 306), respectively. Both PWI and HBCU participants were grouped into five clusters. Four of the six original clusters (assimilated, immersion, low race salience, and miseducated variant) replicated in both samples, and one (multiculturalists) replicated only in the PWI sample. The results indicate that there are generalizable racial identity profiles in the Black population. The authors discuss the implications of the findings.
A Qualitative Examination of Graduate Advising Relationships
Authors: Knox Sarah , Schlosser Lewis Z. , Pruitt Nathan T. , Hill Clara E.
Published: June 2006

Nineteen counseling psychology faculty members were interviewed regarding their advising relationships with doctoral students. Advisors informally learned to advise from their experiences with their advisor and their advisees and defined their role as supporting and advocating for advisees as they navigated their doctoral program. Advisors identified personal satisfaction as a benefit and time demands as a cost of advising. Good advising relationships were facilitated by advisees' positive personal or professional characteristics, mutual respect, open communication, similarity in career path between advisor and advisee, and lack of conflict. Difficult relationships were affected by advisees' negative personal or professional characteristics, lack of respect, research struggles, communication problems, advisors feeling ineffective working with advisees, disruption or rupture of the relationship, and conflict avoidance. Implications for research and training are discussed.
Blacks as Study Objects and Intellectuals in Brazilian Academia
Authors: Lima Ari
Published: June 2006

This article reflects upon the idea of blacks as scientific objects of study and intellectuals in Brazilian academia, using as its primary references anthropological treatises on blacks in Brazil by Raimundo Nina Rodrigues, Ruth Landes, Édison Carneiro, and Thales de Azevedo. The author’s own life experience as a black researcher in academia also serves as a point of reference.
Exploitation: A Modern Approach
Authors: Hahnel Robin
Published: June 2006

Political economists who have abandoned the Marxian labor theory of value during the past few decades due to logical inconsistencies have failed to replace it with a logically sound theory that explains how and why the employment relationship is almost always exploitative even when labor markets are competitive. This article argues for a sacrifice-based theory of economic justice rather than the contribution-based theory implicit in the Marxian labor theory of value and uses a simple theoretical framework to explain not only why the employment relationship is exploitative but also why credit relations and goods trading can be exploitative as well.
A Cost Comparison of Hospice Care in Amyotrophic Lateral Sclerosis and Lung Cancer
Authors: Elman Lauren B. , Stanley Lisa , Gibbons Patricia , McCluskey Leo
Published: June 2006

The authors compare the cost of hospice care provided to 25 amyotrophic lateral sclerosis (ALS) patients and 159 lung cancer patients by the Wissahickon Hospice of the University of Pennsylvania. The mean length of stay was 86.7 days for ALS patients and 35.0 days for patients with lung cancer ( P = .011). The mean per patient cost was $5622.93 for the ALS patients and $2658.91 for patients with lung cancer ( P = .057) The average operating margin excluding administrative costs was $5293.04 for ALS patients and $2126.74 for patients with lung cancer ( P = .008). The longer length of stay (LOS) accounts for this difference. Longer LOS can be accomplished by close clinical monitoring of ALS patients for the development of life threatening respiratory and/or nutritional compromise and by liberalizing the present hospice admission guidelines.
Serving Women Who Use Force in Their Intimate Heterosexual Relationships
Authors: Larance Lisa Young
Published: June 2006

This article explores the author’s practice observations while working with women who use force (WWUF) in their intimate heterosexual relationships. The VISTA Program’s approach to assessment, education and support, and advocacy frames a description of the impact services have had on the lives of WWUF. By contextualizing a woman’s experiences, with the aid of the ecological nested model, VISTA staff tailor services to member needs. This article’s purpose is to provide an extended view of serving WWUF, one grounded in a “healing place” approach that builds on traditional survivors support group strengths and is distinctly different from batterers’ intervention.
American Indian Homicide
Authors: Lanier Christina , Huff-Corzine Lin
Published: June 2006

Research on lethal violence has generally been directed at White and African American populations, with few studies addressing this issue among American Indians. Interestingly, national data indicate that American Indians have one of the highest homicide rates among racial groups. In an effort to identify the etiological underpinnings of this violence, the current study examines whether variation in county-level American Indian homicide rates can be explained by social disorganization theory. Specifically, the authors investigate the impact of economic deprivation, ethnic heterogeneity, mobility, and family disruption on homicide levels among American Indian populations.
Exploring Demographic, Structural, and Behavioral Overlap Among Homicide Offenders and Victims
Authors: Broidy Lisa M. , Daday Jerry K. , Crandall Cameron S. , Sklar David P. , Jost Peter F.
Published: June 2006

Criminologists tend to focus their attention on the dynamics of offending, paying limited theoretical and empirical attention to the well-established relation between offending and victimization. However, a number of criminological theories predict similarities in the correlates and etiology of victimization and offending, suggesting substantial overlap across offender and victim populations. Empirical research confirms this overlap across offender and victim populations, at least among those involved in non-lethal incidents. This research explores whether similarities between offender and victim populations extend to homicide, using criminal justice, health care, and U.S. Census data linked to homicide offenders and victims in Bernalillo County, New Mexico, between 1996 and 2001. Findings indicate substantial overlap in the social contexts and risk behaviors of homicide offenders and victims. However, results also side with more recent suggestions that although many victims overlap with offender populations, there is also a group of victims that appears to be distinguishable from offender groups. These findings have important implications for both theory and intervention.