bluuebunny/crossref_metadata_2025 huggingface dataset:
Coordination of Centrosome Homeostasis and DNA Repair Is Intact in MCF-7 and Disrupted in MDA-MB 231 Breast Cancer Cells
Authors: Acu Ilie D. , Liu Tieju , Suino-Powell Kelly , Mooney Steven M. , D'Assoro Antonino B. , Rowland Nicholas , Muotri Alysson R. , Correa Ricardo G. , Niu Yun , Kumar Rajiv , Salisbury Jeffrey L.
Published: April 2010

When cells encounter substantial DNA damage, critical cell cycle events are halted while DNA repair mechanisms are activated to restore genome integrity. Genomic integrity also depends on proper assembly and function of the bipolar mitotic spindle, which is required for equal chromosome segregation. Failure to execute either of these processes leads to genomic instability, aging, and cancer. Here, we show that following DNA damage in the breast cancer cell line MCF-7, the centrosome protein centrin2 moves from the cytoplasm and accumulates in the nucleus in a xeroderma pigmentosum complementation group C protein (XPC)–dependent manner, reducing the available cytoplasmic pool of this key centriole protein and preventing centrosome amplification. MDA-MB 231 cells do not express XPC and fail to move centrin into the nucleus following DNA damage. Reintroduction of XPC expression in MDA-MB 231 cells rescues nuclear centrin2 sequestration and reestablishes control against centrosome amplification, regardless of mutant p53 status. Importantly, the capacity to repair DNA damage was also dependent on the availability of centrin2 in the nucleus. These observations show that centrin and XPC cooperate in a reciprocal mechanism to coordinate centrosome homeostasis and DNA repair and suggest that this process may provide a tractable target to develop treatments to slow progression of cancer and aging. Cancer Res; 70(8); 3320–8. ©2010 AACR.
The Effect of CXCL12 Processing on CD34+ Cell Migration in Myeloproliferative Neoplasms
Authors: Cho Sool Yeon , Xu Mingjiang , Roboz John , Lu Min , Mascarenhas John , Hoffman Ronald
Published: April 2010

Primary myelofibrosis (PMF) and polycythemia vera (PV) are chronic myeloproliferative neoplasms. PMF and, to a lesser degree, PV are characterized by constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interaction between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal role in determining the trafficking of CD34+ cells between the bone marrow (BM) and the PB. PMF, but not PV, is associated with downregulation of CXCR4 by CD34+ cells due to epigenetic events. Both PV and PMF patients have elevated levels of immunoreactive forms of CXCL12 in the BM and PB. Using electrospray mass spectrometry, the PB and BM plasma of PV and PMF patients was shown to contain reduced amounts of intact CXCL12 but significant amounts of several truncated forms of CXCL12, which are lacking in normal PB and BM plasma. These truncated forms of CXCL12 are the product of the action of several serine proteases, including dipeptidyl peptidase-IV, neutrophil elastase, matrix metalloproteinase-2 (MMP-2), MMP-9, and cathepsin G. Unlike CXCL12, these truncates either lack the ability to act as a chemoattractant for CD34+ cells and/or act as an antagonist to the action of CXCL12. These data suggest that proteolytic degradation of CXCL12 is characteristic of both PV and PMF and that the resulting truncated forms of CXCL12, in addition to the reduced expression of CXCR4 by CD34+ cells, lead to a profound mobilization of HSC/HPC in PMF. Cancer Res; 70(8); 3402–10. ©2010 AACR.
Molecular Mechanism of Chemoresistance by Astrocyte Elevated Gene-1
Authors: Yoo Byoung Kwon , Chen Dong , Su Zhao-zhong , Gredler Rachel , Yoo Jinsang , Shah Khalid , Fisher Paul B. , Sarkar Devanand
Published: April 2010

Our recent findings show that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) samples, and AEG-1 plays a central role in regulating development and progression of HCC. In the present study, we elucidate a molecular mechanism of AEG-1–induced chemoresistance, an important characteristic of aggressive cancers. AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein, resulting in increased efflux and decreased accumulation of doxorubicin, promoting doxorubicin resistance. Suppression of MDR1 by small interfering RNA or chemical reagents, or inhibition of AEG-1 or a combination of both genes, significantly increases in vitro sensitivity to doxorubicin. In nude mice xenograft studies, a lentivirus expressing AEG-1 short hairpin RNA, in combination with doxorubicin, profoundly inhibited growth of aggressive human HCC cells compared with either agent alone. We document that although AEG-1 does not affect MDR1 gene transcription, it facilitates association of MDR1 mRNA to polysomes, resulting in increased translation, and AEG-1 also inhibits ubiquitination and subsequent proteasome-mediated degradation of MDR1 protein. This study is the first documentation of a unique aspect of AEG-1 function (i.e., translational and posttranslational regulation of proteins). Inhibition of AEG-1 might provide a means of more effectively using chemotherapy to treat HCC, which displays inherent chemoresistance with aggressive pathology. Cancer Res; 70(8); 3249–58. ©2010 AACR.
Immunohistochemical Expression of BRCA1 and Lethal Prostate Cancer
Authors: Fiorentino Michelangelo , Judson Gregory , Penney Kathryn , Flavin Richard , Stark Jennifer , Fiore Christopher , Fall Katja , Martin Neil , Ma Jing , Sinnott Jennifer , Giovannucci Edward , Stampfer Meir , Sesso Howard D. , Kantoff Philip W. , Finn Stephen , Loda Massimo , Mucci Lorelei
Published: April 2010

BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4–8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136–9. ©2010 AACR.
Mouse Mammary Tumor Virus–like Sequences in Human Breast Cancer
Authors: Lawson James S. , Glenn Wendy K. , Salmons Brian , Ye Yulan , Heng Benjamin , Moody Patrick , Johal Harpreet , Rawlinson William D. , Delprado Warick , Lutze-Mann Louise , Whitaker Noel J.
Published: April 2010

Mouse mammary tumor virus (MMTV) sequences have been reported to be present in some human breast cancers, but it is unclear whether they have any causal role. In mice, MMTV promotes tumor formation indirectly by insertional mutagenesis of Wnt oncogenes that lead to their activation. In this study, we investigated the status of Wnt-1 in human breast cancers harboring MMTV-like sequences encoding viral envelope (env) genes. We confirmed the detection of env sequences in the nucleus of human breast cancer specimens that are similar in appearance to mouse mammary tumors expressing MMTV env sequences. MMTV env sequences in human breast cancers were also nearly indistinguishable from env sequences in mouse MMTV isolates. Further, Wnt-1 expression was higher in specimens of env-positive ductal carcinoma in situ and invasive ductal carcinoma, relative to env-negative specimens. Our findings extend the evidence that MMTV sequences found in naturally occurring mouse mammary tumors can be found in some human breast cancers, prompting further evaluation of causal roles in these settings. Cancer Res; 70(9); 3576–85. ©2010 AACR.
Targeting the Insulin-like Growth Factor Receptor-1R Pathway for Cancer Therapy
Authors: Zha Jiping , Lackner Mark R.
Published: April 2010

Signaling through the insulin-like growth factor receptor (IGF-1R) is required for neoplastic transformation by a number of oncogenes, and preclinical validation studies have suggested IGF-1R is an attractive target for anticancer therapy. A number of small molecules and antibodies targeting IGF-1R have entered clinical development, and early results have suggested that these agents have generally acceptable safety profiles as single agents. Some evidence of antitumor activity has also been reported. This review highlights key aspects of the IGF-1R signaling pathway that implicate it as an attractive therapeutic target in the management of cancer, as well as some key lessons that have emerged from early clinical development of anti-IGF-1R targeting agents. In addition, we consider the importance of selecting indications characterized by pathological alterations in the signaling pathway, rational selection of combinations based on signaling pathway interactions, and strategies for patient selection based on analysis of predictive biomarkers. Clin Cancer Res; 16(9); 2512–7. ©2010 AACR.
Targeted Chemotherapy for Head and Neck Cancer with a Chimeric Oncolytic Adenovirus Coding for Bifunctional Suicide Protein FCU1
Authors: Dias João D. , Liikanen Ilkka , Guse Kilian , Foloppe Johann , Sloniecka Marta , Diaconu Iulia , Rantanen Ville , Eriksson Minna , Hakkarainen Tanja , Lusky Monika , Erbs Philippe , Escutenaire Sophie , Kanerva Anna , Pesonen Sari , Cerullo Vincenzo , Hemminki Akseli
Published: April 2010

Purpose: Transfer of prodrug activation systems into tumors by using replication-deficient viruses has been suggested to be an effective method for achieving high local and low systemic anticancer drug concentrations. However, most current suicide gene therapy strategies are still hindered by poor efficiency of in vivo gene transfer, inefficient tumor penetration, limited bystander cell killing effect, and need of large prodrug doses. We hypothesized that local amplification provided by a replication competent platform would help overcome these limitations.

Experimental Design: We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Δ24FCU1 expressing the fusion suicide gene FCU1. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil.

Results: We examined the efficacy of Ad5/3-Δ24FCU1 and the replication-defective control Ad5/3-FCU1 with and without 5-FC. FCU1 expression was confirmed by Western blot, whereas enzymatic conversion levels in vitro and in vivo were determined by high-performance liquid chromatography separation. Significant antitumor effect was observed in vitro and in vivo in a murine model of head and neck squamous cell carcinoma. Although we observed a decrease in viral DNA copy number in vitro and in tumors treated with Ad5/3-Δ24FCU1 and 5-FC, suggesting an effect on virus replication, the highest antitumor effect was observed for this combination.

Conclusions: It seems feasible and efficacious to combine adenovirus replication to the FCU1 prodrug activation system. Clin Cancer Res; 16(9); 2540–9. ©2010 AACR.
Signal Transducers and Activators of Transcription 5a–Dependent Cross-talk between Follicular Lymphoma Cells and Tumor Microenvironment Characterizes a Group of Patients with Improved Outcome after R-CHOP
Authors: Taskinen Minna , Valo Erkka , Karjalainen-Lindsberg Marja-Liisa , Hautaniemi Sampsa , Meri Seppo , Leppä Sirpa
Published: April 2010

Purpose: Tumor microenvironment has a strong effect on the survival of follicular lymphoma (FL) patients. The aim of this study was to determine what are the signaling pathways that mediate the cross-talk between lymphoma cells and tumor-infiltrating inflammatory cells and contribute to the clinical outcome of FL patients.

Experimental Design: Gene expression profiling and pathway impact analyses were done from pretreatment lymphoma tissue of 24 patients. The findings were validated immunohistochemically in an independent cohort of 81 patients. All patients were treated with the combination of rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone chemotherapy. In addition, microarray was used to screen the genes differentially expressed between control and rituximab-stimulated B-cell lymphoma cells in culture.

Results: Among the transcripts differentially expressed in the FL tissues between the patients with favorable or adverse outcomes, an overrepresentation of genes associated with the signal transducers and activators of transcription (STAT)5a pathway was observed. In a validation set, a better progression-free survival was observed among the patients with high STAT5a protein expression. In the FL tissue, STAT5a positivity was barely detectable in the neoplastic B cells, but a subpopulation of follicular dendritic cells and T lymphocytes showed prominent STAT5a expression. Rituximab was found to induce the expression of STAT5a-associated interleukin-15 in B-lymphoma cells in culture, thereby providing a possible explanation for the cross-talk between rituximab-stimulated FL cells and their microenvironment.

Conclusion: The findings suggest that STAT5a activity in immunologically active nonmalignant cells acts as molecular predictor for rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone–treated FL patients. Clin Cancer Res; 16(9); 2615–23. ©2010 AACR.
Honokiol Inhibits Epidermal Growth Factor Receptor Signaling and Enhances the Antitumor Effects of Epidermal Growth Factor Receptor Inhibitors
Authors: Leeman-Neill Rebecca J. , Cai Quan , Joyce Sonali C. , Thomas Sufi M. , Bhola Neil E. , Neill Daniel B. , Arbiser Jack L. , Grandis Jennifer R.
Published: April 2010

Purpose: This study aimed to investigate the utility of honokiol, a naturally occurring compound, in the treatment of head and neck squamous cell carcinoma (HNSCC) as well as its ability to target the epidermal growth factor receptor (EGFR), a critical therapeutic target in HNSCC, and to enhance the effects of other EGFR-targeting therapies.

Experimental Design: Human HNSCC cell lines and the xenograft animal model of HNSCC were used to test the effects of honokiol treatment.

Results: Honokiol was found to inhibit growth in human HNSCC cell lines, with 50% effective concentration (EC50) values ranging from 3.3 to 7.4 μmol/L, and to induce apoptosis, as shown through Annexin V staining. These effects were associated with inhibition of EGFR signaling, including downstream inhibition of mitogen-activated protein kinase, Akt, and signal transducer and activator of transcription 3 (STAT3), and expression of STAT3 target genes, Bcl-XL and cyclin D1. Furthermore, honokiol enhanced the growth inhibitory and anti-invasion activity of the EGFR-targeting agent erlotinib. Although HNSCC xenograft models did not show significant inhibition of in vivo tumor growth with honokiol treatment alone, the combination of honokiol plus cetuximab, a Food and Drug Administration–approved EGFR inhibitor for this malignancy, significantly enhanced growth inhibition. Finally, HNSCC cells rendered resistant to erlotinib retained sensitivity to the growth inhibitory effects of honokiol.

Conclusions: These results suggest that honokiol may be an effective therapeutic agent in HNSCC, in which it can augment the effects of EGFR inhibitors and overcome drug resistance. Clin Cancer Res; 16(9); 2571–9. ©2010 AACR.
Activity of the Aurora Kinase Inhibitor VX-680 against Bcr/Abl-Positive Acute Lymphoblastic Leukemias
Authors: Fei Fei , Stoddart Sonia , Groffen John , Heisterkamp Nora
Published: April 2010

The emergence of resistance to tyrosine kinase inhibitors due to point mutations in Bcr/Abl is a challenging problem for Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL) patients, especially for those with the T315I mutation, against which neither nilotinib or dasatinib shows significant activity. VX-680 is a pan-Aurora kinase inhibitor active against all Bcr/Abl proteins but has not been extensively examined in preclinical models of Ph-positive ALL. Here, we have tested VX-680 for the treatment of Bcr/Abl-positive ALL when leukemic cells are protected by the presence of stroma. Under these conditions, VX-680 showed significant effects on primary human Ph-positive ALL cells both with and without the T315I mutation, including ablation of tyrosine phosphorylation downstream of Bcr/Abl, decreased viability, and induction of apoptosis. However, drug treatment of human Ph-positive ALL cells for 3 days followed by drug removal allowed the outgrowth of abnormal cells 21 days later, and on culture of mouse Bcr/Abl ALL cells on stroma with lower concentrations of VX-680, drug-resistant cells emerged. Combined treatment of human ALL cells lacking the T315I mutation with both VX-680 and dasatinib caused significantly more cytotoxicity than each drug alone. We suggest that use of VX-680 together with a second effective drug as first-line treatment for Ph-positive ALL is likely to be safer and more useful than second-line treatment with VX-680 as monotherapy for drug-resistant T315I Ph-positive ALL. Mol Cancer Ther; 9(5); 1318–27. ©2010 AACR.
Deficiency in the 15-kDa Selenoprotein Inhibits Tumorigenicity and Metastasis of Colon Cancer Cells
Authors: Irons Robert , Tsuji Petra A. , Carlson Bradley A. , Ouyang Ping , Yoo Min-Hyuk , Xu Xue-Ming , Hatfield Dolph L. , Gladyshev Vadim N. , Davis Cindy D.
Published: April 2010

Selenium has cancer-preventive activity that is mediated, in part, through selenoproteins. The role of the 15-kDa selenoprotein (Sep15) in colon cancer was assessed by preparing and using mouse colon CT26 cells stably transfected with short hairpin RNA constructs targeting Sep15. Metabolic 75Se labeling and Northern and Western blot analyses revealed that >90% of Sep15 was downregulated. Growth of the resulting Sep15-deficient CT26 cells was reduced (P < 0.01), and cells formed significantly (P < 0.001) fewer colonies in soft agar compared with control CT26 cells. Whereas most (14 of 15) BALB/c mice injected with control cells developed tumors, few (3 of 30) mice injected with Sep15-deficient cells developed tumors (P < 0.0001). The ability to form pulmonary metastases had similar results. Mice injected with the plasmid-transfected control cells had >250 lung metastases per mouse; however, mice injected with cells with downregulation of Sep15 only had 7.8 ± 5.4 metastases. To investigate molecular targets affected by Sep15 status, gene expression patterns between control and knockdown CT26 cells were compared. Ingenuity Pathways Analysis was used to analyze the 1,045 genes that were significantly (P < 0.001) affected by Sep15 deficiency. The highest-scored biological functions were cancer and cellular growth and proliferation. Consistent with these observations, subsequent analyses revealed a G2-M cell cycle arrest in cells with targeted downregulation of Sep15. In contrast to CT26 cells, Sep15-targeted downregulation in Lewis lung carcinoma (LLC1) cells did not affect anchorage-dependent or anchorage-independent cell growth. These data suggest tissue specificity in the cancer-protective effects of Sep15 downregulation, which are mediated, at least in part, by influencing the cell cycle. Cancer Prev Res; 3(5); 630–9. ©2010 AACR.
Combination of Tubularized Island Flap and Ventral Skin Flap Techniques in Single-Stage Correction of Severe Proximal Hypospadias
Authors: Tiryaki Tugrul
Published: April 2010

Objectives: To evaluate the success of the combined tubularized island flap (Duckett technique) and Thiersch-Duplay techniques in one-stage correction of proximal hypospadias. Methods: Thirty-four patients underwent surgical treatment for penoscrotal hypospadias in the last 9 years. Combined tubularized island flap (Duckett technique) and tubularized ventral skin (Thiersch-Duplay) procedures were performed in each case. The proximal urethra was repaired by the Thiersch-Duplay technique through the base of the phallus, and distal urethral repair was conducted via the tubularized island flap procedure. Results: The follow-up lasted from 5 months to 6 years (mean 4.1 years). The overall complication rate was 26%, but no recurrent chordee was detected. Recurrent fistulae were noted in 7 patients (20.5%). Anastomatic stricture was noted in 3 patients (8.8%). Conclusion: A combination of Duckett’s preputial tube and the Thiersch-Duplay procedure was employed to treat 34 cases of severe hypospadias, with a success rate of 74%. In our procedure, the island flap tube is relatively short. Oblique anastomoses of proximal and distal tubes were made, and the pedicule of the flap supported the neourethra following successful interventions. Because of the low complication and high success rates, this combination of two procedures is recommended for repair of severe proximal hypospadias.
Effect of Thioglycolic Acid Instillation to Stop Hair Growth on the Urethral Mucosa after Urethroplasty with Hairy Skin in a Rat Model
Authors: Sunay Melih , Dadalı Mümtaz , Emir Levent , Karabulut Ayhan , Erol Demokan
Published: April 2010

Objective: The aim of this study was to investigate the impact of thioglycolic acid on normal urethral mucosa. Methods: Twenty-four rats were used. Three control and three study groups were formed each consisting of 4 rats. Controls groups were given 0.9% NaCl and study groups received thioglycolic acid instillation. The groups were allocated according to the time of urethral resection and the number of thioglycolic acid instillations (2, 4 or 8 instillations). The urethras of the rats were resected and examined under a light microscope in control and study groups 1, 2 and 3 on days 15, 30 and 60. Results: There was no difference in the urethral mucosa of rats in the study or control groups, and no differences were found when the study groups were compared to each of the other groups at the microscopic level. Conclusion: The application of thioglycolic acid is an easy and inexpensive way of clearing urethral hair and does not cause pathological changes in the normal urethral mucosa.
Renal Cell Carcinoma in Young Adults: A Study of 130 Cases and a Review of Previous Series
Authors: López José I. , Moreno Virginia , García Huberto , Antón Iosu , Robles Antonio , Oñate Juan M. , Baños Ángeles , Escandón Jorge , Ugalde Aitziber
Published: April 2010

Objective: To characterize a large series of renal cell carcinomas (RCCs) in young patients and to compare the data obtained to previously published data. Patients and Methods: A total of 130 RCCs diagnosed in patients <40 years of age were collected from 9 different hospitals in Spain. Cases were re-evaluated following the diagnostic criteria of the 2004 WHO classification of renal tumors. Results: Histologically, tumors were classified as clear cell (50.7%), papillary (8.5%), chromophobe (14.6%), unclassified (16.9%) and clear cell papillary (9.3%) RCCs. Organ-confined disease (OCD) was detected in 83.6% of the cases. Tumor size and Fuhrman’s grade were statistically correlated (Spearman’s ρ = 0.391). CD10 (p = 0.000), CK7 (p = 0.000), CD15 (p = 0.016), CD117 (p = 0.000), 34βE12 cytokeratin (p = 0.034) and e-cadherin (p = 0.000) immunostaining significantly differentiated the five histological categories. Conclusions: OCD was more common in young RCC patients. The clear cell phenotype accounted for only 50% of RCCs in this age group, with an increasing number of chromophobe and unclassified RCCs. Clear cell RCCs with a papillary growth pattern accounted for a significant proportion of the cases.
Male-to-Female Transsexualism: Technique, Results and 3-Year Follow-Up in 50 Patients
Authors: Wagner S. , Greco F. , Hoda M.R. , Inferrera A. , Lupo A. , Hamza A. , Fornara P.
Published: April 2010

Aim: To evaluate the functional and cosmetic results of male-to-female gender-transforming surgery. Patients and Methods: Between May 2001 and April 2008 we performed 50 male-to-female gender-transforming surgeries. All patients had been cross-dressing, living as women, and receiving estrogen and progesterone for at least 12 months, which was sufficient for breast development and atrophy of the testes and prostate to occur. This hormonal therapy was suspended 1 month before the operation. Results: The mean operative time was 190 min and the mean depth of the vagina was 10 cm. On follow-up, the most common complication (10%) was shrinkage of the neovagina, which could be corrected by a second surgical intervention. Of the 50 patients, 45 (90%) were satisfied with the esthetic results; 42 patients (84%) reported having regular sexual intercourse, 2 of whom had pain during intercourse. Of the 50 patients, 35 (70%) reported achieving clitoral orgasm. Conclusion: Male-to-female gender-transforming surgery can assure satisfactory cosmetic and functional results, with a reduced intra- and postoperative morbidity. Nevertheless the experience of the surgeon and the center remains central to obtaining optimal results.
Decreased Expression of FGFR1, SOS1, RAF1 Genes in Cryptorchidism
Authors: Hadziselimovic N.O. , de Geyter Ch. , Demougin P. , Oakeley E.J. , Hadziselimovic F.
Published: April 2010

Background: In recent years, several genes were found to be involved in the process of epididymo-testicular descent, the most frequently cited ones include INSL3, HOXA10, GNRHR, and KAL1. In this study, we analyzed the differences in gene expression profiles between cryptorchid and descended testes. In particular, we analyzed expression of all recently published genes known to be associated with undescended testis. Patients and Methods: Twenty-two testicular biopsies from 18 boys were analyzed. We analyzed gene expression in 16 cryptorchid and 6 descended testes using Affymetrix Human Genome U133 Plus 2.0 GeneChips, and validated the results with qPCR. Results: 3,688 transcripts were differentially expressed with an adjusted p value of <0.05 and a change of at least 1.5-fold. The list contained 1,866 downregulated and 1,822 upregulated transcripts in the cryptorchid testes. A novel observation in our study was that the fibroblast growth factor receptor 1 gene (FGFR1) and its mediators SOS1 and RAF1 were expressed less in undescended testes. Conclusion: Based on our results, it is possible that a subtle dysfunction (expression) of the FGFR1, SOS1 and RAF1 genes is involved in the development of the most common male reproductive tract disorder – unilateral or bilateral cryptorchidism.
A Worksite Vegan Nutrition Program Is Well-Accepted and Improves Health-Related Quality of Life and Work Productivity
Authors: Katcher Heather I. , Ferdowsian Hope R. , Hoover Valerie J. , Cohen Joshua L. , Barnard Neal D.
Published: April 2010

Background/Aims: Vegetarian and vegan diets are effective in preventing and treating several chronic diseases. However, their acceptability outside a clinical trial setting has not been extensively studied. The aim of this study was to determine the acceptability of a worksite vegan nutrition program and its effects on health-related quality of life and work productivity. Methods: Employees of a major insurance corporation with a body mass index ≧25 kg/m2 and/or a previous diagnosis of type 2 diabetes received either weekly group instruction on a low-fat vegan diet (n = 68) or received no diet instruction (n = 45) for 22 weeks. Results: The vegan group reported improvements in general health (p = 0.002), physical functioning (p = 0.001), mental health (p = 0.03), vitality (p = 0.004), and overall diet satisfaction (p < 0.001) compared with the control group. The vegan group also reported a decrease in food costs (p = 0.003), and increased difficulty finding foods when eating out (p = 0.04) compared with the control group. The vegan group reported a 40–46% decrease in health-related productivity impairments at work (p = 0.03) and in regular daily activities (p = 0.004). Conclusions: A worksite vegan nutrition program is well-accepted and can be implemented by employers to improve the health, quality of life, and work productivity of employees.
Core and Suggestive Symptoms of Dementia with Lewy Bodies Cluster in Persons with Mild Dementia
Authors: Rongve Arvid , Brønnick Kolbjørn , Ballard Clive , Aarsland Dag
Published: April 2010

Objectives: To explore how the core and suggestive symptoms of dementia with Lewy bodies (DLB) cluster in persons with newly diagnosed mild dementia, and whether they are associated with a particular pattern of cognitive impairment. Method: Persons with mild dementia (n = 139) were recruited from dementia clinics in western Norway. Symptoms were rated using standardized instruments. A 2-step cluster analysis was applied to classify persons into groups according to scores on scales for hallucinations, parkinsonism, fluctuations and REM sleep behaviour disorder (RBD). Result: Four distinct clusters were revealed: a ‘Lewy body dementia’ (LBD) cluster with high scores for hallucinations, parkinsonism and fluctuation, and a ‘non-LBD’ cluster with low scores on all DLB symptom scales. In addition, 2 clusters with high scores on either RBD or cognitive fluctuation scales emerged. Persons in the LBD cluster had lower scores for visuospatial cognitive abilities as compared to the non-LBD group (p = 0.002). Conclusion: Applying cluster analysis, we identified distinct subgroups in mild dementia based on symptoms such as hallucinations, parkinsonism and cognitive fluctuations. Our findings provide empirical support for diagnosing DLB. Visual hallucinations and motor parkinsonism might be the most distinguishing symptoms for DLB in mild dementia.
Indoxyl Sulfate Upregulates Expression of ICAM-1 and MCP-1 by Oxidative Stress-Induced NF-ĸB Activation
Authors: Tumur Zohra , Shimizu Hidehisa , Enomoto Atsushi , Miyazaki Hitoshi , Niwa Toshimitsu
Published: April 2010

Background/Aim: Indoxyl sulfate, a uremic toxin, is considered a risk factor for cardiovascular disease (CVD) in chronic kidney disease (CKD). The present study aimed to determine whether indoxyl sulfate increases the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemotactic protein-1 (MCP-1) by reactive oxygen species (ROS)-induced activation of nuclear factor-ĸB (NF-ĸB) in vascular endothelial cells. Methods: Human umbilical vein endothelial cells (HUVEC) were incubated with indoxyl sulfate. The expression of ICAM-1 and MCP-1 in HUVEC was analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Phospho-NF-ĸB p65 (Ser 536), an active form of the NF-ĸB subunit, was determined by Western blotting. Results: Indoxyl sulfate significantly increased the mRNA expression of ICAM-1 and MCP-1 in HUVEC in a time- and concentration-dependent manner. Inhibitors of NF-ĸB (ammonium pyrrolidinedithiocarbamate and isohelenin) and an antioxidant (N-acetyl-L-cysteine) suppressed the indoxyl sulfate-induced expression of ICAM-1 and MCP-1 in HUVEC. Indoxyl sulfate increased phospho- NF-ĸB p65 in HUVEC, and N-acetyl-L-cysteine suppressed it. Conclusions: Indoxyl sulfate upregulates the expression of ICAM-1 and MCP-1 by ROS-induced activation of NF-ĸB in vascular endothelial cells. Thus, indoxyl sulfate may play an important role in the development of CVD in CKD by increasing the endothelial expression of ICAM-1 and MCP-1.
Acid-Labile Subunit Deficiency and Growth Failure: Description of Two Novel Cases
Authors: David A. , Rose S.J. , Miraki-Moud F. , Metherell L.A. , Savage M.O. , Clark A.J.L. , Camacho-Hübner C.
Published: April 2010

Background/Aims: Mutations in the acid-labile subunit (ALS) gene (IGFALS) have been associated with circulating insulin-like growth factor I (IGF-I) deficiency and short stature. Whether severe pubertal delay is also part of the phenotype remains controversial due to the small number of cases reported. We report 2 children with a history of growth failure due to novel IGFALS mutations. Methods: The growth hormone receptor gene (GHR) and IGFALS were analyzed by direct sequencing. Ternary complex formation was studied by size exclusion chromatography. Results: Two boys of 13.3 and 10.6 years, with pubertal stages 2 and 1, had mild short stature (–3.2 and –2.8 SDS, respectively) and a biochemical profile suggestive of growth hormone resistance. No defects were identified in the GHR. Patient 1 was homozygous for the IGFALS missense mutation P73L. Patient 2 was a compound heterozygote for the missense mutation L134Q and a novel GGC to AG substitution at position 546–548 (546–548delGGCinsAG). The latter causes a frameshift and the appearance of a premature stop codon. Size exclusion chromatography showed no peaks corresponding to ternary and binary complexes in either patient. Conclusion: Screening of the IGFALS is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.
Impaired Body Weight and Tail Length Gain and Altered Bone Quality after Treatment with the Aromatase Inhibitor Exemestane in Male Rats
Authors: van Gool Sandy A. , Wit Jan M. , De Schutter Tineke , De Clerck Nora , Postnov Andreï A. , Kremer Hovinga Sandra , van Doorn Jaap , Veiga Sergio J. , Garcia-Segura Luis Miguel , Karperien Marcel
Published: April 2010

Background: Estrogen deficiency induced by aromatase inhibitors may be a novel treatment modality for growth enhancement in short children, but may have adverse effects on bone, brain and reproduction. Aim: To assess growth effects and potential adverse effects of aromatase inhibition in male rats. Methods: 26-day-old prepubertal rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week [E10, E30, E100(6)] for 6 weeks, completely covering the sexual maturation phase, or with 3 weeks E100 followed by 3 weeks placebo [E100(3)]. Growth parameters and histology of the testis, seminal vesicle and brain were analyzed. Bone architecture was studied with X-ray microtomography. Results: Exemestane dose-dependently decreased body weight and tail length gain, as well as liver and seminal vesicle weights, but did not affect nose-anus length gain, growth plate width or radial growth. E100(6) decreased trabecular thickness (epiphysis and metaphysis) and number (metaphysis). Normal IGF-I levels and brain, testis and seminal vesicle morphology were observed. E100(3) resulted in decreased tail length gain only. Conclusion: Exemestane treatment during sexual maturation did not augment linear growth in male rats, but caused impaired body weight and tail length gain and osteopenia.
Auditory and Vestibular Assessment of Patients with Ménière’s Disease Who Suffer Tumarkin Attacks
Authors: Perez-Fernandez Nicolas , Montes-Jovellar Lourdes , Cervera-Paz Javier , Domenech-Vadillo Ester
Published: April 2010

Tumarkin attacks are a feature of Ménière’s disease that generate a significant degree of disability. The surprising nature of these events is the main reason behind their associated morbidity. In this study we set out to evaluate auditory and vestibular function, as well as disability, in a population of patients who suffer Tumarkin attacks. We found that patients who suffer Tumarkin attacks are more disabled and experience severer and more frequent autonomic symptoms and that their hearing level is significantly worse in the asymptomatic ear, especially at low frequencies. Accordingly, we consider that treatment must be carefully planned to be as conservative as possible in terms of hearing and that psychiatric and/or psychological treatment must always be considered as an adjuvant therapy.
Fibrates, Glitazones, and Peroxisome Proliferator–Activated Receptors
Authors: Lalloyer Fanny , Staels Bart
Published: April 2010

Several decades ago, fibrates were approved for the treatment of dyslipidemia, whereas thiazolidinediones were screened in animal models to improve glucose homeostasis and were subsequently developed for the treatment of type 2 diabetes mellitus. Relatively recently, these drugs were found to act via peroxisome proliferator–activated receptors, nuclear receptors that control lipid metabolism and glucose homeostasis. In this historical perspective, we discuss the history of discovery of the peroxisome proliferator–activated receptors, from the clinical development of their agonists to the subsequent discovery of these receptors and their mechanisms of action, to finally evoke possibilities of targeted pharmacology for future development of selective peroxisome proliferator–activated receptor modulators.
Variation in Cardiologists’ Propensity to Test and Treat
Authors: Lucas Frances Lee , Sirovich Brenda E. , Gallagher Patricia M. , Siewers Andrea E. , Wennberg David E.
Published: April 2010

Background—

Regional variation in healthcare utilization, including cardiac testing and procedures, is well documented. Some factors underlying such variation are understood, including resource supply. However, less is known about how physician behaviors and attitudes may influence variation in utilization across regions.

Methods and Results—

We performed a survey of a national sample of cardiologists using patients vignettes to ascertain physicians’ self-reported propensity to test and treat patients with cardiovascular problems, computing a Cardiac Intensity Score for each physician based on his/her responses intended to measure the physician’s propensity to recommend high-tech and/or invasive tests and treatments. In addition, we asked under what circumstances they would order a cardiac catheterization “for other than purely clinical reasons.” For some survey items, there was substantial variation in physician responses. We found that the Cardiac Intensity Score was associated with 2 measures of population based healthcare utilization measured within geographic regions, with a stronger association with general healthcare spending than with delivery of cardiac services. Although nearly all physicians denied ordering a potentially unnecessary cardiac catheterization for financial reasons, some physicians acknowledged ordering the test for other reasons, including meeting patient and referring physician expectations, meeting peer expectations, and malpractice concerns. More than 27% of respondents reported ordering a cardiac catheterization if a colleague would in the same situation frequently or sometimes, and nearly 24% reported doing so out of fear of malpractice. These 2 factors were significantly associated with the propensity to test and treat, but only fear of malpractice was associated with regional utilization.

Conclusions—

Variability in cardiologists’ propensity to test and treat partly underlies regional variation in utilization of general health and cardiology services. The factor most closely associated with this propensity was fear of malpractice suits. This factor may be an appropriate target of intervention.
National Law: A Small but Neat Utensil in the Toolbox of International Criminal Tribunals
Authors: van der Wilt Harmen
Published: April 2010

This article explores to what extent the ad hoc tribunals have made use of the national law of the state where the crimes have allegedly been committed in their quest for elements of crimes, concepts of criminal responsibility, grounds for excluding criminal responsibility and guidelines for sentencing. At first sight, one would expect the legislation of the territorial state to feature only as an indication of 'general principles of law' or 'international customary law'. However, the investigation of case law reveals that the law of the territorial state holds a far more prominent place. In search for rationales, the author suggests that, initially, national legislation has been used to plug the legal gaps in international criminal law. However, more recently the ad hoc tribunals have canvassed the national legislation of the territorial state, in order to find out whether this state would qualify to take over criminal proceedings against mid-level perpetrators. The author suggests that the International Criminal Court might follow suit, in order to give shape to its policy of 'positive complementarity'.
Investigating the Crimes of the Franco Regime: Legal Possibilities, Obligations of the Spanish State and Duties Towards the Victims
Authors: Barbeito Mónica Zapico
Published: April 2010

The opening on 16th October 2008 by the Examining Judge of the High Court Baltasar Garzón of the first cause to investigate crimes committed during the Spanish Civil War and Franco's regime has initiated a vigorous debate about not only the convenience, but also the legal possibilities to carry out this research and can meet the demands of the families of the victims, who are dissatisfied with the Law of Historical Memory. This article attempts to analyze the main problems posed by the possibility that these crimes are investigated: the problem of non-retroactivity of criminal law and the classification of the facts committed as crimes against humanity; the question of the permanence of the crime of illegal detention and, in relation to this, the question of the statute of limitations; the existence of an amnesty law; the international obligations of the Spanish State and the duties towards the victims.
Armless Giants: Cooperation, State Responsibility and Suggestions for the ICC Review Conference
Authors: Demirdjian Alexis
Published: April 2010

International criminal courts and tribunals regularly face difficulties in obtaining cooperation from States, a stumbling block that hinders the process of bringing criminals to justice and trying them before a court of law. In doing so, States can be held accountable under the rules of state responsibility. This possibility was raised in key decisions and scholarly texts on the issue. This paper seeks to expand the discussion on the matter and analyze the responsibility of States for their failure to cooperate with international courts. Additionally, this paper suggests amendments to the ICC Rome Statute to strengthen the judicial assistance regime, considering that this court is designed to become the permanent court dealing with war crimes and crimes against humanity and that a review of the Statute is to take place in May or June 2010.
Has the United Nations Security Council Implicitly Removed Al Bashir's Immunity?
Authors: Papillon Sophie
Published: April 2010

On 4 March 2009, the ICC issued an arrest warrant for Omar Hassan Ahmad Al Bashir, the incumbent Head of State of Sudan. This article's purpose is to suggest a legal basis for reconciling the well established rule on personal immunities under customary international law with the prosecution of Heads of State from non-parties to the ICC Statute. While arguing for the legality of Al Bashir's warrant as well as the legality of the warrant's enforcement, this article explores the basis upon which the UN Security Council can remove immunities. By giving special attention to the concept of waivers, the article suggests that the UN organ implicitly removed Al Bashir's immunity when it referred the situation of Sudan to the ICC in 2005.
Negotiating Boundaries and Bonds: Frequency of Young Children’s Socialization to Their Ethnic/Racial Heritage
Authors: Lesane-Brown Chase L. , Brown Tony N. , Tanner-Smith Emily E. , Bruce Marino A.
Published: April 2010

This study addressed intergroup differences in how often U.S. families socialized young children to their ethnic/racial heritage using nationally representative survey data gathered as part of the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999 (ECLS-K).The sample ( N = 18,827) included young White, Black, Hispanic, Asian, Native Hawaiian/Pacific Islander, American Indian, and multiracial children. Among other things, the authors found that families raising young American Indian children were likely to socialize them frequently to their ethnic/racial heritage. Also, most intergroup differences in frequency of ethnic/racial socialization were robust across child gender and parental education.
Continuity in Parenting Strategies: A Cross-Cultural Comparison
Authors: Keller Heidi , Borke Jörn , Chaudhary Nandita , Lamm Bettina , Kleis Astrid
Published: April 2010

This prospective longitudinal study is aimed at contributing to the understanding of cultural diversity concerning maternal parenting behaviors and conversational styles on one hand and continuity in parenting strategies on the other hand. It could be demonstrated that German middle-class families from Berlin and Indian Hindu middle-class families from Delhi represent two different cultural environments embodying different parenting strategies. The Berlin mothers focus on the cultural model of independence, whereas the Delhi mothers focus on the cultural model of autonomous relatedness. These different orientations are expressed in nonverbal and conversational behaviors with 3-month-old babies as well as in the play styles with 19-month-old toddlers. It could also be demonstrated that the parenting styles form continuous socialization environments. Especially the conversation styles that mothers use while talking to their 3-month-old babies were good predictors for the play styles with their 19-month-old toddlers. The results are discussed with an emphasis on parenting strategies as continuous and consistent cultural projects.
Optimistic and Pessimistic Bias in European Americans and Asian Americans: A Preliminary Look at Distinguishing Between Predictions for Physical and Psychological Health Outcomes
Authors: Chang Edward C. , Sanna Lawrence J. , Kim Jean M. , Srivastava Kavita
Published: April 2010

The present research examined optimistic and pessimistic bias in the prediction of positive and negative physical and psychological health outcomes between European American and Asian American college students. Results of between-group and within-group analyses indicated both similarities and differences in predictions for health outcomes. Sex differences were also found. Taken together, these findings point to a need to consider both culture and sex differences in the prediction of health.
Indecisiveness and Culture: Incidence, Values, and Thoroughness
Authors: Yates J. Frank , Ji Li-Jun , Oka Takashi , Lee Ju-Whei , Shinotsuka Hiromi , Sieck Winston R.
Published: April 2010

Three studies examined cultural variations in indecisiveness among Chinese, Japanese, and Americans. In Study 1, validated self-report, comprehensive measures of indecisiveness indicated large cultural differences, with Japanese participants exhibiting substantially more indecisiveness than Chinese or Americans. Study 2 provided evidence that such cultural variations correspond to variations in people’s positive versus negative values for decisive behaviors, suggesting that such values are plausibly an important means for motivating and sustaining cultural differences in indecisiveness. Study 3 provided direct behavioral instances of the differences in indecisiveness implicated in Studies 1 and 2. It also suggested that thoroughness might be an important cognitive mechanism whereby cultural differences in indecision actually occur, with thoroughness being especially prominent among Japanese decision makers. Suggestions for theory concerning the nature and foundations of indecisiveness and its cultural variations are developed and discussed, along with plausible implications for real-life practical issues, for example, in politics and management.