bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Inhibitor of Signal Transducers And Activators Of Transcription 3 Activation Is Efficacious Against Established Central Nervous System Melanoma and Inhibits Regulatory T Cells
Authors: Kong Ling-Yuan , Abou-Ghazal Mohamed K. , Wei Jun , Chakraborty Arup , Sun Wei , Qiao Wei , Fuller Gregory N. , Fokt Izabela , Grimm Elizabeth A. , Schmittling Robert J. , Archer Gary E. , Sampson John H. , Priebe Waldemar , Heimberger Amy B.
Published: September 2008

Purpose: Activation of signal transducers and activators of transcription 3 (STAT3) has been identified as a central mediator of melanoma growth and metastasis. We hypothesized that WP1066, a novel STAT3 blockade agent, has marked antitumor activity, even against the melanoma metastasis to brain, a site typically refractory to therapies.

Experimental Design: The antitumor activities and related mechanisms of WP1066 were investigated both in vitro on melanoma cell lines and in vivo on mice with subcutaneously syngeneic melanoma or with intracerebral melanoma tumors.

Results: WP1066 achieved an IC50 of 1.6, 2.3, and 1.5 μmol/L against melanoma cell line A375, B16, and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of Janus-activated kinase 2 and STAT3 (Tyr705) in these cells. Tumor growth in mice with subcutaneously established syngeneic melanoma was markedly inhibited by WP1066 compared with that in controls. Long-term survival (>78 days) was observed in 80% of mice with established intracerebral syngeneic melanoma treated with 40 mg/kg of WP1066 in contrast to control mice who survived for a median of 15 days. Although WP1066 did not induce immunologic memory or enhance humoral responses to EGFRvIII, this compound reduced the production of immunosuppressive cytokines and chemokines (transforming growth factor-β, RANTES, MCP-1, vascular endothelial growth factor), markedly inhibited natural and inducible Treg proliferation, and significantly increased cytotoxic immune responses of T cells.

Conclusions: The antitumor cytotoxic effects of WP1066 and its ability to induce antitumor immune responses suggest that this compound has potential for the effective treatment of melanoma metastatic to brain.
Association of Common PALB2 Polymorphisms with Breast Cancer Risk: A Case-Control Study
Authors: Chen Peizhan , Liang Jie , Wang Zhanwei , Zhou Xiaoyi , Chen Lu , Li Mian , Xie Dong , Hu Zhibin , Shen Hongbing , Wang Hui
Published: September 2008

Purpose: The PALB2 gene has an essential role in BRCA2-mediated DNA double-strand break repair and intra–S phase DNA damage checkpoint control, and its mutations are moderately associated with breast cancer susceptibility. This study was designed to investigate the common variants of PALB2 and their association with breast cancer risk.

Experimental Design: Four single nucleotide polymorphisms (SNP; rs249954, rs249935, rs120963, and rs16940342) which tagged all 19 of the reported SNPs (minor allele frequency >0.05) covering PALB2 were selected and genotyped in 1,049 patients with breast cancer and 1,073 cancer-free controls in a female Chinese population.

Results: Based on the multiple hypothesis testing with the Benjamini-Hochberg method, tagging SNPs (tSNP) rs249954, rs120963, and rs16940342 were found to be associated with an increase of breast cancer risk (false discovery rate–adjusted P values of 0.004, 0.028, and 0.049, respectively) under the dominant model. tSNP rs249954 was associated with a 36% increase of breast cancer risk [adjusted odds ratio (OR), 1.36; 95% confidence intervals (CI), 1.13-1.64; P = 0.001; TT/TC versus CC genotypes]. The adjusted OR for rs120963 was 1.25 (95% CI, 1.04-1.49; P = 0.014; CC/CT versus TT genotypes). For rs16940342, the adjusted OR was 1.21 (95% CI, 1.02-1.45; P = 0.037; GG/GA versus AA genotypes). Based on an additive model, tSNPs rs249954 and rs120963 were associated with an increase of breast cancer risk (P = 0.005 and 0.019; respectively), with the false discovery rate–adjusted P values being 0.020 and 0.038, respectively.

Conclusions: Our data suggest that the variants of PALB2 confer low-penetrance breast cancer susceptibility in a Chinese population.
Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study
Authors: Personeni Nicola , Fieuws Steffen , Piessevaux Hubert , De Hertogh Gert , De Schutter Jef , Biesmans Bart , De Roock Wendy , Capoen An , Debiec-Rychter Maria , Van Laethem Jean-Luc , Peeters Marc , Humblet Yves , Van Cutsem Eric , Tejpar Sabine
Published: September 2008

Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored.

Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction.

Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005).

Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.
Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor–Associated PDGFRAD842V Mutation
Authors: Dewaele Barbara , Wasag Bartosz , Cools Jan , Sciot Raf , Prenen Hans , Vandenberghe Peter , Wozniak Agnieszka , Schöffski Patrick , Marynen Peter , Debiec-Rychter Maria
Published: September 2008

Purpose: Activating mutations in platelet-derived growth factor receptor-α (PDGFRA) have been reported in ∼5% to 10% of patients with gastrointestinal stromal tumors (GIST). Imatinib efficiently inhibits the juxtamembrane PDGFRA mutations, whereas many tyrosine kinase domain activation loop PDGFRA mutations confer primary resistance to imatinib. In this study, we compared the efficacy of second-line tyrosine kinase inhibitors such as dasatinib, sorafenib, and nilotinib against two GIST-related PDGFRA mutants, PDGFRAD842V and PDGFRAΔDIM842-844. In addition, we sought to investigate the inhibitory effect of the heat shock protein 90 inhibitor, IPI-504, on these mutants.

Experimental Design: Primary imatinib-resistant tumor cells and cell lines expressing imatinib-resistant PDGFRAD842V or imatinib-sensitive PDGFRAΔDIM842-844 mutants were treated with different concentrations of dasatinib, sorafenib, nilotinib, and IPI-504. The effect of treatment on proliferation, survival, and signaling was determined.

Results: All inhibitors tested exhibited a high efficacy toward the PDGFRAΔDIM842-844 mutant. In contrast, ex vivo and in vitro assays revealed that only dasatinib potently inhibited the PDGFRAD842V isoform with an IC50 value of 62 nmol/L. Sorafenib and nilotinib were significantly less efficacious against this mutation, inhibiting the PDGFRA kinase activity at >1,000 and >5,000 nmol/L, and suppressing the proliferation of the cells expressing the PDGFRAD842V mutant with an IC50 value of 239 and 1,310 nmol/L, respectively. IPI-504 treatment potently inhibited PDGFRA kinase activity by inducing the degradation of PDGFRAD842V and PDGFRAΔDIM842-844 at 256 and 182 nmol/L, respectively.

Conclusions: Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRAD842V mutant isoform.
Type III Transforming Growth Factor-β (TGF-β) Receptor Mediates Apoptosis in Renal Cell Carcinoma Independent of the Canonical TGF-β Signaling Pathway
Authors: Margulis Vitaly , Maity Tapati , Zhang Xiu-Ying , Cooper Simon J. , Copland John A. , Wood Christopher G.
Published: September 2008

Purpose: Alterations in transforming growth factor-β (TGF-β) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-β receptor (TβRIII) expression. We evaluated the role of TβRIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma.

Experimental Design: TβR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogen-activated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus.

Results: Restoring TβRIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TβRIII mimicked the induction of apoptosis by full-length TβRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TβRIII-associated apoptosis was not dependent on signaling through the canonical TGF-β/Smad pathway but was mediated through p38 MAPK.

Conclusion: These findings indicate a novel mechanistic antitumor function for TβRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.
Pancreatic Cancer Stem Cells: Implications for the Treatment of Pancreatic Cancer
Authors: Simeone Diane M.
Published: September 2008

Pancreatic cancer is a highly lethal disease that is usually diagnosed at a late stage for which there are few effective therapies. Emerging evidence has suggested that malignant tumors are quite heterogeneous and that they are composed of a small subset of distinct cancer cells (usually defined by cell surface marker expression) that are responsible for tumor initiation and propagation, termed cancer stem cells. These cells are termed cancer stem cells because, like normal stem cells, they possess the ability to self-renew and make differentiated progeny. Recent studies of human pancreatic cancers have shown a population of pancreatic cancer stem cells that have aberrantly activated developmental signaling pathways, are resistant to standard chemotherapy and radiation, and have up-regulated signaling cascades that are integral for tumor metastasis. An improved understanding of the biological behavior of these cells may lead to more effective therapies to treat pancreatic cancer. In this review, approaches to develop and test therapeutics targeting pancreatic cancer stem cells are discussed.
Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN
Authors: Woodward Emma R. , Ricketts Christopher , Killick Pip , Gad Sophie , Morris M.R. , Kavalier Fred , Hodgson Shirley V. , Giraud Sophie , Bressac-de Paillerets Brigitte , Chapman Cyril , Escudier Bernard , Latif Farida , Richard Stéphane , Maher Eamonn R.
Published: September 2008

Purpose: Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients with Birt-Hogg-Dube (BHD) syndrome, caused by germline FLCN mutation. Fewer than 20 kindreds with familial cRCC without VHL disease or a constitutional translocation have been described. The purpose of this investigation was to define the clinical and genetic features of familial non-VHL cRCC (FcRCC) and to evaluate whether unrecognized BHD syndrome might be present in patients with apparent nonsyndromic RCC susceptibility.

Experimental Design: We analyzed the clinical features of, and undertook segregation analysis in, 60 kindreds containing two or more cases of RCC (at least one confirmed case of cRCC) and no evidence of an RCC susceptibility syndrome. We also undertook FLCN analysis to evaluate whether unrecognized BHD syndrome might be present in 69 patients with apparent nonsyndromic RCC susceptibility.

Results: FcRCC was characterized by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumors. Segregation analysis showed autosomal dominant inheritance with sex- and age-dependent penetrance. A germline FLCN mutation was detected in 3 of 69 (4.3%) patients with apparent nonsyndromic RCC susceptibility.

Conclusions: We describe the clinical and genetic features of the largest series of FcRCC and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.
Cytochrome P450 2D6 and Homeobox 13/Interleukin-17B Receptor: Combining Inherited and Tumor Gene Markers for Prediction of Tamoxifen Resistance
Authors: Goetz Matthew P. , Suman Vera J. , Couch Fergus J. , Ames Matthew M. , Rae James M. , Erlander Mark G. , Ma Xiao-Jun , Sgroi Dennis C. , Reynolds Carol A. , Lingle Wilma L. , Weinshilboum Richard M. , Flockhart David A. , Desta Zeruesenay , Perez Edith A. , Ingle James N.
Published: September 2008

Purpose: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer.

Experimental Design: Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central Cancer Treatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6*4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling.

Results: CYP2D6 metabolism and HOXB13/IL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13/IL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% CI, 1.17-8.52; P = 0.024).

Conclusions: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.
Chlamydia Infection and Lymphomas: Association Beyond Ocular Adnexal Lymphomas Highlighted by Multiple Detection Methods
Authors: Ponzoni Maurilio , Ferreri Andrés J.M. , Guidoboni Massimo , Lettini Antonia A. , Cangi Maria Giulia , Pasini Elisa , Sacchi Luciano , Pecciarini Lorenza , Grassi Stefano , Dal Cin Elena , Stefano Rosalba , Magnino Simone , Dolcetti Riccardo , Doglioni Claudio
Published: September 2008

Purpose: Chlamydia psittaci (Cp) has been associated to ocular adnexal lymphomas (OAL) with variable geographic distribution. Herein, we used multiple Chlamydia detection tools to identify Cp elementary bodies–containing cell and to assess Cp prevalence in both nodal and extranodal lymphomas.

Experimental Design: TETR-PCR, immunohistochemistry, immunofluorescence, electron microscopy, and laser-capture microdissection were done in 35 OALs to define their effect in Chlamydia detection and, moreover, to identify the Cp cellular carrier. Cp prevalence was screened by TETR-PCR in 205 extraorbital lymphomas and 135 nonneoplastic controls.

Results: Twenty-six (74%) OALs were associated with Cp infection: immunohistochemistry, immunofluorescence, and laser-capture microdissection-assisted PCR showed that monocytes/macrophages were the Cp carriers; electron microscopy showed the presence of intact Cp elementary bodies into these cells. Immunohistochemistry and TETR-PCR showed a 70% concordance rate (P = 0.001). Cp DNA was equally prevalent in non-OAL, nodal, and extranodal lymphomas: among the latter, it was more common in diffuse large B-cell lymphomas of the skin (P = 0.03) and Waldeyer's ring.

Conclusions: This multiparametric approach shows, for the first time, that monocytes/macrophages are the carriers of Cp, Cp seems preferentially associated with lymphomas arising in organs primarily exposed to antigens. The clinical implications of these findings deserve to be prospectively investigated.
High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies
Authors: Prassas Ioannis , Paliouras Miltiadis , Datti Alessandro , Diamandis Eleftherios P.
Published: September 2008

Purpose: Human tissue kallikreins (KLK) comprise a subgroup of 15 homologous secreted serine proteases. Primarily known for their clinical use as cancer biomarkers (e.g., PSA), KLKs have recently been directly implicated in cancer-related processes, including invasion, angiogenesis, and tumor growth regulation. Therefore, the identification of compounds that would modulate expression of KLKs might be of considerable therapeutic value.

Experimental Design: A cell-based high-throughput screening (HTS) of three small molecule libraries (∼4,500 compounds) was undertaken; KLK expression in the breast cancer cell line MDA-MB-468 was assessed with sensitive ELISAs.

Results: The initial screening resulted in 66 “putative hits” that decreased KLK5 expression by at least 50% over control. Secondary screening and mini-dose-response assays resulted in 21 “validated hits.” These 21 compounds were clustered in only three distinct functional families and were further analyzed in vitro to determine their effectiveness (IC50s). Hits that failed to show dose-responsiveness or interfered with the viability of the cells were excluded. Multiple members of the cardiac glycoside family were found to be novel inhibitors of KLK expression, acting at low concentrations (10-50 nmol/L). Furthermore, members of the same family induced marked decreases in c-MYC and c-FOS expression, in a dose-dependent manner that correlated the KLK inhibition, suggesting a transcriptional mechanism of regulation of KLK expression.

Conclusions: We conclude that cardiac glycosides can dramatically suppress the transcription of KLKs and that these effects may be linked to proto-oncogene (c-myc/fos) expression. These findings may partially explain the recently realized antineoplastic actions of cardiac glycosides.
Elevated Expression of GlutathioneS-Transferase π and p53 Confers Poor Prognosis in Head and Neck Cancer Patients Treated with Chemoradiotherapy but not Radiotherapy Alone
Authors: Schumaker Lisa , Nikitakis Nikolaos , Goloubeva Olga , Tan Ming , Taylor Rodney , Cullen Kevin J.
Published: September 2008

Purpose: To examine the prognostic significance of expression of glutathione s-transferase π (GST-π) and p53 in patients treated with radiation alone for locally advanced head and neck cancer [Radiation Therapy Oncology Group (RTOG), trial 9003] or radiation ± concomitant chemotherapy as postoperative adjuvant therapy (RTOG trial 9501).

Experimental Design: Immunohistochemical staining for p53 and GST-π was done on tissue samples from 393 patients in RTOG 9003 and 142 patients in RTOG 9501. Kaplan-Meier survival analyses were done.

Results: Patients who had low expression of both markers had longer survival than patients who had high expression of both markers. In trial 9003, median survival was 2.4 years for patients with low expression of both markers versus 1.4 years for patients who had elevated expression of both markers (P = 0.07). These differences were highly significant in trial 9501 and were accounted for by the chemotherapy treated arm. In this group, patients with low expression of both markers had a median survival of 7.0 years compared with 1.4 years for patients with elevated expression of both markers (P = 0.006). In both trials, black patients had lower survival rates than did white patients and there was a trend toward higher expression of both markers in blacks compared with whites.

Conclusion: Given the poor outcome of chemoradiotherapy treatment patients with elevated expression of both p53 and GST-π, these patients may not be appropriate candidates for chemoradiotherapy based on standard protocols. Some of the adverse outcome for black patients in both studies may be attributed to elevated expression of p53 and GST-π.
The Translational Research Working Group Developmental Pathway for Lifestyle Alterations
Authors: Hawk Ernest T. , Greenwood Addison , Gritz Ellen R. , McTiernan Anne , Sellers Thomas , Hursting Stephen D. , Leischow Scott , Grad Oren ,   for the Translational Research Working Group
Published: September 2008

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of National Cancer Institute's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of lifestyle alterations, which can, variously, be recommended to prevent cancer, modify a patient's adherence and response to cancer treatment, ameliorate side effects of cancer treatments, or improve prognosis and quality of life in cancer patients and survivors. The lifestyle alteration pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate lifestyle alteration through the translational process up to the point where it could be handed off for definitive testing, when appropriate. This article discusses key issues associated with the development of lifestyle alterations in light of the pathway.
The Translational Research Working Group Developmental Pathway for Interventive Devices
Authors: Dorfman Gary S. , Lawrence Theodore S. , Matrisian Lynn M. ,   for the Translational Research Working Group
Published: September 2008

The interventive device pathway refers to one of six pathways developed by the Translational Research Working Group (TRWG) that, together, describe the core domains of early translational cancer research. This pathway focuses on the development of devices (as classified by the Food and Drug Administration), designed for local ablation of cancer or precancerous lesions (e.g., radiation therapy, microwave, radiofrequency ablation, and high-intensity focused ultrasound systems). This article describes the distinctive features of the pathway and issues that are encountered in the real-world development of interventive devices for the treatment of cancer. The interventive device pathway is envisioned to be a general guideline of the steps required for effective development, optimization, testing, and validation of developing devices, to be dynamic and adaptable, and to form a framework for discussions focused on improving the efficiency and effectiveness of new device development.
Urokinase-Type Plasminogen Activator Receptor: A Beacon of Malignancy?
Authors: Drapkin Ronny , Clauss Adam , Skates Steven
Published: September 2008

Discriminating between benign and malignant disease is a pivotal diagnostic issue in the care of women with pelvic masses. Identification of serum biomakers that can rellably make the distinction would aid in the proper referral for patient care and may provide leads in the development of early detection strategies.
Effects of Nicotine Infusion on Striatal Glutamate and Cortical Non-Protein-Bound Iron in Hypoxic Newborn Piglets
Authors: Andresen Jannicke Hanne , Saugstad Ola Didrik
Published: September 2008

Background: Perinatal asphyxia triggers a large cascade of mechanisms leading to brain damage. Release of glutamate and increased oxidative stress play substantial roles. Non-protein-bound iron (NPBI), which contributes to the production of free radical species through the Fenton reaction, increases in hypoxic-ischemic brain damage. Results from in vitro and adult animal studies show that nicotine can decrease extracellular levels of NPBI and glutamate. Nicotine’s effects have further been shown to be dose-dependent, with lower doses showing neuroprotective, and higher doses showing neurotoxic effects. Objectives: We wished to assess nicotine’s effect on levels of NPBI and glutamate in an animal model of neonatal hypoxic-ischemic brain damage. Methods: 47 anesthetized newborn piglets were randomized to one of four infusions after hypoxia (nicotine 130 µg/kg/h, 260 µg/kg/h, adrenaline 0.05 µg/kg/min, saline 2.6 ml/kg/h). Glutamate in striatum and NPBI in cortex were analyzed in microdialysate. Results: Striatal glutamate presented a significant rise for all the animals from baseline to the end of hypoxia (p < 0.001). There was a significant difference for nicotine 130 µg/kg/h versus saline (p = 0.002) 2 h after hypoxia. Cortical NPBI presented a significant rise from baseline to the end of hypoxia for all the animals (p < 0.001), and a significant difference between nicotine 130 µg/kg/h versus saline 2 h after hypoxia (p = 0.013). Conclusion: Our findings support the hypothesis that nicotine can decrease extracellular levels of glutamate and NPBI in a neonatal model of hypoxic-ischemic brain damage. This suggests possible neuroprotective effects of a low dose of nicotine in neonates, as it has already been shown in adult models.
Cannabis-Induced Psychotic-Like Experiences Are Predicted by High Schizotypy
Authors: Stirling J. , Barkus E.J. , Nabosi L. , Irshad S. , Roemer G. , Schreudergoidheijt B. , Lewis S.
Published: September 2008

Background: Cannabis use has been identified as a possible risk factor for developing schizophrenia. In a previous paper we reported preliminary evidence that cannabis use increases the likelihood of psychosis-like experiences in non-clinical respondents who scored highly on a measure of schizotypy. We now present findings from pooled data from 3 new follow-up studies comprising a sample of 477 respondents, of whom 332 reported using cannabis at least once. Sampling and Methods: As in our previous study, the psychological effects of cannabis were assessed with the Cannabis Experiences Questionnaire, from which 3 subscales can be derived; encompassing pleasurable experiences, psychosis-like experiences and after-effects. The respondents also completed the brief Schizotypal Personality Questionnaire. Results: Cannabis use was reported by 70% of the sample. Use per se was not significantly related to schizotypy. However, high scoring schizotypes were more likely to report both psychosis-like experiences and unpleasant after-effects associated with cannabis use. The pleasurable effects of cannabis use were not related to schizotypy. Exploratory factor analysis of the pooled data from this study and our previous report (providing a sample of >400 cannabis users) suggested a 3-factor solution. These were characterised as a psychotic-dysphoric index (factor 1), an expansive index (factor 2) and an intoxicated index (factor 3). Schizotypy was highly correlated with factors 1 and 3, though not with factor 2. Conclusion: High scoring schizotypes who use cannabis are more likely to experience psychotic-dysphoric phenomena and intoxicating effects during and after use. Our results confirm and expand the findings reported in our previous study. They are consistent with the hypothesis that cannabis use may be a risk factor for full psychosis in this group.
Severe Eosinophilia as a Manifestation of Acute Graft-versus-Host Disease
Authors: Paralkar Vikram R. , Goradia Ami , Luger Selina M. , Loren Alison W.
Published: September 2008

Significant peripheral eosinophilia in association with acute graft-versus-host disease (GVHD) is rare. Here we report a case of eosinophilia in a 30-year-old woman with relapsed acute myelogenous leukemia after an allogeneic bone marrow transplant who was treated with donor lymphocyte infusion (DLI). A month after the DLI, she developed a pruritic erythematous rash, hepatic enzyme elevations and eosinophilia that peaked at 23,300 cells/mm3. A diagnosis of acute GVHD was made and the patient was treated with corticosteroids with a resolution of all of the aforementioned findings. The authors suggest that eosinophilia in a bone marrow transplantation patient should raise suspicion of GVHD.
Hemoglobin Concentrations Are Closely Linked to Renal Function in Patients with Type 1 or 2 Diabetes Mellitus
Authors: Wolf Gunter , Müller Nicolle , Hunger-Battefeld Wilgard , Kloos Christof , Müller Ulrich A.
Published: September 2008

Background/Aims: It has been reported that anemia is more common in patients with diabetes mellitus, and that it occurs early in the disease process. Methods: In this study, we evaluated hemoglobin (Hb) values of patients with diabetes type 1 or 2 from a large collective receiving care from a tertiary center. A total of 751 patients with type 1 diabetes and 3,306 patients with type 2 were studied. Correlations were calculated for Hb with the following parameters: metabolic control (HbA1c and blood glucose), renal function [estimated glomerular filtration rate (eGFR), serum creatinine, albuminuria, proteinuria], blood leukocytes, duration of diabetes and use of ACE inhibitors/AT1-receptor antagonists. Results: 17% of patients with type 1 diabetes and 14% of those with type 2 had anemia [defined as an Hb <8.5 mmol/l (<13.68 g/dl) in men and <7.5 mmol/l (<12.07 g/dl) in women). There was a close positive correlation between Hb and eGFR, and a negative correlation with albuminuria and proteinuria. These close associations were also confirmed with linear regression analysis. A significant negative correlation was observed between serum creatinine levels and Hb. There was no negative correlation between actual Hb and mean HbA1c in the individual follow-up periods. No correlation was found between blood glucose (morning and postprandial blood glucose) and Hb. Blood leukocyte numbers, as a parameter of systemic inflammation, were not correlated with Hb. The use of ACE inhibitors/AT1-receptor antagonists had no adverse effect on Hb in our study cohort. Conclusion: No negative effects of metabolic control on Hb could be demonstrated in this study.
A Tremulous Twiddler
Authors: Israel Zvi , Spivak Alexander
Published: September 2008

Twiddler’s syndrome describes the intentional external manipulation or spontaneous rotation of implanted devices such as cardiac pacemakers. Here we report the same phenomenon occurring in a patient with an implanted deep brain stimulator generator. The clinical syndrome is described and potential technical nuances to prevent its occurrence are suggested.
Human Fetal Striatal Transplantation in Huntington’s Disease: A Refinement of the Stereotactic Procedure
Authors: Gallina Pasquale , Paganini Marco , Di Rita Andrea , Lombardini Letizia , Moretti Marco , Vannelli Gabriella Barbara , Di Lorenzo Nicola
Published: September 2008

Background: Human fetal striatal transplantation (HFST) is an experimental stereotactic intervention in the treatment of Huntington’s disease (HD). This procedure has proved feasible, safe, well tolerated and it offers a potential strategy for brain repair in HD patients. Target areas are the nucleus caudatus caput (NCc) and the precommissural and postcommissural putamen (Pu). A suboptimal spatial distribution of grafts was frequently reported, especially for the postcommissural Pu, because of striatal atrophy and the concurrent ventricular frontal horn enlargement. An improvement of the stereotactic procedure aimed to optimize the intrastriatal placement of grafts is therefore considered a timely issue. Methods: Eight consecutive HD patients underwent bilateral HFST. For the first 6 procedures (first group) we performed both caudate and putaminal tracks through a single frontal entry point. For the following 10 procedures (second group), we adopted two completely distinct routes, with two separate entry points, for NCc and Pu tracks. The average number of stereotactic tracks and the average infused volume of tissue suspension were compared between the two groups. Results: The average number of putaminal tracks and the average infused volume of suspension were significantly higher in the second group. Conclusion: Adopting two separate routes for caudate and putaminal trajectories allowed us to achieve a larger amount of fetal tissue deposits and a better spatial distribution of grafts.
Septic Abortion in the Senegal Bush Baby (Galago senegalensis senegalensis)
Authors: Butler H.
Published: September 2008

Two cases of septic abortion are described in Galago senegalensis senegalensis. The cause was an unknown gram-negative bacillus not found in the vaginal secretions of normal animals which frequently contain Staphylococcus aureus, Staphylococcus epidermidis and Proteus mirabilis.
Reproduction in the Lesser Bushbaby (Galago senegalensis moholi) under Semi-Natural Conditions
Authors: Doyle G. A. , Andersson Annette , Bearder S. K.
Published: September 2008

A brief review of the literature on reproduction in the lesser bushbaby reveals some large sub-specific differences between Northern and Southern varieties in respect of the incidence of twin births, length of the gestation period, birth weight and the incidence of post-partum estrous. Since we have been studying the behaviour of the most Southern variety of the lesser bushbaby, G. s. moholi, over the past five years under semi-natural conditions and, more recently, in the field, we have accumulated a good deal of data on reproduction in this sub-species.
Intergroup Encounters among Free-Ranging Vervet Monkeys
Authors: Cheney D. L.
Published: September 2008

High-ranking vervet monkeys threatened the members of other groups more than did low-ranking individuals, while only low-ranking females and juvenile males interacted affinitively with the members of other groups. Adult males were most aggressive during intergroup encounters with groups from which males transferred. In contrast, females were most aggressive to groups from which males were not observed to transfer. It is postulated that the behavior of individuals during intergroup encounters may be related to benefits derived from excluding intruders from the group’s resources. Furthermore, it seems possible that relations between groups are influenced by previous male transfers, and that female aggression affects the distribution of male movement between groups.
Long-Term Changes and Maintenance of the Pair-Bond in Common Marmosets, Callithrix jacchus jacchus
Authors: Evans S. , Poole T.B.
Published: September 2008

A total of 12 heterosexual pairs of marmosets were observed at different stages after pairing. Social behaviour (including contact, proximity and grooming) and sexual behaviour (mating and soliciting behaviour) were more frequently observed in recently formed pairs than in pairs that had been housed together for longer periods. Some behaviour patterns were performed more frequently by one sex and in general these sex-related differences were evident irrespective of the length of pairing. The performance of simultaneous piloerection and play appeared to be related to the reproductive state of the female. Males became more responsible for initiating contact during the latter part of the females’ pregnancy. Mating continued at low levels during pregnancy.
Male Loud Calls in Macaca silenus and Presbytis johnii
Authors: Herzog M.O. , Hohmann G.M.
Published: September 2008

Analysis of the male loud calls of free-ranging lion-tailed macaques (Macaca silenus) and Nilgiri langurs (Presbytis johnii), two sympatric primates of the South Indian rain forests, revealed remarkable structural similarities: In both species the calls are uttered in long phrases with regular time structure, the units consisting of a tonal exhalation phase with high sound pressure and a more noisy inhalation phase with low sound pressure, but significant sound pressure variations. In both phases the energy is distributed over discrete frequency bands and concentrates on low-frequency ranges. These characteristics are consistent with essential bioacoustic requirements for long-distance propagation of vocal signals in rain forest habitat. Such type of loud call, being typical for langurs and mangabeys, is the first to be found in the Macaca genus. The two species, which belong to quite different genera, resemble each other not only in the vocal patterns of their loud calls, they also display striking similarities in habitus, exclusively arboreal dwelling habits, and in their social organization.
Diurnal Variation in Foraging and Diet in the Wedge-Capped Capuchin Cebus olivaceus
Authors: Robinson John G.
Published: September 2008

Cebus olivaceus monkeys exhibit pronounced diurnal variation in when they forage and what they eat when they are foraging. During the dry season, while foraging bouts occurred throughout the day, the group reliably foraged in the early morning and late afternoon. During the wet season there was no overall pattern to foraging through the day. At all times of the year, animals usually fed on ripe fruit in the early morning, but only certain fruits were taken more frequently at this time. Thereafter they fed on both fruits and invertebrates. I examined whether these diurnal patterns reflects environmental conditions, such as ambient temperature or resource availability, or internal constraints, such as preference for or selection of specific food items.
Démographie et reproduction de Macaca sylvanus dans différents habitats en Algérie
Authors: Ménard Nelly , Vallet Dominique , Gautier-Hion Annie
Published: September 2008

Usually described as a cedar forest monkey, the Barbary macaque in effect has colonized a great variety of habitat types. At the moment, it is not known to what extent these different habitats are suitable for the species’ survival. We tried to answer this question by comparing the demography of three monkey troops: one lives in a deciduous oak forest; the second lives in an nondeciduous cedar-green oak forest while the third is found on rocky ridges of mountains without any arborescent vegetation. In the three sites, there is a true seasonal breeding season with most births taking place in April to May and most matings occurring in November to December. Details are given on reproduction parameters (sexual activity of females; fertility rates; young survival...). Monkeys densities are higher in cedar forest than in deciduous forest. The smallest density is found on mountain ridges. Forest troops are more numerous, highly stable; their growth rate is better and the population is relatively young. The situation is slightly better still in the cedar forest than in the oak forest with a sex ratio more in favor of females and a better survival of the young. The troop of the mountain ridges is an unstable group ranging from 10 to 25 individuals; the population is aging, with a low birth rate and more male infants surviving compared with females. Demographic differences between sites are discussed according to climate, food availability and human influences (tree-clearing and overgrazing). Conclusions are drawn from this situation, for species conservation.
Sexual Dimorphism in the Postcranial Skeleton of New World Primates
Authors: Leutenegger Walter , Larson Susan
Published: September 2008

This study examines sexual dimorphism in 24 dimensions of the postcranial skeleton of four platyrrhine species: Callithrix jacchus, Saguinus nigricollis, Saimiri sciureus, and Cebus albifrons. The two callitrichid species show a relatively small amount of variation in the degree of sexual dimorphism among the different dimensions. Variation is considerably higher in the two cebid species as reflected by a mosaic pattern of sexual dimorphisms with males being significantly larger than females in some dimensions, and females significantly larger than males in others. In dimensions of the pectoral girdle and limb bones, males and females in each of the two cebid species are essentially scaled versions of each other, with males being peramorphic compared to females. This pattern is primarily the result of time hypermorphosis, i.e. an extension of the growth period in time in males. Rate hypermorphosis, i.e. an increase in the rate of growth in time in males, appears to play an additional role, however, in S. sciureus. By contrast, in dimensions of the true pelvis, sex differences in shape are dissociated from those in size. They are interpreted as the result of acceleration, i.e. increase in rate of shape change in females, as an adaptation to obstetrical functions. Interspecific analyses indicate positive allometry of mean degree of postcranial dimorphism with respect to body size. This coincides with previous findings by Leutenegger and Cheverud [1982, 1985] on the scaling of sexual dimorphism in body weight and canine size, and thus supports their model which posits selection on body size as the prime mover for the evolution of sexual dimorphism.
Kondous laventicus, a New Ceboid Primate from the Miocene of the La Venta, Colombia, South America
Authors: Setoguchi Takeshi
Published: September 2008

A new genus and species of fossil primate, Kondous laventicus, part of the Miocene La Venta primate fauna of Colombia, South America, is described here for the first time. Screening at a new quarry within the Monkey Unit of the Honda Formation, the Kyoto Site, has revealed dental remains of this new form of a large-sized ceboid. The La Ventan vertebrate fauna is comparable to the Friasian Land Mammal Age, indicating a middle Miocene age. Biostratigraphic studies suggest a 13.6-15.2 Ma for the Friasian faunal zone. Kondous is most closely allied to extant spider monkeys, Ateles, providing the first fossil evidence of their phylogeny. It also implies a nearly three-fold discrepancy between the molecular and paleontological estimates of the age of the Ateles lineage.
Cytogenetic Study of Complex Hybrids in the Genus Lemur (Primates Prosimians)
Authors: Rumpler Y. , Warter S. , Ratomponirina Ch. , Hauwy M. , Ishak B.
Published: September 2008

A cytogenetic study was carried out of several Lemur hybrids and their progeny. The effects of Robertsonian translocations in the heterozygous state on fertility and the possibility of a preferential transmission of metacentric trivalents are debated.
Individuality in the Female Songs of Wild Kloss’ Gibbons (Hylobates klossii) on Siberut Island, Indonesia
Authors: Haimoff E.H. , Tilson R.L.
Published: September 2008

Observations and recordings were made of the female songs produced by 4 adult and mated female Kloss’ gibbons (Hylobates klossii) from a site on Siberut Island, the largest island of the Mentawai Island chain in Indonesia. A statistical analysis of song characteristics revealed that individuality occurs throughout the entire song. The implications of these findings, as well as comparisons to similar studies of individuality on other gibbon species, are presented.
Evolutionary Effect of the Absence of Felids on the Social Organization of the Macaques on the Island of Simeulue (Macaca fascicularis fusca, Miller 1903)
Authors: van Schaik Card P. , van Noordwijk Maria A.
Published: September 2008

If the claim that predation risk is the main factor favouring group living in diurnal non-human primates is correct, a reduction in the risk of predation should lead to: (1) a reduction in the size of a primate group and of the parties into which it fissions, (2) a change in the relationship between the size of a party and its composition, and (3) (in South-East Asia) to a change in the relationship between party size and height in the canopy, for small parties. These predictions were tested in a comparison between a population of long-tailed macaques (Macaca fascicularis) in a Sumatran site where a variety of felids occurs, and one on the island of Simeulue, where no cats occur. The first two predictions were strongly supported, whereas the third was weakly supported by the data. The Simeulue monkeys were also different in morphology (blackish coats, reduced sexual dimorphism), lived at high densities in small home ranges, and were territorial. All these differences between the populations could be plausibly ascribed to the difference in predation risk from felids. It is concluded that the presence of felids has a profound influence on the social organization of this arboreal primate species.
Volume Comparisons in the Cerebellar Complex of Primates
Authors: Matano Shozo , Baron Georg , Stephan Heinz , Frahm Heiko D.
Published: September 2008

Volumes of medial, interposed, and lateral cerebellar nuclei (MCN, ICN, and LCN) were measured in Insectivora, Scandentia, and Primates, including man. The relative size of the nuclei was expressed in size indices. Insectivora had by far the smallest cerebellar nuclei. The simians, in general, had larger cerebellar nuclei than the prosimians, but there was considerable overlap. From Insectivora to man, the MCN was the least progressive and the LCN the most progressive. The indices are expected to reflect the relative size of the three longitudinal zones of the cerebellum (vermis/MCN, pars intermedius/ICN, hemisphere/ LCN). They, together with those of the ventral pons and cerebellum (part I), are discussed in relation to the predominant locomotor pattern of a species, and with reference to evolutionary trends in primate phylogeny.
Learning Set Formation in Common Tree Shrews (Tupaia glis)
Authors: Ohta Hirohiko , Matsutani Shinji , Ishida Hidemi , Matano Shozo
Published: September 2008

Following the studies on slow lorises (Nycticebus coucang) and ring-tailed lemurs (Lemur catta), the visual discrimination learning set was tested on diurnal common tree shrews (Tupaia glis) under almost the same experimental conditions. Their performance was significantly lower than that of lorises and lemurs (p < 0.001). An error factor analysis was made in the three species’ performance. Performance showed a strong relationship with the degree of neocortical development.