bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Grade Index Is Associated With Response to Chemotherapy in Patients With Breast Cancer
Authors: Liedtke Cornelia , Hatzis Christos , Symmans William Fraser , Desmedt Christine , Haibe-Kains Benjamin , Valero Vicente , Kuerer Henry , Hortobagyi Gabriel N. , Piccart-Gebhart Martine , Sotiriou Christos , Pusztai Lajos
Published: April 2009

Purpose

The genomic grade index (GGI) is a 97-gene measure of histological tumor grade. High GGI is associated with decreased relapse-free survival in patients receiving either endocrine or no systemic adjuvant therapy. Herein we examined whether GGI predicts pathologic response to neoadjuvant chemotherapy in patients with HER-2–normal breast cancer.

Methods

Gene expression data (gene chips) was generated from fine-needle aspiration biopsies (n = 229) prospectively collected before neoadjuvant paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Pathologic response was quantified using the residual cancer burden (RCB) method. The association between the GGI and pathologic response was assessed in univariate and multivariate analyses. The performance of a response predictor combining clinical variables and GGI was evaluated under cross-validation.

Results

Eighty-five percent of grade 1 tumors had low GGI, 89% of grade 3 tumors had high GGI, and 63% of grade 2 tumors had low GGI. Among both estrogen receptor (ER)-positive and -negative cancers, high GGI score was associated with pathologic complete response (RCB-0) or minimal residual disease (RCB-1). A multivariate model combining GGI and clinical parameters had an overall accuracy of 71%, compared with 58% for the GGI alone, for prediction of pathologic response. However, high GGI score was also associated with significantly worse distant relapse-free survival in patients with ER-positive cancer (P = .005), and was not associated with survival in patients with ER-negative cancer.

Conclusion

High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER-positive patients, but it remains a predictor of worse survival in ER-positive patients.
Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan
Authors: Cecchin Erika , Innocenti Federico , D'Andrea Mario , Corona Giuseppe , De Mattia Elena , Biason Paola , Buonadonna Angela , Toffoli Giuseppe
Published: April 2009

Purpose

UGT1A1★28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Patients and Methods

In addition to UGT1A1★28, UGT1A1★60, UGT1A1★93, UGT1A7★3, and UGT1A9★22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available.

Results

UGT1A7★3 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) × (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9★22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1★28, haplotype II (all the variant alleles but UGT1A9★22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1★28 was the only marker associated with TTP.

Conclusion

We propose that UGT1A variants additional to UGT1A1★28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.
Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial
Authors: Dowsett Mitch , Procter Marion , McCaskill-Stevens Worta , de Azambuja Evandro , Dafni Urania , Rueschoff Josef , Jordan Bruce , Dolci Stella , Abramovitz Mark , Stoss Oliver , Viale Giuseppe , Gelber Richard D. , Piccart-Gebhart Martine , Leyland-Jones Brian
Published: April 2009

Purpose

To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy.

Patients and Methods

IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up.

Results

Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab.

Conclusion

There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.
Intensive Dose-Dense Compared With Conventionally Scheduled Preoperative Chemotherapy for High-Risk Primary Breast Cancer
Authors: Untch Michael , Möbus Volker , Kuhn Walther , Muck Bernd Rudolph , Thomssen Christoph , Bauerfeind Ingo , Harbeck Nadia , Werner Christoph , Lebeau Annette , Schneeweiss Andreas , Kahlert Stephen , von Koch Franz , Petry Karl Ulrich , Wallwiener Diethelm , Kreienberg Rolf , Albert Ute-Susann , Lück Hans-Joachim , Hinke Axel , Jänicke Fritz , Konecny Gottfried E.
Published: April 2009

Purpose

To compare preoperative intense dose-dense (IDD) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer (BC).

Patients and Methods

In this randomized phase III trial a total of 668 eligible primary BC patients stratified for tumors ≥ 3 cm (n = 567) or inflammatory BC (n = 101) were randomly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks. All patients received three cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy after surgery.

Results

IDD treatment significantly improved pathologic complete response rate (18% v 10%; odds ratio [OR] 1.89; P = .008), disease-free survival (DFS; hazard ratio [HR], 0.71; P = .011), and overall survival (OS; HR, 0.83; P = .041) compared to epirubicin/paclitaxel. Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial (DFS HR, 1.10; P = .739; OS HR, 1.25; P = .544). In contrast, patients with noninflammatory BC significantly benefited from IDD treatment (DFS HR, 0.65, P = .005; OS HR, 0.77, P = .013). Treatment effects in multivariate analysis were significant for noninflammatory BC (DFS HR, 0.65, P = .015; OS HR, 0.79, P = .034), but not for all patients (DFS HR, 0.76; P = .088; OS HR, 0.82; P = .059). IDD therapy was associated with significantly more nonhematologic toxicities, anemia, and thrombocytopenia, but with similar neutropenia and infection rates.

Conclusion

Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy. IDD was less well tolerated compared to standard treatment, but improved clinical outcomes in patients with noninflammatory high-risk primary BC.
Ovarian Failure and Reproductive Outcomes After Childhood Cancer Treatment: Results From the Childhood Cancer Survivor Study
Authors: Green Daniel M. , Sklar Charles A. , Boice John D. , Mulvihill John J. , Whitton John A. , Stovall Marilyn , Yasui Yutaka
Published: April 2009

These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.
Phase II Study of Tirapazamine, Cisplatin, and Etoposide and Concurrent Thoracic Radiotherapy for Limited-Stage Small-Cell Lung Cancer: SWOG 0222
Authors: Le Quynh-Thu X. , Moon James , Redman Mary , Williamson Stephen K. , Lara Primo N. , Goldberg Zelanna , Gaspar Laurie E. , Crowley John J. , Moore Dennis F. , Gandara David R.
Published: April 2009

Purpose

A SWOG pilot study (S0004) showed that tirapazamine (TPZ) when combined with concurrent chemoradiotherapy yielded a promising median survival of 22 months in limited-stage small-cell lung cancer (LSCLC). We report results of the phase II study designed to confirm this result.

Patients and Methods

The concurrent phase consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. TPZ was given at 260 mg/m2 on days 1, 29, and at 160 mg/m2 on days 8, 10, 12, 36, 38, and 40. Consolidation consisted of two cycles of cisplatin and etoposide. Complete responders received prophylactic cranial irradiation. Results were considered promising if the median survival time was at least 21 months and of no further interest if ≤ 14 months.

Results

S0222 was closed early due to a report of excess toxicity for TPZ in a head and neck cancer trial elsewhere. Of planned 85 patients, 69 were accrued. In 68 assessable patients, 17 (25%) had grade 3 to 4 esophagitis and eight (12%) had grade 3 febrile neutropenia during the concurrent phase. There were three possible treatment-related deaths, two in concurrent phase (one progressive disease not otherwise specified within 30 days, one pericardial effusion) and one in consolidation phase (esophageal hemorrhage). At a median follow-up of 35 months, median progression-free survival was 11 months (95% CI, 10 to 13 months) and median overall survival was 21 months (95% CI, 17 to 33 months).

Conclusion

S0222 showed acceptable levels of toxicity and similar promising median survival as S0004. Further study of hypoxia-targeted therapy is warranted in LSCLC.
Plasma Carboxy-Terminal Provasopressin (Copeptin): A Novel Marker of Insulin Resistance and Metabolic Syndrome
Authors: Saleem Umer , Khaleghi Mahyar , Morgenthaler Nils G. , Bergmann Andreas , Struck Joachim , Mosley Thomas H. , Kullo Iftikhar J.
Published: April 2009

Context: Stress-mediated hypothalamic-pituitary-adrenal axis activation, regulated by arginine vasopressin (AVP), may have a role in the pathophysiology of metabolic syndrome (MetSyn).

Objective: The objective of the study was to investigate whether plasma C-terminal provasopressin fragment (copeptin), a surrogate for circulating AVP, was associated with measures of insulin resistance and presence of MetSyn.

Design, Setting, and Participants: This was a multicenter, community-based study, investigating novel biomarkers for vascular disease. Participants included 1293 African-Americans (AA) (64 ± 9 yr) and 1197 non-Hispanic whites (NHW) (59 ± 10 yr) belonging to hypertensive sibships.

Main Outcome Measures: Plasma copeptin levels were measured by an immunoluminometric assay. MetSyn was defined per Adult Treatment Panel III criteria. Generalized estimating equations were used to assess whether plasma copeptin was associated with measures of insulin resistance and MetSyn.

Results: The prevalence of MetSyn was 50% in AA and 49% in NHW. In each group, after adjustment for age and sex, plasma copeptin levels significantly correlated with body mass index, fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance, triglycerides, and (inversely) high-density lipoprotein cholesterol (P < 0.05 for each variable). In multivariable logistic regression models that adjusted for age, sex, smoking, statin use, serum creatinine, education, physical activity, and diuretic use, plasma copeptin levels in the highest quartile were associated with an increased odds ratio of having MetSyn compared with bottom quartile: odds ratio (95% confidence interval) in AA, 2.07 (1.45–2.95); in NHW, 1.74 (1.21–2.5).

Conclusions: Our findings indicate a novel cross-sectional association between plasma copeptin and measures of insulin resistance and MetSyn.
Samizdat according to Andropov
Authors: Gribanov Alexander , Kowell Masha
Published: April 2009

Among the many documents released one way or another during the early 1990s, there are two that open the window into the perception of samizdat by the top Soviet authorities. The first of them was signed by Yuri Andropov, then the head of the KGB, in the last days of December 1970. It was a memo addressed to the Central Committee of the Communist Party of the Soviet Union reporting on the status of samizdat in the country and suggesting some practical steps that would diminish the spread and impact of uncontrolled publications in the USSR. The second document, dated in the last days of April 1971, was compiled in response to Andropov's memo. It was a statement by the Central Committee regarding samizdat. The Central Committee document for the most part accepted the KGB recommendations but took a broader view of the samizdat phenomenon and for the first time offered a definition of samizdat, which was missing in the KGB memo. The differences between the two documents allow a glimpse of their respective institutional thinking about samizdat. Andropov's document implied that the samizdat phenomenon was so widespread that the repressive apparatus could not cope with it in the framework of its current charter. In response, the Central Committee document expanded the responsibility of the party apparatus with respect to suppression of uncontrolled publications.
INF2 is an endoplasmic reticulum-associated formin protein
Authors: Chhabra Ekta Seth , Ramabhadran Vinay , Gerber Scott A. , Higgs Henry N.
Published: April 2009

In addition to its ability to accelerate filament assembly, which is common to formins, INF2 is a formin protein with the unique biochemical ability to accelerate actin filament depolymerization. The depolymerization activity of INF2 requires its actin monomer-binding WASP homology 2 (WH2) motif. In this study, we show that INF2 is peripherally bound to the cytoplasmic face of the endoplasmic reticulum (ER) in Swiss 3T3 cells. Both endogenous INF2 and GFP-fusion constructs display ER localization. INF2 is post-translationally modified by a C-terminal farnesyl group, and this modification is required for ER interaction. However, farnesylation is not sufficient for ER association, and membrane extraction experiments suggest that ionic interactions are also important. The WH2 motif also serves as a diaphanous autoregulatory domain (DAD), which binds to the N-terminal diaphanous inhibitory domain (DID), with an apparent dissociation constant of 1.1 μM. Surprisingly, the DID-DAD interaction does not inhibit the actin nucleation activity of INF2; however, it does inhibit the depolymerization activity. Point mutations to the DAD/WH2 inhibit both the DID-DAD interaction and depolymerization activity. Expression of GFP-INF2 containing these DAD/WH2 mutations causes the ER to collapse around the nucleus, with accumulation of actin filaments around the collapsed ER. This study is the first to show the association of an actin-assembly factor with the ER.
Commentary—Assumptions, Explanation, and Prediction in Marketing Science: “It's the Findings, Stupid, Not the Assumptions”
Authors: Tsang Eric W. K.
Published: April 2009

In his July–August 2007 editorial of Marketing Science, Steven Shugan argues that the realism of assumptions does not matter as long as a theory or model produces satisfactory predictions and claims further that unrealistic assumptions breed good theories. This commentary discusses the problems of his argument and presents a very different view about the realism of assumptions.

Assumptions need not be realistic if the only goal of science is prediction. However, a major function of theory is also to explain and not just to predict. The role of explanation is more important in the social sciences because it is far more difficult to produce accurate predictions in the social than the natural sciences. Assumptions, especially core assumptions, often constitute the foundation of the mechanismic explanations provided by a theory. Unrealistic assumptions may lead to faulty explanations and false predictions.

Contrary to Shugan's view, the realism of an assumption cannot be assessed just based on the output of a theory. It has to be tested independently of or in conjunction with the hypotheses of the theory. Also, contrary to Shugan's claim, more realistic assumptions result in better theories. As theory development advances, efforts should be directed toward making assumptions more realistic.
Rejoinder—Think Theory Testing, Not Realism
Authors: Shugan Steven M.
Published: April 2009

Eric Tsang's response makes the legitimate point that prediction and explanation can be different goals. However, his arguments also suffer from several errors in logic, most often the converse error. I do not claim that unrealistic assumptions breed good theories. I only claim that breakthrough theories usually have assumptions deemed unrealistic. Hence, unrealistic assumptions breed both good and bad theories. That is why science tests theories, not assumptions.

Moreover, one can easily prove that realistic assumptions are not required. Consider situations when one of two competing theories must be correct. For example, in criminal cases, the prosecution's theory is that the accused committed the crime. The defense's theory is that the accused is innocent. One theory is correct despite the fact that both could make obviously unrealistic assumptions. For example, the prosecution might unrealistically assume that unreliable eyewitness testimony is sufficient to convict. The defense might unrealistically assume that a dubious alibi is sufficient to acquit. Juries decide on all the evidence and not each assumption. I now answer some of Eric Tsang's questions.
Genotypic Intratumoral Heterogeneity in Breast Carcinoma With HER2/neu Amplification
Authors: Brunelli Matteo , Manfrin Erminia , Martignoni Guido , Miller Keith , Remo Andrea , Reghellin Daniela , Bersani Samantha , Gobbo Stefano , Eccher Albino , Chilosi Marco , Bonetti Franco
Published: April 2009

We evaluated intratumoral heterogeneity of 30 ductal breast carcinomas with HER2/neu amplification, scored by the American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) criteria, and 3+ immunoexpression. High-grade (ratio ≥4.0) vs low-grade amplification (ratio >2.2 to <4.0) and chromosome 17 polysomy were also evaluated.

On whole tissue sections, 20 tumors (67%) showed high-grade and 10 (33%) showed low-grade HER2/ neu amplification. Of 20 tumors with high-grade amplification, 14 (70%) showed no intratumoral genotypic heterogeneity; 6 (30%) showed at least 1 core with low-grade amplification. Of 10 cases with low-grade amplification, 6 (60%) showed no intratumoral heterogeneity; 4 (40%) showed chromosome 17 polysomy without gene amplification in 2 of 3 cores per case. Of 30 cases with gene amplification, 4 (13%) showed a “not-amplified pattern” in other parts of the tumor.

The routine assessment of HER2/neu amplification using the ASCO/CAP criteria on whole tissue sections is not significantly confounded by intratumoral heterogeneity in breast cancer with high-grade amplification; however, genetic heterogeneity exists in a subset of breast carcinomas with low-grade amplification. The clinical relevance and impact on treatment outcome of intratumoral heterogeneity in breast cancer with low-grade HER2/neu amplification or chromosome 17 polysomy need further investigation.
Therapy-Related Acute Myeloid Leukemia With t(8;21) (q22;q22) Shares Many Features With De Novo Acute Myeloid Leukemia With t(8;21)(q22;q22) but Does Not Have a Favorable Outcome
Authors: Gustafson Steven A. , Lin Pei , Chen Su S. , Chen Lei , Abruzzo Lynne V. , Luthra Rajyalakshmi , Medeiros L. Jeffrey , Wang Sa A.
Published: April 2009

To determine if therapy-related acute myeloid leukemia (t-AML) with t(8;21)(q22;q22) [t-AML-t(8;21)] harbors similar characteristic clinicopathologic features as de novo AML-t(8;21) (q22;q22), we studied 13 cases of t-AML-t(8;21) and 38 adult cases of de novo AML-t(8;21) diagnosed and treated at our hospital (1995–2008). Of 13 t-AML-t(8;21) cases, 11 had previously received chemotherapy with or without radiation for malignant neoplasms and 2 received radiation alone. The median latency to t-AML onset was 37 months (range, 11–126 months). Compared with patients with de novo AML-t(8;21), patients with t-AML-t(8;21) were older (P = .001) and had a lower WBC count (P = .039), substantial morphologic dysplasia, and comparable CD19/CD56 expression. The AML1-ETO (RUNX1-RUNX1T1) fusion was demonstrated in all 10 cases assessed. Class I mutations analyzed included FLT3 (0/10 [0%]), RAS (0/10 [0%]), JAK2 V617 (0/11 [0%]), and KIT (4/11 [36%]). With a median follow-up of 13 months, 10 patients with t-AML-t(8;21) died; the overall survival was significantly inferior to that of patients with de novo AML-t(8;21) (19 months vs not reached; P = .002). These findings suggest that t-AML-t(8;21) shares many features with de novo AML-t(8;21)(q22;q22), but affected patients have a worse outcome.
2008 ACLPS Panel Discussion on Resident Education in Clinical Pathology
Authors: Luning Prak Eline T. , Young Donald S. , Kamoun Malek , Nachamkin Irving , Alexander C. Bruce , Spitalnik Steven L. , Peerschke Ellinor I. B. , Smith Brian R.
Published: April 2009

A curriculum in clinical pathology (CP) was developed under the auspices of the Academy of Clinical Laboratory Physicians and Scientists (ACLPS) in 2006. At the 2008 ACLPS meeting in Philadelphia, PA, a panel was convened to address the current challenges in resident education and how to overcome them. Current challenges include the heterogeneity of the discipline (which requires analytical, medical, and managerial knowledge), the diverse repertoire of clinical laboratory testing, and the need to better integrate the resident into the work flow of the laboratory, especially with respect to clinical consultation. Recommendations of the panel include the incorporation of active learning, clinical consultation, and competency assessment into CP resident training. A summary of the panel discussion is presented herein.
Differential Expression of Microtubule-Associated Protein 2 in Melanocytic Skin Lesions
Authors: Gambichler Thilo , Rotterdam Sebastian , Radkowski Katharina , Altmeyer Peter , Kreuter Alexander
Published: April 2009

Neoplastic melanocytes may exhibit certain differentiation characteristics of other neural-crest derivatives. We aimed to study the expression of microtubule-associated protein 2 (MAP-2) in different types of melanocytic skin lesions. Paraffin-embedded sections of 42 benign nevi (BN), 22 dysplastic nevi (DN), 45 superficial spreading melanomas (SSMs), and 15 subcutaneous melanoma metastases were immunohistologically assessed using the monoclonal mouse MAP-2ab antibody (Zytomed, Berlin, Germany). The percentage MAP-2 expression of DN and SSMs was significantly increased compared with BN. Moreover, subcutaneous melanoma metastases showed significantly decreased MAP-2 expression compared with DN and SSMs. In SSMs, MAP-2 expression significantly correlated with the Breslow vertical tumor thickness, Clark level, and stage of disease. We observed that MAP-2 is differentially expressed during the development and progression of benign and malignant melanocytic skin lesions. In contrast with the findings of previous studies, our data indicate that MAP-2 is a moderately positive predictor of the progression of SSMs.
Myofibroblastic Sarcoma vs Nodular Fasciitis
Authors: Meng Guo-Zhao , Zhang Hong-Ying , Zhang Zhang , Wei Bing , Bu Hong
Published: April 2009

We investigated the molecular cytogenetic features in myofibroblastic sarcoma (MS) to gain insight into the nature of the controversial entity. DNA copy number changes were analyzed by comparative genomic hybridization in 29 cases of MS and 5 cases of nodular fasciitis. The characteristic chromosomal imbalances in MS were gains at 1p11 → p36.3 (19/29 [66%]), 12p12.2 → p13.2 (13/29 [45%]), 5p13.2 → p15.3 (9/29 [31%]), and chromosome 22 (8/29 [28%]) and loss at 15q25 → q26.2 (7/29 [24%]). In contrast, only 1 of 5 cases of nodular fasciitis showed genetic aberrations. The average number of aberrations in nodular fasciitis (0.4) was significantly lower than that in MS (5.4). Thus, MS displayed complex DNA copy number changes and shared no range of common chromosomal abnormality with nodular fasciitis, indicating that distinct genetic pathways may be involved in the development of these entities.
Chronic Lymphocytic Leukemia With t(2;14)(p16;q32) Involves the BCL11A and IgH Genes and Is Associated With Atypical Morphologic Features and Unmutated IgVH Genes
Authors: Yin C. Cameron , Lin Katherine I-Chun , Ketterling Rhett P. , Knudson Ryan A. , Medeiros L. Jeffrey , Barron Lynn L. , Huh Yang O. , Luthra Rajyalakshmi , Keating Michael J. , Abruzzo Lynne V.
Published: April 2009

The t(2;14)(p16;q32) has been reported previously in only 12 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The clinicopathologic features have been incompletely described. We describe 6 new cases of CLL/SLL with t(2;14)(p16;q32). All had marrow involvement, 4 had absolute lymphocytosis, 4 had lymphadenopathy, and 3 had hepatosplenomegaly. All showed atypical lymphocyte morphologic features with plasmacytoid differentiation and irregular nuclei; 3 had increased prolymphocytes. Flow cytometry demonstrated typical immunophenotypes in 5 and an atypical immunophenotype in 1. All expressed ZAP70; 5 assessed showed unmutated IgVH genes. Karyotyping identified t(2;14)(p16;q32) as the sole abnormality in 1, primary abnormality in 2, and part of a complex karyotype in 3. Fluorescence in situ hybridization analysis revealed BCL11A/IgH rearrangement in all. After chemotherapy, 3 patients died of disease and 3 were alive with disease (median follow-up, 80 months). We conclude that CLL/SLL with t(2;14) (p16;q32) and BCL11A/IgH rearrangement is characterized by atypical morphologic features and unmutated IgVH genes.
Adolescents choosing self‐harm as an emotion regulation strategy: The protective role of trait emotional intelligence
Authors: Mikolajczak Moïra , Petrides K. V. , Hurry Jane
Published: April 2009

Objectives

The present study seeks to extend the understanding of the role of dispositional factors in the aetiology of self‐harm among adolescents. We hypothesized that higher trait emotional intelligence (trait EI) would be associated with a lower likelihood to harm oneself, and that this relationship would be mediated by the choice of coping strategies.

Design and Methods

Trait EI, coping styles and self‐harm behaviours were assessed in 490 adolescents recruited from eight British schools.

Results

The results supported our hypothesis and showed that the relationship between trait EI and self‐harm was partly mediated by the choice of coping strategies. Emotional coping was a particularly powerful mediator, suggesting that self‐harm may be a way to decrease the negative emotions that are exacerbated by maladaptive emotional coping strategies, such as rumination, self‐blame, and helplessness. Trait EI was correlated positively with adaptive coping styles and negatively with maladaptive coping styles, and depression.

Conclusions

These findings emphasize the potential value of incorporating coping coaching programmes in the treatment of self‐harm patients.
Practical Challenges Testing Coupons with Residual Stresses from Cold Expanded Holes
Authors: Reid Len , Ransom Joy
Published: April 2009

Cold expanding holes in metal components is widely used throughout the aerospace industry to extend fatigue life and damage tolerance. The beneficial residual stresses induced by hole cold expansion arrest or significantly retard the growth of fatigue cracks, and in doing so make fatigue or crack growth life prediction more difficult. Under low stress level/high cycle fatigue testing, residual compressive stresses have been shown to increase the fatigue strength of the material leading to an “infinite life” and consequent “run-out” of test coupons at the test hole or changing the location of failure away from the test hole. While advantageous to aircraft operators, it makes statistical life prediction difficult because the incomplete data have to be censored, leading to a knock-down of the beneficial life attained. Conversely, increasing stress levels toward material yield stress; life improvement factors are more definitive and tend toward unity. This paper reviews the derivation of residual stresses induced by hole cold expansion and discusses benefits to the structure/test coupon and how the residual stress field impacts fatigue life and damage tolerance/durability under cyclic load conditions. Challenges observed when testing coupons that have been processed using hole cold expansion including modification of the crack behavior and its effect on material microstructure, relocation of crack initiation, dynamics of the redistribution of stress and the crack growth mechanism as well as scatter of results, are also discussed with a focus on aluminum materials.
Synaptic Output of Individual Layer 4 Neurons in Guinea Pig Visual Cortex
Authors: Sáez Ignacio , Friedlander Michael J.
Published: April 2009

More than 90% of geniculocortical axons from the dorsal lateral geniculate nucleus of the thalamus innervate layer 4 (L4) of V1 (primary visual cortex). Excitatory neurons, which comprise >80% of the neuronal population in L4, synapse mainly onto adjacent L4 neurons and layer 2/3 (L2/3) neurons. It has been suggested that intralaminar L4–L4 connections contribute to amplifying and refining thalamocortical signals before routing to L2/3. To unambiguously probe the properties of the synaptic outputs from these L4 excitatory neurons, we used multiple simultaneous whole-cell patch-clamp recording and stimulation from two to four neighboring L4 neurons. We recorded uEPSCs (evoked unitary synaptic currents) in response to pairs of action potentials elicited in single presynaptic L4 neurons for 102 L4 cell pairs and found that their properties are more diverse than previously described. Averaged unitary synaptic response peak amplitudes spanned almost three orders of magnitude, from 0.42 to 192.92 pA. Although connections were, on average, reliable (average failure rate, 25%), we recorded a previously unknown subset of unreliable (failure rates from 30 to 100%) and weak (averaged response amplitudes, <5 pA) connections. Reliable connections with high probability of neurotransmitter release responded to paired presynaptic pulses with depression, whereas unreliable connections underwent paired-pulse facilitation. Recordings from interconnected sets of L4 triplets revealed that synaptic response amplitudes and reliability were equally variable between independent cell pairs and those that shared a common presynaptic or postsynaptic cell, suggesting local perisynaptic influences on the development and/or state of synaptic function.
Connexin32 Mutations Cause Loss of Function in Schwann Cells and Oligodendrocytes Leading to PNS and CNS Myelination Defects
Authors: Sargiannidou Irene , Vavlitou Natalie , Aristodemou Sophia , Hadjisavvas Andreas , Kyriacou Kyriacos , Scherer Steven S. , Kleopa Kleopas A.
Published: April 2009

The gap junction (GJ) protein connexin32 (Cx32) is expressed by myelinating Schwann cells and oligodendrocytes and is mutated in X-linked Charcot-Marie-Tooth disease. In addition to a demyelinating peripheral neuropathy, some Cx32 mutants are associated with transient or chronic CNS phenotypes. To investigate the molecular basis of these phenotypes, we generated transgenic mice expressing the T55I or the R75W mutation and an IRES-EGFP, driven by the mouseCnppromoter. The transgene was expressed in oligodendrocytes throughout the CNS and in Schwann cells. Both the T55I and the R75W mutants were localized in the perinuclear cytoplasm, did not form GJ plaques, and did not alter the expression or localization of two other oligodendrocytic GJ proteins, Cx47 and Cx29, or the expression of Cx29 in Schwann cells. On wild type background, the expression of endogenous mCx32 was unaffected by the T55I mutant, but was partly impaired by R75W. Transgenic mice with the R75W mutation and all mutant animals withGjb1-null background developed a progressive demyelinating peripheral neuropathy along with CNS myelination defects. These findings suggest that Cx32 mutations result in loss of function in myelinated cells withouttrans-dominant effects on other GJ proteins. Loss of Cx32 function alone in the CNS causes myelination defects.
Differentially Expressed Drl and Drl-2 Play Opposing Roles in Wnt5 Signaling duringDrosophilaOlfactory System Development
Authors: Sakurai Masao , Aoki Tomoko , Yoshikawa Shingo , Santschi Linda A. , Saito Hiroko , Endo Keita , Ishikawa Kyoko , Kimura Ken-ichi , Ito Kei , Thomas John B. , Hama Chihiro
Published: April 2009

InDrosophila, odor information received by olfactory receptor neurons (ORNs) is processed by glomeruli, which are organized in a stereotypic manner in the antennal lobe (AL). This glomerular organization is regulated by Wnt5 signaling. In the embryonic CNS, Wnt5 signaling is transduced by the Drl receptor, a member of the Ryk family. During development of the olfactory system, however, it is antagonized by Drl. Here, we identify Drl-2 as a receptor mediating Wnt5 signaling. Drl is found in the neurites of brain cells in the AL and specific glia, whereas Drl-2 is predominantly found in subsets of growing ORN axons. Adrl-2mutation produces only mild deficits in glomerular patterning, but when it is combined with adrlmutation, the phenotype is exacerbated and more closely resembles theWnt5phenotype. Wnt5 overexpression in ORNs induces aberrant glomeruli positioning. This phenotype is ameliorated in thedrl-2mutant background, indicating that Drl-2 mediates Wnt5 signaling. In contrast, forced expression of Drl-2 in the glia ofdrlmutants rescues the glomerular phenotype caused by the loss of antagonistic Drl function. Therefore, Drl-2 can also antagonize Wnt5 signaling. Additionally, our genetic data suggest that Drl localized to developing glomeruli mediates Wnt5 signaling. Thus, these two members of the Ryk family are capable of carrying out a similar molecular function, but they can play opposing roles in Wnt5 signaling, depending on the type of cells in which they are expressed. These molecules work cooperatively to establish the olfactory circuitry inDrosophila.
Dopamine Release in Dissociable Striatal Subregions Predicts the Different Effects of Oral Methylphenidate on Reversal Learning and Spatial Working Memory
Authors: Clatworthy Philip L. , Lewis Simon J. G. , Brichard Laurent , Hong Young T. , Izquierdo David , Clark Luke , Cools Roshan , Aigbirhio Franklin I. , Baron Jean-Claude , Fryer Timothy D. , Robbins Trevor W.
Published: April 2009

Previous data suggest that methylphenidate can have variable effects on different cognitive tasks both within and between individuals. This is thought to be underpinned by inverted U-shaped relationships between cognitive performance and dopaminergic activity in relatively separate fronto-striatal circuits and reflected by individual differences in trait impulsivity. Direct evidence for this is currently lacking. In this study, we demonstrate for the first time that therapeutic doses of oral methylphenidate administered to young healthy subjects result in different sized changes in D2/D3receptor availability in different regions of the human striatum and that the change in receptor availability within an individual subregion predicts cognitive performance on a particular task. Methylphenidate produced significantly different effects on reversal learning and spatial working memory tasks within individuals. Performance on the reversal learning task was predicted by the drug-induced change in D2/D3receptor availability in postcommissural caudate, measured using [11C]-raclopride radioligand PET imaging, whereas performance on the spatial working memory task was predicted by changes in receptor availability in the ventral striatum. Reversal learning performance was also predicted by subjects' trait impulsivity, such that the most impulsive individuals benefited more from methylphenidate, consistent with this drug's beneficial effects on cognition in attention deficit hyperactivity disorder.
Activity Propagation in an Avian Basal Ganglia-Thalamocortical Circuit Essential for Vocal Learning
Authors: Kojima Satoshi , Doupe Allison J.
Published: April 2009

In mammalian basal ganglia–thalamocortical circuits, GABAergic pallidal neurons are thought to “gate” or modulate excitation in thalamus with their strong inhibitory inputs and thus signal to cortex by pausing and permitting thalamic neurons to fire in response to excitatory drive. In contrast, in a homologous circuit specialized for vocal learning in songbirds, evidence suggests that pallidal neurons signal by eliciting postinhibitory rebound spikes in thalamus, which could occur even without any excitatory drive to thalamic neurons. To test whether songbird pallidal neurons can also communicate with thalamus by gating excitatory drive, as well as by postinhibitory rebound, we examined the activity of thalamic relay neurons in response to acute inactivation of the basal ganglia structure Area X; Area X contains the pallidal neurons that project to thalamus. Although inactivation of Area X should eliminate rebound-mediated spiking in thalamus, this manipulation tonically increased the firing rate of thalamic relay neurons, providing evidence that songbird pallidal neurons can gate tonic thalamic excitatory drive. We also found that the increased thalamic activity was fed forward to its target in the avian equivalent of cortex, which includes neurons that project to the vocal premotor area. These data raise the possibility that basal ganglia circuits can signal to cortex through thalamus both by generating postinhibitory rebound and by gating excitatory drive and may switch between these modes depending on the statistics of pallidal firing. Moreover, these findings provide insight into the strikingly different disruptive effects of basal ganglia and cortical lesions on songbird vocal learning.
Persistent Firing Supported by an Intrinsic Cellular Mechanism in a Component of the Head Direction System
Authors: Yoshida Motoharu , Hasselmo Michael E.
Published: April 2009

The rat postsubiculum has head direction cells that fire persistently when the rat's head is oriented in particular directions. This persistent firing is maintained even if the rat is motionless, when spatial cues are removed from the environment and in the dark, but the mechanism that supports persistent firing of the head direction cells is still unclear. Here, usingin vitrowhole-cell patch recording, we found that a short-triggering stimulus (as few as five induced spikes) can initiate persistent firing in cells of the postsubiculum. Pharmacological results indicated that this persistent firing is driven by a calcium-sensitive nonselective cation current. The distribution of cells with persistent firing in superficial and deep layers in the postsubiculum was similar to that of head direction cells. These results suggest that persistent firing of head direction cells in the postsubiculum could be supported by an intrinsic mechanism.
The Structure of Large-Scale Synchronized Firing in Primate Retina
Authors: Shlens Jonathon , Field Greg D. , Gauthier Jeffrey L. , Greschner Martin , Sher Alexander , Litke Alan M. , Chichilnisky E. J.
Published: April 2009

Synchronized firing among neurons has been proposed to constitute an elementary aspect of the neural code in sensory and motor systems. However, it remains unclear how synchronized firing affects the large-scale patterns of activity and redundancy of visual signals in a complete population of neurons. We recorded simultaneously from hundreds of retinal ganglion cells in primate retina, and examined synchronized firing in completely sampled populations of ∼50–100 ON-parasol cells, which form a major projection to the magnocellular layers of the lateral geniculate nucleus. Synchronized firing in pairs of cells was a subset of a much larger pattern of activity that exhibited local, isotropic spatial properties. However, a simple model based solely on interactions between adjacent cells reproduced 99% of the spatial structure and scale of synchronized firing. No more than 20% of the variability in firing of an individual cell was predictable from the activity of its neighbors. These results held both for spontaneous firing and in the presence of independent visual modulation of the firing of each cell. In sum, large-scale synchronized firing in the entire population of ON-parasol cells appears to reflect simple neighbor interactions, rather than a unique visual signal or a highly redundant coding scheme.
TRPA1 Modulates Mechanotransduction in Cutaneous Sensory Neurons
Authors: Kwan Kelvin Y. , Glazer Joshua M. , Corey David P. , Rice Frank L. , Stucky Cheryl L.
Published: April 2009

Transient receptor potential ankyrin 1 (TRPA1) is expressed by nociceptive neurons of the dorsal root ganglia (DRGs) and trigeminal ganglia, but its roles in cold and mechanotransduction are controversial. To determine the contribution of TRPA1 to cold and mechanotransduction in cutaneous primary afferent terminals, we used theex vivoskin–nerve preparation fromTrpa1+/+,Trpa1+/−, andTrpa1−/−adult mouse littermates. Cutaneous fibers from TRPA1-deficient mice showed no deficits in acute cold sensitivity, but they displayed striking deficits in mechanical response properties. C-fiber nociceptors fromTrpa1−/−mice exhibited action potential firing rates 50% lower than those in wild-type C-fibers across a wide range of force intensities. Aδ-fiber mechanonociceptors also had reduced firing, but only at high intensity forces (>100 mN). Surprisingly, the firing rates of low-threshold Aβ and D-hair mechanoreceptive fibers were also altered. TRPA1 protein and mRNA expression was assessed in DRG neurons and cutaneous innervation by usingTrpa1 in situhybridization, an antibody for TRPA1, and an antibody for placental alkaline phosphatase (PLAP) in mice in whichPLAPwas substituted forTrpa1. DRG neurons of all sizes expressedTrpa1mRNA or PLAP immunoreactivity. TRPA1 or PLAP immunolabeling was detected not only on many thin-caliber axons and intraepidermal endings but also on many large-caliber axons as well as lanceolate and Meissner endings. Epidermal and hair follicle keratinocytes also express TRPA1 message and protein. We propose that TRPA1 modulates mechanotransduction via a cell-autonomous mechanism in nociceptor terminals and possibly through a modulatory role in keratinocytes, which may interact with sensory terminals to modify their mechanical firing properties.
Activation of TRPV1 Mediates Calcitonin Gene-Related Peptide Release, Which Excites Trigeminal Sensory Neurons and Is Attenuated by a Retargeted Botulinum Toxin with Anti-Nociceptive Potential
Authors: Meng Jianghui , Ovsepian Saak V. , Wang Jiafu , Pickering Mark , Sasse Astrid , Aoki K. Roger , Lawrence Gary W. , Dolly J. Oliver
Published: April 2009

Excessive release of inflammatory/pain mediators from peripheral sensory afferents renders nerve endings hyper-responsive, causing central sensitization and chronic pain. Herein, the basal release of proinflammatory calcitonin gene-related peptide (CGRP) was shown to increase the excitability of trigeminal sensory neurons in brainstem slices via CGRP1 receptors because the effect was negated by an antagonist, CGRP8–37. This excitatory action could be prevented by cleaving synaptosomal-associated protein ofMr25,000 (SNAP-25) with botulinum neurotoxin (BoNT) type A, a potent inhibitor of exocytosis. Strikingly, BoNT/A proved unable to abolish the CGRP1 receptor-mediated effect of capsaicin, a nociceptive TRPV1 stimulant, or its elevation of CGRP release from trigeminal ganglionic neurons (TGNs) in culture. Although the latter was also not susceptible to BoNT/E, apparently attributable to a paucity of its acceptors (glycosylated synaptic vesicle protein 2 A/B), this was overcome by using a recombinant chimera (EA) of BoNT/A and BoNT/E. It bound effectively to the C isoform of SV2 abundantly expressed in TGNs and cleaved SNAP-25, indicating that its /A binding domain (HC) mediated uptake of the active /E protease. The efficacy of /EA is attributable to removal of 26 C-terminal residues from SNAP-25, precluding formation of SDS-resistant SNARE complexes. In contrast, exocytosis could be evoked after deleting nine of the SNAP-25 residues with /A but only on prolonged elevation of [Ca2+]iwith capsaicin. This successful targeting of /EA to nociceptive neurons and inhibition of CGRP releasein vitroandin situhighlight its potential as a new therapy for sensory dysmodulation and chronic pain.