bluuebunny/crossref_metadata_2025 huggingface dataset:
In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta
Authors: Panaroni Cristina , Gioia Roberta , Lupi Anna , Besio Roberta , Goldstein Steven A. , Kreider Jaclynn , Leikin Sergey , Vera Juan Carlos , Mertz Edward L. , Perilli Egon , Baruffaldi Fabio , Villa Isabella , Farina Aurora , Casasco Marco , Cetta Giuseppe , Rossi Antonio , Frattini Annalisa , Marini Joan C. , Vezzoni Paolo , Forlino Antonella
Published: May 2009

Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [α1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases.
Stable gene transfer and expression in cord blood–derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system
Authors: Xue Xingkui , Huang Xin , Nodland Sonja E. , Mátés Lajos , Ma Linan , Izsvák Zsuzsanna , Ivics Zoltán , LeBien Tucker W. , McIvor R. Scott , Wagner John E. , Zhou Xianzheng
Published: May 2009

Here we report stable gene transfer in cord blood-derived CD34+ hematopoietic stem cells using a hyperactive nonviral Sleeping Beauty (SB) transposase (SB100X). In colony-forming assays, SB100X mediated the highest efficiency (24%) of stable Discosoma sp red fluorescent protein (DsRed) reporter gene transfer in committed hematopoietic progenitors compared with both the early-generation hyperactive SB11 transposase and the piggyBac transposon system (1.23% and 3.8%, respectively). In vitro differentiation assays further demonstrated that SB100X-transfected CD34+ cells can develop into DsRed+ CD4+CD8+ T (3.17%-21.84%; median, 7.97%), CD19+ B (3.83%-18.66%; median, 7.84%), CD56+CD3− NK (3.53%-79.98%; median, 7.88%), and CD33+ myeloid (7.59%-15.63%; median, 9.48%) cells. SB100X-transfected CD34+ cells achieved approximately 46% engraftment in NOD-scid IL2γcnull (NOG) mice. Twelve weeks after transplantation, 0.57% to 28.96% (median, 2.79%) and 0.49% to 34.50% (median, 5.59%) of total human CD45+ cells in the bone marrow and spleen expressed DsRed, including CD19+ B, CD14+ monocytoid, and CD33+ myeloid cell lineages. Integration site analysis revealed SB transposon sequences in the human chromosomes of in vitro differentiated T, B, NK, and myeloid cells, as well as in human CD45+ cells isolated from bone marrow and spleen of transplanted NOG mice. Our results support the continuing development of SB-based gene transfer into human hematopoietic stem cells as a modality for gene therapy.
Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome
Authors: Poliani Pietro Luigi , Facchetti Fabio , Ravanini Maria , Gennery Andrew Richard , Villa Anna , Roifman Chaim M. , Notarangelo Luigi D.
Published: May 2009

Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with T-negative severe combined immunodeficiency, reticular dysgenesis, and Omenn syndrome. The latter also showed virtual absence of thymic Foxp3+ T cells. In contrast, an IL2RG-R222C hypomorphic mutation permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3+ T cells. Our data provide evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn syndrome.
Development and assessment of a questionnaire for a descriptive cross – sectional study concerning parents' knowledge, attitudes and practises in antibiotic use in Greece
Authors: Panagakou Sotiria G , Theodoridou Maria N , Papaevangelou Vassiliki , Papastergiou Panagiotis , Syrogiannopoulos George A , Goutziana Georgia P , Hadjichristodoulou Christos S
Published: May 2009

Background

Upper Respiratory Infections (URIs) are common in children. The cause is usually viral, but parents' attitude often contributes to inappropriate antibiotic prescribing, promoting antibiotic resistance. The objective is to describe the process of developing a questionnaire to assess parents' Knowledge, Attitude and Practices (KAP) concerning the role of antibiotics when children suffer from URIs, as well as to evaluate the response rates, the completeness and the reliability (Cronbach) of the questionnaires. Finally, to note any limitations of the study.

Methods

Literature review, along with pre – testing yielded a questionnaire designed to assess the parents' KAP – level. A postal survey was set, in a national sample of 200 schools stratified by geographical region. The participants consist of a multistage geographical cluster sample of 8000 parents. The influence of demographic characteristics (i.e. sex, age, education) was analyzed. Cronbach index test and factor analysis were used to assess the reliability of the questionnaire.

Results

The response rate of the parents was 69%. Islands presented the lowest response rate while in Northern Greece the response rate was the highest. Sixty – eight point nine percent of the sample returned questionnaires fully completed, while 91.5% completed 95% of the questions. Three questions out of 70 were answered in a very low rate which was associated mostly with immigrant respondents. The section describing parents' attitude toward antibiotic use was not completed as much as the sections of knowledge or practices. The questions were factor analyzed and 10 out of the 21 extracted factors were finally evaluated, reducing the number of independent variables to 46. The reliability of the questionnaire was 0.55. However, only items that increased the Cronbach when added were eventually included in the final scales raising the internal consistency to 0.68. Limitations of the study, such as the vocabulary and form of the questionnaire and the idiocycrancy of the respondents, emerged during the analysis.

Conclusion

The response rate and the completeness of the questionnaires were higher than expected, probably attributed to the involvement of the teachers. The study findings were satisfactory regarding the development of a reliable instrument capable to measure parents' KAP characteristics.
Reduction in patient burdens with graphical computerized adaptive testing on the ADL scale: tool development and simulation
Authors: Chien Tsair-Wei , Wu Hing-Man , Wang Weng-Chung , Castillo Roberto Vasquez , Chou Willy
Published: May 2009

Background

The aim of this study was to verify the effectiveness and efficacy of saving time and reducing burden for patients, nurses, and even occupational therapists through computer adaptive testing (CAT).

Methods

Based on an item bank of the Barthel Index (BI) and the Frenchay Activities Index (FAI) for assessing comprehensive activities of daily living (ADL) function in stroke patients, we developed a visual basic application (VBA)-Excel CAT module, and (1) investigated whether the averaged test length via CAT is shorter than that of the traditional all-item-answered non-adaptive testing (NAT) approach through simulation, (2) illustrated the CAT multimedia on a tablet PC showing data collection and response errors of ADL clinical functional measures in stroke patients, and (3) demonstrated the quality control of endorsing scale with fit statistics to detect responding errors, which will be further immediately reconfirmed by technicians once patient ends the CAT assessment.

Results

The results show that endorsed items could be shorter on CAT (M = 13.42) than on NAT (M = 23) at 41.64% efficiency in test length. However, averaged ability estimations reveal insignificant differences between CAT and NAT.

Conclusion

This study found that mobile nursing services, placed at the bedsides of patients could, through the programmed VBA-Excel CAT module, reduce the burden to patients and save time, more so than the traditional NAT paper-and-pencil testing appraisals.
Reporting of harm in randomized controlled trials evaluating stents for percutaneous coronary intervention
Authors: Ethgen Morgane , Boutron Isabelle , Steg Philippe Gabriel , Roy Carine , Ravaud Philippe
Published: May 2009

Background

The aim of this study was to assess the reporting of harm in randomized controlled trials evaluating stents for percutaneous coronary intervention.

Methods

The study design was a methodological systematic review of randomized controlled trials. The data sources were MEDLINE and the Cochrane Central Register of Controlled Trials. All reports of randomized controlled trials assessing stent treatment for coronary disease published between January 1, 2003, and September 30, 2008 were selected.

A standardized abstraction form was used to extract data.

Results

132 articles were analyzed. Major cardiac adverse events (death, cardiac death, myocardial infarction or stroke) were reported as primary or secondary outcomes in 107 reports (81%). However, 19% of the articles contained no data on cardiac events. The mode of data collection of adverse events was given in 29 reports (22%) and a definition of expected adverse events was provided in 47 (36%). The length of follow-up was reported in 95 reports (72%). Assessment of adverse events by an adjudication committee was described in 46 reports (35%), and adverse events were described as being followed up for 6 months in 24% of reports (n = 32), between 7 to 12 months in 42% (n = 55) and for more than 1 year in 4% (n = 5). In 115 reports (87%), numerical data on the nature of the adverse events were reported per treatment arm. Procedural complications were described in 30 articles (23%). The causality of adverse events was reported in only 4 articles.

Conclusion

Several harm-related data were not adequately accounted for in articles of randomized controlled trials assessing stents for percutaneous coronary intervention.

Trials Registration

Trials manuscript: 5534201182098351 (T80802P)
Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells
Authors: Das Gaurav , Choi Yoon , Sicinski Piotr , Levine Edward M
Published: May 2009

Background

Maintaining the correct balance of proliferation versus differentiation in retinal progenitor cells (RPCs) is essential for proper development of the retina. The cell cycle regulator cyclin D1 is expressed in RPCs, and mice with a targeted null allele at the cyclin D1 locus (Ccnd1-/-) have microphthalmia and hypocellular retinas, the latter phenotype attributed to reduced RPC proliferation and increased photoreceptor cell death during the postnatal period. How cyclin D1 influences RPC behavior, especially during the embryonic period, is unclear.

Results

In this study, we show that embryonic RPCs lacking cyclin D1 progress through the cell cycle at a slower rate and exit the cell cycle at a faster rate. Consistent with enhanced cell cycle exit, the relative proportions of cell types born in the embryonic period, such as retinal ganglion cells and photoreceptor cells, are increased. Unexpectedly, cyclin D1 deficiency decreases the proportions of other early born retinal neurons, namely horizontal cells and specific amacrine cell types. We also found that the laminar positioning of horizontal cells and other cell types is altered in the absence of cyclin D1. Genetically replacing cyclin D1 with cyclin D2 is not efficient at correcting the phenotypes due to the cyclin D1 deficiency, which suggests the D-cyclins are not fully redundant. Replacement with cyclin E or inactivation of cyclin-dependent kinase inhibitor p27Kip1 restores the balance of RPCs and retinal cell types to more normal distributions, which suggests that regulation of the retinoblastoma pathway is an important function for cyclin D1 during embryonic retinal development.

Conclusion

Our findings show that cyclin D1 has important roles in RPC cell cycle regulation and retinal histogenesis. The reduction in the RPC population due to a longer cell cycle time and to an enhanced rate of cell cycle exit are likely to be the primary factors driving retinal hypocellularity and altered output of precursor populations in the embryonic Ccnd1-/- retina.
Survival in Norwegian BRCA1 mutation carriers with breast cancer
Authors: Hagen Anne Irene , Tretli Steinar , Mæhle Lovise , Apold Jaran , Vedå Nina , Møller Pål
Published: May 2009

Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers.

One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival were recorded. A control group comprising three hundred and four women matched for age, time of diagnosis and stage were used to compare survival.

BRCA1 mutation carriers were found to have a poorer prognosis, which could be explained by neither the mode of surgical treatment nor the use of adjuvant chemotherapy. BRCA1 mutation carriers with node negative breast cancer had worse overall survival than controls.

Our findings confirm the serious prognosis of BRCA1-associated breast cancer even when diagnosed at an early stage, and that type of treatment does not influence prognosis.
Co-evolutionary networks of genes and cellular processes across fungal species
Authors: Tuller Tamir , Kupiec Martin , Ruppin Eytan
Published: May 2009

Background

The introduction of measures such as evolutionary rate and propensity for gene loss have significantly advanced our knowledge of the evolutionary history and selection forces acting upon individual genes and cellular processes.

Results

We present two new measures, the 'relative evolutionary rate pattern' (rERP), which records the relative evolutionary rates of conserved genes across the different branches of a species' phylogenetic tree, and the 'copy number pattern' (CNP), which quantifies the rate of gene loss of less conserved genes. Together, these measures yield a high-resolution study of the co-evolution of genes in 9 fungal species, spanning 3,540 sets of orthologs. We find that the evolutionary tempo of conserved genes varies in different evolutionary periods. The co-evolution of genes' Gene Ontology categories exhibits a significant correlation with their functional distance in the Gene Ontology hierarchy, but not with their location on chromosomes, showing that cellular functions are a more important driving force in gene co-evolution than their chromosomal proximity. Two fundamental patterns of co-evolution of conserved genes, cooperative and reciprocal, are identified; only genes co-evolving cooperatively functionally back each other up. The co-evolution of conserved and less conserved genes exhibits both commonalities and differences; DNA metabolism is positively correlated with nuclear traffic, transcription processes and vacuolar biology in both analyses.

Conclusions

Overall, this study charts the first global network view of gene co-evolution in fungi. The future application of the approach presented here to other phylogenetic trees holds much promise in characterizing the forces that shape cellular co-evolution.
Mechanisms and consequences of efferocytosis in advanced atherosclerosis
Authors: Thorp Edward , Tabas Ira
Published: May 2009

Review on how dangerous atherosclerotic plaques form and the critical role for defective phagocytic clearance (or “efferocytosis”) of apoptotic macrophages in these lesions.

Throughout atherosclerotic lesion development, intimal macrophages undergo apoptosis, a form of death that usually prevents cellular necrosis. In advanced atherosclerotic lesions, however, these apoptotic macrophages become secondarily necrotic and coalesce over time into a key feature of vulnerable plaques, the necrotic core. This event is critically important, as necrotic core formation in these advanced atheromata is thought to promote plaque disruption and ultimately, acute atherothrombotic vascular disease. Increasing evidence suggests that the mechanism behind postapoptotic macrophage necrosis in advanced atherosclerosis is defective phagocytic clearance or “efferocytosis” of the apoptotic cells. Thus, understanding the cellular and molecular mechanisms of efferocytosis in atherosclerosis and why efferocytosis becomes defective in advanced lesions is an important goal. Molecular–genetic causation studies in mouse models of advanced atherosclerosis have provided evidence that several molecules known to be involved in efferocytosis, including TG2, MFG-E8, complement C1q, Mertk, lysoPC, and Fas, play important roles in the clearance of apoptotic cells in advanced plaques. These and future insights into the molecular mechanisms of defective efferocytosis in advanced atheromata may open the way for novel therapeutic strategies for atherothrombotic vascular disease, the leading cause of death in the industrialized world.
Requirement of HMGB1 for stromal cell–derived factor–1/CXCL12–dependent migration of macrophages and dendritic cells
Authors: Campana Lara , Bosurgi Lidia , Bianchi Marco E , Manfredi Angelo A , Rovere–Querini Patrizia
Published: May 2009

Alterations in the capability of CF lung macrophage to respond and clear airway pathogens might contribute to the development of lung disease in cystic fibrosis.

HMGB1 finely tunes the function of DCs, thus influencing their maturation program and eventually the establishment of adaptive, T cell–dependent immune responses. Moreover, it promotes the up–regulation of receptors for lymph node chemokines, regulates the remodeling of the cytoskeleton of migrating cells, and sustains their journey to secondary lymphoid organs via a RAGE–dependent pathway. The inflammatory properties of HMGB1 depend at least partially on the ability to complex with soluble moieties, including nucleic acids, microbial products, and cytokines. Here, we show that bone marrow–derived mouse DCs release HMGB1 during CXCL12–dependent migration in vitro. Macrophages share this property, suggesting that it may be a general feature of CXCL12–responsive leukocytes. The chemotactic response to rCXCL12 of DCs and macrophages abates in the presence of the HMGB1 antagonist BoxA. HMGB1 secreted from DCs and macrophages binds to CXCL12 in the fluid phase and protects the chemokine conformation and function in a reducing environment. Altogether, our data indicate that HMGB1 release is required for CXCL12 ability to attract myeloid–derived cells and reveal a functional interaction between the two molecules that possibly contributes to the regulation of leukocyte recruitment and motility.
HMGB1 loves company
Authors: Bianchi Marco E
Published: May 2009

HMGB1 outside of a cell is both a trigger of inflammation and a stimulus for tissue reconstruction; the balance may depend on the complexes it forms with other molecules.

HMGB1, outside of a cell, is a trigger of inflammation and a stimulus for tissue reconstruction; the balance may depend on the complexes it forms with other molecules. HMGB1 is the prime example of a danger signal that originates from the damaged self rather than from invading pathogens. HMGB1 is released by cells that die traumatically and is secreted by cells destined to die and by activated cells of the innate immunity system. As a danger signal, HMGB1 is expected to trigger inflammation, but recent reports indicate that pure recombinant HMGB1 has no proinflammatory activity and only acts as a chemoattractant and a mitogen. However, HMGB1 forms highly inflammatory complexes with ssDNA, LPS, IL–1β, and nucleosomes, which interact with TLR9, TLR4, IL–1R, and TLR2 receptors, respectively. Thus, HMGB1 has dual activities, solo or in company; I speculate that this may serve our body’s necessity to sacrifice or reconstruct tissues as required by the presence or absence of pathogens.
Experiments of Earthquake Early Warning to Expressway Drivers Using Synchronized Driving Simulators
Authors: Maruyama Yoshihisa , Yamazaki Fumio , Sakaya Masato
Published: May 2009

To reduce the casualties and impacts resulting from earthquakes, the Japan Meteorological Agency (JMA) introduced its earthquake early warning (EEW) system to the general public on 1 October 2007. Interestingly, a side effect of the system is an anticipated increase in traffic accidents that may occur because the EEW transmission will not be received by all drivers. Consequently, the effects of an EEW are investigated using three synchronized driving simulators to replicate the conditions of three cars traveling in close proximity on an expressway. When the EEW was received by all cars, the drivers behaved properly, and no problems occurred. When an EEW was received by just one car, however, some drivers reduced speed immediately, and accidents resulted in two out of 14 test cases. These experiments show the necessity of educating the public on how to respond if an EEW is received while driving on an expressway. In such situations, activating hazard lights and reducing speed gradually is suggested to avoid traffic accidents.
Broadband Simulation of Earthquake Ground Motion by a Spectrum-Matching, Multiple-Pulse Technique
Authors: Gusev Alexander A. , Pavlov Victor M.
Published: May 2009

A kinematic, stochastic fault model and simulation procedure is proposed for realistic, application-oriented simulation of earthquake ground motion. An extended fault plane is discretized as a grid of point subsources. Subsource signal, in its low-frequency part, is produced by a dislocation strip sweeping the fault area. In its high-frequency part, it is defined by random local slip history, represented by a segment of pulsed noise. Subsource signals are convolved with broad-band Green functions for a layered half-space, and stacked, resulting in the ground motion at a site. Through a special choice of subsource signals, the Fourier spectrum of ground motion obeys an observation-based scaling law. Effects of the rupture velocity behavior, rise time, wavenumber spectrum for the final slip, the degree of spikiness of time functions etc can be easily analyzed. For illustration, several near-source 1994 Northridge earthquake records are simulated, and related uncertainties are estimated.
Displacement-Based Seismic Assessment of Low-Height Confined Masonry Buildings
Authors: Terán-Gilmore Amador , Zuñiga-Cuevas Oscar , Ruiz-García Jorge
Published: May 2009

This paper presents a practical displacement-based evaluation procedure for the seismic assessment of low-height regular confined masonry buildings. First, the so-called Coefficient Method established in several FEMA documents is adapted to obtain rapid estimates of inelastic roof displacement demands for regular confined masonry buildings. For that purpose, a statistical study of constant relative strength inelastic displacement ratios of single-degree-of-freedom systems representing confined masonry buildings is carried out. Second, a nonlinear simplified model is introduced to perform pushover analysis of regular confined masonry buildings whose global and local behavior is dominated by shear deformations in the masonry walls. The model, which can be applied through the use of commercial software, can be used to establish the capacity curve of such buildings. Finally, the evaluation procedure is applied to a three-story building tested at a shaking table testing facility.
Epidermal Growth Factor Receptor Mutations in Plasma DNA Samples Predict Tumor Response in Chinese Patients With Stages IIIB to IV Non–Small-Cell Lung Cancer
Authors: Bai Hua , Mao Li , Wang hang Shu , Zhao Jun , Yang Lu , An tong Tong , Wang Xin , Duan chun Jian , Wu na Mei , Guo zhi Qing , Liu yi Xu , Liu hong Ning , Wang ye Yu , Wang Jie
Published: May 2009

Purpose

Mutations in the epidermal growth factor receptor (EGFR) kinase domain can predict tumor response to tyrosine kinase inhibitors (TKIs) in non–small-cell lung cancer (NSCLC). However, obtaining tumor tissues for mutation analysis is challenging. We hypothesized that plasma-based EGFR mutation analysis is feasible and has value in predicting tumor response in patients with NSCLC.

Patients and Methods

Plasma DNA samples and matched tumors from 230 patients with stages IIIB to IV NSCLC were analyzed for EGFR mutations in exons 19 and 21 by using denaturing high-performance liquid chromatography. We compared the mutations in the plasma samples and the matched tumors and determined an association between EGFR mutation status and the patients' clinical outcomes prospectively.

Results

In 230 patients, we detected 81 EGFR mutations in 79 (34.3%) of the patients' plasma samples. We detected the same mutations in 63 (79.7%) of the matched tumors. Sixteen plasma (7.0%) and fourteen tumor (6.1%) samples showed unique mutations. The mutation frequencies were significantly higher in never-smokers and in patients with adenocarcinomas (P = .012 and P = .009, respectively). In the 102 patients who failed platinum-based treatment and who were treated with gefitinib, 22 (59.5%) of the 37 with EGFR mutations in the plasma samples, whereas only 15 (23.1%) of the 65 without EGFR mutations, achieved an objective response (P = .002). Patients with EGFR mutations had a significantly longer progression-free survival time than those without mutations (P = .044) in plasma.

Conclusion

EGFR mutations can be reliably detected in plasma DNA of patients with stages IIIB to IV NSCLC and can be used as a biomarker to predict tumor response to TKIs.
Phase II Clinical Trial of Neoadjuvant Alternating Doublet Chemotherapy With Ifosfamide/Doxorubicin and Etoposide/Cisplatin in Small-Cell Urothelial Cancer
Authors: Siefker-Radtke Arlene O. , Kamat Ashish M. , Grossman H. Barton , Williams Dallas L. , Qiao Wei , Thall Peter F. , Dinney Colin P. , Millikan Randall E.
Published: May 2009

Purpose

Currently, treatment recommendations for small-cell urothelial cancer (SCUC) are based on anecdotal case reports and small retrospective series. We now report results from the first phase II clinical trial developed exclusively for SCUC, to our knowledge.

Patients and Methods

From 2001 to 2006, 30 patients with SCUC provided consent and were treated with alternating doublet chemotherapy. Patients with surgically resectable disease (≤ cT4aN0M0) received a total of four cycles of neoadjuvant chemotherapy, whereas those with unresectable disease (≥ cT4b, N+, or M+) received two cycles beyond maximal response.

Results

Eighteen patients with surgically resectable SCUC received neoadjuvant treatment with a median overall survival (OS) of 58 months; 13 of these patients remain alive and cancer free. For patients with cT2N0M0 SCUC, the 5-year OS rate is 80%; only one of four patients with cT3b-4aN0M0 remains alive (median OS, 37.8 months). For 12 patients with unresectable or metastatic SCUC, the median OS was 13.3 months. Chemotherapy was well tolerated, with transfusion, neutropenic fever, and infection remaining the most frequent grade 3 and 4 toxicities. There was only one postsurgical death. Brain metastases were strongly associated with more advanced-stage disease, developing in eight of 16 patients with either bulky tumors (≥ cT3b) or metastatic disease (P = .004).

Conclusion

These clinical trial results are consistent with previously reported retrospective data demonstrating long-term survival with four cycles of neoadjuvant chemotherapy for surgically resectable SCUC. Once metastases develop, the prognosis remains poor. The strong positive association between disease stage and brain metastases highlights a patient subset that may potentially benefit from prophylactic cranial irradiation.
Connective Tissue-Activating Peptide III: A Novel Blood Biomarker for Early Lung Cancer Detection
Authors: Yee John , Sadar Marianne D. , Sin Don D. , Kuzyk Michael , Xing Li , Kondra Jennifer , McWilliams Annette , Man S.F. Paul , Lam Stephen
Published: May 2009

Purpose

There are no reliable blood biomarkers to detect early lung cancer. We used a novel strategy that allows discovery of differentially present proteins against a complex and variable background.

Methods

Mass spectrometry analyses of paired pulmonary venous-radial arterial blood from 16 lung cancer patients were applied to identify plasma proteins potentially derived from the tumor microenvironment. Two differentially expressed proteins were confirmed in 64 paired venous-arterial blood samples using an immunoassay. Twenty-eight pre- and postsurgical resection peripheral blood samples and two independent, blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls) and 266 participants from the National Heart Lung and Blood Institute Lung Health Study (45 lung cancer and 221 matched controls) determined the accuracy of the two protein markers to detect subclinical lung cancer.

Results

Connective tissue-activating peptide III (CTAP III)/ neutrophil activating protein-2 (NAP-2) and haptoglobin were identified to be significantly higher in venous than in arterial blood. CTAP III/NAP-2 levels decreased after tumor resection (P = .01). In two independent population cohorts, CTAP III/NAP-2 was significantly associated with lung cancer and improved the accuracy of a lung cancer risk prediction model that included age, smoking, lung function (FEV1), and an interaction term between FEV1 and CTAP III/NAP-2 (area under the curve, 0.84; 95% CI, 0.77 to 0.91) compared to CAPIII/NAP-2 alone.

Conclusion

We identified CTAP III/NAP-2 as a novel biomarker to detect preclinical lung cancer. The study underscores the importance of applying blood biomarkers as part of a multimodal lung cancer risk prediction model instead of as stand-alone tests.
Relapse-Related Molecular Signature in Lung Adenocarcinomas Identifies Patients With Dismal Prognosis
Authors: Tomida Shuta , Takeuchi Toshiyuki , Shimada Yukako , Arima Chinatsu , Matsuo Keitaro , Mitsudomi Tetsuya , Yatabe Yasushi , Takahashi Takashi
Published: May 2009

Purpose

In order to aid the development of patient-tailored therapeutics, we attempted to identify a relapse-related signature that allows selection of a group of adenocarcinoma patients with a high probability of relapse.

Patients and Methods

Whole-genome expression profiles were analyzed in 117 lung adenocarcinoma samples using microarrays consisting of 41,000 probes. A weighted voting classifier for identifying patients with a relapse-related signature was constructed with an approach that allowed no information leakage during each training step, using 10-fold cross-validation and 100 random partitioning procedures.

Results

We identified a relapse-related molecular signature represented by 82 probes (RRS-82) through genome-wide expression profiling analysis of a training set of 60 patients. The robustness of RRS-82 in the selection of patients with a high probability of relapse was then validated with a completely blinded test set of 27 adenocarcinoma patients, showing a clear association of high risk RRS-82 with very poor patient prognosis regardless of disease stage. The discriminatory power of RRS-82 was further validated using an additional independent cohort of 30 stage I patients who underwent surgery at a distinct period of time as well as with the Duke data set on a different platform. Furthermore, completely separate training and validation procedures using another data set recently reported by the Director's Challenge Consortium also successfully confirmed the predictive power of the genes comprising RRS-82.

Conclusion

RRS-82 may be useful for identifying adenocarcinoma patients at very high risk for relapse, even those with cancer in the early stage.
BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Biopsy Specimens for Preoperative Risk Stratification in Papillary Thyroid Cancer
Authors: Xing Mingzhao , Clark Douglas , Guan Haixia , Ji Meiju , Dackiw Alan , Carson Kathryn A. , Kim Matthew , Tufaro Anthony , Ladenson Paul , Zeiger Martha , Tufano Ralph
Published: May 2009

Purpose

This study investigated the utility of BRAF mutation testing of thyroid fine-needle aspiration biopsy (FNAB) specimens for preoperative risk stratification in papillary thyroid cancer (PTC).

Patients and Methods

We assessed the T1799A BRAF mutation status in thyroid FNAB specimens obtained from 190 patients before thyroidectomy for PTC and its association with clinicopathologic characteristics of the tumor revealed postoperatively.

Results

We observed a significant association of BRAF mutation in preoperative FNAB specimens with poorer clinicopathologic outcomes of PTC. In comparison with the wild-type allele, BRAF mutation strongly predicted extrathyroidal extension (23% v 11%; P = .039), thyroid capsular invasion (29% v 16%; P = .045), and lymph node metastasis (38% v 18%; P = .002). During a median follow-up of 3 years (range, 0.6 to 10 years), PTC persistence/recurrence was seen in 36% of BRAF mutation–positive patients versus 12% of BRAF mutation–negative patients, with an odds ratio of 4.16 (95% CI, 1.70 to 10.17; P = .002). The positive and negative predictive values for preoperative FNAB-detected BRAF mutation to predict PTC persistence/recurrence were 36% and 88% for overall PTC and 34% and 92% for conventional PTC, respectively.

Conclusion

Preoperative BRAF mutation testing of FNAB specimens provides a novel tool to preoperatively identify PTC patients at higher risk for extensive disease (extrathyroidal extension and lymph node metastases) and those who are more likely to manifest disease persistence/recurrence. BRAF mutation, as a powerful risk prognostic marker, may therefore be useful in appropriately tailoring the initial surgical extent for patients with PTC.
Phase II Trial of Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22) in Patients With Hairy Cell Leukemia
Authors: Kreitman Robert J. , Stetler-Stevenson Maryalice , Margulies Inger , Noel Pierre , FitzGerald David J.P. , Wilson Wyndham H. , Pastan Ira
Published: May 2009

Purpose

To conduct a phase II trial in chemoresistant hairy cell leukemia (HCL) with BL22, a recombinant anti-CD22 immunotoxin which showed phase I activity in HCL.

Patients and Methods

Eligible patients had relapsed/refractory HCL and needed treatment based on blood counts. Patients were stratified into three groups: response to cladribine less than 1 year, those with a response lasting 1 to 4 years, or no response and uncontrolled infection. Patients received BL22 40 μg/kg every other day for three doses on cycle 1. Those achieving hematologic remission (HR), defined as neutrophils ≥ 1,500/mm3, hemoglobin ≥ 11 g/dL, and platelets ≥ 100,000/mm3, were observed. Patients without HR were re-treated at 30 μg/kg every other day for three doses every 4 weeks beginning at least 8 weeks after cycle 1.

Results

Thirty-six patients were enrolled including 26, nine, and one in groups 1 to 3. The response after one cycle (CR, 25%; PR, 25%) improved when 56% were re-treated (CR, 47%; PR, 25%). CR rate was similar in groups 1 and 2 (P = .7). Twenty-two with baseline spleen height lower than 200 mm had higher CR (64% v 21%; P = .019) and OR rates (95% v 36%; P = .0002) compared to 14 with spleens either absent or higher than 200 mm. The only serious toxicity was reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in two patients (6%). High neutralizing antibodies were observed in four patients (11%) and prevented re-treatment.

Conclusion

BL22 activity in HCL is confirmed. Best responses to BL22 after cladribine failure are achieved before the patients develop massive splenomegaly or undergo splenectomy.
Perspectives for Cancer Prevention With Natural Compounds
Authors: Amin A.R.M. Ruhul , Kucuk Omer , Khuri Fadlo R. , Shin Dong M.
Published: May 2009

Cancer is the second leading cause of death in the United States. Despite the estimated 565,650 deaths in 2008 of Americans as a result of cancer, it is mostly a preventable disease. Simply by modification of diet, maintenance of optimum body weight, and regular physical activity, 30% to 40% of all instances of cancer could be prevented. Modification of diet alone by increasing vegetable and fruit intake could prevent 20% or more of all cases of cancer and may potentially prevent approximately 200,000 cancer-related deaths annually. Because of their safety, low toxicity, antioxidant properties, and general acceptance as dietary supplements, fruits, vegetables, and other dietary elements (phytochemicals and minerals) are being investigated for the prevention of cancer. Extensive research over the past several decades has identified numerous dietary and botanical natural compounds that have chemopreventive potential. In this review, we discuss promising natural chemopreventive compounds, their molecular targets, and their mechanisms, which may help the further design and conduct of preclinical and clinical trials.
Outcome in a Prospective Phase II Trial of Medically Inoperable Stage I Non–Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiotherapy
Authors: Baumann Pia , Nyman Jan , Hoyer Morten , Wennberg Berit , Gagliardi Giovanna , Lax Ingmar , Drugge Ninni , Ekberg Lars , Friesland Signe , Johansson Karl-Axel , Lund Jo-Åsmund , Morhed Elisabeth , Nilsson Kristina , Levin Nina , Paludan Merete , Sederholm Christer , Traberg Anders , Wittgren Lena , Lewensohn Rolf
Published: May 2009

Purpose

The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non–small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study.

Patients and Methods

Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume.

Results

Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027).

Conclusion

With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.
Optimal sizing of photovoltaic—battery power systems in a remote region in Kerman, Iran
Authors: Askari I Baniasad , Ameri M
Published: May 2009

A solar energy system is an excellent solution for electrification of remote rural areas where the grid extension is difficult and not economical. This article presents a simple optimization method for calculating the optimum configurations of photovoltaic—battery (PV—bat) systems with high reliability and minimum cost. The proposed method has been applied to design a PV—bat system to supply a typical load requirement in a remote region in Kerman, Iran. To design an optimum stand-alone PV—bat system with high reliability and low costs, the optimization procedure, which is based on the annual electrical demand and solar radiation data, consists of two parts: the model of loss of power supply probability (LPSP) and the model of the levelized cost of energy. For the different desired LPSP requirements at given demand, the optimal numbers of solar array and battery hours of storage are obtained at the minimum system cost.
Personalized Medicine: Boon or Budget-Buster?
Authors: Dean Charles E
Published: May 2009

While the development of personalized or molecular medicine is a laudable goal, there remain multiple barriers to its implementation. For example, little is known about the functions of noncoding regions of DNA, as well as the interplay of drug response, environmental factors, and the patient's genetic profile. In addition, there is a constant influx of new information on genetic factors such as epigenetic variation that could further complicate the development of medications based on the genetic profile, as well as the cost of profiling. However, assuming that clinically relevant genetic factors will be discovered and that drugs can be developed based on the molecular changes induced by those genetic factors, I suggest that the costs involved may substantially exceed the savings brought about by abandoning our current “one drug fits all” approach. While there is no doubt that our current approach is inefficient and expensive, remarkably little attention has been paid to the potential costs of molecular medicine. Given the current economic crisis, the time is ripe for a debate on this issue.
Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant
Authors: White Michel , Ross Heather , Levesque Sylvie , Whittom Lucette , Pelletier Guy B , Racine Normand , Meloche Sylvain , Voisin Laure
Published: May 2009

Background

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied.

Objective

To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart.

Methods

Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting.

Results

The mean dose of valsartan was 114 ± 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal–regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group.

Conclusions

Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.
Community Pharmacist–Provided Extended Diabetes Care
Authors: Doucette William R , Witry Matthew J , Farris Karen B , Mcdonough Randal P
Published: May 2009

Background

Pharmacists in various settings have been effective in initiating diabetes treatment. Patients with diabetes require ongoing disease management, and community pharmacists are in a strategic position to provide such extended care. Little is known, however, about the effects of community pharmacist–provided interventions beyond the initial treatment period.

Objective

To evaluate the effect of community pharmacist–provided extended diabetes care service on primary clinical outcomes, including hemoglobin A1c (A1C), low-density lipoprotein cholesterol (LDL-C), and blood pressure, and on patients' reported self-care activities.

Methods

A randomized controlled trial was conducted in patients with diabetes. Participants had already completed at least 2 diabetes education sessions at a local diabetes education center. Nine specially trained pharmacists administered interventions during up to 4 quarterly visits per patient. Interventions included discussing medications, clinical goals, and self-care activities with patients and recommending medication changes to physicians when appropriate. The main outcome measures were 12-month changes in A1C, LDL-C, blood pressure, and self-report of self-care activities.

Results

Seventy-eight patients participated in the study (36 intervention, 42 control); 66 were included in the final analysis (31 intervention, 35 control). Compared with changes in the control group, patients who received interventions significantly increased the number of days per week that they engaged in a set of diet and diabetes self-care activities (1.25 and 0.73 more days/wk, respectively). The mean 12-month changes for A1C, LDL-C, and blood pressure were not significantly different between the 2 study groups.

Conclusions

Although pharmacist-provided interventions did not demonstrate statistically significant improvements in clinical outcomes over the study period, study results did show that pharmacists were effective at increasing the number of days that patients spent engaging in healthy diet and diabetes self-care activities. Addressing lifestyle and self-care behaviors can be a beneficial component of a pharmacist-provided extended diabetes care service.