bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical values of multiple Epstein-Barr virus (EBV) serological biomarkers detected by xMAP technology
Authors: Gu Ai-Di , Lu Li-Xia , Xie Yan-Bo , Chen Li-Zhen , Feng Qi-Sheng , Kang Tiebang , Jia Wei-Hua , Zeng Yi-Xin
Published: August 2009

Background

Serological examination of Epstein-Barr virus (EBV) antibodies has been performed for screening nasopharyngeal carcinoma (NPC) and other EBV-associated diseases.

Methods

By using xMAP technology, we examined immunoglobulin (Ig) A antibodies against Epstein-Barr virus (EBV) VCA-gp125, p18 and IgA/IgG against EA-D, EBNA1 and gp78 in populations with distinct diseases, or with different genetic or geographic background. Sera from Cantonese NPC patients (n = 547) and healthy controls (n = 542), 90 members of high-risk NPC families and 52 non-endemic healthy individuals were tested. Thirty-five of NPC patients were recruited to observe the kinetics of EBV antibody levels during and after treatment. Patients with other EBV-associated diseases were collected, including 16 with infectious mononucleosis, 28 with nasal NK/T cell lymphoma and 14 with Hodgkin's disease.

Results

Both the sensitivity and specificity of each marker for NPC diagnosis ranged 61–84%, but if combined, they could reach to 84.5% and 92.4%, respectively. Almost half of NPC patients displayed decreased EBV immunoactivities shortly after therapy and tumor recurrence was accompanied with high EBV antibody reactivates. Neither the unaffected members from high-risk NPC families nor non-endemic healthy population showed statistically different EBV antibody levels compared with endemic controls. Moreover, elevated levels of specific antibodies were observed in other EBV-associated diseases, but all were lower than those in NPC.

Conclusion

Combined EBV serological biomarkers could improve the diagnostic values for NPC. Diverse EBV serological spectrums presented in populations with different EBV-associated diseases, but NPC patients have the highest EBV activity.
Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitrostudy
Authors: Zhang Zhe , Zhou Xiaoyun , Shen Hujia , Wang Dexing , Wang Yanhong
Published: August 2009

Background

Sorafenib is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma (HCC), setting a new standard for first-line treatment. However, no one has yet been able to predict sensitivity to sorafenib. Pre-treatment pERK level has been shown to be associated with favorable response to such therapy in a phase II clinical study, indicating that pERK may be a potential biomarker for treatment of HCC with sorafenib.

Methods

The effects of sorafenib and 5-fluorouracil (5-FU) on cell proliferation were evaluated by cell viability assays in four HCC cell lines (SMMC-7721, MHCC97-L, MHCC97-H and HCCLM6) with different metastatic potential and basal pERK expression levels. Expression levels of pERK were determined by immunocytochemical quantification together with western blot analysis, and pERK density values were also calculated. Correlation analyses were then carried out between the IC50 values of drugs and pERK density values. After basal ERK phosphorylation was down-regulated with U0126 in MHCC97-H cells, cellular responsiveness to sorafenib was assessed by cell viability assay.

Results

Basal pERK levels increased stepwise in cell lines in accordance with their metastatic potential. Sorafenib inhibited ERK phosphorylation in a dose-dependent manner in all four cell lines at a concentration between 5 and 20 μM, but the degree of inhibition was significantly different according to their basal pERK expression level (P < 0.0001). In contrast, no significant change was observed after 5-FU treatment. Correlation analyses between the IC50 values and pERK densities revealed that the effects of sorafenib on cell proliferation were significantly correlated with basal pERK levels (Spearman r = -0.8671, P = 0.0003). Resistance to 5-FU was also significantly associated with basal pERK expression in these HCC cell lines (Spearman r = 0.7832, P = 0.0026). After the basal ERK phosphorylation level in MHCC97-H cells was reduced with U0126, they were significantly less sensitive to sorafenib-mediated growth inhibition, with an IC50 of 17.31 ± 1.62 μM versus 10.81 ± 1.24 μM (P = 0.0281).

Conclusion

In this in vitro study, pERK was confirmed to be a potential biomarker predictive of sensitivity to sorafenib in treating HCC. The RAF/MEK/ERK pathway may be involved in drug resistance to traditional chemotherapy in HCC.
Possible role of glial cells in the onset and progression of Lyme neuroborreliosis
Authors: Ramesh Geeta , Borda Juan T , Gill Amy , Ribka Erin P , Morici Lisa A , Mottram Peter , Martin Dale S , Jacobs Mary B , Didier Peter J , Philipp Mario T
Published: August 2009

Background

Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure toBorrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis.

Methods

We inoculated liveB. burgdorferiinto the cisterna magna of rhesus macaques and examined the inflammatory changes induced in the central nervous system (CNS), and dorsal root nerves and ganglia (DRG).

Results

ELISA of the cerebrospinal fluid (CSF) showed elevated IL-6, IL-8, CCL2, and CXCL13 as early as one week post-inoculation, accompanied by primarily lymphocytic and monocytic pleocytosis. In contrast, onset of the acquired immune response, evidenced by anti-B. burgdorferiC6 serum antibodies, was first detectable after 3 weeks post-inoculation. CSF cell pellets and CNS tissues were culture-positive forB. burgdorferi. Histopathology revealed signs of acute LNB: severe multifocal leptomeningitis, radiculitis, and DRG inflammatory lesions. Immunofluorescence staining and confocal microscopy detectedB. burgdorferiantigen in the CNS and DRG. IL-6 was observed in astrocytes and neurons in the spinal cord, and in neurons in the DRG of infected animals. CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis.

Conclusion

Our results support the notion that innate responses of glia toB. burgdorferiinitiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.
Phasing of muscle gene expression with fasting-induced recovery growth in Atlantic salmon
Authors: Bower Neil I , Taylor Richard G , Johnston Ian A
Published: August 2009

Background

Many fish species experience long periods of fasting in nature often associated with seasonal reductions in water temperature and prey availability or spawning migrations. During periods of nutrient restriction, changes in metabolism occur to provide cellular energy via catabolic processes. Muscle is particularly affected by prolonged fasting as myofibrillar proteins act as a major energy source. To investigate the mechanisms of metabolic reorganisation with fasting and refeeding in a saltwater stage of Atlantic salmon (Salmo salar L.) we analysed the expression of genes involved in myogenesis, growth signalling, lipid biosynthesis and myofibrillar protein degradation and synthesis pathways using qPCR.

Results

Hierarchical clustering of gene expression data revealed three clusters. The first cluster comprised genes involved in lipid metabolism and triacylglycerol synthesis (ALDOB, DGAT1 and LPL) which had peak expression 3-14d after refeeding. The second cluster comprised ADIPOQ, MLC2, IGF-I and TALDO1, with peak expression 14-32d after refeeding. Cluster III contained genes strongly down regulated as an initial response to feeding and included the ubiquitin ligases MuRF1 and MAFbx, myogenic regulatory factors and some metabolic genes.

Conclusion

Early responses to refeeding in fasted salmon included the synthesis of triacylglycerols and activation of the adipogenic differentiation program. Inhibition of MuRF1 and MAFbx respectively may result in decreased degradation and concomitant increased production of myofibrillar proteins. Both of these processes preceded any increase in expression of myogenic regulatory factors and IGF-I. These responses could be a necessary strategy for an animal adapted to long periods of food deprivation whereby energy reserves are replenished prior to the resumption of myogenesis.
Acupuncture as a treatment for functional dyspepsia: design and methods of a randomized controlled trial
Authors: Zheng Hui , Tian Xiao-ping , Li Ying , Liang Fan-rong , Yu Shu-guang , Liu Xu-guang , Tang Yong , Yang Xu-guang , Yan Jie , Sun Guo-jie , Chang Xiao-rong , Zhang Hong-xing , Ma Ting-ting , Yu Shu-yuan
Published: August 2009

Background

Acupuncture is widely used in China to treat functional dyspepsia (FD). However, its effectiveness in the treatment of FD, and whether FD-specific acupoints exist, are controversial. So this study aims to determine if acupuncture is an effective treatment for FD and if acupoint specificity exists according to traditional acupuncture meridians and acupoint theories.

Design

This multicenter randomized controlled trial will include four acupoint treatment groups, one non-acupoint control group and one drug (positive control) group. The four acupoint treatment groups will focus on: (1) specific acupoints of the stomach meridian; (2) non-specific acupoints of the stomach meridian; (3) specific acupoints of alarm and transport points; and (4) acupoints of the gallbladder meridian. These four groups of acupoints are thought to differ in terms of clinical efficacy, according to traditional acupuncture meridians and acupoint theories. A total of 120 FD patients will be included in each group. Each patient will receive 20 sessions of acupuncture treatment over 4 weeks. The trial will be conducted in eight hospitals located in three centers of China. The primary outcomes in this trial will include differences in Nepean Dyspepsia Index scores and differences in the Symptom Index of Dyspepsia before randomization, 2 weeks and 4 weeks after randomization, and 1 month and 3 months after completing treatment.

Discussion

The important features of this trial include the randomization procedures (controlled by a central randomization system), a standardized protocol of acupuncture manipulation, and the fact that this is the first multicenter randomized trial of FD and acupuncture to be performed in China. The results of this trial will determine whether acupuncture is an effective treatment for FD and whether using different acupoints or different meridians leads to differences in clinical efficacy.

Trial registration number

Clinical Trials.gov Identifier: NCT00599677.
A cross sectional study of the prevalence, risk factors and population attributable fractions for limb and body lesions in lactating sows on commercial farms in England
Authors: KilBride Amy L , Gillman Claire E , Green Laura E
Published: August 2009

Background

Lesions on sows' limbs and bodies are an abnormality that might impact on their welfare. The prevalence of and risks for limb and body lesions on lactating sows on commercial English pig farms were investigated using direct observation of the sows and their housing.

Results

The prevalence of lesions on the limbs and body were 93% (260/279) and 20% (57/288) respectively. The prevalence of limb and body lesions was significantly lower in outdoor-housed sows compared with indoor-housed sows. Indoor-housed sows had an increased risk of wounds (OR 6.8), calluses (OR 8.8) and capped hock (OR 3.8) on their limbs when housed on fully slatted floors compared with solid concrete floors. In addition, there was an increased risk of bursitis (OR 2.7), capped hock (OR 2.3) and shoulder lesions (OR 4.8) in sows that were unwilling to rise to their feet. There was a decreased risk of shoulder lesions (OR 0.3) and lesions elsewhere on the body (OR 0.2) in sows with more than 20 cm between their tail and the back of the crate compared with sows with less than 10 cm.

Conclusion

The sample of outdoor housed sows in this study had the lowest prevalence of limb and body lesions. In lactating sows housed indoors there was a general trend for an increased risk of limb and body lesions in sows housed on slatted floors compared with those housed on solid concrete floors with bedding. Sows that were less responsive to human presence and sows that had the least space to move within their crates had an additional increased risk of lesions.
Significant differences in alkaloid content of Coptis chinensis (Huanglian), from its related American species
Authors: Kamath Shreya , Skeels Matthew , Pai Aswini
Published: August 2009

Background

The growing popularity of Chinese herbal medicine in the United States has prompted large-scale import of raw herbs from Asia. Many of the Asian herbs have phylogenetically related North American species. We compared three phylogenetically related species, namely Coptis chinensis (Huanglian), Hydrastis canadensis and Coptis trifolia to show whether they can be substituted by one another in terms of alkaloid content.

Methods

We used microwave assisted extraction to obtain alkaloids berberine, coptisine, palmatine and hydrastine. High performance liquid chromatography (HPLC) was used to quantify each alkaloid.

Results

Hydrastis canadensis has the most berberine, whereas Coptis trifolia has the most coptisine. Hydrastine and palmatine were unique to Hydrastis canadensis and Coptis chinensis respectively.

Conclusion

Neither Hydrastis canadensis nor Coptis trifolia contains all the alkaloids found in Coptis chinensis used in Chinese medicine. Substitutes of this Chinese species by its American relatives are not recommended.
Plant cell wall characterization using scanning probe microscopy techniques
Authors: Yarbrough John M , Himmel Michael E , Ding Shi-You
Published: August 2009

Lignocellulosic biomass is today considered a promising renewable resource for bioenergy production. A combined chemical and biological process is currently under consideration for the conversion of polysaccharides from plant cell wall materials, mainly cellulose and hemicelluloses, to simple sugars that can be fermented to biofuels. Native plant cellulose forms nanometer-scale microfibrils that are embedded in a polymeric network of hemicelluloses, pectins, and lignins; this explains, in part, the recalcitrance of biomass to deconstruction. The chemical and structural characteristics of these plant cell wall constituents remain largely unknown today. Scanning probe microscopy techniques, particularly atomic force microscopy and its application in characterizing plant cell wall structure, are reviewed here. We also further discuss future developments based on scanning probe microscopy techniques that combine linear and nonlinear optical techniques to characterize plant cell wall nanometer-scale structures, specifically apertureless near-field scanning optical microscopy and coherent anti-Stokes Raman scattering microscopy.
The role of disclosure in relation to assent to participate in HIV‐related research among HIV‐infected youth: a formative study
Authors: Corneli Amy , Vaz Lara , Dulyx Jennyfer , Omba Serge , Rennie Stuart , Behets Frieda
Published: August 2009

Background

The objective of this study was to develop a culturally appropriate approach for obtaining assent from children aged eight to 17 years to participate in paediatric HIV‐related operational research in Kinshasa, Democratic Republic of Congo (DRC). Included within this objective was to determine whether or not HIV disclosure should be included as part of the assent process prior to research participation, a component of research participation, or not incorporated in any aspect of the child's involvement in the research. Factors that influence parents' and caregivers' decisions to disclose HIV status to children in non‐research contexts were also explored.

Methods

A qualitative formative study was conducted. Semi‐structured interviews were conducted with 19 youth living with HIV, 36 parents and caregivers of youth living with HIV, and 17 health professionals who provide care and support to youth living with HIV and their families. Participants were purposefully selected from three HIV care, treatment and/or psychosocial support programmes in Kinshasa, DRC.

Results

Most youth interviewed believed minors participating in HIV‐related research should be informed of their HIV‐positive status. Parents and caregivers and health professionals had varied perspectives on if and when HIV status should be disclosed to minors during research participation. The age of the youth influenced parents and caregivers' responses, and disclosure to adolescents was more frequently supported than disclosure to children.

Several parents and caregivers, as well as some health professionals, suggested that minors should never be told their HIV‐positive status when participating in HIV‐related research, regardless of their age. Within the context of treatment programmes, disclosure of HIV status to minors was supported by youth, parents and caregivers, and health professionals as a means to improve adherence to medication.

Conclusion

In settings where most minors are unaware of their HIV infection, researchers should consider excluding the term, “HIV”, when explaining HIV‐related research to minors, and omitting it from assent forms or informational sheets related to research participation. However, an individualized disclosure plan should be initiated with parents and caregivers at the time of enrolment in HIV‐related research, particularly in research that involves treatment.
Extracorporeal life support in severe drug intoxication: a retrospective cohort study of seventeen cases
Authors: Daubin Cédric , Lehoux Philippe , Ivascau Calin , Tasle Marine , Bousta Mehdi , Lepage Olivier , Quentin Charlotte , Massetti Massimo , Charbonneau Pierre
Published: August 2009

Introduction

Cardiovascular failure is the leading cause of death in severe acute drug intoxication. In this setting, we report the feasibility, complications, and outcome of emergency extracorporeal life support (ECLS) in refractory shock or cardiac arrest following a drug overdose.

Methods

This is a retrospective cohort study of 17 patients admitted over a 10-year period for prolonged cardiac arrest or refractory shock following a drug overdose and not responding to optimal conventional treatment. Patients were evaluated in the medical ICU and cardiovascular surgery department of a university hospital. ECLS implantation used a centrifugal pump connected to a hollow-fiber membrane oxygenator and was performed in the operating room (n = 13), intensive care unit (n = 3), or emergency department (n = 1). ECLS was employed for refractory shock and prolonged cardiac arrest in 10 and 7 cases, respectively.

Results

The mean duration of external cardiac massage was 101 ± 55 minutes. Fifteen patients had ingested cardiotoxic drugs, including 11 cases of drugs with membrane stabilizing activity. Time from hospital admission to initiation of ECLS was 6.4 ± 7.0 hours. Time to ECLS implant was 58 ± 11 minutes. The mean ECLS flow rate was 3.45 ± 0.45 L/min. The average ECLS duration was 4.5 ± 2.4 days. Early complications included limb ischemia (n = 6), femoral thrombus (n = 1), cava inferior thrombus (n = 1), and severe bleeding at the site of cannulation (n = 2). Fifteen patients were weaned off ECLS support and 13 (76%) were discharged to hospital without sequelae.

Conclusions

Based on our experience, we consider ECLS as a last resort, efficient, and relatively safe therapeutic option in this population. However, the uncontrolled nature of our data requires careful interpretation.
2D seismic exploration of the Ancona landslide (Adriatic Coast, Italy)
Authors: Stucchi Eusebio , Mazzotti Alfredo
Published: August 2009

We have used on- and offshore seismic reflection profiles to determine the extension of a historic landslide at depth and toward the sea. The subsurface landslide structure was delineated by using four separate data sets produced by the combined use of geophone and hydrophone spreads, and of explosive and air-gun sources which also illuminated, through an undershooting configuration, the subsurface below the coastal road and railway. Many noise problems related to the source and environment were overcome and alleviated with several signal-processing routines. The resulting stack and depth-migrated sections reveal the deep geometry of the main landslide body and indicate the emergence location, at the landslide foot, of a deep, potential detachment surface, which previous investigations failed to evidence.
Reduction to the pole and transformations of scattered magnetic data using Newtonian equivalent sources
Authors: Guspí Fernando , Novara Iván
Published: August 2009

We have developed an equivalent-source method for performing reduction to the pole and related transforms from magnetic data measured on unevenly spaced stations at different elevations. The equivalent source is composed of points located vertically beneath the measurement stations, and their magnetic properties are chosen in such a way that the reduced-to-the-pole magnetic field generated by them is represented by an inverse-distance Newtonian potential. This function, which attenuates slowly with distance, provides better coverage for discrete data points. The magnetization intensity is determined iteratively until the observed field is fitted within a certain tolerance related to the level of noise; thus, advantages in computer time are gained over the resolution of large systems of equations. In the case of induced magnetization, the iteration converges well for verticalor horizontal inclinations, and results are stable if noise is taken into account properly. However, for a range of intermediate inclinations near 35°, a factor tending to zero makes it necessary to perform the reduction through a two-stage procedure, using an auxiliary magnetization direction, without significantly affecting the speed and stability of the method. The performance of the procedure was tested on a synthetic example based on a field generated on randomly scattered stations by a random set of magnetic dipoles, contaminated with noise, which is reduced to the pole for three different magnetization directions. Results provide a good approximation to the theoretical reduced-to-the-pole field using a one- or a two-stage reduction, showing minor noise artifacts when the direction is nearly horizontal. In a geophysical example with real data, the reduction to the pole was used to correct the estimated magnetization direction that originates an isolated anomaly over Sierra de San Luis, Argentina.
Application of an integrated wave-equation datuming scheme to overthrust data: A case history from the Chinese foothills
Authors: Yang Kai , Zheng Hong-Ming , Wang Li , Liu Yu-Zhu , Jiang Fan , Cheng Jiu-Bing , Ma Zai-Tian
Published: August 2009

An integrated wave-equation datuming scheme improves the imaging quality of seismic data from overthrust areas. It can be regarded as integrated because upward-layer replacement is included. In this scheme, data are downward continued to a nonplanar datum (such as the base of the weathering layer), followed by upward continuation from the nonplanar datum to a final planar datum using a one-way extrapolator. When compared with a Kirchhoff integral, this method can deal better with the strong lateral velocity variation within the near surface. After a test on synthetic data, the scheme is applied successfully to real 2D overthrust data acquired in the Qi-Lian foothills, western China. Compared with results using static corrections, integrated wave-equation datuming results lead to better reconstruction of the diffractions and reflections, more reliable migration-velocity analyses, and stronger stack and final depth images.
Population Differences in Breast Cancer: Survey in Indigenous African Women Reveals Over-Representation of Triple-Negative Breast Cancer
Authors: Huo Dezheng , Ikpatt Francis , Khramtsov Andrey , Dangou Jean-Marie , Nanda Rita , Dignam James , Zhang Bifeng , Grushko Tatyana , Zhang Chunling , Oluwasola Olayiwola , Malaka David , Malami Sani , Odetunde Abayomi , Adeoye Adewumi O. , Iyare Festus , Falusi Adeyinka , Perou Charles M. , Olopade Olufunmilayo I.
Published: August 2009

Purpose

Compared with white women, black women experience a disproportionate burden of aggressive breast cancer for reasons that remain unknown and understudied. In the first study of its kind, we determined the distribution of molecular subtypes of invasive breast tumors in indigenous black women in West Africa.

Patients and Methods

The study comprised 507 patients diagnosed with breast cancer between 1996 and 2007 at six geographic regions in Nigeria and Senegal. Formalin-fixed and paraffin-embedded sections were constructed into tissue microarrays and immunostained with 15 antibodies. Five molecular subtypes were determined, and hierarchical cluster analysis was conducted to explore subgroups for unclassified cases.

Results

The mean (± standard deviation) age of 378 patients in the first cohort was 44.8 ± 11.8 years, with the majority of women presenting with large (4.4 ± 2.0 cm) high-grade tumors (83%) in advanced stages (72% node positive). The proportions of estrogen receptor (ER) –positive, progesterone receptor–positive, and human epidermal growth factor receptor 2 (HER2) –positive tumors were 24%, 20%, and 17%, respectively. Triple negativity for these markers was predominant, including basal-like (27%) and unclassified subtype (28%). Other subtypes were luminal A (27%), luminal B (2%), and HER2 positive/ER negative (15%). The findings were replicated in the second cohort of 129 patients. The unclassified cases could be grouped into a bad prognosis branch, with expression of vascular endothelial growth factor, B-cell lymphoma extra-large protein, and Cyclin E, and a good prognosis branch, with expression of B-cell lymphoma protein 2 and Cyclin D1.

Conclusion

These findings underscore the urgent need for research into the etiology and treatment of the aggressive molecular subtypes that disproportionately affect young women in the African diaspora.
Determinants of Aggressive End-of-Life Care for Taiwanese Cancer Decedents, 2001 to 2006
Authors: Tang Siew Tzuh , Wu Shiao-Chi , Hung Yen-Ni , Chen Jen-Shi , Huang Ean-Wen , Liu Tsang-Wu
Published: August 2009

Purpose

To assess the association between aggressiveness of end-of-life (EOL) care and patient demographics, disease characteristics, primary physician's specialty, hospital characteristics, and availability of health care resources at the hospital and regional levels in Taiwan for a cohort of 210,976 cancer decedents in 2001 to 2006.

Methods

This retrospective cohort study examined administrative data. Aggressiveness of EOL care was examined by a composite measure adapted from Earle et al. Scores range from 0 to 6, with higher scores indicating more aggressive EOL care.

Results

The mean composite score for aggressiveness of EOL care was 2.04 (mean) ± 1.26 (standard deviation), increasing from 1.96 ± 1.26 in 2001 to 2.10 ± 1.26 in 2006. Each successive year of death significantly increased the composite score. Cancer decedents received more aggressive EOL care if they were male, younger, single, had a higher level of comorbidity, had more malignant and extensive diseases or hematologic malignancies, were cared for by oncologists, and received care in a hospital with a greater density of beds.

Conclusion

Controlling for patient demographics and cormorbidity burden, EOL care in Taiwan was more aggressive for patients with cancer with highly malignant and extensive diseases, for patients with oncologists as primary care providers, or in hospitals with abundant health care resources. Health policies should aim to ensure that all patients receive treatments that best meet their individual needs and interests and that resources are devoted to care that produces the greatest health benefits.
Phase I Study of C-TPF in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Haddad Robert I. , Tishler Roy B. , Norris Charles , Goguen Laura , Balboni Tracy A. , Costello Rosemary , Wirth Lori , Lorch Jochen , Andreozzi Britta , Annino Donald , Posner Marshall R.
Published: August 2009

Purpose

Phase I study to determine the maximum tolerated dose (MTD) of fluorouracil (FU) in the docetaxel/cisplatin/FU (TPF) regimen when combined with cetuximab (C) for induction treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Patients and Methods

Patients with previously untreated SCCHN were enrolled. FU cohorts were 700, 850, and 1,000 mg/m2/d for 4 days via continuous infusion. TPF given every 3 weeks for three cycles and C was given weekly for a total of 9 weeks, starting on day 1 of TPF. All patients received chemoradiotherapy after C-TPF.

Results

A total of 30 patients were enrolled and 28 were assessable. The median age was 57 years, 92% had stage 4 disease, 71% were oropharynx, and 100% had a performance status of 0. No dose-limiting toxicity (DLT) was encountered on dose levels 1 and 2. At dose level 3 of 1000 mg/m2, one DLT was encountered and three more patients were enrolled with no DLTs. In the expansion cohort at the MTD, three DLT's were encountered. The decision was made to decrease the FU from 1,000 mg/m2 to dose level 2 of 850 mg/m2. A total of 13 patients were enrolled at the MTD of 850 mg/m2. The number of average weeks that C was delivered was seven of nine planned.

Conclusion

C-TPF appears to be safe and feasible as given in this study. GI toxicity (mucositis, enteritis, and diarrhea) appears to be the major combined DLT. Reducing the FU in TPF to 850 mg/m2 reduces GI toxicity and is the recommended phase II dose.
Prognostic Significance and Molecular Associations of 18q Loss of Heterozygosity: A Cohort Study of Microsatellite Stable Colorectal Cancers
Authors: Ogino Shuji , Nosho Katsuhiko , Irahara Natsumi , Shima Kaori , Baba Yoshifumi , Kirkner Gregory J. , Meyerhardt Jeffrey A. , Fuchs Charles S.
Published: August 2009

Purpose

Loss of heterozygosity (LOH) at chromosome 18q frequently occurs late during colon cancer development and is inversely associated with microsatellite instability (MSI). 18q LOH has been reported to predict shorter survival in patients with colorectal cancer, whereas MSI-high status has been associated with superior prognosis. However, it is unclear whether 18q LOH in colorectal cancer has any prognostic implication independent of MSI status and other potential predictors of clinical outcome.

Patients and Methods

Among 555 non–MSI-high colorectal cancers (stage I to IV) in two independent prospective cohort studies, we examined 18q LOH in relation to other molecular events and patient survival. Cox proportional hazard models computed hazard ratio of death, adjusted for clinical and tumoral characteristics, including KRAS, BRAF, PIK3CA, β-catenin, p53, CpG island methylator phenotype, LINE-1 methylation, and John Cunningham (JC) virus T antigen.

Results

In multivariate logistic regression, 18q LOH was independently associated with JC virus T antigen (odds ratio [OR] = 1.93; P = .0077), body mass index ≥ 30 kg/m2 (obesity; OR = 2.01; P = .014), high tumor grade (OR = 0.40; P = .018), KRAS mutation (OR = 0.66; P = .40), and LINE-1 hypomethylation (for a 30% decrease; OR = 1.92; P = .045). Five-year colorectal cancer–specific survival was 75% among patients with 18q LOH-positive tumors and 74% among those with 18q LOH-negative tumors (log-rank P = .80). Five-year overall survival was 70% among patients with 18q LOH-positive tumors and 68% among those with 18q LOH-negative tumors (log-rank P = .54). Multivariate analysis did not show prognostic significance of 18q LOH.

Conclusion

In our large prospective study of patients with non–MSI-high colorectal cancer, 18q LOH or allelic imbalance was not associated with patient survival.
Regulation of preprocambial cell state acquisition by auxin signaling inArabidopsisleaves
Authors: Donner Tyler J. , Sherr Ira , Scarpella Enrico
Published: August 2009

The principles underlying the formation of veins in the leaf have long intrigued developmental biologists. In Arabidopsis leaves, files of anatomically inconspicuous subepidermal cells that will elongate into vein-forming procambial cells selectively activate ATHB8 gene expression. The biological role of ATHB8 in vein formation and the molecular events that culminate in acquisition of the ATHB8preprocambial cell state are unknown, but intertwined pathways of auxin transport and signal transduction have been implicated in defining paths of vascular strand differentiation. Here we show that ATHB8 is required to stabilize preprocambial cell specification against auxin transport perturbations, to restrict preprocambial cell state acquisition to narrow fields and to coordinate procambium formation within and between veins. We further show that ATHB8 expression at preprocambial stages is directly and positively controlled by the auxin-response transcription factor MONOPTEROS (MP) through an auxin-response element in the ATHB8promoter. We finally show that the consequences of loss of ATHB8function for vein formation are masked by MP activity. Our observations define, at the molecular level, patterning inputs of auxin signaling in vein formation.
Formation of She2p tetramers is required for mRNA binding, mRNP assembly, and localization
Authors: Müller Marisa , Richter Klaus , Heuck Alexander , Kremmer Elisabeth , Buchner Johannes , Jansen Ralf-Peter , Niessing Dierk
Published: August 2009

In eukaryotic cells, dozens to hundreds of different mRNAs are localized by specialized motor-dependent transport complexes. One of the best-studied examples for directional mRNA transport is the localization ofASH1mRNA inSaccharomyces cerevisiae. For transport,ASH1mRNA is bound by the unusual RNA-binding protein She2p. Although previous results indicated that She2p forms dimers required for RNA binding and transcript localization, it remained unclear if the dimer constitutes the minimal RNA-binding unit assembling in vivo. By using analytical ultracentrifugation we found that She2p forms larger oligomeric complexes in solution. We also identified a point mutant that shows impaired oligomer formation. Size-exclusion chromatography suggests that She2p forms defined tetramers at physiological concentrations. Subsequent structural studies by small-angle X-ray scattering confirmed this finding and demonstrated that the previously observed She2p dimers interact in a head-to-head conformation to form an elongated tetrameric complex. This She2p tetramer suggests the generation of large continuous RNA-binding surfaces at both sides of the complex. Biochemical studies and immunostaining of cells confirmed that She2p tetramer formation is required for RNA binding, efficient mRNP assembly, and mRNA localization in vivo. Our finding on She2p tetramerization resolves previously raised questions on complex formation and mRNP function.
Improvement of a figure copying deficit during subsensory galvanic vestibular stimulation
Authors: Wilkinson David , Zubko Olga , DeGutis Joseph , Milberg William , Potter Jonathan
Published: August 2009

We describe the effects of galvanic vestibular stimulation (GVS) on an individual who, following right hemisphere stroke, is unable to copy figures accurately. His copies contain most of the constituent elements, but are poorly integrated and drawn in a seemingly haphazard manner. To test whether GVS could help overcome these difficulties, we administered the Rey‐Osterrieth complex figure copy task while manipulating both the presence and laterality of the galvanic signal. The signal was applied at a level that was too low to elicit sensation which ensured that the individual was unaware of either when or on what side he was being stimulated. Relative to a sham condition, two consecutive blocks of GVS increased both the accuracy with which the main configural elements of the figure were reconstructed, and there was some, albeit less consistent evidence, that these were drawn in a more wholistic as opposed to piecemeal manner. Improvement was not reliant on the polarity of the stimulating electrodes. These results suggest that GVS can help overcome difficulties in the perception and/or reconstruction of hierarchical visual form, and thereby uncover a new link between vestibular information processing and visual task performance.
Remediation of Harbor Sediments Contaminated by Polycyclic Aromatic Hydrocarbon and Metals
Authors: Nosari Valeriano Pastore Nicola , Geddo Gianluigi
Published: August 2009

The Taranto harbor area is included in the Italian National Priority List of contaminated sites. For the enlargement works of the fourth quay in the Taranto harbor, the remediation of contaminated sediments shall be carried out. The existing jetty was devoted to unloading of iron ore for the nearby ILVA steel mill. The sea depth in the intervention area ranges between 2 and 10 m and contaminated sediments (up to 3 m thick) are deposited on a layer of overconsolidated hard clay. The characterization activity of the area was carried out by ICRAM (a public sea research institute) indicating the presence of both organic (polycyclic aromatic hydrocarbon) and inorganic (metals) contaminants in the sediments. The remediation project consists of the two following phases: Mechanical dredging of highly contaminated sediments (15.500 m3) using low-turbidity tools and hydraulic excavation of sediments with a lower level of contamination (360.000 m3). Abiding by national regulations, the highly contaminated sediments will be treated in a dedicated plant while the sediments with a low level of contamination will be deposited in large ponds. The impact of dredging activities shall be mitigated by specific precautions. The possibility of beneficial reuse of dredged material was also studied, especially for low contamination sediments, as well as compatibility with national regulations. A specific monitoring plan will be enacted for the entire duration of remediation works, which are expected to start in 2010.
Appendix A: Graphical Data Display
Authors: Conley Colleen
Published: August 2009

The graphical data display method provides a visual comparison of JAR data across products and attributes, or both. The objective of this method is to provide a method to visually assess the distribution of JAR data. This is a descriptive/summarization method, not an inferential one.
Appendix B: Graphical Scaling
Authors: Goldman Anne , Mazur Jagoda
Published: August 2009

Graphical scaling is a technique for presenting the results for a JAR scale analysis that graphically illustrates any imbalance around the “Just Right” scale point.
Appendix C: Percent Difference from Norm and Percent Difference from Just Right
Authors: Gaskin Gloria A. , Keith Joni L.
Published: August 2009

The Percent Difference from Norm analysis determines if the % JAR responses meet or exceed an established norm. If they do not, it also determines the direction of the imbalances of the JAR scale responses. The Percent Difference from “Just Right” analysis does not rely on an established norm, but compares the non-JAR responses to those in the “Just About Right” category. If a significant difference is found, the non-JAR responses are compared to each other. The analysis is conducted on one product-attribute combination at a time, but there is no limit as to how many products or attributes may be analyzed.
Appendix E: Mean Direction and Mean Absolute Deviation
Authors: Jones Veronika
Published: August 2009

The mean directional and mean absolute deviations are statistics that can be used to summarize and check the balance of JAR data. The JAR data are analyzed separately for each product and each attribute. The mean directional deviation is the average signed difference of the ratings from the “Just About Right” value. On a 5-point JAR scale, the mean directional ranges from −2 to +2 (“Just Right” =0). Scores that are closer to −2 indicate that respondents thought that attribute was “Too Low.” Scores that are closer to +2 indicate that respondents thought that the attribute was “Too High.” The mean direction deviation is a simple shift of the mean, covered in Appendix D. The mean absolute deviation summarizes the spread of the ratings about the “Just About Right” value. On a 5-point scale, the mean absolute deviation ranges from 0, when all judgments are “Just About Right” to +2, when all judgments are at one or the other extreme end of the scale. Unlike percent “Just-Right” scores, absolute deviations can be calculated for each individual and the mean absolute deviation analyzed by any of the standard parametric statistical procedures. The mean absolute deviation summarizes the average distance to the “Just About Right” value while the mean directional deviation summarizes the average direction the attribute is from the “Just About Right” value (i.e., “Too Low or Too High”).
Appendix F: Mean versus Scale Mid-Point
Authors: Pitts Sandra
Published: August 2009

This method describes a statistical procedure to compare a single mean to its JAR scale mid-point. It will determine if a product attribute is perceived to be significantly different from the ideal. When an attribute is significantly different from the mid-point, conclusions can also be made about the direction of the difference. This analysis is designed to compare a single product/attribute combination to its center-point, and is not appropriate for the comparisons across products or attributes. Comparisons among multiple products in the same test are limited to statements as to how they each relate to the JAR scale mid-point or “Ideal” value. Note that the “Ideal” value refers to the JAR scale mid-point, and is not related to a specific gold standard product.
Appendix G: Methods for Determining Whether JAR Distributions are Similar Among Products (Chi-Square, Cochran-Mantel-Haenszel (CMH), Stuart-Maxwell, McNemar)
Authors: Fritz Carl
Published: August 2009

The following methods can each be used to determine whether JAR score distributions are similar among a set of products: • Chi-square method • Cochran-Mantel-Haenszel (CMH) method [1], [2] • Stuart-Maxwell method [3] • McNemar method [4] The chi-square method and CMH method are the most general of the four methods listed above. Both methods can be used for comparing JAR score distributions among any number of products for any number of JAR scale categories. The chi-square method differs from the other three methods with respect to the design of the consumer test for which it can be used. The use of the chi-square method requires independence among the assessors' responses. This limits the use of the chi-square method to situations where different groups of assessors evaluate each product. The CMH, Stuart-Maxwell, and McNemar methods are all appropriate when the assessors evaluate all of the products. These methods provide an increased level of power over the chi-square method by taking advantage of the positive correlation that typically exists among an individual assessor's ratings on two or more products evaluated during the same consumer test.
Appendix M: Using Grand Mean versus Mean of the Proportion of Respondents Who Scored the Product JAR
Authors: Plaehn Dave , Stucky Gregory , Lundahl David , Horne John
Published: August 2009

The object of traditional penalty analysis is to try to determine the effect “Too Much” or “Too Little” of a product attribute has on overall product liking. These product attributes have been called “Just-About-Right” or JAR variables, they are discrete and the middle value corresponds to a consumer response of “Just About Right.” There are two different approaches in determining the so-called penalties. Both are examined here.
Appendix N: A Regression-Based Approach for Testing Significance of JAR Variable Penalties
Authors: Plaehn Dave , Horne John
Published: August 2009

Traditional penalty analysis attempts to relate JAR variable responses to overall liking or some other “reference” variable. No variance estimates are calculated around the penalties or mean drops, and as a result, significance testing is not done. Consequently, this method does not give any gauge of reliability or importance of the results. Focus is often placed on large penalties that are also associated with a large proportion of respondents; 20 % of respondents on a given side of a “Just About Right” point (e.g., “Too Much” or “Too Little”) is frequently used as a minimum standard of importance. We propose a regression-based approach to better understand which penalties are important for a given product. This approach recodes JAR variable scores into indicator (dummy) variables in order to address the non-linear nature of the typical JAR variable scale (the middle category as “Just About Right” and the other categories as some degree of “Too Much” or “Too Little”). Regression coefficients resulting from the indicator variables are analogous to mean drops of the reference variable. Significance testing can be done on these coefficients parametrically by using the standard error estimates from the regression model itself; semi-parametrically by using standard error estimates from methods such as jackknife and bootstrap; or non-parametrically, for example, by forming “ confidence intervals” from the distribution of a large number of bootstrap samples. All of these methods are presented below. While some parts of this approach can be used to test multiple products and attributes simultaneously, we will consider only one JAR variable/product combination at a time. Along the way we will prove that the regression coefficients from ordinary least-squares (OLS) regression are identical to the traditional penalties assuming the so-called JAR mean is used to determine the penalties.
Appendix P: Opportunity Analysis
Authors: Gualtieri Tony
Published: August 2009

Typical penalty analysis (see Appendix M) assesses the association between JAR scale attributes and Overall Liking. It does not account for the relationship between attribute liking and Overall Liking. Opportunity analysis remedies that lack with an additional computation to address the potential effect of changing an attribute on consumers who already like the product. The analysis provides simple summaries of the relationship between overall and attribute liking for that product. This summary scatter plot illustrates the possible risks (defined as a decrease in the proportion of product likers) and opportunities (defined as an increase in the proportion of product likers) associated with changing a product's attribute liking.
Appendix Q: PRIMO Analysis
Authors: Shvartsburg Efim
Published: August 2009

PRIMO (Product Improvement Opportunity) analysis is a method whose initial step is penalty analysis (see Appendix C), followed by the application of Bayesian theory to identify desired changes in JAR attribute ratings in order to maximize the probability of potential product improvement, according to a given criterion. The criterion can be either categorical, such as Top or Top Two Box scale ratings, or continuous, such as mean Overall Liking. For each attribute, this analysis provides a confidence level that the product can be significantly improved with respect to the chosen criterion, by altering the current level of the attribute. The resulting output is a list of JAR attributes and their respective confidence levels, in descending order, corresponding to the potential product improvement. As a result of PRIMO analysis, researchers gain an understanding on how to alter the product on the attributes that promise a high confidence level for improvement. This procedure puts PRIMO Analysis in the class of Bayesian choice models.