bluuebunny/crossref_metadata_2025 huggingface dataset:
microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma
Authors: Zhao Jian-Jun , Lin Jianhong , Lwin Tint , Yang Hua , Guo Jianping , Kong William , Dessureault Sophie , Moscinski Lynn C. , Rezania Dorna , Dalton William S. , Sotomayor Eduardo , Tao Jianguo , Cheng Jin Q.
Published: January 2010

Mantle cell lymphoma (MCL) is one of the most aggressive B-cell lymphomas. Although several protein-coding genes are altered, expression signature and importance of microRNA (miRNA) have not been well documented in this malignancy. Here, we performed miRNA expression profile in 30 patients with MCL using a platform containing 515 human miRNAs. Eighteen miRNAs were down-regulated and 21 were up-regulated in MCL compared with normal B lymphocytes. The most frequently altered miRNAs are decrease of miR-29a/b/c, miR-142-3p/5p, and miR-150 and increase of miR-124a and miR-155. Notably, expression levels of miR-29 family are associated with prognosis. The patients with significant down-regulated miR-29 had short survival compared with those who express relatively high levels of miR-29. The prognostic value of miR-29 is comparable with the Mantle Cell Lymphoma International Prognostic Index. Furthermore, we demonstrate miR-29 inhibition of CDK6 protein and mRNA levels by direct binding to 3′-untranslated region. Inverse correlation between miR-29 and CDK6 was observed in MCL. Because cyclin D1 overexpression is a primary event and exerts its function through activation of CDK4/CDK6, our results in primary MCL cells indicate that down-regulation of miR-29 could cooperate with cyclin D1 in MCL pathogenesis. Thus, our findings provide not only miRNA expression signature but also a novel prognostic marker and pathogenetic factor for this malignancy.
TNF-α Mediates Eosinophil Cationic Protein-induced Apoptosis in BEAS-2B Cells
Authors: Chang Kun-Che , Lo Chih-Wei , Fan Tan-chi , Chang Margaret Dah-Tsyr , Shu Chih-Wen , Chang Chuan-Hsin , Chung Cheng-Ta , Fang Shun-lung , Chao Chih-Chung , Tsai Jaw-Ji , Lai Yiu-Kay
Published: January 2010

Background

Eosinophilic granulocytes are important for the human immune system. Many cationic proteins with cytotoxic activities, such as eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), are released from activated eosinophils. ECP, with low RNase activity, is widely used as a biomarker for asthma. ECP inhibits cell viability and induces apoptosis to cells. However, the specific pathway underlying the mechanisms of ECP-induced cytotoxicity remains unclear. This study investigated ECP-induced apoptosis in bronchial epithelial BEAS-2B cells and elucidated the specific pathway during apoptosis.

Results

To address the mechanisms involved in ECP-induced apoptosis in human BEAS-2B cells, investigation was carried out using chromatin condensation, cleavage of poly (ADP-ribose) polymerase (PARP), sub-G1 distribution in cell cycle, annexin V labeling, and general or specific caspase inhibitors. Caspase-8-dependent apoptosis was demonstrated by cleavage of caspase-8 after recombinant ECP treatment, accompanied with elevated level of tumor necrosis factor alpha (TNF-α). Moreover, ECP-induced apoptosis was effectively inhibited in the presence of neutralizing anti-TNF-α antibody.

Conclusion

In conclusion, our results have demonstrated that ECP increased TNF-α production in BEAS-2B cells and triggered apoptosis by caspase-8 activation through mitochondria-independent pathway.
Analysis of retinal cell development in chick embryo by immunohistochemistry and in ovo electroporation techniques
Authors: Doh Sung Tae , Hao Hailing , Loh Stephanie C , Patel Tapan , Tawil Haim Y , Chen David K , Pashkova Anna , Shen Andy , Wang Huimin , Cai Li
Published: January 2010

Background

Retinal cell development has been extensively investigated; however, the current knowledge of dynamic morphological and molecular changes is not yet complete.

Results

This study was aimed at revealing the dynamic morphological and molecular changes in retinal cell development during the embryonic stages using a new method of targeted retinal injection, in ovo electroporation, and immunohistochemistry techniques. A plasmid DNA that expresses the green fluorescent protein (GFP) as a marker was delivered into the sub-retinal space to transfect the chick retinal stem/progenitor cells at embryonic day 3 (E3) or E4 with the aid of pulses of electric current. The transfected retinal tissues were analyzed at various stages during chick development from near the start of neurogenesis at E4 to near the end of neurogenesis at E18. The expression of GFP allowed for clear visualization of cell morphologies and retinal laminar locations for the indication of retinal cell identity. Immunohistochemistry using cell type-specific markers (e.g., Visinin, Xap-1, Lim1+2, Pkcα, NeuN, Pax6, Brn3a, Vimentin, etc.) allowed further confirmation of retinal cell types. The composition of retinal cell types was then determined over time by counting the number of GFP-expressing cells observed with morphological characteristics specific to the various retinal cell types.

Conclusion

The new method of retinal injection and electroporation at E3 - E4 allows the visualization of all retinal cell types, including the late-born neurons, e.g., bipolar cells at a level of single cells, which has been difficult with a conventional method with injection and electroporation at E1.5. Based on data collected from analyses of cell morphology, laminar locations in the retina, immunohistochemistry, and cell counts of GFP-expressing cells, the time-line and dynamic morphological and molecular changes of retinal cell development were determined. These data provide more complete information on retinal cell development, and they can serve as a reference for the investigations in normal retinal development and diseases.
Deep sequencing of small RNA libraries reveals dynamic regulation of conserved and novel microRNAs and microRNA-stars during silkworm development
Authors: Jagadeeswaran Guru , Zheng Yun , Sumathipala Niranji , Jiang Haobo , Arrese Estela L , Soulages Jose L , Zhang Weixiong , Sunkar Ramanjulu
Published: January 2010

Background

In eukaryotes, microRNAs (miRNAs) have emerged as critical regulators of gene expression. The Silkworm (Bombyx moriL.) is one of the most suitable lepidopteran insects for studying the molecular aspects of metamorphosis because of its large size, availability of mutants and genome sequence. Besides, this insect also has been amply studied from a physiological and biochemical perspective. Deep sequencing of small RNAs isolated from different stages of silkworm is a powerful tool not only for measuring the changes in miRNA profile but also for discovering novel miRNAs.

Results

We generated small RNA libraries from feeding larvae, spinning larvae, pupae and adults ofB. moriand obtained ~2.5 million reads of 18-30 nt. Sequence analysis identified 14 novel and 101 conserved miRNAs. Most novel miRNAs are preferentially expressed in pupae, whereas more than 95% of the conserved miRNAs are dynamically regulated during different developmental stages. Remarkably, the miRNA-star (miR*) of four miRNAs are expressed at much higher levels than their corresponding miRNAs, and their expression profiles are distinct from their corresponding miRNA profiles during different developmental stages. Additionally, we detected two antisense miRNA loci (miR-263-S and miR-263-AS; miR-306-S and miR-306-AS) that are expressed in sense and antisense directions. Interestingly, miR-263 and miR-306 are preferentially and abundantly expressed in pupae and adults, respectively.

Conclusions

We identified 101 homologs of conserved miRNAs, 14 species-specific and two antisense miRNAs in the silkworm. Our results provided deeper insights into changes in conserved and novel miRNA and miRNA* accumulation during development.
Reference genes for normalising gene expression data in collagenase-induced rat intracerebral haemorrhage
Authors: Cook Naomi L , Kleinig Timothy J , Heuvel Corinna van den , Vink Robert
Published: January 2010

Background

The mechanisms of brain injury following intracerebral haemorrhage (ICH) are incompletely understood. Gene expression studies using quantitative real-time RT-PCR following ICH have increased our understanding of these mechanisms, however the inconsistent results observed may be related to inappropriate reference gene selection. Reference genes should be stably expressed across different experimental conditions, however, transcript levels of common reference genes have been shown to vary considerably. Reference gene panels have therefore been proposed to overcome this potential confounder.

Results

The present study evaluated the stability of seven candidate reference genes in the striatum and overlying cortex of collagenase-induced ICH in rodents at survival times of 5 and 24 hours. Transcript levels of the candidate reference genes were quantified and ranked in order of stability using geNorm. When our gene of interest, transient receptor potential melastatin 2 (TRPM2), was normalised against each reference gene individually, TRPM2 mRNA levels were highly variable. When normalised to the four most stable reference genes selected for accurate normalisation of data, we found no significant difference between ICH and vehicle rats.

Conclusion

The panel of reference genes identified in the present study will enable more accurate normalisation of gene expression data in the acute phase of experimental ICH.
Rationale and design of the CAPAMIS study: Effectiveness of pneumococcal vaccination against community-acquired pneumonia, acute myocardial infarction and stroke
Authors: Vila-Corcoles Angel , Hospital-Guardiola Inmaculada , Ochoa-Gondar Olga , de Diego Cinta , Salsench Elisabet , Raga Xavier , Fuentes-Bellido Cruz M
Published: January 2010

Background

The 23-valent polysaccharide pneumococcal vaccine (PPV-23) is recommended for elderly and high-risk people, although its effectiveness is controversial. Some studies have reported an increasing risk of acute vascular events among patients with pneumonia, and a recent case-control study has reported a reduction in the risk of myocardial infarction among patients vaccinated with PPV-23. Given that animal experiments have shown that pneumococcal vaccination reduces the extent of atherosclerotic lesions, it has been hypothesized that PPV-23 could protect against acute vascular events by an indirect effect preventing pneumonia or by a direct effect on oxidized low-density lipoproteins. The main objective of this study is to evaluate the clinical effectiveness of PPV-23 in reducing the risk of pneumonia and acute vascular events (related or nonrelated with prior pneumonia) in the general population over 60 years.

Methods/Design

Cohort study including 27,000 individuals 60 years or older assigned to nine Primary Care Centers in the region of Tarragona, Spain. According to the reception of PPV-23 before the start of the study, the study population will be divided into vaccinated and nonvaccinated groups, which will be followed during a consecutive 30-month period. Primary Care and Hospitals discharge databases will initially be used to identify study events (community-acquired pneumonia, hospitalisation for acute myocardial infarction and stroke), but all cases will be further validated by checking clinical records. Multivariable Cox regression analyses estimating hazard ratios (adjusted for age, sex and comorbidities) will be used to estimate vaccine effectiveness.

Discussion

The results of the study will contribute to clarify the controversial effect of the PPV-23 in preventing community-acquired pneumonia and they will be critical in determining the posible role of pneumococcal vaccination in cardiovascular prevention.
The path to next generation biofuels: successes and challenges in the era of synthetic biology
Authors: Dellomonaco Clementina , Fava Fabio , Gonzalez Ramon
Published: January 2010

Volatility of oil prices along with major concerns about climate change, oil supply security and depleting reserves have sparked renewed interest in the production of fuels from renewable resources. Recent advances in synthetic biology provide new tools for metabolic engineers to direct their strategies and construct optimal biocatalysts for the sustainable production of biofuels. Metabolic engineering and synthetic biology efforts entailing the engineering of native and de novo pathways for conversion of biomass constituents to short-chain alcohols and advanced biofuels are herewith reviewed. In the foreseeable future, formal integration of functional genomics and systems biology with synthetic biology and metabolic engineering will undoubtedly support the discovery, characterization, and engineering of new metabolic routes and more efficient microbial systems for the production of biofuels.
Factors affecting fungus-induced larval mortality in Anopheles gambiae and Anopheles stephensi
Authors: Bukhari Tullu , Middelman Anthonieke , Koenraadt Constantianus JM , Takken Willem , Knols Bart GJ
Published: January 2010

Background

Entomopathogenic fungi have shown great potential for the control of adult malaria vectors. However, their ability to control aquatic stages of anopheline vectors remains largely unexplored. Therefore, how larval characteristics (Anophelesspecies, age and larval density), fungus (species and concentration) and environmental effects (exposure duration and food availability) influence larval mortality caused by fungus, was studied.

Methods

Laboratory bioassays were performed on the larval stages ofAnopheles gambiaeandAnopheles stephensiwith spores of two fungus species,Metarhizium anisopliaeandBeauveria bassiana. For various larval and fungal characteristics and environmental effects the time to death was determined and survival curves established. These curves were compared by Kaplan Meier and Cox regression analyses.

Results

Beauveria bassianaandMetarhizium anisopliaecaused high mortality ofAn. gambiaeandAn. stephensilarvae. However,Beauveria bassianawas less effective (Hazard ratio (HR) <1) compared toMetarhizium anisopliae. Anopheles stephensiandAn. gambiaewere equally susceptible to each fungus. Older larvae were less likely to die than young larvae (HR < 1). The effect of increase in fungus concentration on larval mortality was influenced by spore clumping. One day exposure to fungal spores was found to be equally effective as seven days exposure. In different exposure time treatments 0 - 4.9% of the total larvae, exposed to fungus, showed infection at either the pupal or adult stage. Mortality rate increased with increasing larval density and amount of available food.

Conclusions

This study shows that both fungus species have potential to kill mosquitoes in the larval stage, and that mortality rate depends on fungus species itself, larval stage targeted, larval density and amount of nutrients available to the larvae. Increasing the concentration of fungal spores or reducing the exposure time to spores did not show a proportional increase and decrease in mortality rate, respectively, because the spores clumped together. As a result spores did not provide uniform coverage over space and time. It is, therefore, necessary to develop a formulation that allows the spores to spread over the water surface. Apart from formulation appropriate delivery methods are also necessary to avoid exposing non-target organisms to fungus.
MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells
Authors: Gubbels Jennifer AA , Felder Mildred , Horibata Sachi , Belisle Jennifer A , Kapur Arvinder , Holden Helen , Petrie Sarah , Migneault Martine , Rancourt Claudine , Connor Joseph P , Patankar Manish S
Published: January 2010

Background

Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.

Results

Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16lowtargets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.

Conclusion

MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.
Mechanisms of cell entry by human papillomaviruses: an overview
Authors: Horvath Caroline AJ , Boulet Gaëlle AV , Renoux Virginie M , Delvenne Philippe O , Bogers John-Paul J
Published: January 2010

As the primary etiological agents of cervical cancer, human papillomaviruses (HPVs) must deliver their genetic material into the nucleus of the target cell. The viral capsid has evolved to fulfil various roles that are critical to establish viral infection. The particle interacts with the cell surface via interaction of the major capsid protein, L1, with heparan sulfate proteoglycans. Moreover, accumulating evidence suggests the involvement of a secondary receptor and a possible role for the minor capsid protein, L2, in cell surface interactions.

The entry of HPV in vitro is initiated by binding to a cell surface receptor in contrast to the in vivo situation where the basement membrane has recently been identified as the primary site of virus binding. Binding of HPV triggers conformational changes, which affect both capsid proteins L1 and L2, and such changes are a prerequisite for interaction with the elusive uptake receptor. Most HPV types that have been examined, appear to enter the cell via a clathrin-dependent endocytic mechanism, although many data are inconclusive and inconsistent. Furthermore, the productive entry of HPV is a process that occurs slowly and asynchronously and it is characterised by an unusually extended residence on the cell surface.

Despite the significant advances and the emergence of a general picture of the infectious HPV entry pathway, many details remain to be clarified. The impressive technological progress in HPV virion analysis achieved over the past decade, in addition to the improvements in general methodologies for studying viral infections, provide reasons to be optimistic about further advancement of this field.

This mini review is intended to provide a concise overview of the literature in HPV virion/host cell interactions and the consequences for endocytosis.
Hodgkin's lymphoma presenting with heart failure: a case report
Authors: Amirimoghaddam Zeinab , Khoddami Malihe , Nayeri Nahid Dehghan , Molaee Somayeh
Published: January 2010

Introduction

Cardiac involvement in malignant lymphoma is one of the least investigated subjects in oncology. This article reports a case of cardiac involvement in Hodgkin's lymphoma which presented as heart failure.

Case presentation

We report the case of an 8-year-old Afghan girl with Hodgkin's lymphoma. The disease presented with systemic signs and symptoms, including abdominal distension, weakness, pallor, chills, fever, generalized edema, hepatosplenomegaly and generalized lymphadenopathy, as well as signs of heart failure. Test results showed a rare form of heart metastasis.

Conclusion

We report a case of Hodgkin's lymphoma with metastasis to the heart, detected premortem. Although the involvement of the heart in a malignancy is relatively common, premortem detection is unusual and only few studies have reported it in the literature.
Carcinoid tumor of the verumontanum (colliculus seminalis) of the prostatic urethra with a coexisting prostatic adenocarcinoma: a case report
Authors: Smith Maxwell , Lucia M Scott , Werahera Priya N , La Rosa Francisco G
Published: January 2010

Introduction

Urethral carcinoid tumors are very rare tumors with only four cases described in the literature.

Case presentation

We present the case of a 61-year-old man with a primary carcinoid tumor of the verumontanum (colliculis seminalis) portion of the prostatic urethra with a coexisting prostatic adenocarcinoma. In addition to whole mount hematoxylin and eosin staining, special immunoperoxidase staining specific for chromogranin A, neuron specific enolase, synaptophysin, pan-cytokeratin and PSA, and a special combined staining for racemase (α-methyl CoA) antigen and p63 antigen were performed. A review of the literature is included.

A single focus of invasive prostatic adenocarcinoma was identified in the periphery of the mid-left, posterior quadrant of the prostate. Approximately 17 mm from this adenocarcinoma, within the verumontanum of the prostatic urethra, there was a 3 mm maximal dimension carcinoid tumor.

Conclusion

Based on different histological features and antigenic profiles, we concluded that the two tumors were distinct.
Complete response to FOLFOX4 therapy in a patient with advanced urothelial cancer: a case report
Authors: Seo Yu Ri , Kim Se Hyung , Kim Hyun Jung , Kim Chan Kyu , Park Seong Kyu , Koh Eun Suk , Hong Dae Sik
Published: January 2010

No standard has been established for salvage therapy in gemcitabine refractory advanced urothelial cancer. We report the complete response to FOLFOX4 therapy of a metastatic urothelial cancer patient, for whom adjuvant gemcitabine plus cisplatin combination chemotherapy had failed. A 54-year-old male patient with urothelial cancer (transitional cell carcinoma) in the right kidney underwent three rounds of adjuvant gemcitabine-cisplatin chemotherapy after extensive radical nephrectomy. However, he had new liver, lung metastases and synchronous two separate primary colon cancer. The lung metastasis lesion was confirmed as a metastatic urothelial cancer via percutaneous transthoracic needle biopsy (PTNB). Liver and lung metastasis lesions disappeared after the 4th cycle of FOLFOX4 chemotherapy. In addition, colon cancer also disappeared after the 8th cycle of FOLFOX4 chemotherapy. The patient was still showing a complete response after 4 months. Clinical trials using the FOLFOX regimen as salvage therapy for gemcitabine-refractory advanced urothelial cancer are warranted.
Integration of HIV/AIDS services into African primary health care: lessons learned for health system strengthening in Mozambique ‐ a case study
Authors: Pfeiffer James , Montoya Pablo , Baptista Alberto J , Karagianis Marina , Pugas Marilia de Morais , Micek Mark , Johnson Wendy , Sherr Kenneth , Gimbel Sarah , Baird Shelagh , Lambdin Barrot , Gloyd Stephen
Published: January 2010

Introduction

In 2004, Mozambique, supported by large increases in international disease‐specific funding, initiated a national rapid scale‐up of antiretroviral treatment (ART) and HIV care through a vertical “Day Hospital” approach. Though this model showed substantial increases in people receiving treatment, it diverted scarce resources away from the primary health care (PHC) system. In 2005, the Ministry of Health (MOH) began an effort to use HIV/AIDS treatment and care resources as a means to strengthen their PHC system. The MOH worked closely with a number of NGOs to integrate HIV programs more effectively into existing public‐sector PHC services.

Case Description

In 2005, the Ministry of Health and Health Alliance International initiated an effort in two provinces to integrate ART into the existing primary health care system through health units distributed across 23 districts. Integration included: a) placing ART services in existing units; b) retraining existing workers; c) strengthening laboratories, testing, and referral linkages; e) expanding testing in TB wards; f) integrating HIV and antenatal services; and g) improving district‐level management. Discussion: By 2008, treatment was available in nearly 67 health facilities in 23 districts. Nearly 30,000 adults were on ART. Over 80,000 enrolled in the HIV/AIDS program. Loss to follow‐up from antenatal and TB testing to ART services has declined from 70% to less than 10% in many integrated sites. Average time from HIV testing to ART initiation is significantly faster and adherence to ART is better in smaller peripheral clinics than in vertical day hospitals. Integration has also improved other non‐HIV aspects of primary health care.

Conclusion

The integration approach enables the public sector PHC system to test more patients for HIV, place more patients on ART more quickly and efficiently, reduce loss‐to‐follow‐up, and achieve greater geographic HIV care coverage compared to the vertical model. Through the integration process, HIV resources have been used to rehabilitate PHC infrastructure (including laboratories and pharmacies), strengthen supervision, fill workforce gaps, and improve patient flow between services and facilities in ways that can benefit all programs. Using aid resources to integrate and better link HIV care with existing services can strengthen wider PHC systems.
Moisture estimation within a mine heap: An application of cokriging with assay data and electrical resistivity
Authors: Rucker Dale
Published: January 2010

Cokriging has been applied to estimate the distribution of moisture within a rock pile of low-grade gold ore, or heap. Along with the primary data set of gravimetric moisture content obtained from drilling, electrical resistivity was used to supplement the estimation procedure by supplying a secondary data set. The effectiveness of the cokriging method was determined by comparing the results to kriging the moisture data alone and through least-squares regression (LSR) modeling of colocated resistivity and moisture. In general, the wells from which moisture data were derived were separated by distances far greater than the horizontal correlation scale. The kriging results showed that regions generally undersampled by drilling reverted to the mean of the moisture data. The LSR technique, which provides a simpletransformation of resistivity to moisture, converted the low resis-tivity to highmoisture, and vice versa. The sparse well locations created a high degree of uncertainty in the transformed data set. Extreme resistivity values produced nonphysical moisture values, either negative for the linear model or values greater than one for the power model. The cokriging application, which considers the correlation scale and secondary data, produced the best results, as indicated through the cross validation. The mean and variance of the cokriged moisture were closer to the measured moisture, and the bias in the residuals was the lowest. The application likely could be improved through optimal well placement, whereby the resistivity results guide the drilling program through gross target characterization, and the moisture estimation could be updated iteratively.
Nodal-Stage Classification in Invasive Lobular Breast Carcinoma: Influence of Different Interpretations of the pTNM Classification
Authors: van Deurzen Carolien H.M. , Cserni Gabor , Bianchi Simonetta , Vezzosi Vania , Arisio Riccardo , Wesseling Jelle , Asslaber Martin , Foschini Maria P. , Sapino Anna , Castellano Isabella , Callagy Grace , Faverly Daniel , Martin-Martinez Maria-Dolores , Quinn Cecily , Amendoeira Isabel , Kulka Janina , Reiner-Concin Angelika , Cordoba Alicia , Seldenrijk Cornelis A. , van Diest Paul J.
Published: January 2010

Purpose

Application of current nodal status classification is complicated in lobular breast carcinoma metastases. The aim of this study was to define the optimal interpretation of the pTNM classification in sentinel node (SN) –positive patients to select patients with limited or with a high risk of non-SN involvement.

Patients and Methods

SN metastases of 392 patients with lobular breast carcinoma were reclassified according to interpretations of the European Working Group for Breast Screening Pathology (EWGBSP) and guidelines by Turner et al, and the predictive power for non-SN involvement was assessed.

Results

Reclassification according to definitions of EWGBSP and Turner et al resulted in different pN classification in 73 patients (19%). The rate of non-SN involvement in the 40 patients with isolated tumor cells according to Turner et al and with micrometastases according to EWGBSP was 20%, which is comparable to the established rate for micrometastases. The rate of non-SN involvement in the 29 patients with micrometastases according to Turner et al and with macrometastases according to EWGBSP was 48%, which is comparable to the established rate for macrometastases. Therefore, the EWGBSP method to classify SN tumor load better reflected the risk of non-SN involvement than the Turner et al system.

Conclusion

Compared with the guidelines by Turner et al, the EWGBSP definitions better reflect SN metastatic tumor load and allow better differentiation between patients with lobular breast carcinoma who have a limited or a high risk of non-SN metastases. Therefore, we suggest using the EWGBSP definitions in these patients to select high-risk patients who may benefit from additional local and/or systemic therapy.
The PI3K Pathway As Drug Target in Human Cancer
Authors: Courtney Kevin D. , Corcoran Ryan B. , Engelman Jeffrey A.
Published: January 2010

The phosphatidylinositol 3-kinase (PI3K) signaling axis impacts on cancer cell growth, survival, motility, and metabolism. This pathway is activated by several different mechanisms in cancers, including somatic mutation and amplification of genes encoding key components. In addition, PI3K signaling may serve integral functions for noncancerous cells in the tumor microenvironment. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them. However, the central role of PI3K signaling in a large array of diverse biologic processes raises concerns about its use in therapeutics and increases the need to develop sophisticated strategies for its use. In this review, we will discuss how PI3K signaling affects the growth and survival of tumor cells. From this vantage, we will consider how inhibitors of the PI3K signaling cascade, either alone or in combination with other therapeutics, can most effectively be used for the treatment of cancer.
Clinical Course of Advanced Non–Small-Cell Lung Cancer Patients Experiencing Hypertension During Treatment With Bevacizumab in Combination With Carboplatin and Paclitaxel on ECOG 4599
Authors: Dahlberg Suzanne E. , Sandler Alan B. , Brahmer Julie R. , Schiller Joan H. , Johnson David H.
Published: January 2010

Purpose

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non–small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes.

Patients and Methods

Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline.

Results

In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%).

Conclusion

Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed.
Multicenter Analysis of 80 Solid Organ Transplantation Recipients With Post-Transplantation Lymphoproliferative Disease: Outcomes and Prognostic Factors in the Modern Era
Authors: Evens Andrew M. , David Kevin A. , Helenowski Irene , Nelson Beverly , Kaufman Dixon , Kircher Sheetal M. , Gimelfarb Alla , Hattersley Elise , Mauro Lauren A. , Jovanovic Borko , Chadburn Amy , Stiff Patrick , Winter Jane N. , Mehta Jayesh , Van Besien Koen , Gregory Stephanie , Gordon Leo I. , Shammo Jamile M. , Smith Scott E. , Smith Sonali M.
Published: January 2010

Purpose

Adult post-transplantation lymphoproliferative disease (PTLD) has a reported 3-year overall survival (OS) of 35% to 40%. The impact of rituximab on the outcome of PTLD is not well defined.

Methods

We examined the clinical features and outcomes among a large cohort of solid organ transplantation (SOT) –related patients with PTLD who were recently treated at four Chicago institutions (from January 1998 to January 2008).

Results

Eighty patients with PTLD were identified who had a median SOT-to-PTLD time of 48 months (range, 1 to 216 months). All patients had reduction of immunosuppression as part of initial therapy, whereas 59 (74%) of 80 patients received concurrent first-line rituximab with or without chemotherapy. During 40-month median follow-up, 3-year progression-free survival (PFS) for all patients was 57%, and the 3-year overall survival (OS) rate was 62%. Patients who received rituximab-based therapy as part of initial treatment had 3-year PFS of 70% and OS 73% compared with 21% (P < .0001) and 33% (P = .0001), respectively, without rituximab. Notably, of all relapses, only 9% (4 of 34 patients) occurred beyond 12 months from PTLD diagnosis. On multivariate regression analysis, three factors were associated with progression and survival: CNS involvement (PFS, 4.70; P = .01; OS, 3.61; P = .04), bone marrow involvement (PFS, 2.95; P = .03; OS, 3.14; P = .03), and hypoalbuminemia (PFS, 2.96; P = .05; OS, 3.64; P = .04). Furthermore, a survival model by multivariate CART analysis that was based on number of adverse factors present (ie, 0, 1, ≥ 2) was formed: 3-year PFS rates were 84%, 66%, 7%, respectively, and 3-year OS rates were 93%, 68%, 11%, respectively (P < .0001).

Conclusion

This large, multicenter, retrospective analysis suggests significantly improved PFS and OS associated with early rituximab-based treatment in PTLD. In addition, clinical factors at diagnosis identified patients with markedly divergent outcomes.
Reduction of Elevated Plasma Osteopontin Levels With Resection of Non–Small-Cell Lung Cancer
Authors: Blasberg Justin D. , Pass Harvey I. , Goparaju Chandra M. , Flores Raja M. , Lee Suzie , Donington Jessica S.
Published: January 2010

Purpose

Plasma osteopontin (OPN) levels in advanced non–small-cell lung cancer (NSCLC) correlate with therapeutic response and survival, but the utility of plasma OPN for diagnosis and monitoring of early-stage NSCLC has not been investigated. We hypothesize that plasma OPN levels are elevated in early-stage NSCLC and decrease with resection.

Patients and Methods

Presurgery plasma OPN levels (in ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA) in a discovery set of 60 patients with early-stage NSCLC and were compared with data from 56 cancer-free smokers. Presurgery OPN was validated in an independent cohort of 96 patients with resectable NSCLC. The presurgery levels in the latter cohort were compared with matched postsurgery levels. Perioperative OPN levels were correlated with demographics, tumor characteristics, and perioperative events. OPN was monitored during follow-up.

Results

Discovery set presurgery NSCLC OPN (271 ± 31 ng/mL) was higher than smokers (40 ± 2 ng/mL; P = .001). Presurgery OPN was similar in the NSCLC validation cohort (324 ng/mL ± 20 ng/mL; P = .134). Postsurgery OPN (256 ng/mL ± 21 ng/mL) measured at mean of 9.8 weeks (range, 2 to 46 weeks) was lower than presurgery OPN (P = .005). Time from surgery significantly impacted postsurgery OPN: OPN ≤ 6 weeks postsurgery (303 n/mL ± 26 ng/mL) was higher than OPN greater than 6 weeks postsurgery (177 ng/mL ± 29 ng/mL; P = .003). Multivariate analysis noted correlations between albumin and creatinine to presurgery OPN and use of thoracotomy to postsurgery OPN. Recurrence rate was 5% at 29 weeks mean follow-up. OPN at recurrence was elevated from postsurgery nadir.

Conclusion

Plasma OPN levels are elevated in early-stage NSCLC. They are reduced after resection and appear to increase with recurrence. Plasma OPN may have utility as a biomarker in early-stage NSCLC.
Membrane protein SMP-1 is required for normal flagellum function inLeishmania
Authors: Tull Dedreia , Naderer Thomas , Spurck Timothy , Mertens Haydyn D. T. , Heng Joanne , McFadden Geoffrey I. , Gooley Paul R. , McConville Malcolm J.
Published: January 2010

Eukaryotic flagella and cilia are surrounded by a membrane that is continuous with, but distinct from, the rest of the plasma membrane. In Leishmania parasites, the inner leaflet of the flagellar membrane is coated with the acylated membrane protein, SMP-1. Here, we provide evidence that SMP-1 stabilizes the flagellar membrane and is required for flagella elongation and function. The expression and flagella targeting of SMP-1 is tightly associated with flagella elongation during amastigote to promastigote differentiation. Deletion of the genes encoding SMP-1 and the flagellar pocket protein SMP-2, led to the production of short flagella and defects in motility. Alterations in the physical properties of the smp-1/smp-2−/− flagellar membrane were suggested by: (1) the accumulation of membrane vesicles in the flagellar matrix, and (2) further retraction of flagella following partial inhibition of sterol and sphingolipid biosynthesis. The flagella phenotype of the smp-1/smp-2−/− null mutant was reversed by re-expression of SMP-1, but not SMP-2. SMP-1 contains a jelly-roll β-sheet structure that is probably conserved in all SMP proteins, and forms stable homo-oligomers in vivo. We propose that the SMP-1 coat generates and/or stabilizes sterol- and sphingolipid-rich domains in the flagellar membrane.
Transient Helium Jet Expansion Into Stagnant Air in Relation to Laser Drilling
Authors: Arshed G. M. , Shuja S. Z. , Yilbas B. S. , Budair M. O.
Published: January 2010

Transient helium jet expansion into a stagnant air environment is modelled to resemble the laser vapour ejection from the cavity during the drilling process. As the metal vapour properties are not known, helium is employed while the previously measured jet inlet velocity profiles are introduced in the simulations. A numerical scheme employing a control volume approach is used to discretize the governing equations of flow. The predictions are validated through a case study associated with an incompressible transient jet flow. It is found that the jet inlet profile influences considerably the self-similar behaviour of the jet. Moreover, the jet expands radially in the early period while as time progresses, the axial penetration of the jet becomes high.
Effect of flow channel dimensions on the performance of a box-frame photovoltaic/thermal collector
Authors: Ji J , Han J , Chow T-T , Han C , Lu J , He W
Published: January 2010

The hybrid photovoltaic/thermal (PV/T) collector technology is a new trend in solar energy application. For the thermal absorber, a box-frame water-channel design is able to enhance better heat transfer between the solar cells and the liquid coolant, thereby improving the combined electrical and thermal performance of the collector. This article reports the findings of the effect of water-flow channel dimensions on the energy performance of a box-frame PV/T collector design. A mathematical model of this PV/T collector system was first developed. Dynamic simulation results the authors obtained show that both the number and the height of the water-flow channels can significantly affect the collector performance. With a reduction in the channel height and an increase in the number of channels per unit width, better convective heat transfer between the working fluid and the channel wall can be achieved. This improves both the thermal and the electrical efficiencies of the collector. However, this also leads to an increase in the friction loss at the water circuit and, therefore, more pumping power is required. The optimal designs are discussed.
Evaluation of a web-based lifestyle coach designed to maintain a healthy bodyweight
Authors: Kelders Saskia M , van Gemert-Pijnen Julia E W C , Werkman Andrea , Seydel Erwin R
Published: January 2010

We evaluated a web-based intervention, the Healthy Weight Assistant (HWA), which was designed to help people with a healthy bodyweight, or those who are slightly overweight, to achieve and maintain a healthy weight. Four evaluation methods were used: (1) pre- and post-test questionnaires; (2) real time usability-tests; (3) log-file analysis; (4) qualitative analysis of forum posts, email messages and free-text responses in the questionnaires. A total of 703 respondents received access to the HWA. Six weeks after receiving access, 431 respondents completed a second questionnaire. The enthusiastic responses showed that many people were interested in using an interactive online application to support achieving and maintaining a healthy weight. The preliminary results suggest that improvements with respect to motivation may lead to large effects, yet require only small changes in the design of the HWA. Sending automatic tailored reminders may enhance motivation to keep using the application. Motivation to change behaviour may be enhanced by emphasizing goal setting and visualizing progress.
Patient use and compliance with medical advice delivered by a web-based triage system in primary care
Authors: Nijland Nicol , Cranen Karlijn , Boer Henk , van Gemert-Pijnen Julia E W C , Seydel Erwin R
Published: January 2010

We studied a web-based triage system which was accessible to the general public in the Netherlands. In a retrospective analysis we investigated the type of complaints that were submitted and the kind of advice provided. Over a period of 15 months, 13,133 different people began using the web-based triage system and 3812 patients went right through the triage process to the end. The most frequent complaints were common cold symptoms, such as cough and a sore throat (22%), itch problems (13%), urinary complaints (12%), diarrhoea (10%), headache (8%) and lower back pain (8%). Most commonly, the system generated the advice to contact a doctor (85%) and in 15% of the cases the system provided fully automated, problem-tailored, self-care advice. A total of 192 patients participated in a prospective study and completed an online survey immediately after the delivery of advice. A follow-up questionnaire on actual compliance was completed by 35 patients. Among these, 20 (57%) had actually complied with the advice provided by the system. A regression analysis revealed that intention to comply was strongly related to actual compliance. In turn, intention to comply was strongly related to attitude towards the advice ( P < 0.001). Web-based triage can contribute to a more efficient primary care system, because it facilitates the gatekeeper function.
Comparison of mitochondrial and nucleolar RNase MRP reveals identical RNA components with distinct enzymatic activities and protein components
Authors: Lu Qiaosheng , Wierzbicki Sara , Krasilnikov Andrey S. , Schmitt Mark E.
Published: January 2010

RNase MRP is a ribonucleoprotein endoribonuclease found in three cellular locations where distinct substrates are processed: the mitochondria, the nucleolus, and the cytoplasm. Cytoplasmic RNase MRP is the nucleolar enzyme that is transiently relocalized during mitosis. Nucleolar RNase MRP (NuMRP) was purified to homogeneity, and we extensively purified the mitochondrial RNase MRP (MtMRP) to a single RNA component identical to the NuMRP RNA. Although the protein components of the NuMRP were identified by mass spectrometry successfully, none of the known NuMRP proteins were found in the MtMRP preparation. Only trace amounts of the core NuMRP protein, Pop4, were detected in MtMRP by Western blot. In vitro activity of the two enzymes was compared. MtMRP cleaved only mitochondrial ORI5 substrate, while NuMRP cleaved all three substrates. However, the NuMRP enzyme cleaved the ORI5 substrate at sites different than the MtMRP enzyme. In addition, enzymatic differences in preferred ionic strength confirm these enzymes as distinct entities. Magnesium was found to be essential to both enzymes. We tested a number of reported inhibitors including puromycin, pentamidine, lithium, and pAp. Puromycin inhibition suggested that it binds directly to the MRP RNA, reaffirming the role of the RNA component in catalysis. In conclusion, our study confirms that the NuMRP and MtMRP enzymes are distinct entities with differing activities and protein components but a common RNA subunit, suggesting that the RNA must be playing a crucial role in catalytic activity.
Molecular mechanisms that funnel RNA precursors into endogenous small-interfering RNA and microRNA biogenesis pathways in Drosophila
Authors: Miyoshi Keita , Miyoshi Tomohiro , Hartig Julia Verena , Siomi Haruhiko , Siomi Mikiko C.
Published: January 2010

In Drosophila, three types of endogenous small RNAs—microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and endogenous small-interfering RNAs (endo-siRNAs or esiRNAs)—function as triggers in RNA silencing. Although piRNAs are produced independently of Dicer, miRNA and esiRNA biogenesis pathways require Dicer1 and Dicer2, respectively. Recent studies have shown that among the four isoforms of Loquacious (Loqs), Loqs-PB and Loqs-PD are involved in miRNA and esiRNA processing pathways, respectively. However, how these Loqs isoforms function in their respective small RNA biogenesis pathways remains elusive. Here, we show that Loqs-PD associates specifically with Dicer2 through its C-terminal domain. The Dicer2–Loqs-PD complex contains R2D2, another known Dicer2 partner, and excises both exogenous siRNAs and esiRNAs from their corresponding precursors in vitro. However, Loqs-PD, but not R2D2, enhanced Dicer2 activity. The Dicer2–Loqs-PD complex processes esiRNA precursor hairpins with long stems, which results in the production of AGO2-associated small RNAs. Interestingly, however, small RNAs derived from terminal hairpins of esiRNA precursors are loaded onto AGO1; thus, they are classified as a new subset of miRNAs. These results suggest that the precursor RNA structure determines the biogenesis mechanism of esiRNAs and miRNAs, thereby implicating hairpin structures with long stems as intermediates in the evolution of Drosophila miRNA.