bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis
Authors: Thiery Jerome , Keefe Dennis , Saffarian Saviz , Martinvalet Denis , Walch Michael , Boucrot Emmanuel , Kirchhausen Tomas , Lieberman Judy 
Published: December 2009

AbstractCytotoxic T lymphocytes and natural killer cells destroy target cells via the polarized exocytosis of lytic effector proteins, perforin and granzymes, into the immunologic synapse. How these molecules enter target cells is not fully understood. It is debated whether granzymes enter via perforin pores formed at the plasma membrane or whether perforin and granzymes are first endocytosed and granzymes are then released from endosomes into the cytoplasm. We previously showed that perforin disruption of the plasma membrane induces a transient Ca2+ flux into the target cell that triggers a wounded membrane repair response in which lysosomes and endosomes donate their membranes to reseal the damaged membrane. Here we show that perforin activates clathrin- and dynamin-dependent endocytosis, which removes perforin and granzymes from the plasma membrane to early endosomes, preserving outer membrane integrity. Inhibiting clathrin- or dynamin-dependent endocytosis shifts death by perforin and granzyme B from apoptosis to necrosis. Thus by activating endocytosis to preserve membrane integrity, perforin facilitates granzyme uptake and avoids the proinflammatory necrotic death of a membrane-damaged cell.
Reconstructing nonlinear dynamic models of gene regulation using stochastic sampling
Authors: Mazur Johanna , Ritter Daniel , Reinelt Gerhard , Kaderali Lars 
Published: December 2009

Abstract

Background
The reconstruction of gene regulatory networks from time series gene expression data is one of the most difficult problems in systems biology. This is due to several reasons, among them the combinatorial explosion of possible network topologies, limited information content of the experimental data with high levels of noise, and the complexity of gene regulation at the transcriptional, translational and post-translational levels. At the same time, quantitative, dynamic models, ideally with probability distributions over model topologies and parameters, are highly desirable.

Results
We present a novel approach to infer such models from data, based on nonlinear differential equations, which we embed into a stochastic Bayesian framework. We thus address both the stochasticity of experimental data and the need for quantitative dynamic models. Furthermore, the Bayesian framework allows it to easily integrate prior knowledge into the inference process. Using stochastic sampling from the Bayes' posterior distribution, our approach can infer different likely network topologies and model parameters along with their respective probabilities from given data. We evaluate our approach on simulated data and the challenge #3 data from the DREAM 2 initiative. On the simulated data, we study effects of different levels of noise and dataset sizes. Results on real data show that the dynamics and main regulatory interactions are correctly reconstructed.

Conclusions
Our approach combines dynamic modeling using differential equations with a stochastic learning framework, thus bridging the gap between biophysical modeling and stochastic inference approaches. Results show that the method can reap the advantages of both worlds, and allows the reconstruction of biophysically accurate dynamic models from noisy data. In addition, the stochastic learning framework used permits the computation of probability distributions over models and model parameters, which holds interesting prospects for experimental design purposes.
A white-box approach to microarray probe response characterization: the BaFL pipeline
Authors: Thompson Kevin J , Deshmukh Hrishikesh , Solka Jeffrey L , Weller Jennifer W 
Published: December 2009

Abstract

Background
Microarrays depend on appropriate probe design to deliver the promise of accurate genome-wide measurement. Probe design, ideally, produces a unique probe-target match with homogeneous duplex stability over the complete set of probes. Much of microarray pre-processing is concerned with adjusting for non-ideal probes that do not report target concentration accurately. Cross-hybridizing probes (non-unique), probe composition and structure, as well as platform effects such as instrument limitations, have been shown to affect the interpretation of signal. Data cleansing pipelines seldom filter specifically for these constraints, relying instead on general statistical tests to remove the most variable probes from the samples in a study. This adjusts probes contributing to ProbeSet (gene) values in a study-specific manner. We refer to the complete set of factors as biologically applied filter levels (BaFL) and have assembled an analysis pipeline for managing them consistently. The pipeline and associated experiments reported here examine the outcome of comprehensively excluding probes affected by known factors on inter-experiment target behavior consistency.

Results
We present here a 'white box' probe filtering and intensity transformation protocol that incorporates currently understood factors affecting probe and target interactions; the method has been tested on data from the Affymetrix human GeneChip HG-U95Av2, using two independent datasets from studies of a complex lung adenocarcinoma phenotype. The protocol incorporates probe-specific effects from SNPs, cross-hybridization and low heteroduplex affinity, as well as effects from scanner sensitivity, sample batches, and includes simple statistical tests for identifying unresolved biological factors leading to sample variability. Subsequent to filtering for these factors, the consistency and reliability of the remaining measurements is shown to be markedly improved.

Conclusions
The data cleansing protocol yields reproducible estimates of a given probe or ProbeSet's (gene's) relative expression that translates across datasets, allowing for credible cross-experiment comparisons. We provide supporting evidence for the validity of removing several large classes of probes, and for our approaches for removing outlying samples. The resulting expression profiles demonstrate consistency across the two independent datasets. Finally, we demonstrate that, given an appropriate sampling pool, the method enhances the t-test's statistical power to discriminate significantly different means over sample classes.
Keratin 18 attenuates estrogen receptor α-mediated signaling by sequestering LRP16 in cytoplasm
Authors: Meng Yuanguang , Wu Zhiqiang , Yin Xiaoyun , Zhao Yali , Chen Meixia , Si Yiling , Yang Jie , Fu Xiaobing , Han Weidong 
Published: December 2009

AbstractBackgroundOncogenesis in breast cancer is often associated with excess estrogen receptor α(ERα) activation and overexpression of its coactivators. LRP16 is both an ERα target gene and an ERα coactivator, and plays a crucial role in ERα activation and proliferation of MCF-7 breast cancer cells. However, the regulation of the functional availability of this coactivator protein is not yet clear.ResultsYeast two-hybrid screening, GST pulldown and coimmunoprecipitation (CoIP) identified the cytoplasmic intermediate filament protein keratin 18 (K18) as a novel LRP16-interacting protein. Fluorescence analysis revealed that GFP-tagged LRP16 was primarily localized in the nuclei of mock-transfected MCF-7 cells but was predominantly present in the cytoplasm of K18-transfected cells. Immunoblotting analysis demonstrated that the amount of cytoplasmic LRP16 was markedly increased in cells overexpressing K18 whereas nuclear levels were depressed. Conversely, knockdown of endogenous K18 expression in MCF-7 cells significantly decreased the cytoplasmic levels of LRP16 and increased levels in the nucleus. CoIP failed to detect any interaction between K18 and ERα, but ectopic expression of K18 in MCF-7 cells significantly blunted the association of LRP16 with ERα, attenuated ERα-activated reporter gene activity, and decreased estrogen-stimulated target gene expression by inhibiting ERα recruitment to DNA. Furthermore, BrdU incorporation assays revealed that K18 overexpression blunted the estrogen-stimulated increase of S-phase entry of MCF-7 cells. By contrast, knockdown of K18 in MCF-7 cells significantly increased ERα-mediated signaling and promoted cell cycle progression.ConclusionsK18 can effectively associate with and sequester LRP16 in the cytoplasm, thus attenuating the final output of ERα-mediated signaling and estrogen-stimulated cell cycle progression of MCF-7 breast cancer cells. Loss of K18 increases the functional availability of LRP16 to ERα and promotes the proliferation of ERα-positive breast tumor cells. K18 plays an important functional role in regulating the ERα signaling pathway.
Production and characterization of recombinant pertactin, fimbriae 2 and fimbriae 3 from Bordetella pertussis
Authors: Xu Yinghua , Wang Yaying , Tan Yajun , Zhang Huajie , Wu Lijie , Wang Lichan , Hou Qiming , Zhang Shumin 
Published: December 2009

AbstractBackgroundBordetella pertussisis a causative agent of pertussis or whooping cough in humans. Pertactin (Prn), fimbriae 2 (Fim2) and fimbriae 3 (Fim3) ofB. pertussisare important virulence factors and immunogens which have been included in some acellular pertussis vaccines. In this present study, we cloned, expressed and purified Prn, Fim2 and Fim3, respectively. The immunogenicity and protective efficacy of the three recombinant proteins (rPrn, rFim2 and rFim3) were investigated in mouse model.ResultsThree recombinant proteins with amount of 12 to 25 mg/L were produced. Compared to the control mice only immunized with adjuvant, serum IgG antibody responses were significantly induced in the mice immunized with rPrn, rFim2 or rFim3 (P< 0.001 for all three proteins). Furthermore, T cell responses characteristic of increased production of IL-2 and TNF-α (only for rPrn) were elicited in the mice immunized with the three proteins (P< 0.05 for all three proteins). Immunization with rPrn, but not with rFim2 or rFim3, significantly enhanced clearance of bacteria in the lungs of mice after intranasal challenge withB. pertussis(P< 0.05). When tested in a lethal intracerebral infection model, certain protection was observed in mice immunized with rPrn.ConclusionsWe have developed an efficient method to produce large amounts of rPrn, rFim2, and rFim3 fromB. pertussis. The three recombinant proteins induced both humoral and cellular immune responses in mice. Immunization with rPrn also conferred protection against pertussis in mouse infection models. Our results indicated that the recombinant proteins still retain their immunological properties and highlighted the potential of the recombinant proteins for the future development of theB. pertussisvaccines.
Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown
Authors: Schrader Jörg , Deuster Oliver , Rinn Birgit , Schulz Martina , Kautz Andreas , Dodel Richard , Meyer Bernhard , Al-Abed Yousef , Balakrishnan Karthikeyan , Reese Jens P , Bacher Michael 
Published: December 2009

Abstract

Background
Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis.

Results
Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1.

Conclusion
Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.
Management of gastro-bronchial fistula complicating a subtotal esophagectomy: a case report
Authors: Martin-Smith James D , Larkin John O , O'Connell Finbar , Ravi Narayanasamy , Reynolds John Vincent 
Published: December 2009

Abstract

Background
The development of a fistula between the tracheobronchial tree and the gastric conduit post esophagectomy is a rare and often fatal complication.

Case presentation
A 68 year old man underwent radical esophagectomy for esophageal adenocarcinoma. On postoperative day 14 the nasogastric drainage bag dramatically filled with air, without deterioration in respiratory function or progressive sepsis. A fiberoptic bronchoscopy was performed which demonstrated a gastro-bronchial fistula in the posterior aspect of the left main bronchus. He was managed conservatively with antibiotics, enteral nutrition via jejunostomy, and non-invasive respiratory support. A follow- up bronchoscopy 60 days after the diagnostic bronchoscopy, confirmed spontaneous closure of the fistula

Conclusions
This is the first such case where a conservative approach with no surgery or endoprosthesis resulted in a successful outcome, with fistula closure confirmed at subsequent bronchoscopy. Our experience would suggest that in very carefully selected cases where bronchopulmonary contamination from the fistula is minimal or absent, there is no associated inflammation of the tracheobronchial tree and the patient is stable from a respiratory point of view without evidence of sepsis, there may be a role for a trial of conservative management.
Prediction of breast self-examination in a sample of Iranian women: an application of the Health Belief Model
Authors: Tavafian Sedigheh Sadat , Hasani Laleh , Aghamolaei Teamur , Zare Shahram , Gregory David 
Published: December 2009

Abstract

Background
Iranian women, many of whom live in small cities, have limited access to mammography and clinical breast examinations. Thus, breast self examination (BSE) becomes an important and necessary approach to detecting this disease in its early stages in order to limit its resultant morbidity and mortality. This study examined constructs arising from the Health Belief Model as predictors of breast self examination behavior in a sample of women living in Bandar Abbas, Iran.

Methods
This study was conducted in eight health centers located in Bandar Abbas, Iran. The sample consisted of 240 eligible women who were selected from referrals to the centers. The inclusion criteria were as follows: aged 30 years and over; and able to read and write Farsi. Women with breast cancer, who were pregnant, or breast feeding, were excluded from the study. Data were collected by using a self administered questionnaire which included demographic characteristics and Champion's Health Belief Model Scale. This instrument measures the concepts of disease susceptibility (3 items), seriousness (6 items), benefits (4 items), barriers (8 items) and self-efficacy (10 items).

Results
The subjects' mean age was 37.2 (SD = 6.1) years. Just under a third of the subjects (31.7%) had performed BSE in the past and 7.1% of them performed it at least monthly. Perceived benefits and perceived self-efficacy of the women who performed BSE were significantly higher compared with women who did not practice BSE (p < 0.03). Furthermore, perceived barriers were lower among those who had performed BSE (p < 0.001). Logistic regression analysis indicated that women who perceived fewer barriers (OR: 0.70, 95% CI: 0.63-0.77, p < 0.001) and had higher self-efficacy (OR: 1.08, 95% CI: 1.02-1.13, p = 0.003) were more likely to perform BSE (R2 = 0.52).

Conclusion
Findings from this study indicated that perceived barriers and perceived self-efficacy could be predictors of BSE behavior among the sample of women. Therefore, BSE training programs that emphasize self-efficacy and address perceived barriers are recommended.
Rapid spread of complex change: a case study in inpatient palliative care
Authors: Penna Richard Della , Martel Helene , Neuwirth Esther B , Rice Jennifer , Filipski Marta I , Green Jennifer , Bellows Jim 
Published: December 2009

Abstract

Background
Based on positive findings from a randomized controlled trial, Kaiser Permanente's national executive leadership group set an expectation that all Kaiser Permanente and partner hospitals would implement a consultative model of interdisciplinary, inpatient-based palliative care (IPC). Within one year, the number of IPC consultations program-wide increased almost tenfold from baseline, and the number of teams nearly doubled. We report here results from a qualitative evaluation of the IPC initiative after a year of implementation; our purpose was to understand factors supporting or impeding the rapid and consistent spread of a complex program.

Methods
Quality improvement study using a case study design and qualitative analysis of in-depth semi-structured interviews with 36 national, regional, and local leaders.

Results
Compelling evidence of impacts on patient satisfaction and quality of care generated 'pull' among adopters, expressed as a remarkably high degree of conviction about the value of the model. Broad leadership agreement gave rise to sponsorship and support that permeated the organization. A robust social network promoted knowledge exchange and built on an existing network with a strong interest in palliative care. Resource constraints, pre-existing programs of a different model, and ambiguous accountability for implementation impeded spread.

Conclusions
A complex, hospital-based, interdisciplinary intervention in a large health care organization spread rapidly due to a synergy between organizational 'push' strategies and grassroots-level pull. The combination of push and pull may be especially important when the organizational context or the practice to be spread is complex.
Differential expression of apoptotic genes PDIA3 and MAP3K5 distinguishes between low- and high-risk prostate cancer
Authors: Pressinotti Nicole Chui , Klocker Helmut , Schäfer Georg , Luu Van-Duc , Ruschhaupt Markus , Kuner Ruprecht , Steiner Eberhard , Poustka Annemarie , Bartsch Georg , Sültmann Holger 
Published: December 2009

Abstract

Background
Despite recent progress in the identification of genetic and molecular alterations in prostate cancer, markers associated with tumor progression are scarce. Therefore precise diagnosis of patients and prognosis of the disease remain difficult. This study investigated novel molecular markers discriminating between low and highly aggressive types of prostate cancer.

Results
Using 52 microdissected cell populations of low- and high-risk prostate tumors, we identified via global cDNA microarrays analysis almost 1200 genes being differentially expressed among these groups. These genes were analyzed by statistical, pathway and gene enrichment methods. Twenty selected candidate genes were verified by quantitative real time PCR and immunohistochemistry. In concordance with the mRNA levels, two genes MAP3K5 and PDIA3 exposed differential protein expression. Functional characterization of PDIA3 revealed a pro-apoptotic role of this gene in PC3 prostate cancer cells.

Conclusions
Our analyses provide deeper insights into the molecular changes occurring during prostate cancer progression. The genes MAP3K5 and PDIA3 are associated with malignant stages of prostate cancer and therefore provide novel potential biomarkers.
The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone
Authors: Kerkar Sid P , Kemp Clinton D , Duffy Austin , Kammula Udai S , Schrump David S , Kwong King F , Quezado Martha , Goldspiel Barry R , Venkatesan Aradhana , Berger Ann , Walker Melissa , Toomey Mary Ann , Steinberg Seth M , Giaccone Guiseppe , Rosenberg Steven A , Avital Itzhak 
Published: December 2009

Abstract

Background
The standard of care for metastatic gastric cancer (MGC) is systemic chemotherapy which leads to a median survival of 6-15 months. Survival beyond 3 years is rare. For selected groups of patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and metastasectomies including peritoneal stripping with continuous hyperthermic peritoneal perfusion (CHPP), liver resection, and pulmonary resection. Median survival after liver resection for MGC is up to 34 months, with a five year survival rate of 24.5%. Similarly, reported median survival after pulmonary resection of MGC is 21 months with long term survival of greater than 5 years a possibility. Several case reports and small studies have documented evidence of long-term survival in select individuals who undergo CHPP for MGC.

Design
The GYMSSA trial is a prospective randomized trial for patients with MGC. It is designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus systemic chemotherapy (GYMS) versus systemic chemotherapy alone (SA). Systemic therapy will be composed of the FOLFOXIRI regimen. The aim of the study is to evaluate overall survival and potential selection criteria to determine those patients who may benefit from surgery plus systemic therapy. The study will be conducted by the Surgery Branch at the National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland. Surgeries and followup will be done at the NCI, and chemotherapy will be given by either the local oncologist or the medical oncology branch at NCI.

Trial Registration
ClinicalTrials.gov ID. NCT00941655
Improved quality monitoring of multi-center acupuncture clinical trials in China
Authors: Zhao Ling , Liang Fan-rong , Li Ying , Zhang Fu-wen , Zheng Hui , Wu Xi 
Published: December 2009

Abstract

Background
In 2007, the Chinese Science Division of the State Administration of Traditional Chinese Medicine(TCM) convened a special conference to discuss quality control for TCM clinical research. Control and assurance standards were established to guarantee the quality of clinical research. This paper provides practical guidelines for implementing strict and reproducible quality control for acupuncture randomized controlled trials (RCTs).

Methods
A standard quality control program (QCP) was established to monitor the quality of acupuncture trials. Case report forms were designed; qualified investigators, study personnel and data management personnel were trained. Monitors, who were directly appointed by the project leader, completed the quality control programs. They guaranteed data accuracy and prevented or detected protocol violations. Clinical centers and clinicians were audited, the randomization system of the centers was inspected, and the treatment processes were audited as well. In addition, the case report forms were reviewed for completeness and internal consistency, the eligibility and validity of the patients in the study was verified, and data was monitored for compliance and accuracy.

Results and discussion
The monitors complete their reports and submit it to quality assurance and the sponsors. Recommendations and suggestions are made for improving performance. By holding regular meetings to discuss improvements in monitoring standards, the monitors can improve quality and efficiency.

Conclusions
Supplementing and improving the existed guidelines for quality monitoring will ensure that large multi-centre acupuncture clinical trials will be considered as valid and scientifically stringent as pharmaceutical clinical trials. It will also develop academic excellence and further promote the international recognition of acupuncture.