bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiome Data Distinguish Patients with Clostridium difficile Infection and Non-C. difficile-Associated Diarrhea from Healthy Controls
Authors: Schubert Alyxandria M. , Rogers Mary A. M. , Ring Cathrin , Mogle Jill , Petrosino Joseph P. , Young Vincent B. , Aronoff David M. , Schloss Patrick D. 
Published: May 2014

ABSTRACT

Antibiotic usage is the most commonly cited risk factor for hospital-acquired
Clostridium difficile
infections (CDI). The increased risk is due to disruption of the indigenous microbiome and a subsequent decrease in colonization resistance by the perturbed bacterial community; however, the specific changes in the microbiome that lead to increased risk are poorly understood. We developed statistical models that incorporated microbiome data with clinical and demographic data to better understand why individuals develop CDI. The 16S rRNA genes were sequenced from the feces of 338 individuals, including cases, diarrheal controls, and nondiarrheal controls. We modeled CDI and diarrheal status using multiple clinical variables, including age, antibiotic use, antacid use, and other known risk factors using logit regression. This base model was compared to models that incorporated microbiome data, using diversity metrics, community types, or specific bacterial populations, to identify characteristics of the microbiome associated with CDI susceptibility or resistance. The addition of microbiome data significantly improved our ability to distinguish CDI status when comparing cases or diarrheal controls to nondiarrheal controls. However, only when we assigned samples to community types was it possible to differentiate cases from diarrheal controls. Several bacterial species within the
Ruminococcaceae
,
Lachnospiraceae
,
Bacteroides
, and
Porphyromonadaceae
were largely absent in cases and highly associated with nondiarrheal controls. The improved discriminatory ability of our microbiome-based models confirms the theory that factors affecting the microbiome influence CDI.

IMPORTANCE
The gut microbiome, composed of the trillions of bacteria residing in the gastrointestinal tract, is responsible for a number of critical functions within the host. These include digestion, immune system stimulation, and colonization resistance. The microbiome’s role in colonization resistance, which is the ability to prevent and limit pathogen colonization and growth, is key for protection against
Clostridium difficile
infections. However, the bacteria that are important for colonization resistance have not yet been elucidated. Using statistical modeling techniques and different representations of the microbiome, we demonstrated that several community types and the loss of several bacterial populations, including
Bacteroides
,
Lachnospiraceae
, and
Ruminococcaceae
, are associated with CDI. Our results emphasize the importance of considering the microbiome in mediating colonization resistance and may also direct the design of future multispecies probiotic therapies.
Mycobacterial Esx-3 Requires Multiple Components for Iron Acquisition
Authors: Siegrist M. Sloan , Steigedal Magnus , Ahmad Rushdy , Mehra Alka , Dragset Marte S. , Schuster Brian M. , Philips Jennifer A. , Carr Steven A. , Rubin Eric J. 
Published: May 2014

ABSTRACT

The type VII secretion systems are conserved across mycobacterial species and in many Gram-positive bacteria. While the well-characterized Esx-1 pathway is required for the virulence of pathogenic mycobacteria and conjugation in the model organism
Mycobacterium smegmatis
, Esx-3 contributes to mycobactin-mediated iron acquisition in these bacteria. Here we show that several Esx-3 components are individually required for function under low-iron conditions but that at least one, the membrane-bound protease MycP
3
of
M. smegmatis
, is partially expendable. All of the
esx-3
mutants tested, including the Δ
mycP

3ms

mutant, failed to export the native Esx-3 substrates EsxH

ms

and EsxG

ms

to quantifiable levels, as determined by targeted mass spectrometry. Although we were able to restore low-iron growth to the
esx-3
mutants by genetic complementation, we found a wide range of complementation levels for protein export. Indeed, minute quantities of extracellular EsxH

ms

and EsxG

ms

were sufficient for iron acquisition under our experimental conditions. The apparent separation of Esx-3 function in iron acquisition from robust EsxG

ms

and EsxH

ms

secretion in the
ΔmycP

3ms

mutant and in some of the complemented
esx-3
mutants compels reexamination of the structure-function relationships for type VII secretion systems.

IMPORTANCE
Mycobacteria have several paralogous type VII secretion systems, Esx-1 through Esx-5. Whereas Esx-1 is required for pathogenic mycobacteria to grow within an infected host, Esx-3 is essential for growth
in vitro
. We and others have shown that Esx-3 is required for siderophore-mediated iron acquisition. In this work, we identify individual Esx-3 components that contribute to this process. As in the Esx-1 system, most mutations that abolish Esx-3 protein export also disrupt its function. Unexpectedly, however, ultrasensitive quantitation of Esx-3 secretion by multiple-reaction-monitoring mass spectrometry (MRM-MS) revealed that very low levels of export were sufficient for iron acquisition under similar conditions. Although protein export clearly contributes to type VII function, the relationship is not absolute.
Detection of Evolutionarily Distinct Avian Influenza A Viruses in Antarctica
Authors: Hurt Aeron C. , Vijaykrishna Dhanasekaran , Butler Jeffrey , Baas Chantal , Maurer-Stroh Sebastian , Silva-de-la-Fuente M. Carolina , Medina-Vogel Gonzalo , Olsen Bjorn , Kelso Anne , Barr Ian G. , González-Acuña Daniel 
Published: May 2014

ABSTRACT
Distinct lineages of avian influenza viruses (AIVs) are harbored by spatially segregated birds, yet significant surveillance gaps exist around the globe. Virtually nothing is known from the Antarctic. Using virus culture, molecular analysis, full genome sequencing, and serology of samples from Adélie penguins in Antarctica, we confirmed infection by H11N2 subtype AIVs. Their genetic segments were distinct from all known contemporary influenza viruses, including South American AIVs, suggesting spatial separation from other lineages. Only in the matrix and polymerase acidic gene phylogenies did the Antarctic sequences form a sister relationship to South American AIVs, whereas distant phylogenetic relationships were evident in all other gene segments. Interestingly, their neuraminidase genes formed a distant relationship to all avian and human influenza lineages, and the polymerase basic 1 and polymerase acidic formed a sister relationship to the equine H3N8 influenza virus lineage that emerged during 1963 and whose avian origins were previously unknown. We also estimated that each gene segment had diverged for 49 to 80 years from its most closely related sequences, highlighting a significant gap in our AIV knowledge in the region. We also show that the receptor binding properties of the H11N2 viruses are predominantly avian and that they were unable to replicate efficiently in experimentally inoculated ferrets, suggesting their continuous evolution in avian hosts. These findings add substantially to our understanding of both the ecology and the intra- and intercontinental movement of Antarctic AIVs and highlight the potential risk of an incursion of highly pathogenic AIVs into this fragile environment.

IMPORTANCE
Avian influenza viruses (AIVs) are typically maintained and spread by migratory birds, resulting in the existence of distinctly different viruses around the world. However, AIVs have not previously been detected in Antarctica. In this study, we characterized H11N2 viruses sampled from Adélie penguins from two geographically different sites in Antarctica and show that the segmented AIV genome diverged between 49 and 80 years ago from other AIVs, with several genes showing similarity and shared ancestry with H3N8 equine influenza viruses. This study provides the first insight into the ecology of AIVs in Antarctica and highlights the potential risk of an introduction of highly pathogenic AIVs into the continent.
The effects of an urban renewal project on health and health inequalities: a quasi-experimental study in Barcelona
Authors: Mehdipanah Roshanak , Rodríguez-Sanz Maica , Malmusi Davide , Muntaner Carles , Díez Elia , Bartoll Xavier , Borrell Carme 
Published: May 2014

BackgroundIn the last decade, the Neighbourhoods Law in Catalonia (Spain) funded municipalities that presented urban renewal projects within disadvantaged neighbourhoods focusing on physical, social and economic improvements. The objective of the study was to evaluate the effects of this law on the health and health inequalities of residents in the intervened neighbourhoods in the city of Barcelona.MethodsA quasi-experimental predesign and postdesign was used to compare adult residents in five intervened neighbourhoods with eight non-intervened comparison neighbourhoods with similar socioeconomic characteristics. The Barcelona Health Survey was used for studying self-rated and mental health in pre (2001, 2006) and post (2011) years. Poisson regression models stratified by sex were used to compute prevalence ratios comparing 2011 with 2006, and later stratified by social class, to study health inequalities.ResultsThe intervened neighbourhoods had a significant decrease in poor self-rated health in both sexes while no significant changes occurred in the comparison group. When stratified by social class, a significant improvement was observed in poor self-rated health in the manual group of the intervened neighbourhoods in both sexes, resulting in a decrease in self-rated health inequalities. Similar results were observed in poor mental health of women, while in men, poor mental health worsens in both neighbourhood groups but mostly in the comparison group.ConclusionsThe Neighbourhoods Law had a positive effect on self-rated health and seems to prevent poor mental health increases in both sexes and especially among manual social classes.
Monoclonal Antibody Targeting of the Cell Surface Molecule TM4SF5 Inhibits the Growth of Hepatocellular Carcinoma
Authors: Kwon Sanghoon , Choi Kyung-Chan , Kim Young-Eun , Ha Yang-Wha , Kim Dongbum , Park Byoung Kwon , Wu Guang , Kim Doo-Sik , Lee Younghee , Kwon Hyung-Joo 
Published: May 2014

Abstract
The cell surface transmembrane receptor TM4SF5 has been implicated in hepatocellular carcinoma (HCC), but its candidacy as a therapeutic target has not been evaluated. Building on findings that immunization with a peptide vaccine targeting human TM4SF5 can exert prophylactic and therapeutic effects in a murine model of HCC, we developed a monoclonal antibody to characterize expression of TM4SF5 in HCC and to target its function there as an anticancer strategy. We found that the antibody modulated cell signaling in HCC cells in vitro, reducing cell motility, modulating E-cadherin expression, altering p27kip1 localization, and increasing RhoA activity. Using a mouse xenograft model of human HCC, we documented the in vivo efficacy of the antibody, which suppressed tumor growth in either tumor prevention or treatment designs. Our work offers a preclinical proof of concept for TM4SF5 as a promising target for antibody therapeutics to treat HCC. Cancer Res; 74(14); 3844–56. ©2014 AACR.
The Applicability of the International Classification of Functioning, Disability, and Health to Study Lifestyle and Quality of Life of Colorectal Cancer Survivors
Authors: van Roekel Eline H. , Bours Martijn J.L. , de Brouwer Carin P.M. , Ten Napel Huib , Sanduleanu Silvia , Beets Geerard L. , Kant IJmert , Weijenberg Matty P. 
Published: May 2014

Abstract
Background: Well-designed studies on lifestyle and health-related quality of life (HRQoL) in colorectal cancer survivors based on a biopsychosocial instead of a traditional biomedical approach are warranted. We report on the applicability of the International Classification of Functioning, Disability, and Health (ICF) as useful biopsychosocial framework to improve research on how lifestyle influences colorectal cancer survivors' HRQoL, using the Energy for life after ColoRectal cancer (EnCoRe) study as an example.
Methods: The ICF was used to develop a conceptual model for studying lifestyle and colorectal cancer survivors' HRQoL, by identifying relevant factors from literature and mapping them within the ICF. Subsequently, this model was used for selection of measurement instruments and biomarkers. By linking meaningful concepts within selected measures to the ICF, we could assess the ICF coverage of our developed conceptual model.
Results: Within selected measures, 450 meaningful concepts were identified, of which 88% were linked to the ICF. The linking process resulted in 132 distinctive ICF categories assigned (38% within “Body Functions,” 2% within “Body Structures,” 46% within “Activities and Participation,” and 14% within “Environmental Factors”).
Conclusions: The selected EnCoRe study measures broadly cover ICF domains relevant to colorectal cancer survivors, stressing the relevance of using a biopsychosocial approach for studying this population's HRQoL.
Impact: The developed conceptual model will guide data analyses and interpretation, and facilitate early transfer of results for development, evaluation, and implementation of personalized multidisciplinary lifestyle interventions. We recommend the ICF as an invaluable framework for improving the quality and scope of HRQoL studies. Cancer Epidemiol Biomarkers Prev; 23(7); 1394–405. ©2014 AACR.
Prognostic and Therapeutic Implications of Aromatase Expression in Lung Adenocarcinomas with EGFR Mutations
Authors: Kohno Mikihiro , Okamoto Tatsuro , Suda Kenichi , Shimokawa Mototsugu , Kitahara Hirokazu , Shimamatsu Shinichiro , Konishi Hideyuki , Yoshida Tsukihisa , Takenoyama Mitsuhiro , Yano Tokujiro , Maehara Yoshihiko 
Published: May 2014

Abstract
Purpose: Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis.
Experimental Design: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib.
Results: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib.
Conclusions: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients. Clin Cancer Res; 20(13); 3613–22. ©2014 AACR.
Blood-Based Analyses of Cancer: Circulating Tumor Cells and Circulating Tumor DNA
Authors: Haber Daniel A. , Velculescu Victor E. 
Published: May 2014

Abstract
The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell–derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments.
Significance: Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. Cancer Discov; 4(6); 650–61. ©2014 AACR.
Whole-Body Irradiation Increases the Magnitude and Persistence of Adoptively Transferred T Cells Associated with Tumor Regression in a Mouse Model of Prostate Cancer
Authors: Ward-Kavanagh Lindsay K. , Zhu Junjia , Cooper Timothy K. , Schell Todd D. 
Published: May 2014

Abstract
Adoptive immunotherapy has demonstrated efficacy in a subset of clinical and preclinical studies, but the T cells used for therapy often are rendered rapidly nonfunctional in tumor-bearing hosts. Recent evidence indicates that prostate cancer can be susceptible to immunotherapy, but most studies using autochthonous tumor models demonstrate only short-lived T-cell responses in the tolerogenic prostate microenvironment. Here, we assessed the efficacy of sublethal whole-body irradiation (WBI) to enhance the magnitude and duration of adoptively transferred CD8+ T cells in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We demonstrate that WBI promoted high-level accumulation of granzyme B (GzB, Gzmb)–expressing donor T cells both in lymphoid organs and in the prostate of TRAMP mice. Donor T cells remained responsive to vaccination in irradiated recipients, but a single round of WBI-enhanced adoptive immunotherapy failed to affect significantly the existing disease. Addition of a second round of immunotherapy promoted regression of established disease in half of the treated mice, with no progression observed. Regression was associated with long-term persistence of effector/memory phenotype CD8+ donor cells. Administration of the second round of adoptive immunotherapy led to reacquisition of GzB expression by persistent T cells from the first transfer. These results indicate that WBI conditioning amplifies tumor-specific T cells in the TRAMP prostate and lymphoid tissue, and suggest that the initial treatment alters the tolerogenic microenvironment to increase antitumor activity by a second wave of donor cells. Cancer Immunol Res; 2(8); 777–88. ©2014 AACR.
Therapeutic In Situ Autovaccination against Solid Cancers with Intratumoral Poly-ICLC: Case Report, Hypothesis, and Clinical Trial
Authors: Salazar Andres M. , Erlich Rodrigo B. , Mark Alexander , Bhardwaj Nina , Herberman Ronald B. 
Published: May 2014

Abstract
Pathogen-associated molecular patterns (PAMP) are stand-alone innate and adaptive immunomodulators and critical vaccine components. We present a strategy of sequential intratumoral (i.t.) and intramuscular (i.m.) injections of the stabilized dsRNA viral mimic and PAMP, polyinosinic–polycytidylic acid-polylysine-carboxymethylcellulose (poly-ICLC, Hiltonol; Oncovir). We report the first treated patient, a young man with an exceptionally advanced facial embryonal rhabdomyosarcoma with extension to the brain. After treatment, the patient showed tumor inflammation consistent with immunotherapy, followed by gradual, marked tumor regression, with extended survival. Sequential i.t. and i.m. poly-ICLC injections mimicking a viral infection can induce an effective, in situ, personalized systemic therapeutic “autovaccination” against tumor antigens of a patient. We postulate a three-step immunomodulatory process: (i) innate-immune local tumor killing induced by i.t. poly-ICLC; (ii) activation of dendritic cells with Th1 cell– and CTL–weighted priming against the released tumor antigens; and (iii) i.m. poly-ICLC maintenance of the systemic antitumor immune response via chemokine induction, facilitation of CTL killing through the induction of costimulators such as OX40, inflammasome activation, and increase in the T-effector/Treg ratio. These results support the use of certain simple and inexpensive i.t. PAMPs to favorably stimulate effective immunity against solid cancers. A phase II clinical trial testing the hypothesis presented has begun accrual (clinicaltrials.gov, NCT01984892). Cancer Immunol Res; 2(8); 720–4. ©2014 AACR.
Functional Status and Patient-Reported Outcome 10 Years After Stroke
Authors: Jönsson Ann-Cathrin , Delavaran Hossein , Iwarsson Susanne , Ståhl Agneta , Norrving Bo , Lindgren Arne 
Published: May 2014

Background and Purpose—
Long-term studies of outcome after stroke are scarce. Our aim was to study functional status and patient-reported outcome 10 years after a first-ever stroke.

Methods—
Ten-year follow-up was conducted among the survivors from a population-based group of 416 patients included in the Lund Stroke Register, Sweden, between March 1, 2001, and February 28, 2002. The Barthel index was used to assess the functional status and the modified Rankin Scale to assess the degree of disability. The EQ-5D scale was used for survivors’ self-reports about health outcome and the specific Short-Form 36 (SF-36) question for rating their overall health. The patients also reported their frequency of physical activity.

Results—
Among 145 survivors 10 years after stroke (median age, 78 years), 59% were men, 90% lived in their ordinary housing, 73% were assessed as independent, and 71% had no or slight disability. The need of assistance with mobility and self-care was reported by 14% and with usual activities by 22%. Moderate pain was reported by 39%, and 4% had a high degree of pain. Moderate anxiety/depression was reported by 28% and high degree only by 1%. Overall health status was reported in positive terms by more than two thirds of the survivors. Almost half the cohort reported the same frequency of physical activity (≥4× weekly) as before stroke onset.

Conclusions—
This study indicates that 10-year stroke survivors in Sweden are mostly independent in daily activities and report good overall health and frequent physical activity, although half of them are ≥78 years.